CH 20 Neoplasms of The Salivary Glands

Chapter
20
Neoplasms of the Salivary Glands

CLASSIFICATION OF m More common in women than in men
NEOPLASMS OF m Occur in all age groups, including children, but
SALIVARY GLANDS with a peak incidence in sixth to seventh decades
of life
Box 20-1 contains the classification of neoplasms of the Majority of salivary gland neoplasms occur in
salivary glands. parotid gland
Majority of salivary gland neoplasms are of
GENERAL CONSIDERATIONS epithelial origin, representing 80% to 90% of all
neoplasms
Salivary gland neoplasms account for between 2% Benign neoplasms represent approximately 75% of
and 6.5% of all neoplasms of the head and neck. all salivary gland neoplasms:
Demographics vary per tumor type, but in general m Most common benign neoplasm is pleomorphic
salivary gland neoplasm are: adenoma
BOX 20-1 Classification of Neoplasms of the Salivary Glands
Benign Neoplasms Mammary analogue secretory carcinoma

Adenocarcinoma, NOS
Epithelial
Adenoid cystic carcinoma
Pleomorphic adenoma
Polymorphous low-grade adenocarcinoma
Basal cell adenoma
Carcinoma ex pleomorphic adenoma
Canalicular adenoma
Invasive
Warthin tumor
Intracapsular
Myoepithelioma
Carcinosarcoma
Oncocytoma
Metastasizing pleomorphic adenoma
Sclerosing polycystic adenosis
Basal cell adenocarcinoma
Cystadenoma
Epithelial-myoepithelial carcinoma
Ductal papillomas:
Clear cell adenocarcinoma; Hyalinizing clear cell carcinoma
Sialadenoma papilliferum
Cystadenocarcinoma
Inverted ductal papilloma
Myoepithelial carcinoma
Intraductal papilloma
Salivary duct carcinoma
Other uncommon adenomas
Intraductal carcinoma (low-grade cribriform
Striated duct adenoma
cystadenocarcinoma; low-grade salivary duct carcinoma)
Intercalated duct adenoma
Squamous cell carcinoma
Lymphadenoma (nonsebaceous)
Adenosquamous carcinoma
Keratocystoma
Lymphoepithelial carcinoma
Lipoadenoma
Neuroendocrine carcinomas
Apocrine adenoma
Undifferentiated (large-cell) carcinoma
Adenofibroma
Oncocytic carcinoma
Tumors with sebaceous differentiation
Mucinous adenocarcinoma
Sebaceous adenoma
Cribriform adenocarcinoma of minor salivary glands
Sebaceous lymphadenoma
(CAMSG)
Salivary gland anlage tumor
Sebaceous carcinoma/lymphadenocarcinoma
Nonepithelial Sialoblastoma
Hemangioma
Nonepithelial
Neurilemmoma/neurofibroma
Hematolymphoid
Lipoma
Non-Hodgkin lymphoma
Others
Hodgkin lymphoma
Malignant Neoplasms Sarcomas
Epithelial Secondary Neoplasms
Mucoepidermoid carcinoma
Acinic cell adenocarcinoma
861
862 SECTION 6 Major and Minor Salivary Glands
Among malignant tumors, mucoepidermoid carci- Several malignant salivary gland neoplasms
noma is most common: may be encapsulated or noninvasive, including:
m True for adult and pediatric ages Mucoepidermoid carcinoma
Mesenchymal neoplasms of salivary glands are rare: Acinic cell carcinoma
m Exception is in infants Adenoid cystic carcinoma
Hemangioma and lymphangioma most Carcinoma ex pleomorphic adenoma (CEPA)
common Epithelial-myoepithelial carcinoma
Sialoblastoma and salivary gland anlage tumors Mammary analogue secretory carcinoma
occur almost exclusively in newborns and Except for CEPA, above list of malignant n
infants. eoplasms has no known benign counterparts,
As compared with neoplasms of major salivary so once requisite diagnostic criteria are estab-
glands, in which benign neoplasms represent the lished, a diagnosis can be rendered in the
greater proportion of tumors, relative to minor sali- absence of invasion
vary glands a greater proportion of neoplasms are m Minor salivary gland neoplasms:
malignant. All are unencapsulated.

Tumor types vary per gland involved More common tumor types include pleomor-
m Some examples of tumors primarily (but not phic adenoma, polymorphous low-grade ade-
exclusively) occurring in major salivary glands nocarcinoma and adenoid cystic carcinoma
include: share growth patterns, cytomorphology, cell
Warthin tumor composition and immunohistochemical reac-
Basal cell adenoma tivity such that differentiation is predicated on
Oncocytoma presence or absence of invasion (e.g., neurotro-
Acinic cell carcinoma pism, LVI, soft tissue, bone)
Mammary analogue secretory carcinoma m Generalizations relative to salivary gland
Basal cell adenocarcinoma neoplasms:
Epithelial-myoepithelial carcinoma Growth patterns:
Carcinoma ex pleomorphic adenoma ALL salivary gland neoplasms are polymor-
Salivary duct carcinoma phic (i.e., more than one growth pattern).
Oncocytic carcinoma Polymorphic growth does not equate to any
m Some examples of tumors primarily (but not specific diagnosis (e.g., polymorphous low-
exclusively) occurring in minor salivary glands grade adenocarcinoma).
include: Cytomorphology:
Canalicular adenoma (lip) Some benign (e.g., pleomorphic adenoma)
Ductal papillomas (lip, oral cavity) and some histologically low-grade malignant
Cystadenoma salivary gland neoplasms (e.g., polymor-
Polymorphous low-grade adenocarcinoma phous low-grade adenocarcinoma, adenoid
(intraoral minor salivary glands) cystic carcinoma) may be composed of
Cribriform adenocarcinoma of minor salivary similar isomorphic cell type(s) lacking sig-
glands (tongue, oral cavity) nificant nuclear pleomorphism, increased
Cystadenocarcinoma mitotic activity.
Features associated with major versus minor salivary Dual cell composition:
glands: Many benign and malignant neoplasms com-
m Major salivary gland neoplasms: posed of admixture of epithelial cells and

All are encapsulated. myoepithelial cells as identified by:
Invasion beyond the capsule generally is diag- Light microscopy
nostic for malignancy. Immunohistochemical staining (cytokera-
Extension into the capsule does not represent tins, p63, p40, calponin, S100 protein,
invasion. SMA, and/or GFAP)
Invasion includes lesional cells into adjacent Given above overlapping features between
salivary gland parenchyma, perineural inva- some benign and some malignant salivary
sion, lymph-vascular invasion, invasion into gland neoplasms, in limited biopsies especially
connective tissues. those including tissue fragments composed
Rare exceptions to the above include: entirely or near entirely of lesional cells without
Lymph-vascular permeation in pleomor- surrounding tissue to evaluate for invasion,
phic adenomas differentiation often cannot be achieved and
Metastatic pleomorphic adenoma a diagnosis of salivary gland neoplasm, not
CHAPTER 20 Neoplasms of the Salivary Glands 863
further specified is advised with the recom- Diffuse and strong mammaglobin and S100
mendation for conservative but complete protein staining in mammary analogue secre-
excision. tory carcinoma
Risk factors linked to the development of salivary Androgen receptor and salivary duct
gland neoplasia include: carcinoma
Radiation exposure m However, there is substantial overlap in the
Familial or genetic predisposition immunohistochemical antigenic profile among a

Tobacco use: wide variety of tumor types such that differentiat-
Strong association between tobacco use and ing cannot be determined by immunohistochemi-
the development of Warthin tumor cal staining alone.
m Microorganisms: m Immunohistochemical findings of selected sali-
Epstein-Barr virus linked to lymphoepithelial vary gland neoplasms are detailed in Table 20-1.
carcinoma m SRY-related HMG-box 10 (Sox10) protein:
m Exposure to industrial chemicals Transcription factor crucial in development of

Similar to the thyroid gland, fine-needle aspiration neural crest, Schwann cells, and melanocytes
biopsy (FNAB) represents the initial diagnostic Positive expression found in major salivary
modality in assessing the pathology of a salivary gland
gland mass; FNAB is: Sox10 expression in salivary gland neoplasms
m Cost effective and efficient reported as:
m Has a sensitivity rate reported to be 81% to 98% Positive in acinic cell carcinoma, adenoid
m Has a specificity rate reported to be 60% to 75% cystic carcinoma, epithelial-myoepithelial

m Has a false negative rate reported to be 5% to 10%: carcinoma, myoepithelial carcinoma, pleo-
Cytologically diagnosed as malignant but his- morphic adenoma, and carcinoma ex pleo-
tologically proven to be benign morphic adenoma:
m Has a false positive rate reported to be 0% to 6%: Sox10 expression specific to nuclei of acini,
Cytologically diagnosed as malignant and his- luminal, and abluminal cells of intercalated
tologically proven to be benign ducts but not in other sites
Those tumors in which the FNAB diagnosis is equiv- Negative in salivary duct carcinomas, muco-
ocal or inconclusive likely result in intraoperative epidermoid carcinomas, oncocytic carci-

consultation (i.e., frozen section analysis) to clarify noma, oncocytomas, and Warthin tumor
and/or confirm the diagnosis (see Chapter 21 for the In other organ sites (e.g., breast, prostate, other) the
intraoperative diagnoses of salivary gland tumors). identification of two cell types (e.g., ductal and myo-
In general, the light microscopic features of salivary epithelial or basal cells) may correlate to a benign
gland neoplasms are distinctive so that use of immu- neoplasm, whereas the presence of a single cell type
nohistochemistry is not necessarily required to arrive may correlate to an adenocarcinoma; these criteria
at a diagnosis; however, exceptions to this rule exist are not necessarily applicable to salivary gland, in
and immunohistochemical analysis may be required that there are benign neoplasms composed of only a
in the diagnosis and differential diagnosis of salivary single cell type (e.g., monomorphic adenomas) and
gland neoplasms: malignant tumors composed of dual cell types (e.g.,
m Immunohistochemical antigenic profile of sali- adenoid cystic carcinoma, epithelial-myoepithelial
vary gland neoplasms often correlates to the his- carcinoma, others).
togenetic derivation of the tumor. Cytogenetics and molecular genetics (Table 20-2):
Tumors derived from the distal segments of the m Recent studies have identified genes correlating to
salivary duct system (intercalated ducts and specific tumor types, which can be used as
acini) may take origin from a combination of adjuncts to light microscopic and immunohisto-
epithelial and myoepithelial cells and may have chemical staining in diagnosis and differential
different and diagnostic immunoreactivity as diagnosis.
compared with those neoplasms that originate With increasing understanding of the biology of
from more proximal segments of the duct salivary gland neoplasms and identification of
system (striated and excretory ducts) in which characteristic molecular signatures and genomic
myoepithelial cells are absent. alterations of specific histologic subtypes, such neo-
Some neoplasms have relatively unique markers plasms may be amenable to molecular targeted
or combination of markers, including (but not therapy:
limited to): m Clinical trials exploring this approach are cur-
DOG1 immunoreactivity in acinic cell rently under way, and their efficacy remains to be
carcinoma determined.
TABLE 20-1 Immunohistochemistry* of Selective Salivary Gland Neoplasms

Tumor PanK LMWK HMWK p63 p40 S100 DOG-1 MGB AR GATA-3 Her-2 CD117 PLAG1
PA + + + + + + v v +
BCA/BCAdC + + + + + + v v v
MYO + + + + + + v v +
MEC + + + + + v v
ACC + + + +
MASC + + + + + + (n)
AdCC + + + + + + +
+ (lum)
PLGA + + + + + v v
SDC + + + + (n) + (n) v (memb)
EMC + + + + + + +

CCC/HCCC +/+ +/+ +/+ /+ / / / / / / / /
*Staining characteristics vary widely among tumor types and even within the same tumor type. This table details ideal staining
characteristics per tumor type, and although these staining patterns generally remain consistent, any given tumor listed may defy
convention and show reactivity for a marker usually not associated with that tumor or may lack a marker usually associated with
that tumor (e.g., p63 in myoepithelial cells).
Frequently positive often showing distinctive combined apical ductal and membranous/cytoplasmic myoepithelial staining profile.
ACC, Acinic cell carcinoma; AdCC, adenoid cystic carcinoma; AR, androgen receptor; BCA, basal cell adenoma; BCAdC, basal cell
adenocarcinoma; CCC, clear cell carcinoma, including hyalinizing type; DOG-1, discovered on GIST1; EMC, epithelial-myoepithelial
carcinoma; GATA-3, GATA binding protein 3; HCCC, hyalinizing clear cell carcinoma; HMWK, high molecular weight cytokeratin (e.g.,
CK5/6, CK14); LMWK, low molecular weight cytokeratin (e.g., CK7, CK8, CK19); lum, strong staining luminal cells; MASC, mammary
analogue secretory carcinoma; MEC, mucoepidermoid carcinoma; memb, membranous; MGB, mammaglobin; MYO, myoepithelioma;
n, nuclear; PA, pleomorphic adenoma; PanK, pancytokeratin (e.g., AE1/AE3; CAM5.2); PLAG1, pleomorphic adenoma gene 1; PLGA,
polymorphous low-grade adenocarcinoma; SDC, salivary duct carcinoma; V, variably positive.
Specific staining characteristics:
DOG1: should be admixture of strong apical membranous, cytoplasmic and complete membranous staining
Mammaglobin: should be strong and diffuse cytoplasmic staining in MASC (same for S100 protein in this tumor)
PLAG1 immunohistochemical staining may not be confirmed by FISH analysis even for PA.
TABLE 20-2 Salivary Gland Neoplasms: Chromosomal Translocations

Tumor Chromosomal Translocation Gene Fusion Percentage of Cases
Pleomorphic adenoma Rearrangement of 8q12: PLAG1; Approximately 70%
t(3;8)(p21;112) HMGA2
t(5;8)(p13;q12)
Rearrangement of 12q13-15:
t(3;12)(p14.2;q14-5)
ins(9;12)(p23;q12-15)
Mucoepidermoid carcinoma t(11;19)(q21;p13) CRTC1-MAML2 60% to 80%
t(11;15)(q21;q26) CRTC3-MAML2 6% or less
Adenoid cystic carcinoma t(6;9)(q22-23;p23-24) MYB-NFIB 80% to 90%
Mammary analogue secretory t(12;15)(p13q25) ETV6-NTKR3 Translocation 80%
carcinoma ETV6 break 99%
Hyalinizing clear cell carcinoma t(12;22)(q13;q12) EWSR1-ATF1 For HCCC 80%
(HCCC) For CCMC 39%
Clear cell variant of
myoepithelial carcinoma
(CCMC)
Cribriform cystadenocarcinoma t(1;14)(p36.11;q12) t(X;14) ARID1A-PRKD1 To be determined but
of salivary glands (p11.4;q12) DDX3X-PRKD1 could be as high as 80%
Other abnormalities of
PRKD2, PRKD3
Epithelial-myoepithelial No translocation but a HRAS exon3, codon 61 27%*
carcinoma mutation
*Chiosea SI, Miller M, Seethala RR: HRAS mutations in epithelial-myoepithelial carcinoma, Head Neck Pathol 8:146-150, 2014.
Includes de novo CCMC and CCMC ex pleomorphic adenoma. From Skalova A, Weinrib I, Hyrcza M, et al: Clear cell myoepithelial carcinoma
of salivary glands showing EWSR1 rearrangement, Am J Surg Pathol 39:338-348, 2015.
Prognostic factors in salivary gland tumors include: require a node dissection, whereas high-
Clinical staging (see below) grade tumors often disseminate to regional
Microscopic grading: lymph nodes, requiring a neck dissection.
Some neoplasms by definition are considered Intermediate-grade tumors may or may not
to be histologically low grade (e.g., acinic cell disseminate to regional lymph nodes and
carcinoma, polymorphous low-grade adeno- require clinical and radiographic evaluation
carcinoma, epithelial-myoepithelial carci- to determine whether there is or is not evi-
noma, basal cell adenocarcinoma, others) dence of nodal metastasis; the result of this
and other tumors are considered to be evaluation usually dictates the need for a
histologically high grade (e.g., salivary duct neck dissection.
carcinoma, most cases of carcinoma ex pleo- m Tumor location:
morphic adenoma, others). Some tumors occurring in a specific site have a

Exceptions to the above occur such that his- better prognosis than the identical tumor
tologically low-grade carcinomas may trans- occurring in a different location.
form to high-grade tumors (e.g., acinic cell Mucoepidermoid carcinoma (MEC) of the
adenocarcinoma, others); further, there are parotid gland has an overall better prognosis
low-grade variants of typically high-grade than MEC of the submandibular gland.
carcinomas, including low-grade carcinoma m Facial nerve involvement:
ex pleomorphic adenoma. Tumor involvement of the facial nerve is associ-

Some tumors such as adenocarcinoma, not oth- ated with increased morbidity (e.g., recurrence)
erwise specified, are histologically divided into and mortality.
low, intermediate, and high grade based on a m Demographics:
variety of cytomorphologic findings. Tumors occurring in younger patients and in

Similarly, mucoepidermoid carcinoma is histo- females are reported to have a more favorable
logically divided into low, intermediate and outcome.
high grade based on a combination of architec- m Observed association salivary gland cancer and
tural and cytomorphologic findings. breast cancer noted for decades with recent evi-
Often but not always the histologic grade cor- dence of a connection between BRCA gene muta-
relates to the clinical stage: tions and salivary gland cancers.
Low-grade tumors tend not to disseminate to TNM classification of salivary gland carcinomas
regional lymph nodes and generally do not (Table 20-3)
BENIGN NEOPLASMS
PLEOMORPHIC ADENOMA (PA) Slightly more common in women than men;

(Figs. 20-1 to 20-15) occur over a wide age range but are most com
monly seen in the third through sixth decades of
Definition: Benign neoplasm composed of cells demon- life:
strating epithelial and myoepithelial differentiation: m Most common salivary gland neoplasm in chil-
m Considered a pure epithelial neoplasm with dren and adolescents

divergent differentiation that may also include Most common site of occurrence is tail of the parotid
mesenchymal-appearing elements (myxoid, gland but it may also occur in the deep lobe of the
hyaline, chondroid, and osseous areas). parotid, in the submandibular and sublingual glands,
Synonym: Benign mixed tumor and in all minor salivary glands throughout the
upper and lower respiratory tract:
m PA of parotid gland occurs primarily (but not
Clinical exclusively) in the superficial lobe (i.e., superficial

Represents most common neoplasm of salivary plane to facial nerve)
glands, accounting for 40% to 70% of all neoplasms m PAs of deep lobe of parotid gland may present as
of the parotid, submandibular glands, and minor a parapharyngeal space mass.

salivary glands; PA of the sublingual glands is rare: m Involvement of minor salivary glands occurs most
m 80% occur in parotid gland frequently on the palate (hard and soft), but other
m 10% occur in submandibular gland common sites include the upper lip and buccal
m 10% occur in minor salivary glands mucosa.
TABLE 20-3 TNM Classification of Salivary Gland Carcinomas*

Primary Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor 2cm or less in greatest dimension without extraparenchymal extension
T2 Tumor more than 2cm but not more than 4cm in greatest dimension without extraparenchymal extension
T3 Tumor more than 4cm in greatest dimension with extraparenchymal extension
T4a Moderately advanced disease
Tumor invades skin, mandible, ear canal, and/or facial nerve
T4b Very advanced disease
Tumor invades skull base and/or pterygoid plates and/or encases carotid artery
Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single ipsilateral lymph node, 3cm or less in greatest dimension
N2 Metastasis in a single ipsilateral lymph node, more than 3cm but not more than 6cm in greatest
dimension, or metastasis in multiple ipsilateral lymph nodes, none more than 6cm in greatest dimension,
or metastasis in bilateral or contralateral lymph nodes, none more than 6cm in greatest dimension
N2a Metastasis in a single ipsilateral lymph node, more than 3cm but not more than 6cm in greatest dimension
N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6cm in greatest dimension
N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6cm in greatest dimension
N3 Metastasis in a lymph node more than 6cm in greatest dimension
Distant Metastasis (M)
M0 No distant metastasis
M1 Distant metastasis present
Anatomic Stage/Prognostic Groups
Stage I T1N0M0
Stage II T2N0M0
Stage III T1N1M0
T2N1M0
T3N1M0
Stage IVA T4aN0M0
T4aN1M0
T1N2M0
T2N2M0
T3N2M0
T4aN2M0
Stage IVB T4b AnyN M0
Any T N3 M0
Stage IVC Any T Any N M1
*Classification applies only to carcinoma of the major salivary glands, including parotid, submandibular and sublingual glands, and does
not apply to carcinomas arising in the minor salivary glands of the upper respiratory tract.
Extraparenchymal extension is clinical and macroscopic evidence of invasion of soft tissues. Microscopic evidence alone does not
constitute extraparenchymal extension for classification purposes.
From Edge SB, etal: AJCC Cancer Staging Manual, ed 7, New York, 2010, Springer, p 80.
m May occur in the sinonasal tract: In parotid gland, the tumor typically occurs outside
Involve the septum (bony or cartilaginous of the facial nerve, and facial nerve involvement typi-
portion) but may arise in the lateral wall fied by facial nerve paralysis is rare and, if present,
Tend to be myoepithelial-predominant neo- should be suspicious for malignancy:
plasms m Infarcted PAs may uncommonly be associated
Multiple tumors or bilateral tumors are uncommon. with pain or facial palsy.
Symptoms vary according to site: Parapharyngeal space PAs:
m Most are slow-growing, painless masses present m Represent most common tumor of the parapha-
for periods up to several years. ryngeal space (followed by peripheral nerve

m Other symptoms, in particular those occurring in sheath tumors)
the minor salivary glands, may include: m Usually present as an asymptomatic (cervical or
Difficulties in chewing, dysphagia, dyspnea, intraoral) mass; other symptoms may include
hoarseness, and epistaxis obstruction, unilateral conductive hearing loss,
May ulcerate overlying mucosa and serous otitis media
Fig. 20-1. Pleomorphic adenoma.

Pleomorphic adenomas may occur in major salivary glands, as well as minor salivary glands. A, Palpable parotid mass at
the angle of the mandible that was firm, freely movable, and painless. B, Submucosal palatal swelling with intact surface
epithelium. C, Large exophytic mass originating in the nasopharynx, hanging into the posterior oral cavity, where it was
visible through the mouth. D, Resected large nasal septal large neoplasm (note elastic cartilage in center of image) that is
circumscribed to encapsulated and on cut section appears predominantly with glistening (gelatinous) appearance.
Parapharyngeal space is a potential space between

m sections and of histomorphologic regions by
the lateral wall of the pharynx, internal pterygoid finding co-localized molecular signals
muscle, and cervical vertebrae: m Spatial segmentation of MALDI-imaging data is
Other structures located within this space algorithmic method for finding regions of similar
include cranial nerves IX through XII, great proteomic composition as functionally similar
vessels of the neck, mature adipose tissue, and regions.
lymph nodes. m MALDI-imaging of pleomorphic adenoma (two
Despite efforts in localization of key proteins using cases reported to date):

immunohistochemistry, the complex proteomic com- Spatial segmentation subdivided tissue in good
position of pleomorphic adenomas (PA) has not yet accordance with the tissue histology
been characterized. Numerous molecular signals co-localized
Matrix-assisted laser desorption/ionization imaging with histologically defined tissue regions were
mass spectrometry (MALDI-imaging): found.
m Allows label-free and spatially resolved detection Highlighted cellular trans-differentiation
of hundreds of proteins directly from tissue within the PA
Fig. 20-2. Axial contrast-enhanced CT scans of three different patients.

In A, a contrast-enhanced image, there is a large, nonhomogeneous, slightly lobulated mass in the left parotid gland.
There is scattered enhancement. In B, there is a lobulated mass in the right parotid gland with scattered areas of
calcification. In C, there is a large, nonhomogeneous mass in the left parotid gland. All of these patients had pleomorphic
adenomas. (From Som PM, Curtin HD: Head and neck imaging, ed 5, Philadelphia, 2011, Elsevier, Figure 40-129, p 2531.)
m Spatial segmentation of MALDI-imaging data m May demonstrate cystic change

represents promising approach in emerging field m Ulceration of overlying skin does not occur.
of digital histologic analysis and characterization Vary in size from a few centimeters up to large, dis-
of tumors. figuring masses
Cause Minor salivary gland tumors are polypoid or lobu-
m No known etiologic factors lated, encapsulated or well-delineated, tan-white,
m Familial occurrence rare usually measuring 1 to 2cm but capable of attaining
sizes of 7cm or more.
Pathology Recurrent tumors tend to be multinodular.
Gross
Firm, freely movable, unifocal mass: Fine-Needle Aspiration Biopsy
m Encapsulated or well-demarcated, tan-white, and Usually readily diagnosed by FNAB due to the pres-
solid in appearance ence of epithelial and stromal elements
A B
Fig. 20-3. CT and MR of pleomorphic adenoma.

A and B, Axial contrast-enhanced CT scans show a mass in the left parotid gland with unsharp margins. C, Coronal
T2-weighted MR image of the same patient shows a lobulated solitary mass in the left parotid gland. The lesion is far
better seen than on the CT scans. This patient had a pleomorphic adenoma. (From Som PM, Curtin HD: Head and neck
imaging, ed 5, Philadelphia, 2011, Elsevier, Figure 40-131, p 2532.)
Morphologic diversity including: Tyrosine-like crystals appearing as crystalline

m
m Background filled with mucoid to fibromyxoid deposits resembling the petals of a flower:
ground substance varying from fibrillar to myxo- Not pathognomonic for pleomorphic adenoma
matous to chondroid and appearing: as can be seen in nonneoplastic salivary gland
Bright pink or magenta on Romanovsky stain lesions (e.g., parotid cysts) and in other neo-
Bluish purple on Papanicolaou stain plasms (e.g., polymorphous low-grade adeno-
m Clusters of plasmacytoid or spindle-shaped (myo- carcinoma, others)
epithelial) cells: m Intranuclear inclusions
Embedded in stromal matrix Degree of cellularity varies from case to case and
m Cohesive groups of epithelial cells with bland even within the same case.
cytology including round to oval nuclei with fine- Cellular pleomorphic adenomas:
appearing chromatin: m Presence of cellular aspirate and relative absence
Identified in continuity with the stromal of stromal component, especially if nuclear atypia
material is present, may present diagnostic problems in
Other cellular elements and/or findings that can be recognition as benign and in differentiating from
seen include: carcinomas.
m Squamous cells (with or without keratinization) m Cellular aspirates lacking stromal component
m Oncocytic cells and lacking nuclear atypia can be diagnosed as

m Sebaceous cells a salivary gland neoplasm, not otherwise
Fig. 20-4. Parotid pleomorphic adenoma.

Resected pleomorphic adenoma from the superficial lobe
of the parotid gland, showing a circumscribed to
encapsulated tumor that on cut section is solid with a
tan-white appearance.
B
specified, which would then prompt surgical
removal and histologic evaluation.
Histology
Typical (Classic) PA
In major salivary glands are encapsulated but fibrous
capsule varies in thickness and may be thin or even
absent:
m Prominently myxoid tumors often have incom-
plete capsules and there may be juxtaposition of

the tumor to adjacent normal salivary gland.
m May be multinodular:
Nodules may be separate from one another.

Not diagnostic for malignancy C
m May have irregular growth along periphery of
lesion, including lesional cells extending into Fig. 20-5. Fine needle aspiration.
capsule and/or fat:
Capsular extension not diagnostic for carci- Pleomorphic adenoma, fine-needle aspiration biopsy.
noma A, Background is filled with mucoid to fibromyxoid ground
substance appearing bluish-purple with fibrillar appearance
Fat may be inherent component of tumor so
and associated spindle (myoepithelial) cells. B, Cohesive
that lesional cells extending into fat but still groups of epithelial cells with bland cytology including
within the confines of a capsule are still within round to oval nuclei with fine nuclear chromatin and
the spectrum of a benign neoplasm and not associated magenta-appearing mucoid ground substance.
diagnostic for malignancy. C, Clusters of plasmacytoid (myoepithelial) cells with
In minor salivary glands generally not encapsulated associated chondroid-appearing matrix.
but typically circumscribed or well demarcated:
m Extension and involvement of surface epithelium
not diagnostic feature for malignancy

Histologic appearance includes an admixture of epi-
thelial, myoepithelial, and stromal components.
A B
C D
E F
Fig. 20-6. Pleomorphic adenoma.

A, In major salivary glands, pleomorphic adenomas are encapsulated sharply demarcated from the unremarkable parotid
gland parenchyma. B, In minor salivary glands such as seen in this palatal lesion, pleomorphic adenomas are
circumscribed but not encapsulated. C, Characteristic components in a pleomorphic adenoma include admixture tubules/
ductules and matrix stroma, the latter including hyaline (arrows) and myxoid foci. D and E, Acini or tubules are lined by
ductal epithelial cells surrounded by an outer layer of modified myoepithelial cells of varying thickness. F, PLAG1 (nuclear)
immunoreactivity.
A B
Fig. 20-7. Cellular epithelial-predominant pleomorphic adenoma.

A, At low magnification there is a cellular neoplasm with residual identifiable chondromyxoid stroma. B, At higher
magnification, cytomorphologically bland-appearing epithelial cells predominate lining ductules as well as in the cellular
areas.
A B
C D
Fig. 20-8. Cellular myoepithelial-predominant pleomorphic adenoma.

The myoepithelial cells may include (A) solid growth composed of plasmacytoid (hyaline) and/or (B) fascicular pattern of
growth composed of spindle shaped cells. C, Myoepithelial cells are strongly p63 (nuclear) positive whether appearing
spindle-shaped as seen here or plasmacytoid (hyaline) (not shown). D, Diffuse PLAG1 (nuclear) immunoreactivity.
E F
Fig. 20-8, contd

E, The myoepithelial cells may be arranged in a reticular or lattice-like growth pattern within myxoid stroma or show
(F) fascicular growth (lower right) adjacent to lattice-like growth pattern (upper left).
A B
Fig. 20-9. Chondromyxoid predominant pleomorphic adenoma.

A, Low magnification showing predominance of chondromyxoid matrix with variable cellularity including identifiable
tubules along the periphery (left) of the neoplasm. B, At higher magnification, identifiable tubules lined by dual cell type
are present extending (melting) into the dominant chondromyxoid stroma. C, In some examples only very focal isolated
tubules remain (arrowheads) in a neoplasm with predominant chondromyxoid-appearing stroma.
A B
Fig. 20-10. Metaplastic and retrogressive changes following aspiration.

Postfine-needle aspiration biopsy changes may include (A) squamous metaplasia (arrows) with keratinization and
intercellular bridges; (B) mucous cell metaplasia (arrowheads) and squamous metaplasia. This combination of cell types
may raise concern for a possible diagnosis of mucoepidermoid carcinoma, but the presence of keratinization and
intercellular bridges are not features typically associated with mucoepidermoid carcinomas. The latter are composed of
epidermoid cells lacking keratinization and intercellular bridges. C, Infarction (bottom) with squamous metaplasia.
Morphologic variability (i.e., polymorphism) can Plasmacytoid myoepithelial cells are oval with
be seen from case to case and within a single round nuclei eccentrically located and abun-
neoplasm: dant eosinophilic hyaline cytoplasm
m Growth patterns may include tubular/ductular, Absence of perinuclear Golgi zone
solid, cystic, trabecular, cribriform, papillary, Stromal component, the product of myoepithelial
reticular, or lattice-like and schwannoma-like. cells, varies in appearance from myxoid to (hyaline)
Duct-lining epithelial cells form the inner layer of chondroid to chondromyxoid and may also appear
acini or tubules and appear flattened, cuboidal, or fibrous and vascular:
columnar with round to oval nuclei and a variable m Any one or all of these components may coexist
amount of cytoplasm appearing eosinophilic to in the same neoplasm.

amphophilic. m Quantity ranges from case to case and even
Myoepithelial component forms the outer layer and within a given case and may be abundant or
may appear: scanty.
m Spindle-shaped, plasmacytoid (hyaline), cuboi- Presence of any stromal component as
dal, epithelioid, clear-appearing cells detailed above allows for classification as
A B
C D
E F
Fig. 20-11. Variant histologic findings in pleomorphic adenomas.

Other histologic findings that can be seen in association with pleomorphic adenomas may include (A) cribriform growth,
which may suggest a diagnosis of adenoid cystic carcinoma, but in the setting of pleomorphic adenoma cribriform growth
tends to be limited, occurring in a background of characteristic findings of pleomorphic adenoma; (B and C) schwannoma-
like foci including perivascular hyalinization (B) and (C) wavy buckled appearing nuclei; (D) cells in schwannoma-like foci
are strongly and diffusely p63 positive (nuclear), indicative of myoepithelial cells; (E) oncocytic cells focally or more
extensive, the latter referred to as oncocytic type of pleomorphic adenoma; (F) sebaceous cells (arrow) within focus of
squamous metaplasia; Continued
Fig. 20-11, contd

(G) (extracellular) tyrosine-like crystals; and (H) psammoma bodies (arrow).
A B
Fig. 20-12. Growth characteristics of pleomorphic adenoma.

Growth patterns that may raise concern but that are not diagnostic for carcinoma in pleomorphic adenomas may include
(A and B) multinodular growth, including satellite nodules separate from the main mass; this finding is still acceptable
within the spectrum of changes associated with pleomorphic adenomas; (C-E) capsular extension by (C) mushroom-like
growth;
D E
F G
Fig. 20-12, contd

(D) protrusion into the capsule, or (E) scattered tubules (arrows) extending into the capsule. Such capsular extension may
be a diagnostic feature for carcinoma in other organs (e.g., thyroid gland) but not in relationship to salivary gland
neoplasms. Extension beyond the capsule into adjacent salivary gland parenchyma or fibroconnective tissue is considered
invasive growth that generally equates to malignancy in salivary gland neoplasms. F, Extension into fat (arrows); the fat is
within (part of) the neoplasm lying within the capsule (arrowheads) separating the tumor from the surrounding parotid
gland parenchyma. G, Vascular permeation with tumor adherent to the vessel wall and not floating in the lumen as may
be indicative of an artifactual change. Vascular permeation can infrequently be seen in a neoplasm with histologic features
characteristic of pleomorphic adenoma and has generally been shown not to be associated with untoward behavior such
as metastatic tumor.
pleomorphic adenoma rather than monomor- Clear cells, sebaceous cells, oncocytic cells
m
phic adenoma. Calcification and fat

m
Extracellular crystalloids may be identified, particu- Minor salivary pleomorphic adenomas tend to be
larly in the nonepithelial areas: cellular and are circumscribed but unencapsulated.
m Crystalloids are more often present in PA than in m Those occurring in the nasal cavity (particu
any other salivary gland tumor but may be present larly the septum) tend to have an increased
in other tumor types, including polymorphous plasmacytoid-appearing myoepithelial compo-
low-grade adenocarcinoma. nent.
Other cell components may include: Multicentric pleomorphic adenomas are rare.
m Squamous cells with or without keratinization Recurrent tumors are often multinodular and fre-
m Mucous cells quently chondromyxoid-predominant.
A B
C D
Fig. 20-13. Potential confounding findings in pleomorphic adenomas.

Cytomorphologic findings that may raise concern but that are not diagnostic for carcinoma in pleomorphic adenomas may
include (A) presence of mitotic figures (arrow); numerous mitotic figures can be seen in any given pleomorphic adenoma
but increased mitotic activity is not diagnostic for carcinoma. The presence of atypical mitoses (not shown) would
represent a more worrisome feature for carcinoma but additional findings would still be required for a diagnosis of
carcinoma. B, Enlarged pleomorphic and hyperchromatic bizarre-appearing (monster) nuclei. Generally such bizarre nuclei
are focally and not diffusely identified and are thought to represent a reactive process. Diffuse nuclear atypia would
represent a more worrisome feature for carcinoma but additional findings would still be required for a diagnosis of
carcinoma. C and D, Broad zones of acellular hyalinization. The presence of prominent areas of acellular hyalinization is
considered an atypical finding in pleomorphic adenomas that are not diagnostic for malignancy but may portend or be
associated with malignant transformation (i.e., carcinoma ex pleomorphic adenoma).
Postfine-needle aspiration biopsy changes: Necrosis/infarction

m Secondary changes may occur following prior Spontaneous necrosis in a PA may occur, but
manipulation or fine-needle aspiration biopsy the presence of necrosis/infarction in the

and may include: absence of prior manipulation should raise
Squamous metaplasia, including keratinization concern for the possibility of malignancy.
and/or intercellular bridges
Mucous cell metaplasia Cellular Pleomorphic Adenoma
Hemorrhage and cholesterol granuloma Neoplasm showing residual foci diagnostic for pleo-
formation morphic adenoma, even if only limited in extent, but
Calcifications and psammomatoid concretions dominated by epithelial, myoepithelial, or stromal
Pseudoinvasion or bulging into the capsule component
A B
Fig. 20-14. Recurrent multinodular and multifocal pleomorphic adenoma.

A and B, Serial coronal T2-weighted MR images on a patient who had a prior left parotidectomy. There are multiple
well-delineated masses in the left postoperative parotid bed. This patient had multiple recurrences of pleomorphic
adenomas. C, Axial CT scan of a different patient who had a left parotidectomy. There are multiple low-attenuation
well-delineated masses within the left parotid postoperative bed. This patient also had multiple recurrences of pleomorphic
adenomas. These recurrences indicate that the original tumor capsule was violated at the time of the initial surgery. (From
Som PM, Curtin HD: Head and neck imaging, ed 5, Philadelphia, 2011, Elsevier, Figure 40-146, p 2541.)
Neoplasms with overabundance of epithelial cells, raising additional concern for possible diagnosis of
myoepithelial cells, or mesenchymal component cat- malignancy:
egorized respectively as: m Typically, bizarre cells are limited in extent
m Epithelial-predominant pleomorphic adenoma and often relegated to focal areas of the

m Myoepithelial-predominant pleomorphic ad tumor.
enoma m Mitotic figures may be identified in any given
m Chondromyxoid-predominant pleomorphic ad tumor but often are limited in number.

enoma Increased mitotic figures can be seen in any
In association with increased cellularity there may be given neoplasm and solely in the absence of
nuclear pleomorphism, including bizarre-appearing other findings does not constitute a diagnostic
(monster) cells and scattered mitotic figures, feature for carcinoma
spillage caused by tumor injury presumably by

prior fine-needle aspiration or surgery.
Despite the presence of increased cellularity even
with bizarre cells and mitoses, there is absence of
features raising concern for malignancy.
Atypical Pleomorphic Adenoma

Atypical histologic features seen in PAs that may
portend transformation to a carcinoma include:
m Diffuse nuclear atypia (anaplasia)
m Atypical mitoses
m Prominent zones of (acellular) hyalinization
Pleomorphic adenomas with prominent zones

of hyalinization are more likely to develop car-
A cinoma than pleomorphic adenomas without
such hyalinization.
m Coagulative tumor necrosis
Presence of atypical features should prompt exten-

sive sectioning and histologic examination of the
specimen to exclude findings that may be diagnostic
for malignancy.
Recurrent Pleomorphic Adenoma

Often but not always tend to be chondromyxoid
predominant
Often multinodular and may include:
m Innumerable variably sized, well-circumscribed
nodules
m Extensive involvement of soft tissues of the neck,
B including into skeletal muscle and fat

m In spite of multinodularity retain benign cyto-
morphologic features
Fig. 20-15. Recurrent PA. For all pleomorphic adenomas:
Recurrent pleomorphic adenomas may vary in their Histochemistry:
histologic appearance but not infrequently are m Intraluminal epithelial mucin may be demon-
chondromyxoid predominant and may include numerous strated by diastase-resistant, periodic acid Schiff
nodules in soft tissue of the neck. A, Multiple positive, and mucicarmine-positive material.
chondromyxoid-predominant pleomorphic adenoma m Stromal component is alcian blue positive but
nodules within skeletal muscle. B, The nodules are mucicarmine negative
composed of benign cellular features lacking malignancy
Immunohistochemistry (IHC):
cellular features. Similar to capsular extension and vascular
m Epithelial cells:
permeation, the presence of multiple nodules of otherwise
cytologically benign lesional cells is acceptable within Cytokeratins, CEA and EMA positive
the spectrum of changes associated with (recurrent) May be CD117 (c-kit) positive
pleomorphic adenomas and not diagnostic for metastatic m Myoepithelial cells:
carcinoma. Cytokeratins, p63, p40, calponin, S100 protein,

glial fibrillary acidic protein, actin and vimen-
Presence of atypical mitotic figures not typi- tin positive
cally found in pleomorphic adenomas CEA and EMA negative
Rare cases may show vascular permeation but by m Pleomorphic adenoma gene 1 (PLAG1) consis-
itself this feature is not indicative of malignancy: tently positive in PAs (nuclear) in epithelial and
m Intravascular location of neoplastic cells can myoepithelial cells
be confirmed by CD31, CD34, and factor VIII m SOX10 positive (nuclear) in epithelial and myo-
related antigen immunostains. epithelial cells

m Biologic significance not completely clear but m Low proliferation indicates by Ki67 (MIB1)
evidence supports innocuous phenomenon in a staining typically less than 5%:

majority of cases likely related to artifactual Although not definitively
Absent to rare p53 reactivity

m polymorphous low-grade adenocarcinoma (PLGA)
Weak bcl-2 reactivity
m and adenoid cystic carcinoma (AdCC) include:
NOTE: IHC staining characteristics of PAs variable PA: p63 + (68%; 21/31) and p40+ (42%;
from case to case and even within a given case and 13/31) immunophenotype
do not necessarily show consistent staining patterns Discordant p63+/p40 staining pattern seen
reported in the literature only in overtly mesenchymal chondromyxoid
Molecular biology: stroma
m 70% of PAs are karyotypically abnormal, Cellular PA: concordant p63+/p40+ or p63/
including: p40 immunophenotypes
8q12 rearrangements: PLGA: consistent p63+ (100%; 11/11) and
Translocations include t(3;8)(p21;q12) and p40 (100%; 11/11) immunophenotype
t(5;8)(p13;q12) AdCC: p63 + (90%; 91 of 101) and p40+
Target gene, pleomorphic adenoma gene 1 (89%; 90/101) immunophenotype
(PLAG1), mapped to 8q12 Single discordant p63+/p40 case was solid
12q14-15 rearrangements: variant with high-grade features

Translocations include t(9;12)(p24;q14-15) Proliferation indices (Ki67):
or ins(9;12)(p24;q12q15) Low proliferation indices seen in association
Target gene is the high mobility group protein with PA, cellular PA, and PLGA typically less
gene, high mobility group AT-hook 2 than 5%
(HMGA2) Proliferative indices reported to be signifi-
NOTE: To date, PLAG1 and HMGA2 not reported in cantly higher in AdCC (up to approximately
any other salivary gland neoplasms (except carcinoma 20%)
ex pleomorphic adenoma) Increased proliferation indices may not be
Sporadic or clonal changes not 8q12 or 12q present in all cases of AdCC and by itself
13-15 rearrangements does not unequivocally differentiate it
Normal karyotype may be present. from PA, cellular PA, and PLGA.
CAUTIONARY NOTE: Although a p63/p40 immuno-
Differential Diagnosis (Table 20-4) histochemical panel can be a valuable tool for making
In general, diagnosis of pleomorphic adenoma does distinction between PA, PLGA, and AdCC, it is not
not present difficulties; however, in cellular tumors infallible and any given example may demonstrate
with a variety of growth patterns, particularly involv- divergence from the reported p63/p40 immunopheno-
ing minor salivary glands (i.e., intraoral), pleomor- type.
phic adenomas may prove difficult to differentiate Mucoepidermoid carcinoma (MEC):
from other tumors including: m In those examples of PA with squamous and
m Monomorphic adenoma (MA): mucinous cell metaplasia differentiation from

Presence or absence of mesenchymal compo- MEC can be somewhat problematic:
nent differentiates PA from MA. Presence of keratinization and intercellular
Identification of mesenchymal component in bridges associated with squamous metaplasia
any given case can be problematic, but in such of PA contrasts to the epidermoid component
a situation decision is between two benign neo- of MEC typically lacking keratinization and
plasms so treatment and prognosis are similar. intercellular bridges.
m Polymorphous low-grade adenocarcinoma Metaplastic PAs do not harbor translocations
(PLGA) of minor salivary gland origin: t(11;19) and anticipated t(11;15) resulting
Many overlapping findings with PAs so in in CRTC1-MAML2 and CRTC3-MAML2
limited sampling will be problematic in differ- fusion transcripts, respectively, and/or MAML2
entiating it from PA (see immediately below for gene rearrangement found in association
use of p63/p40 immunostaining in the differ- with MEC.
ential diagnosis) Deep-seated dermal adnexal neoplasm
m Adenoid cystic carcinoma: Mesenchymal neoplasm:
In contrast to PAs, adenoid cystic carcinomas m Peripheral nerve sheath tumor
reported to have: m Smooth muscle neoplasms
Increased proliferation indices
Increase in p53 staining Treatment and Prognosis

Strong bcl-2 staining Complete surgical excision is preferred treatment:
m Further IHC findings including pairing p63 and m Parotid gland tumors usually require lobectomy
p40 reported to assist in differentiating PA from with preservation of the facial nerve.
TABLE 20-4 Intraoral Minor Salivary Gland Neoplasms: Selective Differential Diagnosis
Tumor Encapsulation Growth Patterns Cytomorphology Stroma IHC Cytogenetic
PA Absent Polymorphic Dual cell population: Chondromyxoid; Positive for PLAG1
but well including ducts/glands and crystalloids may epithelial and HMGA2
circumscribed tubules, ribbons, myoepithelial cells; no be present myoepithelial
sheets, cords, necrosis or increased markers: CKs,
cysts, trabeculae mitotic activity; p63, p40, S100
intercellular hyaline protein, PLAG1
material may be others; low
present proliferation
indices
CPA (E Absent but Polymorphic Dual cell population: Scanty but Positive for PLAG1
or M) well including ducts/glands and identifiable epithelial and HMGA2
circumscribed tubules, ribbons, myoepithelial cells; for chondromyxoid myoepithelial
sheets, cords, myoepithelial stroma; markers: CKs,
cysts, trabecular, predominant tumors crystalloids may p63, S100 protein,
fascicular, lesional cells include be present others; low
anastomosing spindle-shaped and proliferation
cords plasmacytoid cells but indices
ducts/glands focally
seen; no necrosis or
increased mitotic
activity; intercellular
hyaline material may
be present
PLGA Absent and Polymorphic Isomorphic cells Slate gray Positive for None known
infiltrative including with minimal myxoid; epithelial and although
tubular/ductules, pleomorphism; no crystalloids may myoepithelial PRKD2
cribriform, solid, necrosis or increased be present markers: CKs, rearrangement
linear single cell, mitotic activity; p63, S100 protein, reported in a
streaming intercellular hyaline others; p40 single case
along periphery, material may be negative*; PLAG1
papillary present usually negative;
low proliferation
indices
AdCC Absent and Polymorphic Basaloid cells with Myxoid-hyaline Positive for MYB-NFIB
tubular, infiltrative including uniform, angulated, stroma epithelial and
cribriform cribriform, hyperchromatic nuclei, myoepithelial
tubular/ductules, scanty cytoplasm; no markers: CK, p63,
islands, cysts, necrosis or increased p40, S100 protein,
nests, cords, mitotic activity; others; PLAG1
solid intercellular hyaline negative; increase
material present proliferation
indices
*p40 not necessarily consistently negative in PLGA or positive in the other neoplasms.
Increase proliferation indices may not be present in all cases of AdCC and by itself does not definitively differentiate it from PA, cellular
PA and PLGA.
AdCC, Adenoid cystic carcinoma; CKs, cytokeratins; CPA, cellular pleomorphic adenoma; E, epithelial predominant; M, myoepithelial
predominant; PA, pleomorphic adenoma; PLGA, polymorphous low-grade adenocarcinoma.
Submandibular gland tumors usually necessitate

m Variable capsular thickness coupled with ten-
m
complete removal. dency of tumor to invade capsule and/or bulge

m Minor salivary glands neoplasms require com- through capsule
plete but conservative excision. m Young age
Incomplete excision irrespective of site results in Recurrent tumors may be multifocal and in some
recurrent tumor: cases may be widely distributed throughout the soft
Increase risk of recurrence associated with: tissues of the neck, precluding surgical resection to
m Inadequate surgery: control local disease:
Enucleation m Low-dose radiation may be used in this
Rupture or spillage during surgery situation.
m Chondromyxoid-predominant PAs: m Presence of scar tissue in association with
Diffluent nature results in spillage. the recurrent tumor may present difficulties
relative to the facial nerve with adherence to the

nerve. WARTHIN TUMOR (WT)
m Preservation of the nerve with excision of the scar (Figs. 20-16 through 20-22)
tissue and the entire parotid gland is recom-
mended for recurrent tumor. Definition: Benign salivary gland tumor characterized
Overall prognosis for PA is excellent with: by its readily recognizable morphologic appearance
m 5-year recurrence-free rate of 97% composed of bilayered epithelium, including inner
m 10-year recurrence-free rate of 94% columnar oncocytic cells surrounded by smaller basa-
Complications include malignant transformation loid cells, and forming multiple cysts and papillary
(carcinoma ex pleomorphic adenoma) and the rare structures that are separate from a mature lymphocytic
occurrence of so-called benign metastasizing pleo- cell stroma.
morphic adenoma. Synonyms: Papillary cystadenoma lymphomatosum;
Surgical complications may include nerve damage adenolymphoma; cystadenolymphoma
and Frey syndrome (gustatory sweating).
Features that may indicate a greater likelihood of
malignant transformation include:
m Occurrence in submandibular gland
m Older patient age
m Long-standing tumor
m Larger tumor size
m Prominent areas of acellular hyalinization
m Increased mitotic activity including atypical

mitoses
Any salivary gland PA may show histologic features
that raise concern for malignancy:
m Neoplastic tissue within or extending through the
fibrous capsule causes concern for malignant

transformation; however, by itself capsular
involvement in an otherwise unremarkable PA is
acceptable and is not an indication of malignant A
transformation.
m Rare cases of PA may show vascular permeation
but by itself this feature is not indicative of

malignancy.
m Recurrent PA often have multiple foci of tumor
within the normal salivary gland but these foci

are usually discrete and circumscribed without
cytologic atypia (they may show a prominent
chondromyxoid stroma).
Treatment for an atypical pleomorphic adenoma is
similar to conventional pleomorphic adenoma
albeit perhaps with more vigilant follow-up.
MONOMORPHIC ADENOMAS
B
Definition: Benign tumors of salivary glands character-
ized by a lack of the mesenchyme-like stromal compo-
nent as seen in pleomorphic adenomas and composed Fig. 20-16. Imaging features of Warthin tumor.
exclusively of the epithelial component or less com- Axial contrast-enhanced CT scan (A) and T2-weighted
monly, myoepithelial component, and arranged in a (B) MR image show a partially cystic mass in the left
variety of morphologic patterns. parotid gland with a thick tumor nodule along the posterior
Monomorphic adenomas encompass a whole wall. This patient had a Warthin tumor. (From Som PM,
group of neoplasms that are not pleomorphic Curtin HD: Head and neck imaging, ed 5, Philadelphia, 2011,
adenomas. Elsevier, Figure 40-157, p 2547.)
A B
Fig. 20-17. Bilateral Warthin tumor.

Oblique frontal technetium sialograms show multiple masses with intense uptake in both parotid glands. This patient had
bilateral Warthin tumors. (From Som PM, Curtin HD: Head and neck imaging, ed 5, Philadelphia, 2011, Elsevier, Figure 40-152, p
2544.)
More common in men than in women:

m Recent evidence shows marked decline in inci-
dence in men with increased prevalence in women.

m These demographic changes have been linked to
smoking habits with a decline in use by men and

an increase of use in women.
m Smoking has been considered as an established
risk factor for the development of Warthin tumor.

Occurs over a wide age range but is most common
in the fifth through seventh decades of life; uncom-
mon to occur in the first three decades of life
Almost exclusively involves parotid gland, particu-
larly in the superficial lobe along the inferior pole
adjacent to the angle of the mandible; rare cases
reported in submandibular gland, palate, lip, tonsil,
larynx, and maxillary sinus
Bilateral tumors can be seen in up to 10% of cases
and multifocal tumors in up to 12% of cases:
m Bilateral or multifocal tumors may occur syn-
chronously or metachronously.
Fig. 20-18. Warthin tumor. Most common symptom is painless mass; rarely is
The resection specimen shows a solid and multicystic pain an associated complaint.
lesion; the solid areas have a nodular appearance. May occur synchronously or metachronously with
other salivary gland tumors, including:
m Pleomorphic adenoma (most common), mono-
morphic adenomas, oncocytoma, basal cell

adenoma, acinic cell adenocarcinoma, ductal
Clinical adenocarcinoma, and adenoid cystic carcinoma
Represents second most common benign salivary Radiology:
gland tumor (following pleomorphic adenoma) m CT scan:
accounting for approximately 5% to 6% of all sali- Well-defined area of increased density in the
vary gland tumors and up to 12% of benign parotid posteroinferior segment of the superficial lobe
gland tumors of the parotid
Pathogenesis
m Thought to develop from neoplastic transforma-
tion of entrapped salivary duct epithelium within

intra- and periparotid lymph nodes during embry-
ologic development; in support of this theory
includes:
Ontogenically, parotid gland is last of the sali-
vary glands to be encapsulated, resulting in
either incorporation/entrapment of lymphoid
tissue within the parotid or incorporation/
entrapment of parotid ducts and acini within
the periparotid lymph node epithelium
A Identification in some cases of subcapsular
sinuses, a normal feature of lymph nodes and
not a normal feature of non-lymph node tissues
(i.e., salivary glands)
Occurrence in periparotid lymph nodes
Presence of B- and T-cell markers in the lym-
phoid component of Warthin tumors
Pathology
Gross
Encapsulated, soft and fluctuant, round to oval mass
with a smooth or lobulated surface composed of
tan-brown tissue with multiple cystic spaces from
B which a mucoid or brown exudate may be expressed;
within the cystic spaces papillary projections are
seen
Fig. 20-19. Warthin tumor, fine-needle aspiration Solid areas can be identified and are noted for a
biopsy. white nodular appearance representative of lym-
A, Cytologic features are characterized by the presence phoid follicles.
of oncocytic-appearing epithelial cells and mature Measures from 1 to 8cm in diameter
lymphocytes (Diff-Quik). B, Cohesive cluster of oncocytic
epithelial cells with honeycomb arrangement and scattered Fine-Needle Aspiration Biopsy
lymphocytes (Papanicolaou). Combination of oncocytic-appearing epithelial cells
and mature lymphocytes
Oncocytic epithelial cells appear in cohesive clusters
as well as individual cells and may take on a honey-
Radionucleotide imaging:
m comb arrangement; these cells are characterized by
Increased uptake of technetium-99m, which the presence of:
does not wash out following dialogue admin- m Abundant granular and eosinophilic-appearing
istration; this finding plays an important role cytoplasm

in diagnosis and is related to the presence of m Uniform round nuclei often centrally located with
oncocytes and their increased mitochondrial identifiable nucleoli

content. m Distinct cell borders
Cause: m Absence of lymphocytes in the epithelial cluster
m Strong link with cigarette smoking Occasionally, squamous (metaplastic) cells may be
m Radiation exposure has been linked as a tumori- identified.
genetic factor. Background of aspirate may appear dirty with
m Role of Epstein-Barr virus (EBV) in the develop- cellular debris and associated lymphoid cells:
ment of Warthin tumor is controversial: m Given cystic character of Warthin tumor, FNAB
Some studies document the presence of EBV in may yield thick, tan-brown fluid.
the cytoplasm of luminal cells of WT, whereas m The fluid may suggest the presence of mucus.
other studies do not identify EBV in WT. m In conjunction with epithelial clusters and lym-
No substantiation that EBV plays a role in phoid cells this overall appearance may engender
development of WT. a diagnosis of mucoepidermoid carcinoma.
A B
Fig. 20-20. Warthin tumor.

A, The tumor is encapsulated separated from the adjacent parotid parenchyma and characterized by cystic and papillary
appearance and associated lymphoid proliferation. B, Slightly higher magnification shows the characterized features,
including cyst formation and papillary architecture lined by oncocytic epithelial cells, which are demarcated from stromal
lymphocytic cell infiltrate. C, At higher magnification the epithelial component lining the cystic spaces and papillary
projections is composed of a double cell layer including inner (luminal) cells (arrowheads) composed of nonciliated, tall
columnar cells with nuclei aligned toward the luminal aspect and prominent granular eosinophilic (oncocytic) cytoplasm
and outer (basal) cells (arrows) composed of round to cuboidal cells with vesicular nuclei. The epithelial cells are sharply
demarcated from the stromal lymphoid component.
Histology
Papillary and cystic lesion composed of epithelial Outer or basal cells:
m
and lymphoid components Round, cuboidal, or polygonal cells with vesic-

Epithelial component lining the papillary projections ular nuclei
composed of double layer of granular eosinophilic Lymphoid component predominantly composed of
cells (referred to as oncocytic epithelia): mature lymphocytes containing lymphoid follicles
m Inner or luminal cells: with germinal centers:
Nonciliated, tall columnar cells with nuclei m Epithelial component is sharply demarcated from
aligned toward the luminal aspect the lymphoid component.

Prominent oncocytic appearance of the cells is m Other inflammatory cells that may be seen include
due to the presence of increased mitochondrial plasma cells, histiocytes, mast cells, and occa-
content. sional multinucleated (Langhans type) giant cells.
Fig. 20-21. Post needle aspiration changes in Warthin tumor.

Postfine-needle aspiration biopsy findings in WT may include (A) tumor infarction retaining cystic and papillary
architecture and (B) residual ghost outlines of columnar-appearing oncocytic epithelial cells; C, squamous metaplasia
including mitotic figures (arrows); D, squamous and mucous cell metaplasia. The presence of squamous and mucous cell
metaplasia may raise concern for a possible diagnosis of mucoepidermoid carcinoma but the changes are focal, occurring
in the presence of other reactive and degenerative changes supporting a benign reactive (metaplastic) process rather than
malignant transformation.
Mucus-secreting (goblet) cells and sebaceous glands Acute and chronic inflammation
can be seen. Fibrosis
Squamous metaplasia and focal necrosis may be seen Hemorrhage (recent and remote)
in association with secondary inflammation. Pseudoinfiltrative pattern
Lumens of the cysts may contain thick secretions, Metaplastic or infarcted variant of Warthin tumor:
cholesterol crystals, cellular debris, or corpora m Accounts for less than 10% of all Warthin
amylacealike laminated bodies. tumors

Postfine-needle aspiration biopsy changes: m Most likely develops following prior manipula-
m As is true of other tumors with prominent onco- tion (e.g., fine-needle aspiration biopsy)
cytic cells, these tumors are subject to degenera- m Extensive necrosis is present with ghost-like pap-
tive alterations either spontaneously or following illary structures remaining

needle aspiration (or biopsy), including: m Squamous and mucous cell metaplasia may be
Infarction and necrosis present.

Cytologic atypia m Cytologic atypia may be prominent.
Metaplasia (squamous cell, mucous cell) m Increased mitotic figures but absence of atypical
Granulation tissue mitoses

Immunohistochemistry:
m Epithelial cells: cytokeratins positive
m Lymphoid cells: reactivity for B-cell (CD20) and
T-cell (CD3) markers, as well as CD56, CD4

(helper cells), and CD8 (suppressor cells).
m Sox10 negative
Cytogenetics and molecular genetics:

m Absence of CRTC1-MAML2 fusion:
Documentation in literature of this gene fusion,

commonly found in mucoepidermoid carcino-
mas (see below), in WT but not substantiated
A Differential Diagnosis
Histology of WT so characteristic that its diagnosis
presents limited difficulty
Cystadenoma
Oncocytic papillary cystadenoma (for those cases
identified in unusual sites)
Salivary gland tumors/lesions with oncocytic cells
either focally or a predominant component
including:
m Oncocytoma; oncocytosis; mucoepidermoid car-
cinoma, acinic cell carcinoma, others

Mucoepidermoid carcinoma:
m In those examples of WT with squamous and
mucinous cell metaplasia differentiation from

MEC can be somewhat problematic:
B Metaplastic WTs do not harbor translocations
t(11;19) and anticipated t(11;15) resulting in
CRTC1-MAML2 and CRTC3-MAML2 fusion
Fig. 20-22. Malignant transformation of WT. transcripts, respectively, and/or MAML2 gene
Rare example of a Warthin tumor with malignant rearrangement found in association with MEC.
(carcinomatous) transformation. A, Warthin tumor (center
and right) characterized by cystic and papillary growth with Treatment and Prognosis
more solid areas seen along the peripheral aspect of the Complete surgical excision is the preferred treatment
tumor on the left. B, At higher magnification the solid and should include an adequate margin of unin-
component is a malignant undifferentiated (large-cell) volved tissue as well as preservation of facial nerve.
carcinoma characterized by marked nuclear pleomorphism,
Locally recurrent tumor may occur and is related to
enlarged vesicular nuclei with prominent eosinophilic
inadequate excision or to multicentrically occurring
nucleoli and increased mitotic activity.
neoplasms.
Transformation to malignant Warthin tumor is
Extensive fibrosis with dense collagen and reac-
m exceedingly rare with an incidence of less than 0.1%
tive myofibroblasts are present along the periph- and may include the:
ery of the tumor. m Epithelial component (carcinoma ex Warthin
m Mixed acute and chronic inflammation, including tumor):

neutrophils, mature lymphocytes, histiocytes, and Squamous cell carcinoma (most common),
foamy macrophages may be present. oncocytic carcinoma, adenocarcinoma not
m Additional alterations may include lipogranulo- otherwise specified, undifferentiated carci-
mas, cholesterol granulomas noma, mucoepidermoid carcinoma, Merkel
m Residual noninfarcted foci of Warthin tumor may cell carcinoma:
be present. Metastasis to regional lymph nodes may
Histochemistry: occur.
m Phosphotungstic acid-hematoxylin (PTAH) stains Rarely, distant metastasis may occur.
demonstrate mitochondria as seen by blue-black m Lymphoid component:
granules in the cytoplasm of both epithelial cell Malignant lymphoma, usually non-Hodgkin
layers. type
Fig. 20-23. Basal cell adenoma.

The clinical presentation and appearance of a monomor- B
phic adenoma are similar to those of a pleomorphic
adenoma and include (A) enlarged parotid mass at angle
of mandible just inferior to the ear that was painless; Fig. 20-24. Cytology of basal cell adenoma.
(B) resected parotid lesion appearing circumscribed to Basal cell adenoma of the parotid gland, fine-needle
encapsulated and solid (lower left). aspiration. A, Cellular aspirate including tubular structures
composed of uniform basaloid cells with hyperchromatic
BASAL CELL ADENOMA round to oval nuclei, high nuclear-to-cytoplasmic ratio, and
scanty cytoplasm. B, Basement membranelike material is
(Figs. 20-23 through 20-27) present, appearing as amorphous eosinophilic deposits in
association with the cellular proliferation. The basement
Definition: Benign neoplasm characterized by pro membrane material, especially seen in association with the
liferation of basaloid-appearing cells and absence of membranous type of basal cell adenoma, may create
mesenchyme-like stromal component seen in pleomor- diagnosis difficulties in differentiation with adenoid cystic
phic adenoma. carcinoma.
Subdivided into four histologic subtypes based on
morphologic pattern, including:
m Solid
m Trabecular Most common site of occurrence is major salivary

m Tubular glands particularly in the parotid gland (superficial
m Membranous types: only one associated with lobe):
unique clinicopathologic findings (see below) m 70% occur in parotid gland
Synonym: Dermal analogue tumor is another name that m Up to 20% occur in the upper lip
has been used for the membranous type of basal cell m Involvement of other minor salivary glands occurs
adenoma. but is uncommon

Symptoms vary according to site but most frequently
Clinical presents as a freely mobile, asymptomatic mass with
Accounts for approximately 2% of all salivary gland a growth period ranging from months to several
tumors decades
No gender predilection; occurs over a wide age range m Lip or palatal tumors may be associated with
from the fourth to ninth decades of life ulceration.

A B
Fig. 20-25. Basal cell adenoma, solid type.

A, The tumor is encapsulated and sharply demarcated from the surrounding parotid gland parenchyma and appears solid
and cellular. B, At higher magnification the cellular component includes basaloid cells with uniform, hyperchromatic, round
to oval nuclei, indistinct cytoplasm and peripheral palisading; scant stroma is present from which the epithelial islands are
sharply demarcated by an intact membrane.
A B
C D

Growth patterns that can be see in basal cell adenoma include (A) trabecular, characterized by the presence of elongated,
ribbon-like pattern; (B) tubular, composed of multiple small duct-like structures; (C) membranous (so-called dermal
analogue tumor), characterized by the presence of thick eosinophilic basement membrane-like material surrounding and
separating the epithelial islands; (D) the eosinophilic basement membrane-like material is highlighted by periodic acid
Schiff (PAS) staining.
C D

A, B, Admixture of more peripherally located smaller cells with hyperchromatic nuclei and indistinct cytoplasm and more
centrally located larger polygonal-shaped cells with vesicular nuclei and more abundant cytoplasm. B, Reduplicated
basement membrane-like material within and external to the tumor nests. C, Squamous eddies (keratin pearls) with
whorled appearance as well as foci of abrupt keratinization. D, Higher magnification of squamous eddies, which may be
very focally identified (or even absent) in basal cell adenomas. Although foci of squamous differentiation can be seen in a
variety of salivary gland neoplasms, it is generally absent in adenoid cystic carcinoma, making its presence a potential
useful finding in excluding adenoid cystic carcinoma.
Cause unknown Somatic mutations of gene found in sporadic

Membranous type of basal cell adenoma: cases
m Also referred to as dermal analogue tumor
m Distinctive variant:
Pathology
90% occurrence in men Fine-Needle Aspiration Cytology (FNAB)
Frequently multicentric/multifocal and FNAB diagnosis may be problematic given overlap-
unencapsulated ping features with pleomorphic adenoma, adenoid
m Familial cases associated with: cystic carcinoma, and basal cell adenocarcinoma.
Dermal cylindroma (most common) Cellular aspirate including sheets, trabeculae, and
Trichoepithelioma tubular structures composed of uniform cells with
Eccrine spiradenoma hyperchromatic round to oval nuclei and scanty
Milia cytoplasm:
m Germline mutation of cylindromatosis gene m Cells are small with high nuclear-to-cytoplasmic
(CYLD), tumor suppressor gene located at chro- ratio.

mosome 16q12-q13 implicated in familial cases Stromal component tends to be scanty.
Extracellular basement membranelike material may Solid basal cell adenoma:

be present, especially in the membranous type of m Most common histologic variant
basal cell adenoma, appearing as amorphous eosino- m Solid masses of basal cells composed of
philic material, including spheric globules, findings small, isomorphic cells with uniform, hyperchro-
that may raise the diagnosis of adenoid cystic matic, round to oval nuclei and indistinct
carcinoma. cytoplasm
Collagenous stroma interdigitates with adjacent m Peripheral aspect of these nests are characterized
tumor cells: by nuclear palisading

m This feature has been suggested as useful in dif- m Scant stroma is present from which the epithelial
ferentiating basal cell adenoma from adenoid islands are sharply demarcated by an intact
cystic carcinoma. membrane.
m Squamous cells and squamous whorled eddies
Gross (keratin pearls) can be seen as a terminal

Major glands: expansion of the epithelial islands.
m Encapsulated, tan-white to red-pink, solid mass m Mitoses are generally absent.
measuring up to 4cm in diameter Trabecular basal cell adenoma:

Minor salivary glands: m Basal cell proliferation growing in elongated,
m Similar to those of major salivary glands except ribbon-like (trabecular) pattern with the cell
that, although well circumscribed, they often are islands separated by proliferation of a prominent
unencapsulated vascular (capillary) stroma.
m May be associated with surface ulceration Tubular basal cell adenoma:
m Basal cell proliferation composed of multiple
Histology small duct-like structures lined by columnar-

Encapsulated neoplasm that may show variety appearing cells with uniform, hyperchromatic,
of growth patterns allowing for subclassification round to oval nuclei
into: m Tubules are well-demarcated from the stroma by
m Solid an intact membrane.

m Trabecular m Stroma is noteworthy for the presence of promi-
m Tubular nent vascular pattern consisting of capillaries and

m Membranous types venules.
m Combination of patterns can be seen in any given m Mitoses are generally absent.
case. Tubular-trabecular adenoma:

m Cribriform growth may be present. m Presence of tubular and trabecular patterns
Irrespective of growth composed of two cell m Cellular stroma composed of myoepithelial

types: cells
m Small cells with hyperchromatic nuclei and indis- Membranous basal cell adenoma:
tinct cytoplasm usually (but not always) seen at m In contrast to the other types, the membranous
the periphery of the cell nests: basal cell adenoma may be multilobular and fre-
These cells may be arranged in a palisading quently unencapsulated (present in only approxi-
pattern around the periphery of tumor cords or mately 50% of cases).
islands in manner similar to cutaneous basal m Characterized by the presence of thick eosino-
cell carcinomas but usually without retraction philic hyalin membranes surrounding and
artifact from the surrounding stroma. separating cell islands and creating a jigsaw
m Larger polygonal-shaped cells with pale- puzzle appearance; this material represents
staining nuclei, more abundant but indistinct reduplicated basal lamina and its appearance
cytoplasm usually more centrally located in cell is similar to that of the dermal cylindroma,
nests prompting the synonym of dermal analogue
m In addition, these cells may form squamous tumor.
whorls or eddies. m Eosinophilic hyalin material can also be seen
Myoepithelial rich stroma may be present in some within the tumor islands and is diastase-resistant
cases characterized by: periodic acid-Schiff positive.
m Stromal spindle-shaped cells m Tumor nests are often separated by normal sali-
m S100 positive but p63 and actin negative vary gland parenchyma, giving the appearance of
m Presence of stromal myoepithelial cells assists in multifocal growth.
differentiation from adenoid cystic carcinoma, m Mitoses are generally absent.
which lacks such stromal cells m Perineural invasion is not seen.

Cribriform basal cell adenoma Treatment and Prognosis

m Composed of jigsaw puzzlelike lobules with Complete surgical excision is preferred treatment
multiple cystic spaces (cribriform growth) in at and is curative.
least 30% of a given tumor Prognosis is excellent.
m Merge with more characteristic foci of basal cell Local recurrences are unusual but may be seen and
adenoma relate to inadequate surgical excision.
m Absence of invasive growth Membranous basal cell adenoma is most commonly
m May be mistaken for adenoid cystic carcinoma associated with recurrence:
Immunohistochemistry: m Recurrence rate of 25% reported
m Staining patterns support ductal and myoepithe- m May be consequence of inadequate resection due
lial differentiation, including: to characteristic multifocal growth

Epithelial cells: Malignant transformation of basal cell adenomas is
Cytokeratin (low molecular weight), CEA, exceedingly rare:
EMA positive m Gives rise to other basal cell carcinomas:
Myoepithelial cells: Basal cell adenocarcinoma or adenoid cystic

p63, calponin, S100 protein, actin and carcinoma
vimentin positive Tumors composed of a basal cell adenoma and
m Nuclear -catenin staining may be present. adenoid cystic carcinoma and have been termed
m bcl-2 and c-kit (CD117) reactivity may be present. hybrid tumors
Electron microscopy: m Gives rise to non-basal cell carcinomas:
m Ductal cells: Adenocarcinoma, not otherwise specified

Microvilli, tight junctions, desmosomes Salivary duct carcinoma
m Myoepithelial cells: m Malignant transformation highest in association
Abundant microfilaments, desmosomes, junc- with the membranous type of basal cell adenoma:
tional complexes, reduplicated basal lamina Reported as high as 28%
m Presence of CTNNB1 (-catenin) gene mutation
m Loss of heterozygosity at 16q12-13: CANALICULAR ADENOMA

Similar finding as seen in dermal cylindroma (Figs. 20-28 through 20-30)
Association of Basal Cell Adenoma and Intercalated
Duct Lesions (IDL) Definition: Benign neoplasm with predilection for upper
m IDL found to coexist with salivary and nonsali- lip and distinct histomorphologic appearance, including
vary neoplasms. branching and interconnecting cords of single and
m Among salivary tumors, basal cell adenoma double cell thick rows of columnar epithelium and a
appears to be associated most frequently with loose stromal component.
IDL. NOTE: Originally considered to be a variant of basal
m Tubular variant most commonly associated with cell adenoma but recognized as a distinct salivary gland
IDL: neoplasm.
Less frequently, nontubular variants of basal
cell adenoma may harbor foci of IDL. Clinical
m Unique hybrid lesion containing basal cell No gender predilection, although reports have varied
adenoma and IDL with transitional area as to male predominance and female predominance;
described occurs over a wide age range from the fourth to
m These findings have led to the hypothesis that IDL ninth decades of life but most common in seventh
could be a precursor of basal cell adenoma. decade
Almost exclusively limited to oral cavity, in particu-
lar, upper lip, which accounts for 70% to 90% of
Differential Diagnosis these tumors:
Pleomorphic adenoma: m Other sites of occurrence include the buccal
m From a therapeutic and prognostic perspective mucosa.

there is no difference in therapy or outcome m Infrequently, arises in parotid gland and palate
between pleomorphic and monomorphic Symptoms include gradually enlarging, nonpainful,

adenomas. and nonulcerated nodule/mass:
Adenoid cystic carcinoma (solid type in particular) m Symptoms may be present for long periods of
Basal cell adenocarcinoma time (decades).

Ameloblastoma m Multifocal nodular growths may be seen.
Clinically, may be confused for a mucocele, seba-

ceous cyst, or lipoma
Pathology
Fine-Needle Aspiration
Cellular aspirate that may include elongated, duct-
like structures or tubules lined by columnar-appearing
cells
Gross
Circumscribed and/or encapsulated, tan-pink to
yellow-brown, rubbery to firm nodule measuring
from 0.5 to 3cm in diameter
Surface ulceration may be seen but is not common.
Cystic spaces and a gelatinous mucoid material may
be identified in transecting the tumor.
Histology
Encapsulated or well-circumscribed nodules
Not infrequently include multifocal nodules
m Scattered nodules may be small (clinically unde-
tectable) and may be unencapsulated.

Consistent pattern of growth (unlike basal cell
adenoma and other tumor types) and includes:
m Double rows of columnar (basaloid) epithelial
cells forming branching and interconnecting

cords
Fig. 20-28. Canalicular adenoma.
Somewhat parallel arrangement of the rows of
cells forms elongated duct-like structures
Canalicular adenoma of the upper lip appearing as a resembling canals, hence the terminology of
subepithelial swelling. canalicular adenoma
m Cystic dilatation of the canalicular structures may
be present and may even be prominent in a given

tumor.
m Cords cut in cross-section may result in the pres-
ence of isolated tubules.

m Alternating areas of tubules separated with closely
apposed tubules is referred to as beading, cre-

ating an image of beads on a string.
Elongated duct-like structures or tubules are lined by
cuboidal to columnar cells with uniform, hyperchro-
matic, round to oval nuclei, variable amount of
eosinophilic to amphophilic cytoplasm, and indis-
tinct cell borders; mitoses are generally absent.
Tubules are well demarcated from stroma by an
intact membrane.
Stroma is edematous and noteworthy for the relative
absence of cellularity (scattered fibroblasts are
present) and for the presence of prominent vascular
pattern consisting of capillaries and venules, some
with an eosinophilic cuff likely representing basal
Fig. 20-29. Canalicular adenoma, fine-needle lamina and collagen.
aspiration biopsy. Histochemistry:
Cellular aspirate composed of uniform, basaloid-appearing m Diastase-sensitive, PAS-positive cytoplasmic
(including a row of columnar-appearing) epithelial cells. granularity is seen.
A B
Fig. 20-30. Canalicular adenoma.

Histologically, canalicular adenoma is characterized by (A) multifocal, well-circumscribed nodules; the presence of
multifocal tumor should not be misconstrued as invasion; (B and C) growth pattern that includes interconnecting cords
and parallel arrangement of the rows of cells to form elongated duct-like structures resembling canals; and (D) cellular
component that includes double rows of columnar (basaloid) epithelial cells with uniform, hyperchromatic, round to oval
nuclei, variable amount of eosinophilic cytoplasm, and indistinct cell borders. The canals and tubules are well demarcated
from the stroma.
Immunohistochemistry: EM:
m Cytokeratins (pancytokeratin, CK7, CK13), S100 Abundant junctional complexes, including
protein and vimentin positive desmosomes and hemidesmosomes

m Variable EMA reactivity Junctional complexes are associated with
m Distinctive GFAP linear immunoreactive pattern large aggregates of cytoplasmic intermediate

among cells in proximity to connective tissue filaments.
interface reported Focal microvillus projections forming inter-
m Little to no myoepithelial differentiation: absence cellular lumina lined by abundant junctional

of p63, calponin, smooth muscle actin, smooth complexes
muscle myosin heavy chain Abundant cytoplasmic rough endoplasmic
m Recent evidence based on morphologic, immuno- reticulum (rER) adjacent to the intercellular
histochemical, and ultrastructural findings lumina and in apical aspects of the cells; rER
support a cell of origin demonstrating features of is also seen near the basal lamina
intercalated duct cells and striated duct luminal
epithelial cells, including: Differential Diagnosis
IHC: Basal cell adenoma
Positive nuclear staining for S100 protein, Adenoid cystic carcinoma
absence of CEA and GFAP Pleomorphic adenoma
Striated duct adenoma (SDA): cytoplasm due to the presence of increased intracyto-
m Has immunohistochemical similarities to cana- plasmic mitochondrial content and the absence of myo-
licular adenoma, including positivity for S100 epithelial or basal cells.
and essentially absent myoid markers and p63 Synonym: Oxyphilic adenoma
staining NOTE: Oncocytic cells in salivary glands occur in the
m Histologic findings in SDA that are distinct from following settings:
canalicular adenoma (CA) include: m Oncocytic metaplasia
SDA has relatively eosinophilic cytoplasm as m Oncocytosis (nodular or diffuse)
compared with CA owing to abundance of m Oncocytoma
mitochondria in the striated ductal cell m Oncocytic carcinoma
cytoplasm. m Variety of other lesions/tumors that may have
Absence in SDA of characteristic beading oncocytic cells (e.g., Warthin tumor, oncocytic
pattern and prominent stroma present in cana- variant of mucoepidermoid carcinoma, others)
licular adenoma
Ameloblastoma Clinical
Cutaneous basal cell carcinoma Rare tumor composing less than 1% of all salivary
The multifocal growth of this neoplasm that is often gland neoplasms
devoid of a capsule can be mistaken for a carcinoma No gender predilection; most commonly occurs in
with invasion into the minor salivary gland paren- the sixth to eighth decades of life
chyma; awareness of this tendency reduces the likeli- Most frequently involves parotid gland but may also
hood of the erroneous diagnosis of carcinoma. occur in the submandibular gland as well as in minor
salivary glands throughout respiratory tract
Treatment and Prognosis Symptoms vary according to the site of occurrence
Conservative but complete surgical excision is and most frequently present as a painless mass; other
the preferred treatment; enucleation is not symptoms include nasal or airway obstruction.
recommended. May occur synchronously with Warthin tumor
Recurrence following complete excision is Radiology:
uncommon. m Similar to Warthin tumors and as a result of
the mitochondrial hyperplasia, radionucleotide

imaging demonstrates increased uptake of
ONCOCYTOMA (Fig. 20-31) technetium-99m.
Stimulus for induction of oncocytic change is
Definition: Benign tumor of salivary gland origin exclu- unknown but generally considered age related, rarely
sively composed of oncocytes, which are large epithelial seen under 50 years of age and nearly always present
cells with characteristic bright eosinophilic, granular above 70 years old:
A B
Fig. 20-31. Parotid gland oncocytoma.

A, Thinly encapsulated tumor showing solid growth exclusively composed of cells with prominent oncocytic cytoplasm;
B, trabecular growth pattern;
C D
E F
Fig. 20-31, contd

C, organoid growth pattern. D, At high magnification the cells are polygonal, characterized by the presence of abundant
granular eosinophilic cytoplasm with round to oval, vesicular-appearing nuclei with small nucleoli; overall the cells are
rather bland appearing without cytomorphologic features of malignancy. E, Many cases show an admixture of cells with
oncocytic and clear-appearing cytoplasm. F, Clear cell variant oncocytoma in which there is partial or complete
replacement of granular eosinophilic cytoplasm by cells with clear, nongranular-appearing cytoplasm; other than
cytoplasmic appearance, the findings are similar to the more conventional type of oncocytoma. G, p63-positive cells
interspersed along periphery and/or around oncocytic lesional cells represent basal cells that are not readily identifiable by
light microscopy.
m Oncocytic cell changes are not limited to Absence of residual normal salivary gland paren-
salivary glands but are seen in other organs, chyma such as serous acini or ductal epithelial struc-
including: tures within the oncocytic proliferation:
Thyroid gland, parathyroid glands, adrenal m Contrasts to presence of such normal compo-
glands, kidney, pancreas, others nents in oncocytosis

Pathogenesis remains unclear. Some theories support Cellular pleomorphism, mitoses, and necrosis are
a neoplastic growth, whereas others suggest a infrequently seen.
hyperplastic/metaplastic phenomenon: Tyrosine-like crystals, appearing needle shaped or
m Oncocytic tumorigenesis secondary to acquired platelike, may be present in the tumor or in adjacent
mitochondrial dysfunction has been proposed as tissues:
a plausible mechanism, but few tumors harbor m Psammoma bodies may be identified.
mtDNA alterations within the control region to Other cell types that may be present include:
support this theory. m Sebaceous cells
m Squamous cells
Pathology m Mucous (goblet) cells (rare and must exclude
Fine-Needle Aspiration Biopsy oncocytic variant of mucoepidermoid carcinoma)

Smears show oncocytic cells characterized by cells Oncocytes are easily traumatized and prone to
with granular-appearing cytoplasm. degenerative alterations either spontaneously or fol-
Oncocytic cells are arranged in sheets, papillary frag- lowing manipulation (e.g., after fine-needle aspira-
ments, and as individual cells. tion biopsy), including:
Cytologic atypia is absent or focal/limited in extent. m Infarction and necrosis
Typically, there is an absence of a lymphocytic cell m Cytologic atypia
component, but scattered lymphoid cells may be m Metaplasia (squamous cell)
present: m Granulation tissue
m Presence of lymphocytes in association with m Acute and chronic inflammation
oncocytic cells may raise the diagnostic consider- m Fibrosis
ation of a Warthin tumor. m Hemorrhage (recent and remote)
Clear cell oncocytoma:

Gross m Histologic variant of the classic oncocytoma
Major salivary glands: composed of clear cells:

m Well-circumscribed, encapsulated, lobulated, Partial or complete replacement of granular
solid mass with an orange to rust-colored appear- eosinophilic cytoplasm by cells with clear,
ance, rarely measuring more than 5.0cm in nongranular-appearing cytoplasm
diameter Transition areas of typical oncocytes to clear
Minor salivary glands: cells may be present.
m Unencapsulated with less well-delineated borders Other than cytoplasmic appearance, histol
with similar appearance and measurements as ogy and histochemical staining are similar to
those of major glands; cystic change may be seen the more conventional type of oncocytoma.
Clear cytoplasm is due in part to fixation and
Histology tissue processing artifact, and to accumulation
Encapsulated tumor with solid, trabecular, cord-like of glycogen within the cytoplasm, which dis-
or organoid growth pattern separated by a thin places the mitochondria to the periphery of the
fibroconnective tissue stroma; tumors involving cells.
minor salivary glands tend to be unencapsulated Metastatic renal cell carcinoma must be
with an irregular growth pattern and may demon- ruled out.
strate invasion of adjacent structures Histochemistry:
Oncocytic cells represent a cytoplasmic alteration m Phosphotungstic acid-hematoxylin (PTAH) stains
(metaplasia) of epithelial and/or myoepithelial cells demonstrate mitochondria as seen by blue-black

with swelling of the cytoplasm by mitochondrial granules in the cytoplasm; intracytoplasmic gly-
hyperplasia, giving the cell a characteristic granular cogen is demonstrated by diastase-sensitive, PAS-
eosinophilic appearance by light microscopy. positive granules.
Predominant/exclusive cell is enlarged and polyhe- Immunohistochemistry:
dral in shape with a distinct cell membrane and m Cytokeratin, epithelial membrane antigen positive
characterized by an abundant granular eosinophilic m S100 protein, glial fibrillary acidic protein, actin,
cytoplasm and a centrally placed round, vesicular- thyroglobulin, TTF-1, CD10, renal cell marker,
appearing nucleus. and Sox10 negative
p63 and high-molecular-weight cytokeratin

m m Warthin tumor
(CK14) positive in cells interspersed along periph- m Papillary oncocytic cystadenoma
ery and/or around oncocytic lesional cells: m Pleomorphic adenoma
Represent basal or myoepithelial cells m A number of usual salivary gland carcinomas
m Low proliferation indices by Ki67 staining may have oncocytic cells as either a part of the
Electron microscopy: tumor or as the predominant cell type; these
m Ultrastructural characteristic that defines the tumors are included in the differential diagnosis
oncocyte is the presence of mitochondria within of oncocytoma, including:
the cell cytoplasm almost to the exclusion of Oncocytic carcinoma
other cell organelles Mucoepidermoid carcinoma
m Other organelles can be seen as well as basement Acinic cell adenocarcinoma
membrane and desmosomes. Adenoid cystic carcinoma
Clear cell carcinoma
Differential Diagnosis Metastatic renal cell carcinoma and thyroid
Oncocytic metaplasia: carcinoma
m Transformation of ductal and acinar epithelium
to oncocytes Treatment and Prognosis

m Metaplastic process is an aging phenomenon and Complete surgical excision is the preferred
as such oncocytic metaplasia is generally not seen treatment.
in patients less than 50 years of age from which Radiotherapy is not indicated as oncocytes are
time the percentage of the population with onco- radioresistant.
cytic metaplasia increases Prognosis is excellent following removal.
m In contrast to oncocytoma, oncocytic metaplasia Locally recurrent tumors are uncommon.
represents nonmass-forming focal or limited Transformation to an oncocytic carcinoma is rare.
changes in one or more areas within the salivary
gland.
m May be seen in tumor cells of nearly all salivary MYOEPITHELIOMA
gland tumors, including most commonly in pleo- (Figs. 20-32 through 20-36)
morphic adenoma and mucoepidermoid
carcinoma Definition: Benign salivary gland tumor predominantly
Oncocytosis (also referred to as oncocytic [adenoma- or exclusively composed of cells with myoepithelial dif-
tous] hyperplasia): ferentiation, including spindle cells, plasmacytoid cells,
m Proliferation of oncocytic cells within the salivary epithelioid cells, or clear cells, but lacking ductal
gland differentiation or chondroid/myxochondroid stroma.
m Typically appear as nodular foci referred to as Sometimes may have abundant acellular mucoid or hya-
nodular oncocytic hyperplasia or nodular linized stroma.
oncocytosis
m May represent a diffuse alteration in the affected
salivary gland referred to as diffuse oncocytosis

m In either nodular or diffuse form may present as
a clinically detectable mass lesion, presenting

difficulties in differentiation from oncocytoma;
the differentiation of oncocytosis from oncocy-
toma may not be possible due to overlapping
histologic features and this differentiation may be
more of an academic than practical issue because
treatment and prognosis are essentially similar;
however, features seen in oncocytosis that may
assist in differentiating it from oncocytoma
include:
Multiple separate nodules (two or more)
Unencapsulation
Presence within the oncocytic nodules of resid- Fig. 20-32. Myoepithelioma.
ual nononcocytic salivary gland parenchyma, Parotid gland myoepithelioma appearing as a well-
including ductular epithelium and serous demarcated, smooth, and bosselated solid lesion with a
acinar cells tan-yellow appearance (right).
Gross
Well-demarcated, smooth, and bosselated solid
lesion with a tan-white to tan-yellow appearance
measuring up to 5cm in diameter
Histology
Encapsulated cellular neoplasm composed of spindle-
shaped, plasmacytoid (hyaline) cells, epithelioid or
clear cells:
m Capsule varies in thickness but often is thin.
m Tumors originating in minor salivary glands are
circumscribed but not encapsulated.

Growth patterns may include:
m Fascicular
m Solid
Fig. 20-33. Myoepithelioma of the palate.
m Trabecular
The tumor is circumscribed separate from adjacent minor m Reticular:
salivary glands and composed of a monomorphic cellular Uncommon pattern characterized by intercon-
proliferation lacking ductal differentiation. necting cords with associated loose vascular-
ized stroma (reticulated)
Synonyms: Myoepithelial adenoma; benign myoepithe- Majority of myoepitheliomas are of spindle
lial tumor cell type:
m Spindle-shaped cells have uniform, centrally
Clinical located nuclei with dispersed nuclear chromatin
Accounts for approximately 2% of all salivary gland and eosinophilic granular to fibrillar-appearing
neoplasms cytoplasm
No gender predilection; occurs over a wide age range m Growth patterns include fascicular or swirling.
but is most commonly seen in the third to sixth Other cell types may include:
decades of life m Plasmacytoid (hyaline) cells:
Although all salivary gland sites may be affected, the Polygonal with round to oval pyknotic-
most common site of involvement is the parotid appearing nuclei, which may be eccentrically
gland. located as a result of the accumulation of eosin-
m Second most common site is the palate (hard and ophilic hyaline material in the cytoplasm
soft palate) A paranuclear clear zone (hof) and methyl
m Other sites may include the submandibular gland green pyronine staining are not present.
and oral minor salivary glands (e.g., retromolar Growth patterns include islands, sheets, cords,
region, upper lip). or isolated cells
Most commonly present as a slow-growing, painless Tumors composed predominantly of plasmacy-
mass toid myoepithelial cells occur in the palate.
A mucinous stroma may be seen in the plasma-
Pathology cytoid cell type.
Fine-Needle Aspiration Biopsy m Epithelioid cells:
Smears show bundles of uniform-appearing spindle- Large polygonal cells with central nuclei and
shaped, epithelioid/plasmacytoid, and stellate cells in eosinophilic cytoplasm
sheets and dissociated forms: Growth patterns include reticular, trabecular
m Nuclear atypia is absent or limited in extent. solid
m Occasionally, nuclear grooves intranuclear inclu- Hyalinized stroma may be present and in
sions may be identified. conjunction with the tumor cells showing
m Glandular/tubular structures not identified narrow interconnecting cords (so-called
m By May-Grnwald-Giemsa staining most of the reticular pattern); confusion with the tubulo-
cells have a reddish cytoplasm. trabecular type of basal cell adenoma may
m Red to purple, myxoid matrix appearing as scanty arise.
fibrillar substance and as globules surrounded by m Clear cells:
tumor cells may be present and may suggest a Abundant clear cytoplasm rich in glycogen
diagnosis of adenoid cystic carcinoma. (diastase-sensitive, PAS-positive)
A B
Fig. 20-34. Myoepithelioma.

A variety of growth patterns can be seen in myoepitheliomas including (A) fascicular to storiform; (B) solid; (C) reticular
characterized by interconnecting cords with associated loose vascularized stroma; (D) trabecular with stromal and
perivascular hyalinization.
Oncocytic cells:
m actin, smooth muscle myosin heavy chain,
Characterized by presence of abundant granu- glial fibrillary acidic protein (GFAP), vimentin,
lar eosinophilic-appearing cytoplasm EMA, and muscle-specific actin variably
m Mucinous cells referred to as mucinous variant of positive
myoepithelioma: m Desmin, thyroglobulin, TTF-1, CD10, and renal
Characterized by cells with abundant eosino- cell carcinoma marker negative

philic to foamy-appearing grayish-blue Electron microscopy:
cytoplasm m Epithelial features in the form of desmosome,
Contain abundant intracellular mucin tight junction

material m Myoid features in the form of intracytoplasmic
For all cell types, mild to moderate cellular pleomor- myofilaments with focal densities, pinocytotic
phism may be seen but increased mitotic activity and vesicles
necrosis are uncommon. Molecular biology:
Stroma may be hyalinized and/or appear m Typically lacks PLAG1 rearrangement:
myxomatous. At least one study reported PLAG1 immuno-

m Tyrosine-like crystals may be present. histochemical staining in 8 myoepitheliomas
Immunohistochemistry: m Lacks EWSR1-POU5F1 or EWSR1-PBX1
m Cytokeratins (pancytokeratin, CK14), EMA, gene fusion seen in soft tissue myoepithelial
p63, calponin, S100 protein, smooth muscle tumors
A B
C D
E F

A variety of cell types can be seen in myoepitheliomas including (A) spindle-shaped (most common); (B) plasmacytoid;
(C) epithelioid; (D) spindle-shaped and epithelioid; (E) oncocytic; and (F) clear.
A B
C D

Immunohistochemical staining in myoepithelioma may include (A) cytokeratin (AE1/AE3); (B) p63 (nuclear); (C) S100
protein (nuclear and cytoplasmic); (D) calponin; and (E) vimentin.
m Structural alterations in chromosomes 1, 9, 12, the majority of which occurs as a de novo

and 13: malignancy.
t(1;12)(q25;q12) m Identification of EWSR1-POU5F1 or EWSR1-
del(9)(q22.1q22.3) PBX1 gene fusion

del(13)(q12q22) Subset of cutaneous and superficial soft tissue myo-
epithelial tumors display distinct ductal component,
Differential Diagnosis closely resembling pleomorphic adenomas of sali-
Myoepithelial-predominant pleomorphic adenoma: vary gland:
m Although myoepithelial cells predominate, resid- m Recurrent PLAG1 rearrangement by FISH
ual foci of pleomorphic adenoma in the form of detected in cutaneous and benign soft tissue myo-
myxochondroid stroma are present. epithelial tumors, majority with abundant tubulo-
Basal cell adenoma ductal differentiation
Myoepithelial carcinoma m Leukemia inhibitory factor receptor (LIFR)-
Epithelial-myoepithelial carcinoma PLAG1 fusion confirmed by FISH in one soft
Extracranial meningioma tissue myoepithelial tumor with tubular
Peripheral nerve sheath tumors (i.e., neurilemmoma formation
and malignant schwannoma) m Findings indicate that subset of cutaneous and
Smooth muscle tumors (i.e., leiomyoma and soft tissue myoepithelial tumors appear geneti-
leiomyosarcoma) cally linked to salivary gland counterparts with
Extramedullary plasmacytoma frequent PLAG1 gene rearrangements and occa-
Spindle cell squamous carcinoma sionally LIFR-PLAG1 fusion.
For clear cell dominant or exclusive tumors, the dif-
ferential diagnosis may include metastatic renal cell
carcinoma or thyroid carcinoma. SCLEROSING POLYCYSTIC
ADENOSIS (SPA)
Treatment and Prognosis (Figs. 20-37 and 20-38)
Complete surgical excision is the preferred treatment
and should include a portion of surrounding unin- Definition: Rare neoplastic process of salivary glands
volved tissue; if appropriate, a superficial parotidec- with histologic similarities to mammary gland fibrocys-
tomy should be performed. tic disease.
Local recurrence is related to inadequate excision. NOTE: Reported presence of associated/superimposed
There is no relationship between cell type (e.g., foci of carcinoma in situ, invasive carcinoma, local
spindle, plasmacytoid, epithelioid, clear) and recurrence, and clonality support classification as true
prognosis. neoplastic lesion rather than nonneoplastic proliferation
Malignant transformation is rare and occurs in the as initially considered.
setting of a long-standing tumor and/or multiply
recurrent tumor. Clinical
Uncommon lesion
More common in women than in men; occurs over
wide age range from the first to the tenth decades of
Soft Tissue Myoepithelial Tumors life with a mean of 33 years
Primary myoepithelial tumors of soft tissues are Most common site of occurrence is parotid gland:
uncommon. m Much less often submandibular gland and intra-
Classification includes: oral salivary minor glands are affected.

m Benign neoplasm (myoepithelioma) m Rare cases reported in other sites, including sino-
m Malignant neoplasms (myoepithelial carcinoma); nasal tract

see Myoepithelial Carcinoma later in chapter Patients present with a slow-growing asymptomatic
As compared with their salivary gland counterpart: mass; rarely, pain and/or a tingling sensation have
m A higher proportion of myoepithelial tumors of been described.
soft tissues are malignant. Majority of cases present as a de novo process but
m Unlike salivary gland myoepithelial carcinoma, in a few cases have been described in association
which a majority arise in association with a pleo- with recurrent pleomorphic adenomas or recurrent
morphic adenoma (i.e., myoepithelial carcinoma chronic parotitis
ex pleomorphic adenoma), this occurrence is rare Familial occurrence reported in two sisters, suggest-
relative to soft tissue myoepithelial carcinoma, ing genetic predisposition
A B
C D
Fig. 20-37. Sclerosing polycystic adenosis.

A, Circumscribed nodular lesion demarcated from the adjacent parotid parenchyma (left) and characterized by variably
sized cysts and the presence of sclerotic stroma. B, Variably sized ductules with associated sclerotic stroma. C, Ducts are
lined by columnar to cuboidal epithelium. D, Cells may show the presence of brightly eosinophilic cytoplasmic granules
and/or eosinophilic hyaline globules (arrow) that are considered highly characteristic (although not pathognomonic) for the
diagnosis. Other cell types that can be seen include (E) apocrine-appearing cells;
Continued
F G
Fig. 20-37, contd

(F) sebaceous cells; and (G) squamous metaplasia (arrow).
A B
Fig. 20-38. Sclerosing polycystic adenosis.

Additional findings may include (A) intraductal hyperplasia; note presence of outer layer of flattened myoepithelial cells
(arrowheads), which is reactive for p63 as well as other markers for myoepithelial cells (not shown); (B) micropapillary
hyperplasia; (C) areas with atypical (enlarged and hyperchromatic) nuclei (arrow).
a balloon-like appearance resembling sebaceous

Pathology cells.
Fine-Needle Aspiration Biopsy Intraluminal epithelial proliferation may show
Aspirate characterized by flat cohesive sheets of epi- a spectrum of alterations ranging from nondescript
thelial cells with moderate amounts of finely granu- with mild atypia to higher degrees of epithelial
lar oncocytic cytoplasm and enlarged round nuclei dysplasia, including moderate to severe, that at
with indistinct nucleoli. times border on ductal carcinoma in situ
Some epithelial groups form glandular structures (DCIS):
with lumens. m DCIS is histologically identical to mammary
Background may contain small amounts of delicate ductal carcinoma in situ, and similar to the breast
mucoproteinaceous material. lesions, the salivary gland lesions retain a myo-
Markedly vacuolated cells as well as cells with apo- epithelial cell layer (see below).
crine change manifested by well-defined apical snout- m To date, single case of invasive carcinoma arising
ing may be identified. in SPA reported:

Invasive component composed of isolated
pleomorphic cells with eosinophilic cytoplasm,
Gross large nuclei, and prominent nucleoli diffusely
The lesions usually appear as a single, well- infiltrating normal salivary gland and with
circumscribed mass but may be multinodular, ranging focal entrapment of normal salivary ducts
in size from 1 to 5cm in greatest dimension. Carcinoma in situ identified adjacent to inva-
On cut section the lesions are rubbery to firm with sive carcinoma
a pale, glistening appearance. Histochemistry:
Small cystic foci may be apparent on gross m Granules in cells with acinar differentiation show
examination. diastase-resistant PAS-positive material.

These granules are mucicarmine negative, but
faint mucicarmine-positive staining can be seen
Microscopic in scattered duct-lining cells.
Most lesions appear as well-circumscribed and par- Immunohistochemistry:
tially encapsulated nodules with a peripheral rim of m Tubuloacinar cells are immunoreactive for cyto-
normal salivary parenchyma. keratin, CEA, BRST2, progesterone receptor

Characterized by presence of abundant sclerotic col- (80%), and estrogen receptor (20%).
lagenous tissue containing lobular proliferations of Absence of HER-2
epithelial cells with ductal/tubular and acinous m Myoepithelial cells reactive with variety of myo-
differentiation: epithelial cell markers, including p63, calponin,

m Ducts vary in size from cystically dilated spaces S100 protein, and smooth muscle actin
to small ductules. Cytogenetics and molecular genetics:
m Epithelial lining includes simple columnar to flat- m PCR analysis of patterns of X-chromosome
tened cuboidal epithelium. inactivation using human androgen receptor
Hyperplasia of ductal and acinar epithelial cells can (HUMARA) locus has shown monoclonal popu-
be identified with interconnecting bridges or anasto- lation of cells indicative of monoclonality.
mosing cords creating a cribriform pattern, as well
as papillary growth. Differential Diagnosis
Some cells may demonstrate the presence of intensely Polycystic (dysgenetic) disease (see Chapter 19):
eosinophilic cytoplasmic granules and/or hyaline m Lobular collection of cystic ducts frequently with
globules: apocrine metaplasia

m Considered highly characteristic although not m Unlike SPA, polycystic disease is usually:
absolutely pathognomonic Bilateral

In addition, apocrine metaplasia, mucous cells, Involves entire gland
squamous cells, and sebaceous-like cells can be Shows no acinar proliferation and has minimal
present. fibrosis and inflammation
Degenerative changes that can be found include: Sclerosing sialadenitis:
m Partial or completely denuded epithelium of the m Shows similarities to SPA including presence of
cystic ducts with replacement by foamy (xantho- fibrosis and inflammation

matous) macrophages m In contrast to SPA, fibrosis is not nodular nor are
m Cytoplasm of the epithelial cells may be replaced xanthomatous cells seen in association with the
by abundant pale, reticulated cytoplasm, creating duct ectasia.
m Cysts vary in size.

Treatment and Prognosis m Most are multicystic with cysts separated by a
Complete surgical resection is preferred treatment: limited amount of intervening dense, fibrous
m Facial nerve sacrifice not indicated stroma.
Recurrence of the lesion may occur following incom- m Intervening stroma may be absent.
plete excision: m Patchy collections of chronic inflammatory cells
m 30% recurrence rate reported in some studies. are often present.

Prognosis is very good with the caveat that until Epithelial lining cells include single layer of cuboidal
longer follow-up becomes available in these patients to columnar epithelium with bland nuclei lacking
the biologic behavior may not be completely atypical features and absent mitotic figures.
known. m Tumors with two or more cell layers thick may
To date, no reported metastatic disease or death due be present but cytologic atypia is absent.
to disease reported Other cell types that may be seen include mucous,
oncocytic, sebaceous, and squamous cells:
m Usually, when these cell types are seen they are
CYSTADENOMA (Fig. 20-39) scattered and admixed with the cuboidal or

columnar cells.
Definition: Rare benign epithelial tumor characterized m Rarely, one of these cell types, in particular
by its predominantly cystic (unicystic, multicystic) mucous cells and oncocytic cells, may
growth and variable appearing benign epithelial-lining predominate.
cells. Unicystic lesions often have luminal papillary
Synonym: Cystic duct adenoma growth:
m Papillae vary from thin to widened and ramifying
Clinical projections.
Rare tumor type m Fibrovascular cores are present.
More common in women than in men; occurs over Mucinous cystadenoma:

a wide age range from the second to ninth decades m Includes columnar cells with basally located
but most common in the sixth decade of life; rarely nuclei and intracytoplasmic mucin-positive
occur in the first two decades of life. material
Majority occurs in minor salivary glands, including: m Combination of epidermoid, intermediate, and
m Lips > cheek > palate mucous cells not identified

m Slightly less than half (approximately 45%) occur Cystadenomas associated with oncocytic features
in the parotid gland and papillary growth are termed oncocytic papillary
m Minority of cases (less than 10%) occur in sub- cystadenoma:
mandibular gland. Often seen in association with minor
Majority present as slowly growing, painless masses; salivary glands, in particular the larynx (see
minor salivary gland lesions appear as mucosa- Section 5)
covered smooth nodules resembling mucoceles. Usually composed of a single epithelial
layer
Pathology Other findings may include:
Gross m Cystic spaces containing eosinophilic fluid that
On cut section these tumors show multiple, variably may be inspissated

sized (small) cysts surrounded by salivary gland m Admixed epithelial cells and inflammatory cells
parenchyma; occasionally a single large cyst may be may be present.

present. m Intraluminal psammomatoid concretions and/or
Tumor size in major glands varies; typically measure crystalloids may be identified.
less than 1cm in minor salivary gland sites Prominent solid, extraluminal growth is unusual
and, if present, should be suspicious for a malignant
Histology neoplasm.
Circumscribed lesions that may or may not be
encapsulated: Differential Diagnosis
m Presence of a capsule is variably seen Cystic lesions associated with duct obstruction:
m If fibrous capsule is present, it may completely or m Such lesions include duct ectasia, as well as sali-
incompletely encapsulate lesion. vary duct cyst.

Characterized by presence of a unicystic or multicys- m Typically, duct obstruction primarily affects sub-
tic lesion: mandibular gland

A B
Fig. 20-39. Cystadenoma.

A, Multicystic circumscribed to encapsulated parotid gland lesion; cystic spaces containing eosinophilic fluid; the cyst
epithelial lining varies from case to case and may even vary within a given case to include (B) single layer of cuboidal cells;
(C) single layer of columnar cells and cuboidal appearing cells (arrowhead); (D) multilayered oncocytic cells; (E) multilayered
epithelium with intracystic papillary growth. In all illustrated examples, there is an absence of cytologic atypia.
Secondary changes to duct obstruction include

m
fibrosis, acinar atrophy, squamous metaplasia,

Sialadenoma Papilliferum (Fig. 20-40)
chronic inflammation, and periductal Definition: Benign salivary gland tumor characterized
hyalinization. by exophytic (papillary) and endophytic epithelial pro-
m In comparison with cystadenoma, the ectatic or liferation of mucosa or salivary duct origin.
cystic ducts in obstructive lesions are widely sepa- Synonym: So named because of its similarity to the
rated, may be seen connected to or tracking to cutaneous syringocystadenoma papilliferum
the obstructed duct, and usually lack the greater
cytologic variability of the intraluminal epithelial Clinical
proliferation seen in cystadenoma. Uncommon tumor
Warthin tumor: More common in men than in women; occurs over
m Characteristic bilayered epithelial layer and a wide age range but is most frequently seen in the
prominent dense lymphoid stroma with sixth to seventh decades of life.
germinal centers of Warthin tumor not seen in Most common site of occurrence is the palate (greater
cystadenoma, including papillary oncocytic than 80%), particularly at junction of the hard and
cystadenoma soft palates.
Intraductal papilloma: m Other minor salivary glands sites of involvement
m Almost invariable a unicystic lesion include buccal mucosa, retromolar region, tonsil-
m Occurs in association with a dilated salivary lar pillar, lip, and nasopharynx (adenoids).
gland duct m Major gland involvement is rare and in major
m Intraluminal papillations are more complex and glands parotid gland is most commonly affected.
numerous than papillae of cystadenoma. Usually presents as an asymptomatic (painless) lesion
Cystadenocarcinoma: generally discovered incidentally; clinical appearance
m Presence of invasive growth differentiates cystad- often mistaken for a papilloma; duration of symp-
enoma from cystadenocarcinoma. toms may be from months to years.
Mucoepidermoid carcinoma, low-grade: Origin is disputed; evidence supports salivary
m May share overlapping features with cystade- gland excretory duct rather than intercalated duct
noma origin.
m Noncystic epithelial component of mucoepider-
moid carcinoma includes an admixture of Pathology

mucous, epidermoid, intermediate cells, which Gross
are absent in cystadenoma Well-circumscribed, papillary or verrucoid, round to
m Invasive growth, a feature often (but not always) oval, tan-pinkappearing lesion measuring from a
seen in mucoepidermoid carcinoma absent in few millimeters to as large as 7.0cm
cystadenoma Base of lesion is broad or pedunculated.
Polycystic (dysgenetic) disease:
m Presence of diffuse involvement of the affected Histology
gland, apocrine lining epithelial cells and sphero- Exophytic and endophytic proliferation of surface
liths seen in polycystic (dysgenetic) disease assists and ductal epithelium
in differentiating it from cystadenoma. Surface has papillary to verrucoid growth composed
of a stratified squamous epithelium with a fibrovas-
Treatment and Prognosis cular connective tissue core; acanthosis and para-
Complete (conservative) surgical resection is keratosis of the squamous epithelium can be seen.
curative. Merging with surface epithelium and lying immedi-
Recurrent tumor and malignant transformation ately subjacent to squamous epithelium is an endo-
rarely occur. phytic proliferation of ductal epithelium forming
dilated and tortuous structures:
DUCTAL PAPILLOMAS m An abrupt transition from stratified squamous
epithelium covering the mucosal papillary prolif-

Definition: Group of uncommon benign epithelial sali- eration to columnar epithelium lining the ducts
vary gland neoplasms with unique histologic features identified
allowing for easy identification. m Glandular component is unencapsulated.
Classification includes three types: m Glandular component is composed of rounded or
m Sialadenoma papilliferum elongated and dilated ductlike structures.

m Intraductal papilloma m In deeper portions ductal structures have papil-
m Inverted ductal papilloma lary luminal projections and microcysts.

A C
Fig. 20-40. Sialadenoma papilliferum.

A, Exophytic appearance. B, Endophytic appearance.
C, The ductal epithelium is composed of an outer or
luminal layer of tall columnar cells with an eosinophilic
granular cytoplasm and an inner or basal cell layer of
cuboidal cells with an eosinophilic granular cytoplasm;
the stromal component consists of a predominantly
plasma cell infiltrate admixed with mature lymphocytes
B
forming dilated and tortuous structures.
m Absence of encapsulation and presence of poor

circumscription at the base of the lesion may
simulate invasive growth and be mistaken for a
malignancy.
Ductal epithelium composed of two cell layers:
m Outer or luminal layer: tall columnar cells with
an eosinophilic granular cytoplasm

m Inner or basal cell: cuboidal cells with an eosino-
philic granular cytoplasm

Mucous cells can be seen admixed and interspersed
throughout the ductal cells and in the squamous
component; oncocytic cells may also be seen.
Chronic inflammatory cell infiltrate predominantly
composed of plasma cells admixed with mature lym-
phocytes is present within the lamina propria of the
squamous mucosal component and in the stroma of
the glandular component.
m Ductal luminal cells:
Cytokeratins (AE1/AE3, CK7, CK19, CAM5.2),

CEA, EMA, S100 protein positive
m Basal cells:
CK7, CK14, S100 protein, and vimentin

positive
m Dendritic (Langerhans) cells identified within the
epithelial component stain for S100 protein and

CD1a positive.
Differential Diagnosis
Papilloma of surface epithelial origin
Warty dyskeratoma Fig. 20-41. Intraductal papilloma.
Verrucous carcinoma
Mucoepidermoid carcinoma, low grade Intraductal papilloma consisting of a unicystic cavity lined
by one or two layers of cuboidal or columnar epithelium
Treatment and Prognosis which give rise to numerous papillary fronds having a thin
fibrovascular connective tissue core.
Complete conservative surgical excision is the pre-
ferred treatment and is curative.
Recurrence rarely occurs.
Rare examples of malignant transformation reported,
including: Intraoral minor salivary glands most frequently
m Epithelial-myoepithelial carcinoma involved:
m Mucoepidermoid carcinoma m Buccal mucosa and lips are most commonly
m Carcinoma in situ affected.

m Other sites of occurrence include floor of mouth,
soft palate, and tongue.

Intraductal Papilloma (Fig. 20-41) m Involvement of major glands is rare.
Definition: Benign salivary gland neoplasm character- Symptoms relate to a painless, well-delineated, and
ized by unicystic duct dilatation of luminal papillary solitary (submucosal) mass.
proliferation arising from a segment of interlobular or
excretory duct. Pathology
Gross
Clinical Well-circumscribed, mucosa-covered nonulcerated
Uncommon tumor nodule measuring from 0.5 to 2cm in diameter.
No gender predilection; affects primarily adults, oc Cut section reveals a unicystic lesion containing
curring in the fourth through seventh decades of life friable tissue.
Histology
Unicystic cavity lined by one or two layers of cuboi-
dal or columnar epithelium with eosinophilic cyto-
plasm, which give rise to numerous papillary fronds
filling the cavity; papillations are covered by a similar
epithelium.
Cytologic atypia is absent; no significant increase in
mitotic activity
Mucocytes in form of goblet cells are seen admixed
within the ductal epithelium
Papillations have a thin fibrovascular connective
tissue core.
Continuity of papillary projections to cyst wall is
present but depending on the sections the papillae
may not be seen in continuity to the cyst wall and
appear to float within the lumen.
Epithelial component is confined to cyst cavity and
there are no extensions into the adjacent stromal
tissue.
Papillary cystadenoma
Low-grade papillary adenocarcinoma of the
nasopharynx
Treatment and Prognosis

Complete conservative surgical excision is the pre-
ferred treatment and is curative. A
Inverted Ductal Papilloma (Fig. 20-42)

Definition: Benign salivary gland neoplasm character-
ized by a luminal papillary projection occurring in the
terminal portions of excretory ducts arising at the junc-
tion of a salivary gland duct and oral mucosal surface
epithelium with a characteristic inverted (endophytic)
growth.
Synonym: Epidermoid papillary adenoma
NOTE: This minor salivary gland tumor shares histo-
logic features with sinonasal (Schneiderian) inverted
papilloma but does not share in the biologic behavior B
of the sinonasal (Schneiderian) inverted papilloma.
Clinical Fig. 20-42. Inverted ductal papilloma.

Rare neoplasm A, Well-demarcated, endophytic epithelial growth
No gender predilection; occurs primarily in adults composed of thick, bulbous proliferations contiguous with
over a wide age range but is most frequently seen in but not protruding from the surface epithelium;
the sixth decade of life communication with the surface by a narrow opening is
Most common sites of occurrence include: seen. B, The neoplasm consists of basaloid-appearing
m Lower lip and the buccal (vestibular) mucosa
epithelial cells composed of cuboidal or columnar cells
m Other sites of involvement include the upper lip,
with a papillary appearance along the luminal surface and
squamous/epidermoid cells between which are
floor of mouth, and soft palate.
interspersed mucous cells and microcytes.
Generally asymptomatic and presents as a slow-
growing painless, nodular submucosal swelling
Pathology Clinical
Gross Rare tumor type with very few reported cases
Submucosal firm nodule measuring up to 1.5cm in Most common site of occurrence is parotid gland
diameter; a small surface pore may be seen, which is m May occur less often in minor salivary glands
contiguous with the lumen of the tumor. (palate)

Present as a palpable mass
Histology
Unencapsulated but well-demarcated, endophytic Pathology
epithelial growth composed of thick, bulbous prolif- Well-circumscribed to encapsulated lesion ranging in
erations that are contiguous with but not protruding size from 0.5 to 3.0cm
from the surface epithelium; communication with Composed of closely apposed small ducts with
the surface by a narrow opening may be seen. minimal intervening stroma admixed with cystic
Consists of basaloid and squamous/epidermoid cells ductal spaces that may include:
between which mucous cells and microcysts may be m Prominent areas with cystic changes containing
interspersed; cytologic atypia is absent and there is colloid-like luminal contents with scalloped edges
no significant increase in mitotic activity. reminiscent of thyroid parenchyma
Luminal surface epithelium composed of cuboidal or m Focal cysts
columnar cells with a papillary appearance m Absence of cystic spaces
Tumor grows downward and appears to fill a luminal Ductal epithelial cells:
cavity: m Single layer of cuboidal to columnar eosinophilic
m Endophytic growth is pushing into the submu- cells with bland nuclei, eosinophilic cytoplasm,
cosa rather than demonstrating invasion or and prominent cell membranes similar to stria-
infiltration. tions of normal striated ducts:
Histochemistry: Eosinophilic intranuclear inclusions may be
m Mucous cells stain positively with mucicarmine seen.
and are diastase resistant, PAS positive. Focal clear cell cytoplasmic change may be
present.
Differential Diagnosis m Absence of epithelial beading pattern with
Inverted papilloma abundant stroma seen in canalicular adenoma

Sialadenoma papilliferum m Absence of chondromyxoid stroma, basal lamina-
Mucoepidermoid carcinoma like material

m Absence of mitotic activity and necrosis
Treatment and Prognosis m Absence of visible bilayering composed of

Conservative but complete local excision is the pre- ductal cells surrounded by basal or myoepithelial
ferred treatment and is curative. cells:
In contrast, normal excretory and intercalated
ducts contain diffuse bilayering with basal or
OTHER UNCOMMON BENIGN myoepithelial markers.
EPITHELIAL NEOPLASMS Psammoma bodies and an associated adipocytic
component may be identified.
Rare to uncommon benign epithelial neoplasms of Immunohistochemistry:
salivary glands include: m Keratins (CK7, pankeratin) consistently present
m Striated duct adenoma m S100 protein in >80%
m Intercalated duct adenoma m CK5/6 (75%)
m Lymphadenoma (nonsebaceous) m Generally devoid of myoepithelial cells:
m Keratocystoma Smooth muscle actin (SMA) negative

m Lipoadenoma Isolated cells may be p63 positive
m Adenofibroma Pattern identical to striated ducts
m Apocrine adenoma Focal calponin and smooth muscle myosin

m Salivary gland anlage tumor heavy chain may be present, forming incom-
plete rim around ducts
m Thyroglobulin and TTF1 negative
Striated Duct Adenoma Highly vascular lesions with numerous small capil-
Definition: Unilayered ductal tumor that recapitulates laries, some containing large ecstatic staghorn
normal striated ducts. vessels
m Cystic foci may contain proteinaceous material.

Treatment and Prognosis m Papillary architecture may occasionally be seen.
Complete resection curative m Cells types include squamous cells in the solid
No recurrence or metastases nests, cuboidal to columnar cells lining cysts, but

an absence of sebaceous cells.
Intercalated Duct Adenoma m Cellular components are rather bland, lacking
atypical features, significant increase in mitotic

(Fig. 20-43) activity, and an absence of necrosis.
Definition: Rare benign neoplasm of intercalated duct m Epithelial components are intimately associated
epithelium. See discussion in Chapter 19 on intercalated with a lymphoid stroma that includes a dense
duct lesions. mature lymphocytic cell infiltrate with identifi-
able lymphoid follicles; this lymphoid component
Pathology is believed to represent the tumor-associated lym-
Presence of discrete, rounded, partially to completely phoid stroma, a finding that can be seen in asso-
encapsulated nodules with well-defined contours ciation with other salivary gland tumors.
m Fibrous capsule may vary in thickness and may m Absence of atypical features, mitotic activity,
contain entrapped, irregular-appearing ducts. and necrosis assists in differentiating lymphade-

Composed of intercalated ducts lined by single layer noma from a malignancy (either a primary
of cuboidal to columnar cells with small round nuclei salivary gland carcinoma or metastatic
and eosinophilic to amphophilic cytoplasm: adenocarcinoma).
m There is an absence of nuclear pleomorphism or
increased mitotic activity. Treatment and Prognosis

m Minimal intervening stroma present Surgical excision is curative.
Occasionally acinic cells may be interspersed among
the ductular structures.
Keratocystoma
m Luminal cells reactive for cytokeratin (CK7), Definition: Benign salivary gland tumor composed of
DOG1 (apical and membranous), S100 protein, multiple cystic structures and solid nests of purely squa-
and lysozyme mous cells.
m Basal/myoepithelial markers including p63, cal-
ponin, CK14, or smooth muscle actin highlight Clinical

thin layer of myoepithelial cells around ducts: Rare tumor type
Basal/myoepithelial cells are indistinct by light No gender predilection; occurs over wide age range,
microscopy. including pediatric and adult ages
To date, all cases limited to parotid gland
Lymphadenoma (Nonsebaceous) Present as slowly growing tumors
(Fig. 20-44) Pathology
Definition: Rare benign tumor that is circumscribed to Cut surface shows multilocular cystic lesions filled
encapsulated and composed of epithelial nests including with keratin materials.
glands with associated prominent lymphocytic compo- Histologically:
nent but without islands of sebaceous cells (unlike seba- m Multicystic spaces and solid epithelial islands
ceous lymphadenoma). containing lamellated-appearing keratin

m Lined by stratified squamous epithelium with
Clinical keratinization, including orthokeratosis and

Uncommon tumor type but more common than parakeratosis but absence of granular layer
sebaceous lymphadenoma m Stratification of epithelium always regularly ori-
No gender predilection; primarily disease of adults ented from the outer basal to the inner keratotic
Most commonly arises in parotid gland: cell layer
m Less commonly arises in submandibular gland m Basal cell layer demarcated by basement mem-
brane from surrounding inflamed fibrous

Pathology stroma
Solid or cystic epithelial tumor islands: m Focally, outer layer shows bud-like protrusions.
m Solid foci may show trabecular growth or m Solid squamous cell islands surrounded by base-
tubules surrounded by a basement membrane ment membrane enveloped within collagenous

like material. stroma may be present.
A B
C D
Fig. 20-43. Intercalated duct adenoma.

A, Intraparotid circumscribed to encapsulated cellular proliferation. B, Discrete, rounded nodule with well-defined contour.
C, The tumor is composed of ducts lined by single layer of cells with small round nuclei and eosinophilic cytoplasm; there
is an absence of nuclear pleomorphism or increased mitotic activity. D, The basal/myoepithelial component is highlighted
by p63 staining. E, Luminal cells show apical membranous DOG-1 staining.
Lipoadenoma
Definition: Benign neoplasm composed predominantly
of mature adipose tissue admixed with adenomatous
elements.
Synonym: Sialolipoma
Clinical
More common in men than in women; occurs
over a wide age range from third to eighth
decades
Arises primarily in parotid gland:
m Less often may occur in submandibular gland and
oral minor salivary glands

A
Pathology
Solitary and well-circumscribed with light brown to
yellow appearance on cut section
Histologically, composed of an admixture of cells,
including:
m Mature adipose tissue:
Usually dominates, representing more than

90% but reported in as little as 5% of a given
tumor
m Benign salivary gland epithelial parenchymal
components:
Sharply demarcated from fat
Composed of ducts and acini:
Ductal dilatation may be present.
B Extensive oncocytic cell population often

present
Other cell types may include sebaceous cells
Fig. 20-44. Parotid gland lymphadenoma. and squamous cells.
A, Circumscribed to thinly encapsulated tumor that at low Irrespective of cellular components there is an
magnification is dominated by dense lymphoid proliferation absence of cytologic atypia.
with interspersed spaces representing the adenomatous Other common features include the presence of
component. B, At higher magnification tubules and serous acini, ductal elements, sebaceous glands, and
ductular structures composed of cuboidal to columnar cells a patchy chronic inflammation.
lacking sebaceous cells are present associated with a
benign lymphoid cell stroma. Treatment and Prognosis
Complete surgical resection is curative.
m Cystic and solid structures randomly distributed No recurrences reported
without definite lobular architecture
m Lesional cells composed of uniform, bland nuclei
and abundant eosinophilic cytoplasm

Apocrine Adenoma
m Scattered mitotic figures may be seen usually Rare tumor type of major and minor salivary
limited to outer epithelial layer; atypical mitoses glands
not present Composed of closely packed small glands lined by
m Foreign-body giant cell reaction to keratin debris cells with apocrine features
may be present.
m Immunoreactivity for cytokeratins (AE1/AE3,
CK5/6, CK14) but negative for CAM5.2, S100
Adenofibroma
protein, actin, and calponin Extremely rare tumor type
Composed of admixture of adenomatous glands and
Treatment and Prognosis cellular spindle cell stroma:
Complete surgical resection is curative. m Spindle cells are CD34 positive but negative for
No recurrences reported p63, S100 protein, and actin

Salivary Gland Anlage Tumor Pathology

Definition: Benign tumor with mixed epithelial and mes- Gross
enchymal elements recapitulating early stages in the Well-circumscribed, solid and cystic, tan-white to
embryology of salivary glands between fourth and yellow-appearing lesion ranging up to 3.0cm in
eighth weeks of development. greatest dimension
Synonym: Congenital pleomorphic adenoma
See Section 3, Pharynx, for detailed discussion
including illustrations. Histology
Encapsulated tumors:
m Capsule may be complete or partial
m In relationship to cysts capsular irregularities are
TUMORS WITH SEBACEOUS present so that a well-defined capsule is not

DIFFERENTIATION identified.
Composed of solid nests or islands as well as cysts
Sebaceous tumors of salivary glands are rare and are surrounded by fibrous stroma
thought to originate from sebaceous cells or seba- Neoplastic cells often predominated by squamous
ceous glands found in salivary glands. cells with associated sebaceous cells; however, seba-
Normal sebaceous cells or glands can be found in ceous cells may predominate:
the oral mucosa, parotid gland, and submandibular m Sebaceous cells are characterized by:
gland; sebaceous cells can also be found in intra- and Vacuolated or multivacuolated cytoplasm
periparotid lymph nodes. Nuclei that are centrally located and scalloped
Salivary gland sebaceous cells or glands are histo- due to lipid imprints
logically similar to their cutaneous counterparts. Instead of solid nests, some examples have microcys-
Benign sebaceous tumors of salivary glands include: tic foci of closely associated ductal or cyst-like struc-
m Sebaceous adenoma tures lined by squamous and sebaceous cells, and
m Sebaceous lymphadenoma separated by a fibrous stroma
Other cellular elements that can be seen include
mucous cells and oncocytic cells.
Cellular components lack atypical features with no
Sebaceous Adenoma significant increase in mitotic activity and absent
Definition: Rare benign epithelial salivary gland tumor necrosis.
that is encapsulated with solid and cystic growth and Fibrous stroma contains a variable amount of chronic
composed of cells with sebaceous differentiation, as well inflammatory cells:
as squamous differentiation. m Foreign body giant cell reaction, lipogranuloma
formation and collections of foamy histiocytes

Clinical may be identified.
Rare tumor accounting for 0.1% of all salivary gland Histochemistry:
tumors. m Sebaceous cells contain lipid that can be stained
More common in men than in women; occur over a by oil red O on frozen section.
wide age range from the third to tenth decades of m Epithelial mucin stains are negative.
life, and a mean in the sixth decade of life Immunohistochemistry:

Most common site of occurrence is parotid m Sebaceous cells are EMA positive.
gland
m Other sites of occurrence include the subman- Differential Diagnosis
dibular gland and oral cavity: Sebaceous lymphadenoma
Sites of involvement in oral cavity include the Sebaceous carcinoma
buccal mucosa and posterior mandibular Mucoepidermoid carcinoma
region.
Given the presence of sebaceous cells in oral Treatment and Prognosis
mucosa (unassociated with minor salivary Conservative but complete surgical resection is
gland), a definitive minor salivary gland origin curative.
cannot be confirmed. Unlike their cutaneous counterparts, salivary gland
Generally asymptomatic and presents as a slow- sebaceous adenomas not associated with increased
growing, painless, firm mass; duration of symptoms risk of visceral carcinomas as may occur in Muir-
may be from months to years. Torre syndrome
A B
C D
Fig. 20-45. Parotid gland sebaceous lymphadenoma.

A and B, Circumscribed to encapsulated epithelial-lined multicystic tumor with lymphoid cells in the cyst wall; lymphoid
follicles are present. C, At higher magnifications the cyst lining includes oncocytic-appearing cells, sebaceous cells and
attenuated flattened epithelium. D, A foreign body giant cell reaction to extravasated sebum is seen within the stroma
(lower left).
Sebaceous Lymphadenoma m Other much less sites of occurrence include ante-

rior midline neck and oral cavity.
(Fig. 20-45)
Generally asymptomatic presenting as slow-growing,
Definition: Rare benign tumor that is circumscribed to painless mass; duration of symptoms may be from
encapsulated composed epithelial nests and islands of months to years.
sebaceous cells surrounded by lymphocytes, including Association with Warthin tumor and basal cell
lymphoid follicles. adenoma, membranous type reported
Similar to Warthin tumor, the suggestion has been
Clinical made that sebaceous lymphadenoma may arise in
Rare tumor salivary gland inclusions within a lymph node;
No gender predilection; occurs primarily in the sixth however, there is no definitive proof that this tumor
to eighth decades of life is arising in a lymph node but rather represents the
Majority (more than 90%) occur in parotid gland or so-called tumor-associated lymphoid stroma (TALP),
in periparotid region a phenomenon that can be seen in association with
other salivary gland tumors (e.g., acinic cell carci- Cellular epithelial components lack atypical features
noma, mucoepidermoid carcinoma, others). with no significant increase in mitotic activity and
absent necrosis.
Pathology Histochemistry:
Cytology m Sebaceous cells contain lipid that can be stained
Fine-needle aspiration biopsy: by oil red O on frozen section.

m Smears show clusters of epithelial cells in back- m Epithelial mucin stains are negative.
ground of abundant lymphoid cells, macrophages, m Duct epithelial cells may show mucicarmino-
and abundant proteinaceous materials. philia.

m Predominant epithelial cells are large polygonal Immunohistochemistry:
cells with abundant cytoplasm filled with multi- m Sebaceous cells are EMA positive.
ple, uniform, small, and clear vacuoles, ill-defined m Epithelial cells express basal cell markers includ-
cytoplasmic borders, and small centrally located ing p63, 34BE12, and/or CK5/6.
round nuclei with finely granular chromatin, m Luminal glandular cells express CK7.
conspicuous nucleoli, and indented nuclear m Lymphoid stroma is reactive for both B- and
membranes. T-cell markers.

m Other cells include polygonal or flat cells with m No evidence of HPV, EBV, and HHV-8
less or more dense cytoplasm, indistinct cell

borders, and round or oval small nuclei with Differential Diagnosis
smooth nuclear membranes corresponding to Sebaceous adenoma
basaloid cells. Lymphadenoma, nonsebaceous, of salivary gland
m Large three-dimensional clusters of nonkera- origin:
tinized squamous cells with oval nuclei contain- m Similar to sebaceous lymphadenoma but lacks
ing evenly distributed chromatin, and scant to sebaceous cell component

moderate dense cytoplasm arranged in stream m See previously in chapter for more complete
of fish pattern discussion.

m Rare granulomas and cystic contents (degener- Warthin tumor
ated cells, inflammatory cells, macrophages, and Lymphoepithelial sialadenitis
abundant granular debris/proteinaceous mate- Mucoepidermoid carcinoma
rial) may also be seen. Lymphoepithelial carcinoma
Metastatic adenocarcinoma to periparotid or intra-
Gross parotid lymph node
Well-circumscribed to encapsulated, solid to multi-
cystic, yellow- to yellow-whiteappearing lesion Treatment and Prognosis
ranging up to 6.0cm in greatest dimension Conservative but complete surgical resection is
curative.
Histology Rarely, single cases of malignant transformation to
May have a complete capsule but may also be par- sebaceous carcinoma and basal cell adenocarcinoma
tially encapsulated or unencapsulated: reported
m Unencapsulated tumors have delineated or cir-
cumscribed periphery that may abut but does not

infiltrate adjacent salivary gland parenchyma or BENIGN SOFT TISSUE TUMORS
connective tissues.
Consists of islands and ductlike structures composed Benign mesenchymal tumors of salivary glands are
of squamous cells and sebaceous cells; cuboidal, uncommon, accounting for approximately 2% to
columnar, and oncocytic cells may also be present 5% of all major salivary gland neoplasms.
Cysts may also be identified lined by admixture of Mesenchymal neoplasms of salivary glands are rare:
squamous, sebaceous, and columnar cells; small m In first 2 decades of life mesenchymal tumors
intraluminal nodular excrescences may be present. represent a significant proportion of all parotid
Epithelial component intimately associated with gland tumors and may in fact be more common
dense lymphoid component: than epithelial tumors.
m Well-developed lymphoid follicles can be seen in Hemangioma and lymphangioma most
many cases. common
Generally devoid of myoepithelial cells Benign mesenchymal tumors of salivary glands much
Foreign body giant cell reaction and collections of more common than salivary gland sarcomas
histiocytes may be identified in stroma, representing Benign mesenchymal tumors account for less than
secondary reaction to extravasated sebum. 5% of all salivary gland tumors
Parotid gland is most common site of occurrence: m Consumptive coagulopathy disorder (i.e.,
m >95% arise in parotid gland Kasabach-Merritt syndrome)
Although virtually any mesenchymal tumor can Intraparotid hemangiomas in adults are
occur, among all salivary gland mesenchymal tumors uncommon.
the most common are of vascular origin, including
hemangiomas.
m Much less common benign mesenchymal tumors
Pathology
that may be seen in salivary glands include: Gross
Lymphangioma Lobulated, dark red tumor measuring from 2 to
Lipoma 8cm in diameter
Benign peripheral nerve sheath tumors (i.e., Overlying skin may have a bluish discoloration
schwannoma, neurofibroma) accentuated by crying episodes
Solitary fibrous tumor
Nodular fasciitis Histology
Giant cell tumor Majority of cases are in proliferative phase charac-
terized by:
m Unencapsulated cellular neoplasm with intralob-
Hemangioma, Capillary Type or ular growth and replacement of salivary gland

Infantile (Juvenile) Hemangioma acini:
Despite replacement by a cellular proliferation,
(Fig. 20-46) residual ducts and acini remain identifiable.
Definition: Benign vascular tumor of infancy. m Near-solid masses of small capillaries consisting
Synonyms: Benign (infantile) hemangioendothelioma; of epithelioid to plump endothelial cells and

congenital or juvenile hemangioma; cellular hemangi- peripherally placed pericytes that invest endothe-
oma; immature capillary hemangioma lial cells
m Distinct lobular architecture with lobules lacking
Clinical encapsulation or fibrosis; lobules are separated by

Common benign vascular tumor of infancy (affect- normal tissue elements and/or stroma of the
ing approximately 4% of children) involved site, and an intralobular central feeding
Approximately 60% occur in head and neck. artery may be identified.
m Most common in the skin and subcutis m Evidence of vascular differentiation (i.e.,
m May occur in other locations, including salivary endothelial-lined lumina) may be limited:
(parotid) glands Vascular lumina may be compressed and indis-
Represents most common salivary gland tumor in tinct due to increased cellularity.
pediatric population, accounting for greater than Evidence of vascular differentiation may
90% of parotid gland tumors in children less than 1 best be identified at the periphery of the
year old tumor.
More common in females than in males; may occur m Capillaries lined by two or more layers of endo-
over a wide age range but most frequently seen in thelial cells, which have oval to spindle-shaped
the first decade of life nuclei and eosinophilic granular cytoplasm
Almost exclusively involves parotid gland: m Mitoses frequently seen and may be numerous,
m Occasionally the submandibular gland may be but atypical mitoses are not present
affected. m Mast cells are present.
Usually discovered at birth as a unilateral, compress- m Neural pseudoinvasion, in which intralesional
ible mass and bluish discoloration of overlying skin nerves show peri- and intraneural invasion by
that may be accentuated during crying lesional capillaries:
m Rapid enlargement and facial asymmetry may be Neural pseudoinvasion is a commonly identi-
seen, raising clinical suspicion for a malignancy fied and diagnostic feature as it is rarely seen
m Extension to adjacent sites such as the hypophar- in other benign vascular lesions.
ynx may occur. Presence of neural pseudoinvasion and
m Ulceration of the overlying skin may occur. increased mitotic activity invasion do not
Generally appearing within weeks after birth, prolif- render a diagnosis of malignancy and have no
erate rapidly during the first year of life, and then impact on behavior.
spontaneously involute over a period of several years m Histochemistry:
No association with: Reticulin stain delineates the outlines of the

m Familial disorders such as von Hippel-Lindau vascular sheath, within which is the endothelial
syndrome or hereditary telangiectasia cell proliferation.
A B
C D
E F
Fig. 20-46. Infantile hemangioma involving the parotid gland.

A, The tumor is unencapsulated, multilobular, and cellular with intralobular growth. B, Variably sized blood-filled vascular
channels replacing the salivary gland parenchyma; despite replacement by a cellular proliferation, residual ducts and acini
remain identifiable. C and D, The tumor is composed of capillary-sized vessels, although many of the vascular lumina are
compressed and indistinct due to increased cellularity. E, Neural pseudoinvasion (arrowhead) characterized by the
presence of lesional capillaries located around nerves; this is a common finding and essentially diagnostic feature and is
not indicative of malignancy. F, In addition to typical immunoreactivity for endothelial cell markers including CD31, CD34,
and Factor 8related antigen (not shown), lesional cells are characteristically reactive for glucose transporter 1 (GLUT1).
Note the absence of expression in a nerve (arrowhead) surrounded by tumor, but GLUT1 expression is seen in peripherally
situated normal perineurial cells, which is a consistent finding.
m Tendency to occur in older children and adults
Lesional cells are immunoreactive for: Female predilection
Glucose transporter protein isoform 1 Primarily involve parotid gland
(GLUT1) Involve the extralobular connective tissue
Presence of GLUT1 reactivity (as well as Characterized by presence of dilated, thin-
other markers including Lewis Y antigen, Fc walled vessels lined by flattened endothelial
gamma receptor II, merosin, and others) is cells
similar to that of the vasculature of the pla- GLUT1 negative
centa demonstrating that infantile hemangio- Do not regress and therefore requires complete
mas have a placenta-associated phenotype surgical excision
(NOTE: there is an absence of trophoblastic Lymphatic malformation (lymphangioma/cystic
elements and villous architecture) in infantile hygroma):
hemangiomas m See Section 4, Neck, for more complete
CD31, CD34, factor VIIIrelated antigen discussion.
m A minority (approximately 15%) of cases, vascu- m Involvement of the parotid gland is less common
lar lesions may be relatively prominent at birth than hemangiomas.

following a static or rapidly involuting course m Most occur during childhood.
referred to as congenital nonprogressive heman- m Histology is similar to lymphangiomas of more
giomas, which are further subdivided into: common locations, including the presence of vari-
Rapidly involuting congenital hemangioma ably sized, endothelial-lined spaces with or
(RICH) without intraluminal eosinophilic material, and
Noninvoluting congenital hemangioma (NICH) surrounding collagenous stromal tissue
m Congenital nonprogressive hemangiomas are his- m Complete surgical resection is the preferred
tologically and immunophenotypically distinct treatment.
from infantile hemangiomas: Epithelioid hemangioma:
Overall histology of lesional cellular prolifera- m Formerly referred to as angiolymphoid hyperpla-
tion similar to that of infantile hemangioma sia with eosinophilia

In contrast to infantile hemangioma: m Rarely involves salivary glands
Tumor lobules are separated by dense fibrous m See Section 7, Ear and Temporal Bone, for com-
tissue rather than normal tissue elements plete discussion.

and/or stroma. Angiosarcoma
Sclerosis often extends into tumor lobules. Kaposi sarcoma
In cutaneous sites (most common location) Hemangioendothelioma
there is skin atrophy with loss of dermal
adnexal appendages. Treatment and Prognosis
Small foci of extramedullary hematopoiesis Majority (75% to 90%) involute by 7 years of age;
can be found. current recommendation in absence of an enlarging
Small arterial feeders can be found but neoplasm with compromise of external ear canal
typically lack intralobular central feeding and/or facial distortion, is delay surgery until an
artery. older age in the hope that the tumor will involute
Absence of neural pseudoinvasion (spontaneously regress) over time.
Absence of GLUT1 immunoreactivity as well m Regression (involution) may occur in phases, ini-
as other markers that may suggest a placenta- tially slowly over the first 5 years of life and then
associated phenotype with continuous regression through the first
With regression there is increased interstitial fibrosis; decade of life.
infarction secondary to thrombosis may be present. Variable success has been reported with the use of
Immunohistochemistry: corticosteroids, interferon, and compression therapy.
m Factor VIIIrelated antigen, Ulex europaeus, (Oral) propranolol has replaced corticosteroids as
CD31, and CD34 positive preferred first-line therapy for management of infan-
m Glucose transporter protein isoform 1 (GLUT1) tile hemangiomas:
negative >94% of patients demonstrate response to
treatment with size reduction, color changes,
Differential Diagnosis softened texture, and/or healing of ulceration.
Adult hemangiomas: Topical -blocker timolol now an alternative to
m May uncommonly be identified in salivary glands oral propranolol with watchful waiting for
and are noted for: smaller infantile hemangiomas
In presence of a rapidly enlarging lesion and/or dis- a greater incidence of damage to the facial
figuring lesion complete surgical excision is preferred nerve.
treatment with preservation of the facial nerve Rarely, life-threatening growth may occur:
m Facial nerve in infants is in a more superficial m In this situation, preoperative combined radiation
location than in an older age; therefore surgical and chemotherapy may be indicated.
intervention in infancy may be associated with Malignant transformation does not occur.
MALIGNANT NEOPLASMS
MUCOEPIDERMOID m For low-grade and intermediate-grade MEC:
CARCINOMA (MEC) Slow-growing, solitary, painless mass
(Figs. 20-47 through 20-56) m For high-grade MEC:
Generally presents as rapidly enlarging, painful

Definition: Malignant epithelial salivary gland mass
neoplasm composed of a variable admixture of epider- m Additional symptomatology may include drain-
moid, mucous, and intermediate cells. age from the ipsilateral ear, dysphagia, trismus,
m No benign counterpart, so the presence of a neo- and facial paralysis.
plasm with a marked cellular proliferation includ- m Two thirds of patients are asymptomatic.
ing requisite cell types is diagnostic for MEC, m In the majority of patients, the duration of symp-
whether invasive or noninvasive toms is within a 6-month period of time and

average period is 11 2 years.
Clinical Duration of symptoms may be greater, includ-
Most common malignant salivary gland tumor and ing years to decades
second to pleomorphic adenoma as most frequent In minor salivary glands symptoms may include
occurring neoplasm among all salivary gland tumors: pain, paresthesia, numbness, dysphagia.
m Represents approximately 30% of all malignant Etiology:
salivary gland tumors of major and minor sali- m May be related to prior therapeutic radiotherapy
vary glands with latent periods from the time of radiation to

m Represents approximately 10% to 15% of all the head and neck to the development of a MEC
salivary gland neoplasms of 7 to 32 years
Slightly more common in women than in men; occurs m Human papillomavirus (HPV):
over a wide age range but most frequently seen in Recent studies implicated HPV as a cause of
the third to seventh decades of life with a mean age MEC.
in the fifth decade of life: However, other studies using RNA in situ
m In pediatric age group, MEC represents most hybridization targeting high-risk HPV mRNA
common malignant salivary gland neoplasm, in E6/E7 transcripts did not detect HPV in any
particular in the second decade of life MECs with or without MAML2 rearrange-
Occurs in major and minor salivary glands: ment (see below).
m Slightly more than 50% occur in major salivary High-risk HPV does not appear to play
glands: any significant role in the development of
Among major glands, MEC by far is most MEC.
common in parotid gland (45%) followed
(much less frequently) by the submandibular Pathology
gland (7%) and then sublingual gland (1%). Gross
m Most common minor salivary gland site of Unencapsulated or incompletely encapsulated, delin-
involvement is palate; additional minor salivary eated to invasive, round to oval, predominantly
gland sites of occurrence in decreasing order solid, tan-white to pink mass measuring from less
include the buccal mucosa, lips (lower > upper), than 1cm up to 12cm in greatest dimension
retromolar region, and tongue (base of tongue) Cysts of variable size and prominence can be seen
m May occur in sinonasal tract and nasopharynx on sectioning of the tumor.
but are considered uncommon in these sites Mucosal lesions (e.g., palate) may appear as bluish
Clinical presentation in major glands may vary swelling underneath an intact mucosa and simulate
according to histologic grade: the appearance of a mucocele; less often, mucosal
Fig. 20-48. Low-grade mucoepidermoid carcinoma,

fine-needle aspiration biopsy.
The aspirate includes aggregates of cells, including
epidermoid cells and scattered mucocytes; in addition,
intermediate cells composed of bland cells with round to
A oval nuclei are present. These findings are diagnostic for
low-grade mucoepidermoid carcinoma.
m Extracellular mucin may be the dominant finding:

May simulate the appearance of the mesenchy-
mal component of pleomorphic adenoma but
in contrast to mesenchymal component of
pleomorphic adenomas, mucin:
Does not appear fibrillar
Does not stain as intensely
m Aggregates of cells, including epidermoid cells
and mucocytes (mucus-secreting cells):

Epidermoid cells:
B May appear relatively bland and result in the
false impression of a nonneoplastic lesion or

Fig. 20-47. Mucoepidermoid carcinoma. a benign neoplasm
Mucocytes:
A, Mucoepidermoid carcinoma of the parotid gland Cells with distended cytoplasm and or peri-
appearing as large ovoid mass at the angle of the
nuclear vacuoles due to presence of mucin
mandible. The tumor was slowly enlarging and painless.
Mucin appears as intracytoplasmic, red gran-
B, The resected and transected specimen revealing a
poorly delineated solid and cystic neoplasm; cystic spaces ular material by Romanowsky staining.
Due to intracytoplasmic mucin the nucleus is
were filled with clear to blood-tinged fluid. Histologically,
the tumor proved to be low grade. eccentrically located.
In histologic sections mucocytes often repre-
sent a small percentage of the neoplastic

cells, so they also tend to be limited by FNAB.
tumors may have a papillary or granular-appearing Predominantly cystic MECs often have a
surface mucosa. larger percentage of mucocytes, which trans-

lates into more readily identifiable mucocytes
Fine-Needle Aspiration Biopsy (FNAB) by FNAB.
Low-grade MEC: m Intermediate cells appear as bland cells with
m Due to cystic nature aspirates may be acellular or round to oval nuclei with moderate amount of
hypocellular. cytoplasm.
A B
Fig. 20-49. Low-grade mucoepidermoid carcinoma, parotid gland.

A and B, Infiltrative cystic and solid neoplasm with readily identifiable and numerous mucocytes. C and D, At high
magnification the neoplasm is comprised of an admixture of mucous cells, epidermoid cells characterized by polygonal
shaped cells with eosinophilic cytoplasm and smaller more hyperchromatic-appearing intermediate cells with less
cytoplasm. E, Extravasated mucin into fibroconnective tissue with associated inflammatory cell infiltrate and fibrosis.
F, Epidermoid cells are diffusely and strongly p63 positive (nuclear staining) but mucocytes are negative for p63.
Fig. 20-50. Cystic low-grade mucoepidermoid carcinoma.

A, Encapsulated predominantly cystic lesion with area of more densely cellular intracystic proliferation with solid, papillary,
and cribriform growth; focally, the tumor is separate from the parotid parenchyma (extreme right) but is infiltrative into
the cyst wall (arrow), extending toward uninvolved parotid parenchyma. Although too difficult to appreciate at this
magnification the remainder of the cyst is lined by a cuboidal epithelium lacking the overall diagnostic features for
mucoepidermoid carcinoma. B, Another predominantly cystic encapsulated neoplasm with area of more densely cellular
intracystic proliferation; tumor-associated lymphoid proliferation (TALP) is present (arrows) lying in between the cystic
tumor and the surrounding parotid gland. The remainder of the cyst is lined by nondescript cuboidal epithelium focally
exclusively comprised of mucous cells (arrowhead) lacking the overall diagnostic features for mucoepidermoid carcinoma.
C and D, Proliferative areas comprised of an admixture of mucous cells, epidermoid cells, and intermediate cells
diagnostic for mucoepidermoid carcinoma. In the presence of invasive growth the diagnosis is readily established but
even in the absence of invasion, the presence of mucous cells, epidermoid cells, and intermediate cells would be
diagnostic for mucoepidermoid carcinoma.
High-grade MEC: Histology

m Readily identifiable as malignant but due to the Characteristic features for all histologic grades
scarcity of mucocytes even in tissue sections, a (see below) include the presence mucous cells
specific diagnosis of high-grade MEC may not be (mucocytes), epidermoid cells, and intermediate
achievable. cells:
m In face of an aspirate with obviously high-grade m Mucous cells identified lining cystic spaces
malignant cytology, a definitive diagnosis of MEC or admixed within nests or solid areas with
is less important as the treatment for high-grade epidermoid cells are large, ovoid, goblet,
malignant epithelial tumors of the salivary glands balloon-shaped, or columnar cells with distinct
should be similar. cell borders composed of pale-staining or
A B
Fig. 20-51. Intermediate-grade mucoepidermoid carcinoma.

A, In comparison with low-grade tumors, intermediate-grade mucoepidermoid carcinomas are more solid and predominantly
composed of epidermoid cells with residual cystic foci that include mucous cells (upper right). B, There is a shift in the
ratio of mucous cells to epidermoid and intermediate cells with a larger percentage of the latter cells identified. C, In
comparison to the low-grade cancers the cells in intermediate grade show a greater degree of nuclear pleomorphism as
compared with low-grade mucoepidermoid carcinoma but significantly less nuclear pleomorphism, mitotic activity, and
necrosis as compared with high-grade mucoepidermoid carcinoma.
foamy-appearing cytoplasm with peripherally Keratin (squamous) pearls, extensive kerati-

placed, small, dark staining nuclei: nization, and intercellular bridges do not
Most numerous and readily identifiable in low- predominate.
grade MEC Foci of keratinization (individual cell and/or
Less numerous but still readily identifiable in keratin pearl formation) may occur in
intermediate-grade MEC inflamed tumors.
Least numerous and not readily identified Absence of keratin (squamous) pearls, exten-
without histochemical staining (e.g., mucicar- sive keratinization, and intercellular bridges
mine, PAS with diastase) in high-grade MEC assist in separating mucoepidermoid carci-
m Epidermoid cells form nests and/or solid areas noma from such tumors as adenosquamous
have a pavement-like arrangement and are polyg- carcinoma.
onal with vesicular nuclei and abundant eosino- m Intermediate cells include both small basal cells
philic cytoplasm. and larger polygonal cells appearing in clusters of

In some examples epidermoid cell differentia- solid sheets or scattered and admixed with the
tion may be focal and limited in extent. other cell types:
Individual cell keratinization and keratin pearl Basal cells: characterized by the presence of
formation may be seen but are considered round to oval, small, dark-staining nuclei and
uncommon. scanty, eosinophilic cytoplasm
Larger polygonal cells: round to ovoid cells

with vesicular chromatin and more abundant
cytoplasm
Transitional areas from smaller basal cells to
larger polygonal cells can be seen.
Other cell types that may be seen include:
m Clear cells composed of round to oval cells with
distinct cell borders, peripherally placed, small,

dark nuclei and their hallmark clear cytoplasm:
May range from very focally identified to pre-
dominating (i.e., clear cell variant, see below)
m Oncocytic cells characterized by presence of a
brightly eosinophilic and granular-appearing

cytoplasm
Often can be seen focally and occasionally pre-
Fig. 20-52. Mucoepidermoid carcinoma.
dominate (i.e., oncocytic variant, see below)
m Columnar cells can be seen lining cysts and duct-
High-grade mucoepidermoid carcinoma appearing as a like structures and tend to be less numerous than
large, ulcerating and necrotic hard palate mass. mucous cells.
Fig. 20-53. High-grade mucoepidermoid carcinoma.

A, Neoplastic proliferation with solid growth composed of epithelial cells. B, Marked nuclear pleomorphism with increased
mitotic activity. C, Rare mucocytes (arrow) may be seen by light microscopy. D, Intracytoplasmic mucicarmine positive
material.
A B
Fig. 20-54. Clear cell variant of mucoepidermoid carcinoma.

A, Cellular components predominated by cells with clear cytoplasm with admixed foci of epidermoid cells (arrows) and
mucous cells (arrowheads). B, Higher magnification shows predominant clear cell component with identifiable mucocytes.
C, Mucocytes show the presence of intracytoplasmic mucin-positive material but the clear cells are mucicarmine negative.
The clear cells contain glycogen as evidence of the presence of diastase-sensitive, PAS-positive material (not shown).
m Spindle-shaped cells may focally be present. varying cell types, including mucocytes and
m Rarely pigmentation (melanin-containing) cells epidermoid cells:
may be present. Degree of cellular proliferation is much
Tumors may be encapsulated or unencapsulated with greater in MEC than in these other lesions.
or without invasion: Intermediate cells are typically absent in
m Diagnosis of MEC can be established even in the these nonmalignant lesions but may also be
absence of invasive growth based on identifying difficult to appreciate in MECs
the constituent cell types (see above): Growth patterns include predominantly cystic, pre-
Benign neoplastic counterpart to MEC com- dominantly solid, or admixture of cystic and solid:
posed of mucous cells, intermediate cells, and m Additional growth patterns may include papil-
epidermoid cells not known to exist lary, glandular, or duct-like:

Encapsulated (noninvasive) MECs tend to be Cysts are lined by mucous, columnar, and epi-
histologically lower grade. dermoid cells.
Benign nonneoplastic lesions as well as benign Origin from duct epithelium may occasionally
neoplasms may be cystic and composed of be identified.
A B
Fig. 20-55. Oncocytic cell variant of mucoepidermoid carcinoma.

A, The tumor is predominated by cells with oncocytic cytoplasmic change but scattered identifiable mucous cells are
present. B, The mucocytes show the presence of intracytoplasmic diastase-resistant, PAS-positive material. The presence
of mucocytes usually would differentiate oncocytic mucoepidermoid carcinoma from other oncocytic lesions/neoplasms
(e.g., oncocytoma, oncocytic carcinoma). Residual foci of usual mucoepidermoid carcinoma, including epidermoid cells,
mucous cells, and intermediate cells (which may or may not be present) and/or diffuse p63 reactivity would confirm a
diagnosis of oncocytic MEC.
A B
Fig. 20-56. Sclerosing variant of mucoepidermoid

carcinoma.
A, At low magnification the tumor is composed of cohesive
tumor nests separated by prominent keloid-like sclerosis.
Tumor-associated lymphoid proliferation (TALP) separates
the tumor from the surrounding parotid parenchyma (lower
left). B, At higher magnification tumor nests with typical
cellular components of mucoepidermoid carcinoma are
present, separated by keloid-like sclerosis. This variant lacks
a significant eosinophilic infiltrate contrasting to the findings
seen in association with sclerosing mucoepidermoid
carcinoma with eosinophilia. C, Psammomatoid concretions
can be seen in a variety of salivary gland lesions/neoplasm,
C
including sclerosing variant of mucoepidermoid carcinoma.
Stroma is often fibrous and may be sclerotic/ m Perineural and/or lymph-vascular invasion may
hyalinized: be identified:
m Tumors with extensive stromal sclerosis have More commonly seen in histologically higher-
been referred to as sclerosing MEC (see below). grade MEC
Prominent lymphoid tissue with or without lym-
phoid follicles may be evident: Histologic (Microscopic) Grading
m Referred to as tumor-associated lymphoid prolif- Three histologic grades recognized:
eration (TALP) m Low grade
TALP may lead to mistaken interpretations of m Intermediate grade
primary tumors as nodal metastasis or benign m High grade
lymphoepithelial lesion. Basis for histologic grading into low, intermediate,

Primary salivary gland tumors including MEC and high categories dependent on:
may originate from salivary gland parenchyma m Architectural growth pattern
incorporated within peri- and intranodal lymph m Cellular components
nodes; as such, TALP must be differentiated m Cytomorphology
from tumor within a lymph node. Microscopic grading remains subject of debate
Presence or absence of a subcapsular sinus Criteria for histologic grading include (single or in
will differentiate bona fide lymph node combination):
parenchyma (with subcapsular sinuses) from m Proportion of the tumor composed of cystic
non-lymph node parenchyma (without sub- spaces relative to solid growth

capsular sinuses). m Proportion of cell types
Intraluminal mucus can be seen in cysts and/or m Degree of maturation of cell types
gland-like structures: m Mitotic rate
m Extravasation of mucin appearing as extracellu- m Extent of invasiveness, including pattern of

lar mucous pools or cysts may be seen. invasion, neurotropism, and vascular space
Cellular pleomorphism, mitoses, necrosis, and hem- invasion
orrhage are generally absent: m Presence of necrosis
m Such findings when identified are more common A quantitative grading system based on specific his-
in histologically higher-grade tumors. tologic features suggested (Table 20-5):
A variable degree of local invasion may be seen: m According to Armed Forces Institute of Pathology
m Invasion into surrounding cyst wall, fibroconnec- (AFIP) grading scheme:

tive tissue, residual nonneoplastic salivary gland 0 to 4 are considered low grade (Grade I)
parenchyma often is present 5 to 6 are considered intermediate grade
Such invasive growth essentially similar irre- (Grade II)
spective of histologic grade 7 or more are considered high grade (Grade III)
TABLE 20-5 Mucoepidermoid Carcinoma: Microscopic Grading

Feature Grade Tumor Grade Point Score
Auclair etal*; Goode etal
Intracystic component less than 20% 2 Low-grade 0-4
Neural invasion 2 Intermediate-grade 5-6
Necrosis 3 High-grade 7 or more
Four or more mitoses 3
Anaplasia 4
Brandwein etal
Intracystic component less than 25% 2 Low-grade 0
Tumor front invades in small nests and islands 2 Intermediate-grade 2-3
Pronounced nuclear atypia 2 High-grade 4 or more
Lymph-vascular invasion 3
Bony invasion 3
Four or more mitoses 3
Perineural invasion 3
Necrosis 3
*Cancer 69:2021-2030, 1992.
Cancer 82:1217-1224, 1998.
Am J Surg Pathol 25:835-845, 2001.

m According to Brandwein etal grading scheme: Immunohistochemistry:

0 are considered low grade (Grade I) m Cytokeratin (pancytokeratin, CK5/6, others) and
2 to 3 are considered intermediate grade epithelial membrane antigen (EMA) positive

(Grade II) m p63 positive (strong nuclear staining)
4 or more are considered high grade (Grade III) m S100 protein, calponin, glial fibrillary acidic
Most useful features for histologic grading, particu- protein, muscle-specific actin, and carcinoembry-
larly in predicting high-grade tumors, include: onic antigen are at best variably positive and
m Intracystic component of less than 20% (predom- more often negative.
inantly solid growth) m May be mammaglobin positive but typically focal
m Four or more mitotic figures per 10 high-power lacking moderate to strong staining in significant
fields proportion of cells (i.e., more than 25%)
m Cellular anaplasia, necrosis, neural invasion, m GATA3 (nuclear) staining may be present but
angioinvasion, and osseous invasion when present is focal rather than diffuse:
With exceptions, typical histologic features associ- Diffuse GATA3 staining in salivary gland neo-
ated with different histologic grades include: plasm typically limited to salivary duct carci-
m Low grade: noma and mammary analogue secretory
Numerous cystic spaces carcinoma
All three cell types identified including m Androgen receptor negative
numerous/readily identifiable mucocytes m HER-2 overexpression typically absent
Overall absence of nuclear pleomorphism, m Sox10 negative
increased mitotic activity, and necrosis m Express membrane-bound mucins, including:
Absence of perineural invasion MUC1, MUC4, MUC5AC, and MUC5B

m Intermediate grade: Electron microscopy:
Predominantly solid but still cystic m Presence of two cell types, including luminal
Composed of all three cell types perhaps with cells with microvilli, goblet cell formation,
greater percentage of epidermoid cells and less and mucus secretion, and the nonluminal inter-
percentage of mucocytes mediate cells felt to represent the counterpart of
Greater degree of nuclear pleomorphism as the modified myoepithelial cells seen in mixed
compared to low-grade MEC but significantly tumors
less nuclear pleomorphism, mitotic activity, Cytogenetics and molecular biology:
and necrosis as compared with high-grade m Mucoepidermoid carcinoma translocated 1
MEC (MECT1) and mastermind-like gene family
m High grade: (MAML2) translocation located at chromosome
Diffuse sheet-like or solid growth 19p13 and 11q21 represent most frequent genetic
Cystic spaces make up less than 20% of the alteration
tumor or Detected by RT-PCR or fluorescence in situ
Cellular anaplasia with marked nuclear pleo- hybridization
morphism, increased mitotic activity, including Identified in large proportion of MEC
atypical mitoses and necrosis Present in 66% MEC
Limited identifiable mucocytes 100% non-MEC negative for translocation
Tend to be extensively infiltrative, including Low- to intermediate-grade MEC higher fre-

perineural invasion and lymph-vascular quency of translocation (75%) than high-grade
invasion MEC (46%)
Percentage of cell types do not necessarily correlate CRTC1 (CREB-regulated transcription
with behavior. coactivator-1) used in place of MECT1
Histochemistry: Presence of CRTC1-MAML2 translocation
m Mucocytes: identified as useful adjunct to histologic scoring
Intracytoplasmic diastase-resistant, PAS- as prognostic indicator:
positive, and mucicarmine-positive staining Low-grade, fusion-positive MEC with no or
m Gland-like spaces: few genomic imbalances and favorable

Intraluminal diastase-resistant, PAS-positive, prognosis
and mucicarmine-positive staining High-grade, fusion-positive MEC with mul-
m Epidermoid cells may be faintly PAS positive but tiple genomic imbalances and unfavorable
are mucicarmine negative. prognosis
m Intermediate cells and clear cells show no staining Heterogeneous group of high-grade, fusion-
with either PAS or mucicarmine. negative adenocarcinomas with multiple

genomic imbalances and unfavorable Predominantly but not exclusively a parotid gland
outcome neoplasm:
m A less common gene fusion includes CRTC3 m May occur in submandibular gland and minor
(CREB-regulated transcription coactivator-3) on salivary glands

chromosome 15q26 and MAML2:
Associated with favorable prognosis Sclerosing Variant
m PLAG1 translocation negative Histologically typical MEC albeit with prominent
m ETV6 translocation negative central (keloid-like) sclerosis
m May be paucicellular in areas of sclerosis with
Histologic Variants of MEC more typically neoplastic foci along periphery
Clear Cell Variant Associated lymphoplasmacytic infiltrate located
Characterized by predominance of large cells with along periphery of the neoplasm
clear-appearing cytoplasm and discrete cell Absence of significant eosinophilic infiltrate
membranes Absolute number of IgG4 plasma cells as well as
Residual foci of usual or classic MEC typically proportion of IgG4/IgG plasma cells increased in
present including mucocytes containing epithelial sclerosing MEC as compared with the regular type
mucin Possible relationship to IgG4-related diseases remains
Typically histologically low-grade lacking significant to be determined.
nuclear pleomorphism, increased mitotic activity,
and necrosis Sclerosing MEC with Eosinophilia
Histochemical stains show the presence of intracyto- Rare variant and may be related to sclerosing variant
plasmic diastase-sensitive, PAS-positive material without eosinophilia
indicative of glycogen Histologically composed of epithelial nests that may
Mucicarmine negative include mucin-containing cells embedded in a scle-
Cytokeratins and p63 positive rotic stroma
EWSR1-ATF1 gene fusion identified in clear cell car- Fibrosclerotic stroma densely infiltrated by chronic
cinoma of salivary glands is negative in clear cell inflammatory (lymphoplasmacytic) cells and
variant of MEC. eosinophils
More common variant relative to palate MEC Lesional cells may appear squamoid including pres-
ence of keratinization.
Oncocytic Variant Inflammatory infiltrate and stromal fibrosclerosis
Characterized by cells with abundant granular eosin- may also be seen in non-neoplastic salivary gland
ophilic cytoplasm (i.e., oncocytes) but percentage of tissue adjacent to tumor.
oncocytic cells necessary for diagnosis not well Immunohistochemically, many plasma cells may be
defined IgG4-positive.
Predominantly solid growth pattern Postoperative serum IgG4 level may be elevated.
Scattered mucocytes containing epithelial mucin Possible relationship to IgG4-related diseases remains
(mucicarmine and/or diastase-resistant, PAS-positive) to be determined.
identified:
m Presence of mucocytes usually but not always Differential Diagnosis (Table 20-6)
differentiates oncocytic MEC from other onco- Low and intermediate MEC:
cytic lesions/neoplasms that may rarely contain m Necrotizing sialometaplasia
such cells, including: m Non-neoplastic true epithelial cystic lesions,

Oncocytosis, oncocytoma, oncocytic carcinoma including:
m Presence of foci of classic MEC and/or diffuse Lymphoepithelial cyst and salivary duct cyst
p63 reactivity assist in confirming diagnosis of m Pleomorphic adenoma with squamous and
oncocytic MEC mucous cell metaplasia
Typically lack significant nuclear pleomorphism, m Metaplastic Warthin tumor
increased mitotic activity, and necrosis m Sclerosing polycystic adenosis
Residual foci of usual or classic MEC may or may m Cystadenoma and cystadenocarcinoma
not be present. m Acinic cell adenocarcinoma
CRTC1-MAML2 translocation present m Mammary analogue secretory carcinoma
In spite of solid growth, this variant is histologically High-grade MEC:

(and biologically) low grade: m Conventional squamous cell carcinoma (primary
m Single reported case purportedly of a high-grade or secondary)

oncocytic MEC m Adenosquamous carcinoma
TABLE 20-6 Mucoepidermoid Carcinoma: Differential Diagnosis

MEC, Low Grade SCC NS
Architecture/growth Haphazard, infiltrative growth; Haphazard, infiltrative growth Retention of lobular
may be encapsulated architecture
Cellular components Admixture of mucous, Nests and cords of squamous Smooth round to oval nests
intermediate (basaloid), and cells characterized by of metaplastic squamous
epidermoid cells; bland keratinization and intercellular epithelium with bland
cytology; irregular cell nests bridges with irregular outlines cytology; may show residual
and variable amount of ductal lumina with mucous
cytologic atypia; may entrap cells
residual glands but the tumor
itself contains no mucin
Cyst formation Present (prominent Absent Absent
component)
Surface epithelium Uninvolved; not connected Often dysplastic and/or in May show PEH; usually not
with tumor direct continuity with the connected with NS
carcinoma; may be ulcerated
Extravasated mucin May be present Absent May be present
Necrosis Absent May show tumor necrosis Lobular necrosis of salivary
gland acini
Inflammation May be prominent with mucin May be present; associated May be prominent
extravasation desmoplasia
Cytogenetics CRTC1-MAML2 translocation None known None known
MEC, Mucoepidermoid carcinoma; NS, necrotizing sialometaplasia; PEH, pseudoepitheliomatous hyperplasia; SCC, squamous cell
carcinoma.

m submandibular gland) and minor salivary
Cystadenoma and cystadenocarcinoma
m glands considered uncommon not necessarily
Clear cell variant MEC: warranting elective neck dissection unless clini-
m Clear cell carcinoma cally suspicious neck disease
m Metastatic renal cell carcinoma Likelihood of occult cervical lymph node
Oncocytic variant MEC: metastasis for patients with clinical N0 sali-

m Oncocytosis vary gland carcinoma of major and minor
m Oncocytoma salivary glands low and driven predomi-
m Oncocytic carcinoma nantly by histologic subtype; reported inci-
dence of 21% (25 of 110):
Treatment and Prognosis Highest among patients with high-grade
Therapy is primarily surgical: MEC and adenocarcinoma, high-grade,

m Stages I and II treated by: not otherwise specified
Wide local surgical excision with preservation Most common site of cervical lymph node
of the facial nerve (for parotid neoplasms) metastasis level II > level III > level IB
Patients with partial parotidectomies with clear Adjuvant radiotherapy does not offer any
surgical margins fare as well as patients who advantage over complete surgical extirpation
undergo total parotidectomies. with free surgical margins for low-grade and
May recur locally if incompletely excised but intermediate-grade tumors:
metastatic disease infrequently occurs Radiation may be useful in the local control
Submandibular gland tumors should be treated of disease if residual tumor is found at the
by complete surgical glandectomy. surgical margins in a patient no longer ame-
Palatal-based lesions that are small (less than nable to surgery.
2cm) and do not involve bone can be managed Due to worse prognosis associated with sub-
by wide local excision down to the periosteum mandibular gland tumors, combined surgery
with at least 1-cm clear lateral surgical margins: and radiotherapy have been advocated as the
Block excision of underlying bone is done if initial planned treatment.
there is evidence of bone destruction. m High-grade MEC:
Regional nodal metastasis for low- and Treatment depends on clinical stage but in
intermediate-grade MECs of major (except general wide block surgical excision is
preferred treatment, which may necessitate sac- m Mortality rates based on histologic grade include:
rifice of the facial nerve (parotid gland tumors) For AFIP, mortality rates based on their grading
or the hypoglossal and lingual nerves (subman- scheme include:
dibular tumors). Grade I: 0
Radical palatectomy is required for palatal- Grade II: 5%
based large lesions with involvement of bone. Grade III: 46%
Associated with high rates of recurrence For Brandwein etal, mortality rates based on
and metastasis and owing to frequency of their grading scheme include:
metastasis to regional lymph nodes, neck dis- Grade I: 0
sections are usually included in the surgical Grade II: 5%
management. Grade III: 65%
Adjuvant postoperative radiotherapy is advo- m CRTC1-MAML2 fusion-positive MEC, regard-
cated for patients with high-stage disease less of grade, manifest a more stable genome and
(Stages III and IV), especially for high-grade better clinical behavior.
tumors with tumor margins involved. m Negative prognostic factors include:
Role of chemotherapy in the treatment of sali- High histologic grade

vary gland carcinomas remains speculative. Advanced clinical stage
Prognosis: Perineural invasion
m In general, low-stage and/or low-grade and inter- Positive surgical margins
mediate-grade tumors have excellent prognosis Extraparenchymal extension
with approximately 90% 5-year survival rates. Submandibular location
In children (who have predominantly histo- Nodal metastases
logic low-grade and/or low-stage tumors), Distant metastases
5-year overall survival of 98% and 10-year CRTC1-MAML2 fusionnegative cases repre-
overall survival of 94% reported sent distinctly different pathway characterized
m No difference in outcome reported between low by marked genomic instability and relatively
and intermediate grade in all grading schemes aggressive tumors
m Overall 40% 5-year survival rates for high-stage Aneuploidy, high proliferation indices (>10%)
and/or high-grade MEC Increase expression of MUC1 (>75%)
Factors influencing prognosis:
m Histologic grade influential in prognosis (Table ACINIC CELL CARCINOMA
20-7), with the exception of submandibular gland (Figs. 20-57 through 20-61)
involvement, which is not felt to be as reliable a
predictor of behavior as compared with other Definition: Malignant epithelial salivary gland neoplasm
salivary gland sites characterized by a variety of histologic growth patterns
and tendency for neoplastic cells to recapitulate appear-
TABLE 20-7 Mucoepidermoid Carcinoma: ance of normal serous acinous cells characterized by the
Microscopic Grading and Prognosis presence of cytoplasmic (zymogen type) secretory
granules.
Percent Dead of Disease or
Microscopic Grade Prognosis
Clinical
Auclair et al*; Goode et al
Low grade 0 Represents approximately 18% of all malignant sali-
Intermediate grade 5 vary gland neoplasms and 6.5% of all salivary gland
High grade 46 neoplasms
Brandwein et al Slightly more common in women than in men; wide
Low grade No recurrences, metastases, or age range from children to older adults with a peak
deaths
Intermediate grade Local recurrence 30%; nodal
incidence in the seventh decade of life:
metastasis 18%; 5% dead of m Approximately 4% occur in children.
disease m In children, the majority of cases occurs in the

High grade Local recurrence 70%; nodal second decade of life.
metastasis 63%; 65% dead
m Represents second most common malignant epi-
of disease
thelial neoplasm to occur in children; mucoepi-
*Cancer 69:2021-2030, 1992.
dermoid carcinoma is most common pediatric

Cancer 82:1217-1224, 1998.
malignant salivary gland neoplasm
Am J Surg Pathol 25:835-845, 2001.
Reflects cumulative statistics from Auclair et al and Goode et al Majority of cases (more than 80%) arise in the
studies, including major and minor salivary glands. parotid gland:
Pathology
Gross
Well-demarcated and/or encapsulated, round or mul-
tilobulated, soft to rubbery, tan-gray to yellow or
pink mass usually measuring from 1 to 3cm in
greatest diameter but occasionally may reach sizes
up to 13cm
Most neoplasms have homogeneous appearance but
may be cystic and hemorrhagic.
Recurrent neoplasms are less well demarcated and
tend to be multinodular in appearance.
Fine-Needle Aspiration Biopsy

Aspirates tend to be cellular except for the papillary-
Fig. 20-57. Cytology of acinic cell adenocarcinoma. cystic and follicular variants, which may have low
Acinic cell adenocarcinoma of the parotid, fine-needle numbers of serous acinar cells.
aspiration biopsy. Cellular aspirate composed of serous Cytologic diagnosis rests on presence of identifying
acinar cells characterized by large cells with round, serous acinar cells characterized by:
relatively uniform, centrally situated nuclei, inconspicuous m Large cells with round, relatively uniform dark-
to conspicuous nucleoli, and abundant, granular-appearing staining nuclei, inconspicuous to conspicuous

cytoplasm. nucleoli, and abundant, granular-appearing
cytoplasm
Uncommon but may also be identified in the sub-
m m Appearance in clusters resembling normal acini
mandibular and sublingual glands or as individual cells

m May also occur in all minor salivary glands, espe- m Presence of stripped or naked nuclei may be
cially those of intraoral sites: present in the background and may be mistaken
Most common intraoral sites are the buccal for lymphocytes.
mucosa and upper lip. m Centrally situated nuclei lacking polarity, which
NOTE: Prior to diagnosing acinic cell carcinoma of a contrasts to normal (non-neoplastic) serous
nonparotid gland site, exclusion of other diagnostic acinar cells, in which the cells have basally ori-
considerations, especially mammary analogue secretory ented nuclei
carcinoma (MASC), is mandatory as many acinic cell An associated benign lymphocytic cell infiltrate may
carcinomas of nonparotid gland sites have been reclas- be apparent in aspirates.
sified as another tumor type (e.g., MASC). Psammomatoid concretions may be identified in
Bilateral parotid gland, and less often submandibu- aspirates.
lar gland, involvement may uncommonly occur Serous acinar cells may be mistaken for oncocytic
(approximately 3% of cases): cells and in conjunction with a lymphocytic cell infil-
m Represents most common malignant salivary trate may be misdiagnosed as Warthin tumor.
gland neoplasm to present with bilateral disease
Most common presentation is that of a slow-growing, Histology
solitary mass without fixation to surrounding May be circumscribed, encapsulated, or infiltrative
structures: Characterized by a variety of growth patterns
m Associated pain may or may not be present. including solid, microcystic, papillary-cystic, and
m Facial paralysis may occur in up to 10% of follicular:
patients. m Solid and microcystic:
m Fixation to surrounding structures may uncom- Most common patterns and often seen in asso-
monly occur. ciation with each other
m Duration of symptoms typically is less than a Solid growth consists of sheets or aggregates
year but may occur from several years to of tumor cells in lobules or organoid
decades. arrangement
Thought to arise from distal (terminal) portions of Microcystic consists of numerous small cystic
the salivary duct system, specifically the intercalated spaces.
duct reserve/stem cells Microcysts may appear as empty spaces
Etiology: or may contain eosinophilic to basophilic
m No known causes material.
Fig. 20-58. Acinic cell carcinoma.

Multiple growth patterns can be seen from case to case and even within a single case including (A) solid and focally
cystic; (B) microcystic; (C) papillary-cystic; and (D) follicular. E, A coexisting lymphoid cell infiltrate referred to as tumor-
associated lymphoid proliferation (TALP) is often but not uniquely seen in association with acinic cell carcinoma. The
presence of TALP may suggest tumor within a lymph node but the absence of subcapsular sinuses would allow
discrimination from tumor within a (periparotid) lymph node. F, The epithelial proliferation may appear to be floating in
cystic spaces with bulging of the epithelial cells into the lumen in an uneven manner resulting in a hobnail or tombstone
row appearance.
A B
C D
Fig. 20-59. Acinic cell carcinoma.

The cytomorphologic features in acinic cell carcinoma include (A and B) polyhedral cells with eccentrically placed nuclei
and characteristic abundant basophilic granular cytoplasm with admixed vacuolated cells characterized by clear cytoplasmic
vacuoles; (C) intercalated duct-like cells characterized by amphophilic cytoplasm and sparse to absent basophilic granules;
(D) nonspecific glandular cells are round to polygonal shaped with round nuclei, amphophilic to eosinophilic cytoplasm and
indistinct or ill-defined cell borders; (E) DOG1 immunoreactivity is positive in acinic cell carcinoma showing complex
mixture of intense apical membranous, complete membranous and cytoplasmic staining.
m Acinic or acinar cells:

These cells are diagnostic (pathognomonic).
Polyhedral with small, dark, eccentrically
placed nuclei and characteristic abundant
basophilic cytoplasm with cytoplasmic
(zymogen-like secretory) granules; zymogen-
like secretory granules define these as acinar
cells.
These cells may predominate in well-
differentiated tumors, but in any given tumor
they may represent a minority of neoplastic
cells.
May be vacuolated that in contrast to vacuo-
lated (nonacinar) cells retain their cytoplasmic
A diastase-resistant, PAS-positivity
m Intercalated duct-like cells:
Cuboidal or columnar with centrally placed

small dark nuclei and eosinophilic to ampho-
philic cytoplasm
Found in majority of tumors but usually rep-
resent a smaller percentage of cellular
components
May predominate in about one third of
cases
m Vacuolated cells:
Contain clear cytoplasmic vacuole, which may

be numerous, vary in size, and distend the cell
membranes.
These cells are more commonly seen in acinic
B cell adenocarcinoma than in other salivary
gland neoplasms but are identified in other
salivary gland neoplasms and are not in and
Fig. 20-60. Acinic cell carcinoma. of themselves diagnostic for acinic cell
Psammoma bodies can be identified but are not unique to carcinoma.
acinic cell carcinoma, being present in other salivary gland m Clear cells:
neoplasms. Round to oval cells with distinct cell borders,

peripherally placed, small, dark nuclei and
hallmark clear cytoplasm
Result from fixation and/or tissue processing
Papillary-cystic and follicular:
m Considered an uncommon cell type in acinar
Less common patterns (papillary/cystic more cell carcinoma
common than follicular) Likely pure clear cell variant of acinic cell
Papillary-cystic consists of variable-sized cystic carcinoma does not exist.
spaces associated with papillary projections m Nonspecific glandular cells:
supported by a thin fibrovascular core: Lack specific features seen in other cell types
Epithelial proliferation may appear to be Are round to polygonal with round nuclei,
floating in cystic spaces amphophilic to eosinophilic cytoplasm, and
Epithelial cells may bulge into the lumen in indistinct or ill-defined cell borders
an uneven manner, resulting in a tombstone Tend to be more cellular and pleomorphic with
row appearance. a syncytial growth
Follicular pattern resembles thyroid paren- Although a single growth pattern and cell type may
chyma with epithelial-lined lumens containing predominate in any given tumor, it is not uncommon
eosinophilic proteinaceous material lined by to see multiple growth patterns and cell types in a
cuboidal to columnar cells. single tumor.
Cytologic variation present from case to case and No established histologic grading system associated
even within a given case, including presence of: with acinic cell carcinomas
A B
C D
Fig. 20-61. High-grade transformation (dedifferentiation) of acinic cell carcinoma.

A, Infiltrative parotid gland tumor with trabecular and solid growth; in areas residual foci of (differentiated) acinic cell
carcinoma characterized by (B) microcystic growth pattern and (C) cells with basophilic granular cytoplasm were seen;
(D) transformation to high-grade undifferentiated carcinoma; (E) invasive growth with perineural invasion.
Cellular pleomorphism and mitotic activity are typi- m Papillary-cystic pattern:

cally absent. Intraluminal and extracellular PAS-positive
Typically, stroma is scant but occasionally may be and mucicarmine-positive material may be
dense and hyalinized. present.
A prominent lymphoid component with germinal m Follicular pattern:
centers representing tumor-associated lymphoid pro- Luminal material may be PAS positive and
liferation (TALP) present in many tumors. weakly mucicarmine positive.
Occasionally, psammomatoid concretions similar to Immunohistochemistry:
those seen in thyroid papillary carcinoma may be m Discovered on GIST-1 (DOG-1) positive:
present. Relative to salivary gland lesions/neoplasms

Hemorrhage may be present including in connective considered marker of acinar cells and to a
tissue and within epithelial cells: lesser extent intercalated duct differentiation
m Intracytoplasmic hemosiderin pigment appears All acinic cell carcinomas reported to be
finely granular. DOG-1 positive
m Most often seen in association with the papillary- Demonstrates complex mixture of intense (3+)
cystic growth pattern apical membranous, cytoplasmic, and com-
m Not uniquely seen in acinic cell carcinoma plete membranous staining:
Diagnosis can be rendered even in the absence of Strong staining used to support diagnosis of
invasive growth based on architecture, cytomorphol- acinic cell carcinoma

ogy, and immunohistochemical staining (see below) Other tumor types that may express DOG-1
as there is no known benign counterpart to acinic include adenoid cystic carcinoma and epithelial-
cell carcinoma. myoepithelial carcinoma, showing distinctive
Marked reactive and degenerative may be seen combined apical ductal and membranous/
occurring spontaneously or secondary to prior trau- cytoplasmic myoepithelial staining profile
matic event such as a fine-needle aspiration biopsy but lack intensity associated with acinic cell
that may include: carcinoma
m Infarction m Pancytokeratins, low-molecular-weight cytokera-
m Cystic degeneration tins (AE1/AE3, CAM5.2, CK7, CK8, CK19),

m Hemorrhage including recent and remote with EMA and CEA positive
hemosiderin deposition in lesional cells, fibrocon- m Amylase positive:
nective tissue, and histiocytes Of limited diagnostic utility as only a minority

m Mixed chronic inflammatory cell infiltrate of cases (15%) express amylase
m Cholesterol granuloma formation m Sox10 positive
m Lipogranulomatous reaction m Variable immunoreactivity seen with S100 protein
Rarely, amyloid deposition may be present and vimentin:

Histochemistry: S100 protein may be positive but typically
m Acinar cells and intercalated duct cells: focal or limited in extent.
Diastase-resistant, PAS-positive cytoplasmic m Mammaglobin typically absent but may be focally
granules positive
Mucicarmine and alcian blue typically negative m p63, calponin, actins negative
but may be weakly positive: m GATA-3 (nuclear) staining may be present but
Presence of some intracytoplasmic mucicar- when present is focal rather than diffuse:
minophilic material can be seen and does not Diffuse GATA-3 staining in salivary gland
exclude the diagnosis. neoplasm typically limited to salivary duct
m Vacuolated cells: carcinoma and mammary analogue secretory
PAS negative carcinoma
Mucicarmine and alcian blue negative m Low labeling indices as seen by Ki67 staining
m Clear cells: m Absence of thyroglobulin and TTF1
PAS negative Electron microscopy:

Mucicarmine and alcian blue negative m Ultrastructural findings are characterized by the
m Nonspecific glandular cells: presence of numerous round, electron-dense cyto-

PAS negative plasmic secretory granules.
Mucicarmine and alcian blue negative m Rough endoplasmic reticulum and mitochondria
m Microcystic pattern: are present; junctional complexes and microvilli

Eosinophilic to basophilic material may stain may be identified.
for PAS and mucicarmine. m Basal lamina separates tumor cells from stroma.
Cytogenetics and molecular biology: m Mucoepidermoid carcinoma

m Absence of ETV6 translocation m Epithelial-myoepithelial carcinoma
m No specific findings: m Clear cell adenocarcinoma
Alterations of chromosome 4p, 5q, 6p, m Metastatic renal cell carcinoma
and 17p Acinic cell adenocarcinomas with follicular pattern

Loss of heterozygosity (LOH) in at least one of may simulate thyroid follicular epithelial
the 20 loci on chromosomes 1, 4, 5, 6, and 17 neoplasms.
High-Grade Transformation Treatment and Prognosis

(Dedifferentiated) of Acinic Cell Carcinoma Complete surgical excision is preferred treatment
Composed of histomorphologically conventional and may consist of either conservative parotidec-
acinic cell carcinoma with associated high-grade tomy when the tumor is limited to the superficial
carcinoma lobe or total parotidectomy when the deep lobe of
May occur rarely at initial presentation or in a long- the parotid is involved.
standing or recurrent tumor Radiation therapy is generally not used as a primary
Clinical presentation may include rapidly enlarging mode of treatment but may be used for:
lesion, pain, cranial neuropathy (e.g., facial nerve m Tumors that cannot be completely resected
palsy) m Metastatic disease
High-grade carcinoma may include undifferentiated/ Generally are indolent neoplasms cured by complete
poorly differentiated carcinoma or poorly differenti- surgical removal, however:
ated adenocarcinoma characterized by presence of m Approximately 35% recurrence rate
sheets of epithelial cells sometimes with cribriform m Approximately 16% metastatic rate:
growth lacking evidence of cellular differentiation Depending on primary site of occurrence

with marked nuclear pleomorphism, increased regional lymph node metastasis may include
nuclear-to-cytoplasmic ratio, increased mitotic the pre-auricular lymph nodes (parotid tumor),
figures including atypical mitoses, necrosis, and high submandibular and upper jugular chain lymph
proliferation indices. nodes (submandibular tumor), submental
Immunohistochemical staining of high-grade com- lymph nodes (lip tumor), base of skull (palate
ponent may be characterized by strong membrane tumor), submandibular, post-auricular and
staining for CK18 and beta-catenin, and nuclear level II accessory lymph nodes (intraoral
staining for cyclin-D1. tumors)
Associated with poor prognosis Distant visceral spread includes lungs, liver,
bone, and brain
Differential Diagnosis m Approximately 16% disease-associated death
Normal salivary gland parenchyma: rate
m Retention of normal lobular architecture of the Most recurrences and metastases occur within 5
salivary gland parenchyma as well as the presence years of initial therapy; however, recurrent tumor
of other salivary gland cellular components (e.g., and metastatic disease may occur years/decades after
striated ducts, interlobular ducts) assist in dif- initial treatment.
ferentiating normal gland from acinic cell Survival statistics include:
adenocarcinoma. m 5-year 91%
Mammary analogue secretory carcinoma (MASC): m 10-year 83%
m Share overlapping histomorphologic features m 20-year 67%
with acinic cell carcinoma but in contrast to Adverse prognostic factors may include:
acinic cell carcinomas, MASCs: m Multiple recurrences and metastasis (regional
Lack cells with basophilic cytoplasm and lymph nodes, distant visceral)
zymogen-like secretory granules m Short duration of symptoms
Show diffuse and strong mammaglobin and m Submandibular tumors more aggressive than
S100 protein parotid tumors
Have ETV6 translocation m Patients more than 30 years of age
Mucoepidermoid carcinoma m Neoplasms larger than 3cm
Cystadenocarcinoma Clinical staging is better predictor of prognosis than

Salivary and nonsalivary gland neoplasms contain- histology with poorer outcome associated with:
ing clear cells, including: m Large size and infiltrative growth
m Oncocytoma m Involvement of the deep lobe of parotid
m Myoepithelioma m Incomplete resection

Favorable prognostic factors may include: m Intact clusters with sheet-like or papillary
m Occurrence in minor salivary glands structures
m Longer duration of symptoms m Dispersed and dissociated cells
m Patients under 30 years of age Cytomorphology consists of bland tumor cells with
m Presence of dense lymphoid stroma with well- small to medium-sized round to oval nuclei, with
developed germinal centers a smooth contour and indistinct or small nucleoli,
Histologic high-grade transformation associated and vacuolated cytoplasm lacking intracytoplasmic
with poor prognosis: zymogen granules
m Increase in locoregional (lymph node) and distant Many histiocytes, some of which contained hemo-
visceral metastases: siderin pigments, and variously shaped mucinous
High propensity for nodal metastases indicates material may be evident in background or within the
need for neck dissection at the time of epithelial clusters.
diagnosis. Absence of matrix tissue or stromal spindled
m Increase in mortality rates due to tumor cells
dissemination
m Median overall survival of 4.3 years reported Histology
with range of 1 to 9 years Circumscribed but unencapsulated lesion often with
Histologic features that may be associated with lobulated appearance divided by fibrous septa
adverse prognosis include: Growth patterns may include microcystic, (macro)
m High proliferation indices (more than 5%) cystic, tubular, papillary, solid, and follicular
m Neurotropism (thyroid-like):
m Anaplasia m Multiple growth patterns may be seen in a single
m Necrosis case.
m Depletion of lymphocytes in stroma Invasion often present, including infiltration of non-
neoplastic salivary gland parenchyma and fibrocon-
nective tissue:
m Perineural and lymph-vascular invasion may be
MAMMARY ANALOGUE present.
SECRETORY CARCINOMA m Extraparenchymal extension may be identified.
(MASC) (Figs. 20-62 through 20-66) Lesional cells are cuboidal to polygonal with
round to oval nuclei with vesicular to finely granular
Definition: Distinctive recently described low-grade sali- chromatin, small distinct centrally located nucleoli
vary gland neoplasm with features resembling acinic cell surrounded by pale pink granular or vacuolated-
carcinoma and (low-grade) cystadenocarcinoma dis- appearing cytoplasm:
playing strong similarities to secretory carcinoma of m Serous acinar differentiation in form of
breast including t(12;15)(p13;q25) translocation result- intracytoplasmic basophilic granules not a
ing in ETV6-NTRK3 gene fusion. feature
Synonym: Zymogen-poor acinic cell carcinoma: in all Intraluminal secretions including bluish to eosino-
likelihood all/most previous designations as zymogen- philic material variably present within microcystic
poor acinic cell carcinomas are in reality MASCs. and tubular spaces
Absence of significant nuclear pleomorphism,
Clinical increased mitotic activity, or necrosis
Slightly more common in males than females; occurs Reactive and degenerative changes similar to those
over a wide age range of 21 to 75 years, with a mean seen in acinic cell carcinoma may be present,
age of 46 years including:
Most common in parotid gland but may occur in m Infarction and necrosis
other major glands as well as in minor salivary m Hemorrhage, recent and remote (i.e., hemosid-
glands erin deposition):

Most common presentation is as a painless mass Intracytoplasmic hemosiderin deposition can
Etiology: be seen within tumor cells
m No known causes m Cholesterol granuloma formation
m Calcifications
Pathology Histochemistry:
Fine-needle aspiration biopsy: m Intraluminal secretory material positive for muci-
Variably cellular smears carmine, PAS with and without diastase, and
Architectural patterns may include: alcian blue
A B
C D
Fig. 20-62. Mammary analogue secretory carcinoma.

A, Circumscribed but unencapsulated lesion with lobulated appearance divided by fibrous septa composed of solid tumor
nests. Additional growth patterns that may be seen from case to case and even within the same case include (B) tubular
(secretory); (C) microcystic and solid; (D) papillary and cystic; (E) follicular (thyroid-like). Intraluminal eosinophilic appearing
secretions are variably present within microcystic and tubular spaces.
A B
C D
Fig. 20-63. Macrocystic mammary analogue secretory carcinoma.

A-D, Uncommonly, the tumor may have predominant or exclusive macrocystic growth. Limited but identifiable
characteristic cellular foci are seen (arrowhead in A and seen at higher magnification in B). Note the single layer of lesional
cells lining the cyst are histologically similar to those in the cellular foci.
Immunohistochemistry: In conjunction with diffuse and strong mam-

m Mammaglobin maglobin staining as well as appropriate histo-
Diffuse and strong reactivity ranging from logic findings, can be used to diagnose MASC
50% to 100% of cells (mean 91%) even without cytogenetic testing (see below)
Present in cytoplasm and intraluminal secre- m GATA binding protein 3 (GATA-3):
tory material A member of GATA family of zinc finger

Mammaglobin highly sensitive for MASC but transcription factors that regulate normal
may be present in variety of tumors that do not development of various tissue and cell types
harbor the ETV6 translocation including breast, T-lymphocytes, kidney, nerve,
Absent or limited (focal) reactivity in acinic cell and skin
carcinoma Initially, immunohistochemical nuclear stain-
Should not be indiscriminately used as a con- ing for GATA-3 believed to be restricted mostly
firmatory test for MASC to neoplasms of breast and urothelial origin
m S100 protein Evidence now shows GATA-3 staining in sali-
Diffuse and strong reactivity vary gland neoplasms but consistent strong and
Seen in a wide variety of salivary gland lesions/ diffuse (nuclear) staining (i.e., >50% of cells)
neoplasms limited to MASC and salivary duct carcinoma
A B
C D

A through D, Lesional cells are cuboidal to polygonal with round to oval nuclei, vesicular to finely granular chromatin, small
distinct to larger nucleoli surrounded by pale pink granular or vacuolated-appearing cytoplasm. Focally intracytoplasmic
hemosiderin deposition may be seen within lesional cells (D, arrowheads). The overall features are reminiscent of those
seen in acinic cell carcinoma, except there is an absence of serous acinar differentiation in the form of intracytoplasmic
basophilic granules. Nevertheless, immunohistochemical staining and/or molecular analysis may be required to
differentiate mammary analogue secretory carcinoma from acinic cell carcinoma.
among GATA-3 positive salivary gland histologically would not be confused with
neoplasms: MASC, including oncocytoma and Warthin
Other GATA-3+ salivary gland tumors tumor
include: m Cytokeratins:
Acinic cell carcinoma, adenoid cystic car- Diffuse and strong staining for AE1/AE3,
cinoma, epithelial-myoepithelial carci- CAM5.2, CK7, CK8, CK18, CK19
noma, mucoepidermoid carcinoma, m Other markers:
oncocytic carcinoma, oncocytoma, pleo- Diffuse and strong vimentin, EMA and STAT5a
morphic adenoma, Warthin tumor (signal transducer and activator of transcrip-
Staining in these other neoplasms tends to tion 5a) staining
be less than diffuse and/or strong. Significant reactivity for gross cystic disease
Some of these other neoplasms may include fluid protein 15 (GCDFP-15) especially intra-
diffuse and/or strong reactivity but luminal secretory material
A B

Intraluminal secretory material is positive for (A) mucicarmine and (B) periodic acid Schiff with diastase.
A B

Immunohistochemical staining includes diffuse reactivity for (A) mammaglobin, (B) S100 protein, and (C) GATA3 (nuclear).
Basal cell/myoepithelial cell markers:

m m Cells of both components showed focal staining
p63, calponin, CK14, smooth muscle actin, with EMA, GCDFP-15, and STAT5a
and CK5/6 are essentially negative m Staining with calponin, CK14, CK5/6, CK20,
Isolated nuclear p63 positive may be p63 protein, androgen receptor, and HER-2/neu
identified. negative in both components
m Discovered on GIST1 (DOG-1): Analysis for presence of the ETV6-NTRK3 fusion
Typically negative transcript revealed positivity in both high-grade and
Cytogenetics and molecular genetics: conventional or low-grade component of MASC
m t(12;15)(p13;q25) chromosomal translocation in two of three cases reported:
resulting in ETV6-NRTK3 gene fusion m One case was negative in both its elements for the
To date, restricted to MASCs t(12;15) translocation, but ETV6 gene rearrange-

May be identified by FISH or RT-PCR ment was detected in both components in all
three cases.
High-Grade Transformation Analysis of TP53 and CTNNB1 gene mutations in
(Dedifferentiated) of MASC the HG component of MASCs as well as detection
Rare and recently reported occurrence in three cases of copy number aberration of EGFR and CCND1
located in parotid gland gene did not harbor any abnormalities.
Characterized by accelerated clinical course in a All three patients died of disseminated disease within
long-standing lesion (23 years), relatively recent 2 to 6 years after diagnosis:
identified lesion (2 years), or recurrent neoplasm m Locoregional (nodal) metastasis, with or without
Histologically, composed of two distinct sharply extranodal extension

delineated carcinomatous components including: m Distant metastasis
m Conventional MASC (see previous)
m High-grade transformation characterized by ana- Differential Diagnosis

plastic cells arranged in trabecular pattern with Acinic cell carcinoma:
marked nuclear pleomorphism and absence of m Presence of cells with basophilic granular
intraluminal secretory material cytoplasm
Perineural invasion, necrosis (comedotype), m Presence of DOG1 immunoreactivity
and desmoplastic stroma consistently m Absence of diffuse and strong mammaglobin,
identified S100 protein, and GATA-3 staining

Extraglandular invasion including into skin m Absence of ETV6-NRTK3 gene fusion
consistently identified Low-grade cribriform cystadenocarcinoma

Immunohistochemical staining included: Mucoepidermoid carcinoma, low grade
m Ki67 (MIB1)
For low-grade component median proliferation Treatment and Prognosis

index was 23% (range 15 to 35) Complete surgical resection is preferred treatment.
For high-grade component, significant increase Efficacy of radiotherapy (preoperative or postopera-
in proliferative activity with Ki67 index tive) uncertain
between 45% and 70% (median 53%) In a limited number of studies with long-term
m Strong membranous staining for EGFR particu- follow-up to date, overall indolent clinical course
larly in high-grade component reported:
m Median cyclin-D1 index higher in high-grade m Mean disease-free survival of 92 months
component (50%; range 40% to 60%) as com- m Majority of cases reported without evidence of
pared with low-grade component (8.3%; range disease from 27 months to 10 years
5% to 15%) m Minority of cases with recurrent and/or meta-
m p53 protein absent in low-grade component in static disease

two of three cases, but increased p53 immunore-
activity in high-grade component in all three
cases ADENOCARCINOMA, NOT
m High-grade component revealed strong mem- OTHERWISE SPECIFIED (NOS)
brane staining for EGFR and -catenin, (Figs. 20-67 through 20-71)
cytoplasmic/nuclear staining for S100 protein
m Cytokeratins (AE1/AE3, CK7, CK8, CK18, Definition: Malignant epithelial salivary gland neoplasm
CK19), vimentin, S100 protein and mammaglo- with glandular or ductal differentiation but without
bin stained both components with equally strong other specific histologic features allowing for a more
and diffuse intensity definitive classification.
A
A
B
B
Fig. 20-68. Parotid gland adenocarcinoma,
Fig. 20-67. Adenocarcinoma, NOS. low-grade, NOS.
Parotid gland adenocarcinoma, NOS, high-grade, fine- A, At low magnification the tumor is infiltrative with solid
needle aspiration biopsy. Cell clusters showing high-grade and cribriform growth. B, At higher magnification there is
cytologic features and formation of gland- or duct-like back-to-back glandular (cribriform) growth composed of a
structures. uniform single cell type characterized by cuboidal to round
vesicular nuclei, minimal nuclear pleomorphism, and
absence of increased mitotic activity. There are no
features diagnostic for a more specific salivary gland
tumor, hence the designation not otherwise specified
(NOS).
Clinical
Shrinking category of salivary gland neoplasms given
identification of more specific tumor types but still Symptoms relate to site of occurrence:
considered among more common malignant salivary m In major glands symptoms vary and may include:
gland neoplasms Solitary, asymptomatic mass

More common in women than in men; occurs over Pain, cranial nerve paralysis occurs in minority
a wide age range but is most frequently seen in the of patients (approximately 20%)
fifth to eighth decades of life; rarely occurs in chil- Pain more common in submandibular gland
dren and adolescents tumors

Occurs in major and minor salivary glands: Cutaneous involvement (fixation) may occur.
m In major glands, most common site of occurrence m In minor glands:
is parotid gland, representing single most common Asymptomatic submucosal mass with ulcer-
site of occurrence; may also occur in subman- ation and/or osseous involvement in a minority
dibular and rarely in the sublingual glands of cases
m Among minor salivary gland sites, most com- m Duration of symptoms varies from months to
monly occur in intraoral sites particularly palate years.

followed by buccal mucosa, tongue, and lips Etiology:
(upper greater than lower) m No known causes
B Fig. 20-70. Parotid gland adenocarcinoma,

high-grade, NOS.
Large parotid mass that was clinically painful involving the
Fig. 20-69. Parotid gland adenocarcinoma,
facial nerve causing facial nerve paralysis and facial
intermediate-grade, NOS.
distortion/asymmetry.
A, Parotid tumor with invasion into the adjacent salivary
gland parenchyma (right) showing trabecular and glandular
growth. B, At higher magnification the glands are absence of epidermoid differentiation or other
composed of cells with greater nuclear pleomorphism and differentiation that may be indicative of another
more solid growth as compared with low-grade tumors but tumor type:
lacking the marked nuclear pleomorphism, increased m Polymorphous growth patterns, including glan-
mitotic activity, atypical mitoses, and necrosis seen in
dular or ductular structures, as well as solid,
higher-grade tumors.
sheetlike, tubular, cribriform, lobular, cell nests,
islands, and cord-like growth:
Multiple growth patterns seen from case to
Pathology case and even within same case
Gross m Cystic and papillary growth may be focally
Varies from delineated and/or circumscribed to present but is limited in extent as more
poorly demarcated and infiltrative extensive cystic and papillary growth likely
Firm to hard, tan-white mass measuring from 2 to would be indicative of another tumor (e.g.,
10cm in diameter cystadenocarcinoma).
Hemorrhage, necrosis, and cystic change may be m In higher grade neoplasms, glandular features
seen. may require diligent searching or may be repre-

sented by primitive attempts at gland or duct
Histology formation.
Display histologic heterogeneity but common to all Cytomorphologic diversification also seen ranging
growth patterns and cytologic appearances is the from cells having uniform appearance and distinct
presence of an infiltrative neoplasm showing evi- cell borders to cells with marked nuclear pleomor-
dence of glandular or ductular features and an phism and indistinct cell borders.
A B
C D
Fig. 20-71. Parotid gland adenocarcinoma, high-grade, NOS.

A, Parotid tumor that is unencapsulated and infiltrative into parotid gland parenchyma; there was also extensive
extraglandular invasion with infiltrative growth into subcutaneous tissue and dermis (not shown); (B) complex glandular
growth; (C) at higher magnification residual gland formation is present (arrowheads) with neoplastic cells characterized by
enlarged and pleomorphic nuclei, prominent nucleoli, mitotic figures, and necrosis; (D) peri- and intraneural invasion.
Cell types that can be seen include: nucleoli, abundant cytoplasm, distinct cell
m Cells with clear cytoplasm borders, and little nuclear pleomorphism with
m Cells with oncocytic cytoplasm few mitotic figures
m Plasmacytoid-appearing cells m Intermediate grade:
m Sebaceous cells Glands or duct-like structures are readily seen.

m Absence of mucocytes and epidermoid cells In comparison to low-grade tumors there are
Histologic grading into low, intermediate, and high greater cellular pleomorphism and more
is based on degree of gland formation (differentia- mitoses but usually atypical mitoses are not
tion), cellular pleomorphism, and mitotic activity: identified.
m Low grade: m High grade:
Well circumscribed but at least focally Generally grow in solid sheets

invasive Cells marked by anaplastic cytologic features,
Numerous gland or duct-like structures including enlarged, hyperchromatic and pleo-
Relatively uniform cytomorphologic features morphic nuclei, small to prominent nucleoli,
composed of a single cell type characterized by numerous mitoses, including atypical forms,
cuboidal to round tumor cells with small necrosis, and hemorrhage
Presence of glandular differentiation may m Metastatic tumor more common in histologically

require extensive searching or the use of special higher-grade tumor and in patients previously
stains (e.g., mucicarmine). treated
Stroma may be collagenized and occasionally may Most accurate factor in predicting survival is clinical
appear myxoid or mucinous. stage:
Extensive infiltrative growth generally seen in m 15-year survival rates include:
higher grade lesions and may include neurotropism, 54% for stage I
lymph-vascular invasion, invasion into fibroconnec- 31% for stage II
tive tissue, and extraparenchymal invasion into soft 3% for stage III
tissues Histologically higher grade tumors tend to be
Some tumors may contain areas with focal features clinically stage III tumors.
of other tumor types (e.g., adenoid cystic carcinoma, Histologically lower grade tumors tend to be
acinic cell adenocarcinoma, epithelial-myoepithelial clinically stage I tumors.

tumor); however, these foci are very limited and do m Other factors correlating with prognosis include:
not justify exclusion from classification as adenocar- Histologic grade:

cinoma, NOS. Lower histologic grade lower rate of local
Histochemistry: recurrence(s) or metastatic (regional or

m Intraluminal mucicarmine and diastase-resistant, distant) disease and the longer disease-free
PAS-positive material survival
m Intracytoplasmic mucin generally not identified Higher histologic grade the higher the rate of
m Diastase-sensitive, PAS-positive intracytoplasmic local recurrence(s) or metastatic (regional or

material indicative of glycogen may be present. distant) disease and the shorter the disease-
Immunohistochemistry: free survival
m Epithelial markers positive including cytokeratins Site of involvement:
(e.g., AE1/AE3, CAM5.2, CK7), CEA, and EMA Intraoral tumors more favorable prognosis
m Myoepithelial-related markers generally negative than parotid gland and submandibular gland
including p63, calponin tumors
m May be positive for mammaglobin and A higher percentage of submandibular
GCDFP-15 gland adenocarcinomas are high-grade

neoplasms as compared with parotid-based
Differential Diagnosis neoplasms accounting for greater likeli-
Pleomorphic adenoma hood of submandibular adenocarcinomas
Monomorphic adenomas metastasizing to regional lymph nodes
Epithelial-myoepithelial carcinoma than lesions of parotid gland or intraoral
Adenoid cystic carcinoma minor salivary glands.
Polymorphous low-grade adenocarcinoma
Cystadenocarcinomas
High-grade mucoepidermoid carcinoma
Metastatic adenocarcinoma ADENOID CYSTIC CARCINOMA
(Figs. 20-72 through 20-81)
Complete surgical excision is preferred treatment: Definition: Malignant epithelial salivary gland neoplasm
m Extent of the surgery dependent on location and predominantly composed of modified myoepithelial or
clinical stage of disease (subtotal versus total basal (abluminal) cells with a minor component com-
glandectomy) posed of ductal (luminal) structures characterized by its
Neck dissection dependent on presence of overt neck histologic appearance, tendency to invade nerves, and
disease or clinical suspicion of nodal involvement protracted but nonetheless relentless clinical course.
Postoperative adjuvant radiotherapy used in Synonyms: Cylindroma (old term used for cribriform
advanced clinical stage neoplasms type)
Local recurrence not uncommon, especially in high-
grade neoplasms Clinical
Metastatic disease occurs in approximately 26% of Represent approximately 10% to 12% of all malig-
patients with cervical lymph nodes and lungs most nant salivary gland neoplasms
commonly affected sites: Slightly more common in women than in men; occurs
m Other metastatic sites may include bone, skin, over wide age range but most commonly occurs in
and abdominal sites. the fifth through seventh decades of life:
Fig. 20-72. Adenoid cystic carcinoma.

Adenoid cystic carcinoma may originate anywhere in the upper aerodigestive tract, including (A) parotid gland;
(B) submandibular gland; (C) hard palate; (D) soft palate; and (E) lip.
Fig. 20-74. Adenoid cystic carcinoma, fine-needle

B
aspiration biopsy.
The aspirate is characterized by the presence of spheres,
Fig. 20-73. Adenoid cystic carcinoma, resection globules, and elongated cylinders of acellular stroma
specimens. surrounded by uniform-appearing basaloid cells.
A, Submandibular gland replaced by a solid neoplasm
replacing most of the gland; the tumor in part appears
circumscribed but has infiltrative borders. B, Maxillary without associated pain or cranial nerve (e.g., facial
sinus neoplasm that invaded through the palate with nerve) paralysis:
involvement of the oral cavity. m Other symptoms include:
Airway obstruction, epistaxis, otalgia, and

Generally uncommonly encountered prior to the
m hoarseness
third decade of life Rarely, may present as a rapidly enlarging mass
In major salivary glands, primarily involves parotid Ulceration is often present in mucosal-based
and submandibular glands: tumors.
Nearly half arise in minor salivary glands: Fixation to surrounding tissues is often present.
m May involve minor salivary glands throughout Etiology:
upper respiratory tract but most commonly m No known cause
involves intraoral sites:

Palate most common intraoral site Pathology
Second only to parotid gland as most Gross
common site of occurrence Circumscribed, unencapsulated, partly encapsulated,
m Other minor salivary gland sites of involvement poorly circumscribed to infiltrative, solid, rubbery to
include: firm, tan-white to gray-pink mass measuring from 2
Tongue, sinonasal tract, ceruminal glands of to 4cm in greatest dimension
external auditory canal, and lacrimal gland:
More common tumor type of lacrimal glands Fine-Needle Aspiration Biopsy
Symptoms vary according to site involved but most Aspirates are characterized by presence of relatively
common complaint is a slow-growing mass with or uniform cells associated with (surrounded by or
A B

A, Infiltrating neoplasm with multiple (polymorphous) growth patterns including cribriform, solid, tubular/ductular and
trabecular. B, Classic cribriform growth is present (lower portion of the illustration) with prominent intracystic and
extracellular hyalinized eosinophilic (reduplicated basement membrane-like) material.

A, Cribriform pattern creating a Swiss cheese configuration includes pseudocysts lined by abluminal (modified
myoepithelial) cells containing basophilic mucinous material. B, Tubular growth pattern with intraluminal eosinophilic
to basophilic-appearing material. C, Cystic spaces filled with eosinophilic hyaline (basement membranelike) material.
D, Extracellular eosinophilic hyaline (basement membranelike) material resulting in trabecular and cord-like growth.
A A B
Fig. 20-78. Adenoid cystic carcinoma, solid variant.

A, Tumor cells arranged in solid nests and present in at
least 30% of a given tumor. B, The cellular component in
the solid variant tends to include larger more pleomorphic
nuclei with increased mitotic activity.

A and B, The abluminal (modified myoepithelial) cells
dominate in any given tumor but true luminal (epithelial)
cells can be seen forming glandular spaces (arrows in A;
arrowheads in B) but may be limited in extent and difficult
to identify.
A
clinging to) spheres, globules, and elongated cylin-
ders of acellular stroma:
m Diagnosis often can be made by FNAB.
m Matrix globules appear metachromatic by

Romanowsky staining, purple to pink by Giemsa
staining, and pale green or light orange by Papa-
nicolaou staining.
m Similar to pleomorphic adenoma, the diagnosis is
based on the presence of characteristic extracel-

lular matrix material.
m Matrix of pleomorphic adenomas tends to be
fibrillar and less well defined as compared to the

extracellular matrix material associated with B
adenoid cystic carcinoma. However, overlapping
features between the extracellular matrix mate-
rial of adenoid cystic carcinoma, pleomorphic Fig. 20-79. Adenoid cystic carcinoma.
adenoma, basal cell adenoma, acinic cell adeno- A, Characteristically perineural invasion (neurotropism) is
carcinoma, and other tumors may create difficul- identified. B, Less frequently invasion into soft tissues,
ties in the cytologic diagnosis. including skeletal muscle, may be identified.
A
Fig. 20-81. Adenoid cystic carcinoma vs PLGA.
The differentiation between adenoid cystic carcinoma and
polymorphous low-grade adenocarcinoma (PLGA) can be
extremely challenging. Although there is suggestion that
staining patterns of p63 and p40 may contrast between
these two lesions, thereby allowing for differentiation,
such findings are not consistently identified. Differentiation
may be predicated on the cytomorphologic findings.
Left, In adenoid cystic carcinoma the lesional cells are
composed of smaller isomorphic hyperchromatic nuclei
lacking significant pleomorphism and mitotic activity;
right, in PLGA the lesional cells are comprised of larger
isomorphic vesicular nuclei lacking significant
pleomorphism and mitotic activity.
Fig. 20-80. Adenoid cystic carcinoma. MYB immunohistochemical staining in FNAB speci-
Immunohistochemical staining is not typically required in mens potentially useful in diagnosis of adenoid cystic
diagnosing adenoid cystic carcinoma but among the carcinoma (positive nuclear staining) and in differ-
markers and staining patterns seen include (A) p63 ential diagnosis from pleomorphic adenoma (nega-
dedicated to the abluminal (myoepithelial) cells but not tive staining)
luminal lining cells; (B) CD117 dedicated to luminal lining m Reported sensitivity of MYB on FNAB of 80%
cells but not abluminal (myoepithelial) cells. NOTE: CD117 and specificity of 100% relative to pleomorphic
is not uniquely identified in adenoid cystic carcinoma but adenoma
can be seen in other salivary gland neoplasms, including
benign and malignant neoplasms. Histology
Typically unencapsulated and infiltrative with varied
Cells of adenoid cystic carcinoma are small with growth patterns (i.e., polymorphic) including cribri-
uniform, hyperchromatic nuclei, limited cytoplasm, form, tubular/ductular, and solid:
high nuclear-to-cytoplasmic ratio, and indistinct cell m Individual neoplasms may have single growth but
borders. characteristically are composed of multiple pat-

Cells may be arranged individually or in loose syn- terns of which any one may predominate.
cytial fragments. m Some cases may be encapsulated without invasive
In solid variant of adenoid cystic carcinoma: growth with diagnosis predicated on characteris-
m Cells may be larger with greater variability in the tic light microscopic features.
size and shape of the nuclei. m Common to all histologic patterns (see below) is
m Nucleoli may be identifiable. proclivity to peri- and, less often, intraneural

m There is often loss of cellular cohesion with over- invasion:
lapping of cells. Not pathognomonic for adenoid cystic
m Necrosis and mitoses may be seen. carcinoma
Seen in a variety of other salivary gland and

nonsalivary gland tumors Tubular Pattern
In adenoid cystic carcinoma tendency for infil- Often seen in association with cribriform pattern
tration along nerves beyond main tumor Cells are arranged in ducts or tubules.
m In addition to neurotropism, invasion into adja- Dual cell differentiation (i.e., ductal and myoepithe-
cent structures including salivary gland paren- lial cells) present with readily identifiable epithelial-
chyma, fibroconnective tissues (e.g., fat, skeletal lined true ducts surrounded by myoepithelial
muscle) and lymph-vascular or angioinvasion (abluminal) cells.
m Generally tend to be resistant to presence of squa- Ducts or tubules may be empty or contain faintly
mous differentiation: eosinophilic mucinous material.
Identification of squamous component (cells
with intercellular bridges, keratinization, squa- Solid Pattern
mous eddies) supports an alternative diagnosis Least common pattern
rather than adenoid cystic carcinoma Neoplastic cells arranged in sheets or nests of varying
Cellular components: size and shape
m Basaloid-appearing (abluminal) cells: Little tendency to form cystic spaces, tubules, or
Represent modified myoepithelial or basal ducts
cells Cytomorphology similar to cribriform and tubular
Dominant cell type patterns but findings in solid pattern may include:
Surround pseudocysts m Tendency for cells to be larger with larger nuclei
Composed of uniform angular to oval, m Greater nuclear pleomorphism
hyperchromatic nuclei with absent nucleoli m Increased mitotic activity (5 or more mitoses per
and scanty cytoplasm with indistinct cell 10 high-power fields)

borders: m Necrosis (confluent foci and individual cell)
Occasional cells with small nucleoli may be Histologic grading:

seen m Grade I:
Eosinophilic to clear-appearing cytoplasm Mostly tubular with some cribriform patterns

may be present Absence of solid pattern
Nuclear pleomorphism and mitotic activity are Absence of nuclear pleomorphism and increased
typically not present. mitotic activity
Low or 1:1 nuclear-to-cytoplasmic ratio. m Grade II:
m Ductal (luminal) structures: Pure cribriform pattern or mixed tubular/

True glandular spaces cribriform; solid patterns may be present but
Scattered among basaloid cells and may be dif- not >30%
ficult to identify Slightly greater degree of nuclear pleomor-
Characterized by presence of cells with round phism and mitotic activity than Grade I
nuclei and eosinophilic-appearing cytoplasm Grade III:
Interstitial stroma, from which the epithelial compo- >30% solid pattern
nent is sharply demarcated, varies in appearance More significant nuclear pleomorphism and
from myxoid to mucinous to hyalinized increased mitotic activity over Grade II:
Larger cells with larger nuclei
Cribriform Pattern 5 or more mitoses per 10 high-power fields
Most characteristic (classic) pattern Necrosis often present:

Arrangement of cells in Swiss cheese or sieve-like Confluent foci and individual cell
configuration with many oval or circular microcystic Histochemistry:

(pseudocystic) spaces m Pseudocysts contain diastase-resistant, PAS-
Microcysts are pseudocysts (not true epithelial lined positive, and mucicarmine-positive material.
glandular lumens) contiguous with stromal connec- Immunohistochemistry:
tive tissue and contain basophilic mucinous sub- m Myoepithelial or basal (abluminal) cells:
stance and/or hyalinized eosinophilic material: Cytokeratins, p63, p40, S100 protein, cal-
m Cystic spaces are pseudocysts, which are ponin, smooth muscle actin, smooth muscle
extracellular and lined by replicated basement myosin heavy chain, and vimentin positive
membrane. Cytokeratin tends to be less intensely reac-
m Basophilic mucinous substance is alcian blue tive as compared to ductal cells

positive. Glial fibrillary acidic protein may be focally
m Hyalinized eosinophilic material is PAS positive. positive.
m Ductal (luminal) cells: GATA-3 staining may be present but not dif-
Cytokeratins (pancytokeratin, CK7, CK14, fusely as seen in salivary duct carcinoma and
CK17, CK19), S100 protein, epithelial mem- mammary analogue secretory carcinoma.
brane antigen (EMA) and carcinoembryonic Sox10 variably positive in abluminal and
antigen (CEA) and c-kit (CD117) positive: luminal cells
Cytokeratin tends to be more intensely No immunoreactivity for neuroendocrine
reactive as compared to myoepithelial or markers (e.g., synaptophysin, chromogranin),
basal cells. GDCP15, and PLAG1
m IHC findings including pairing p63 and p40 Ultrastructure:
reported to assist in differentiating pleomorphic m Ductal (luminal) cells:
adenoma (PA) from polymorphous low-grade Microvilli, desmosomes, tonofilaments, and

adenocarcinoma (PLGA) and adenoid cystic car- rough endoplasmic reticulum
cinoma (AdCC) include: m Myoepithelial (abluminal) cells:
PA: p63+/p40+ Variable findings including cytoplasmic pro-

Cellular PA: concordant p63+/p40+ or p63/p40 cesses, cytoplasmic filaments, dense bodies,
PLGA: consistent p63+/p40 desmosomes, tonofilaments
AdCC: p63+/p40+ Pseudocysts contain reduplicated basal
CAUTIONARY NOTE: While p63/p40 IHC lamina.
panel can be a valuable tool for making distinc- Basal lamina surround epithelial islands.
tion between PA, PLGA, and AdCC it is not Cytogenetic and molecular genetics:
infallible and any given example may demon- m Specific chromosomal translocation t(6;9)(q22-
strate divergence from the reported p63/p40 23;p23-24) involving the v-myb avian myeloblas-
immunophenotype. tosis viral oncogene homolog (MYB) and
m Additional immunohistochemical findings may nuclear factor I/B (NFIB) genes results in MYB-
include: NFIB gene fusion identified in adenoid cystic
Expression of MYB protein (see below under carcinomas:
Cytogenetics): Identified in adenoid cystic carcinomas irre-
Identified in translocation-positive and spective of site of occurrence, including
translocation-negative adenoid cystic salivary glands, sinonasal tract, larynx, tra-
carcinomas cheobronchial tree, lacrimal gland, as well as
More than 80% of adenoid cystic carcino- nonhead and neck sites (e.g., breast, vulva)
mas reported to stain positive for MYB Gene fusion found in 30% to 50% of cases
protein with increase to 86% when performed on
14% of nonadenoid cystic carcinoma neo- frozen specimen
plasms also reported to express MYB MYB-NFIB gene fusion in dermal cylin
protein dromas strengthening evidence for common
MYB immunostaining may be useful for molecular pathways for development of benign
diagnosis of adenoid cystic carcinoma, but and malignant salivary, adnexal, and breast
neoplasms in differential diagnosis may tumors
also express MYB protein. Not detected in other salivary gland
Ki67 (MIB1) staining: neoplasms:
Proliferative indices reported to be signifi- 1 purported case of polymorphous low-
cantly higher in adenoid cystic carcinoma grade adenocarcinoma reported to express

(21%) as compared with polymorphous low- adenoid cystic carcinomaassociated MYB-
grade adenocarcinoma (2%) NFIB by RT-PCR analysis
Increased proliferation index may not be Molecular consequences of this alteration
present in all cases of adenoid cystic carci- incompletely understood but suggest impor
noma and by itself does not unequivocally tant role in development of adenoid cystic
differentiate it from polymorphous low- carcinoma
grade adenocarcinoma. m Dysregulated microRNAs (miRNA) found in
Reactivity for mammaglobin may be present, adenoid cystic carcinomas:

including cases with positive staining and cases No significant differences in miRNA expres-
with negative staining. sion between MYB-NFIB fusion-positive and
May be DOG-1 positive, showing distinctive fusion-negative cases
combined apical ductal and membranous/ Of highly dysregulated miRNA in adenoid
cytoplasmic myoepithelial staining profile cystic carcinoma, overexpression of miR-17
and miR-20a was significantly associated with

poor outcome. High-Grade Transformation
Upregulation of miR-17-92 may play a role in (Dedifferentiation) in Adenoid
biology of ACC and could potentially be tar- Cystic Carcinoma
geted in future therapeutic studies. Unusual occurrence of a histologically low-grade
m Additional mutations identified in adenoid cystic adenoid cystic carcinoma transforming to a high-
carcinoma include: grade carcinoma and/or progression from solid
PIK3CA, ATM, CDKN2A, SF3B1, SUFU, adenoid cystic carcinoma to a high-grade carcinoma:
TSC1, and CYLD m Male predominance
Mutations in SPEN (split ends, homolog of m Age range of fourth to eighth decades with
Drosophila), which encodes an RNA-binding median age in seventh decade (61 years)
coregulatory protein, suggest that other changes m Occurs most often in association with sinonasal
in transcriptional regulation may involve and submandibular adenoid cystic carcinomas

NOTCH, FGFR, or other signaling pathways m Most common morphologies for high-grade com-
in which SPEN participates. ponent include poorly differentiated cribriform

Mutations in genes encoding chromatin-state adenocarcinoma and solid undifferentiated
regulators, such as SMARCA2, CREBBP, carcinoma
and KDM6A, reported suggesting aberrant epi- m Micropapillary and squamoid patterns occasion-
genetic regulation in adenoid cystic carcinoma ally identified

oncogenesis. m Histologically high-grade transformation distin-
Mutations in genes central to DNA damage guished from conventional adenoid cystic carci-
response and protein kinase A signaling also noma by presence of:
implicated Nuclear pleomorphism with enlargement and
Recurrent mutations in FGF-IGF-PI3K pathway irregularity
(30% of tumors) Higher mitotic counts
Might represent new avenues for therapy Loss of the biphasic ductal-myoepithelial
differentiation
Hybrid Tumors Prominent comedonecrosis
Rare occurrence of neoplasm composed of two or Fibrocellular desmoplasia
more histologic distinct types, each of which con- Ki-67 and p53 labeling indices elevated in high-
forms with an exactly defined tumor category having grade components
an identical origin within same topographic area Loss or diminished p63 and calponin staining
m In contrast, biphasically differentiated tumors in high-grade components
are a mixture of two cellular patterns correspond- m Behavior follows that of less differentiated com-
ing to a specific classification (e.g., epithelial- ponent and often characterized by:
myoepithelial carcinoma, adenoid cystic Aggressive growth
carcinoma, adenosquamous carcinoma, others) Nodal metastases
Most common tumor types include: Distant metastases
m Adenoid cystic carcinoma Poor prognosis with increased mortality:
m Salivary duct carcinoma Death often occurring within 5 years of
m Epithelial-myoepithelial carcinoma diagnosis with median overall survival of

Other tumor types that may be seen in hybrid tumors 12 months
include:
m Basal cell adenoma
m Warthin tumor Differential Diagnosis (Table 20-8)

m Canalicular adenoma Pleomorphic adenoma
m Acinic cell carcinoma Basal cell adenoma:
m Basal cell adenocarcinoma m May show cribriform growth
m Myoepithelial carcinoma m Absence of infiltrative growth:
Combinations may include multiple malignant tumor Occasional cases of adenoid cystic carcinoma
types, multiple benign tumor types, and admixture may not be invasive.
of benign and malignant tumor types. m Cell types, including cells with larger more vesic-
May occur in initial clinical presentation or in recur- ular nuclei with identifiable nucleoli combined
rent tumor with basaloid hyperchromatic nuclei and squa-
Prognosis predicated on highest histologic grade mous differentiation, should allow distinction
malignancy (e.g., salivary duct carcinoma) from adenoid cystic carcinoma.
TABLE 20-8 Adenoid Cystic Carcinoma: Differential Diagnosis

Squamous
Tumor Growth Characteristics Histology Differentiation Neurotropism Cytogenetics
AdCC, Invasive, polymorphous Predominantly Absent Yes, as well as MYB-NFIB
cribriform/ including Swiss composed of uniform invasive into
tubular cheese, microcysts, basaloid cells other structures
tubules, and ductules; surrounding
reduplicated basement pseudocysts with
membrane material angular to oval,
present hyperchromatic nuclei
(myoepithelial cells)
with admixed epithelial
cells lining glandular
spaces with round
nuclei and eosinophil-
appearing cytoplasm
(ductal cells); nuclear
palisading typically
absent
AdCC, Invasive; sheets and Similar to cribriform Absent Yes, as well as MYB-NFIB
solid nests of varying size tubular but cells are invasive into
and shape with little larger with larger other structures
tendency to form cystic nuclei, greater nuclear
spaces, tubules or pleomorphism,
ducts; reduplicated increased mitotic
basement membrane activity (5 or more
material uncommon mitoses per 10
high-power fields) and
necrosis (confluent foci
and individual cell);
nuclear palisading
typically absent
PLGA Invasive, polymorphous Isomorphic single-cell May be present Yes, as well as None known,
with cribriform, tubular, type with vesicular typically as invasive into although PRKD2
solid, single cell, nuclei, minimal metaplastic foci other structures rearrangement
papillary, microcystic; pleomorphism and following FNAB or reported in a
reduplicated basement absent mitotic activity; biopsy single case
membrane material nuclear palisading
present typically absent
CPA Encapsulated, may be Irrespective of cell May be present No PLAG1
polymorphous; type (ductal or typically as HMGA2
reduplicated basement myoepithelial) or metaplastic foci
membrane material degree of cellularity following FNAB or
present there usually is an biopsy
absence of significant
pleomorphism, mitotic
activity, and no
necrosis; nuclear
palisading typically
absent
BCA Encapsulated, Combination of Present but usually No None known
reduplicated basement basaloid cells, cells limited in extent
membrane material with larger more including squamous
present vesicular nuclei; eddies
peripheral nuclear
palisading may be
present
BCACA Invasive reduplicated Basaloid cells with Present but usually Yes, as well as None known
basement membrane variable nuclear limited in extent invasive into
material present pleomorphism and including squamous other structures
increased mitotic eddies
activity; peripheral
nuclear may be present
TABLE 20-8 Adenoid Cystic Carcinoma: Differential Diagnosiscontd

Squamous
Tumor Growth Characteristics Histology Differentiation Neurotropism Cytogenetics
BSCC Invasive, lobular, solid, Predominantly basaloid Present but usually Yes, as well as None known
nested, trabecular, cells with marked limited in extent and invasive into
organoid, cribriform; pleomorphism, high may include other structures
reduplicated basement mitotic rate and intraepithelial
membrane material necrosis; nuclear dysplasia and/or
may be present palisading typically abrupt keratinization
absent and/or differentiated
invasive squamous
with keratinization and
intercellular bridges
EMC Invasive, tubular/ Biphasic cell pattern Absent to rare Yes, as well as Limited cases
ductular; typically lacks including inner invasive into have HRAS
reduplicated basement epithelial cells and other structures exon 3 codon
membrane material outer myoepithelial 61 mutation
present cells
ACC, Adenoid cystic carcinoma; BCA, basal cell adenoma; BCACA, basal cell adenocarcinoma; BSCC, basaloid squamous cell carcinoma;
CPA, cellular pleomorphic adenoma; EMC, epithelial-myoepithelial carcinoma; PLGA, polymorphous low-grade adenocarcinoma.
Presence of squamous differentiation repre- Recurrence rates range from 16% to 85% and high
sents feature not typically associated with recurrence rates directly relate to inadequate surgical
adenoid cystic carcinoma excision.
m Absence of MYB-NFIB gene fusion Regional lymph node metastases are uncommon,
Polymorphous low-grade adenocarcinoma ranging from 5% to 25%:
m Overlapping features with adenoid cystic m Neck dissection at time of surgical removal of
carcinoma primary tumor is generally not warranted.

m Purported differential staining of p63 and p40 Usually occur in association with tumors of
than that seen in adenoid cystic carcinoma: submandibular gland origin
Consistent p63+/p40 as compared with Distant metastasis ranges from 25% to 55%:
adenoid cystic carcinoma showing consistent m Generally occur late in disease course following
p63+/p40+ multiple local recurrences

Basal cell adenocarcinoma m Occurs primarily to lungs, bone, brain, and liver
Basaloid squamous cell carcinoma m Although prolonged survival may occur after
Epithelial-myoepithelial carcinoma metastases, death usually follows within 1 year

of identification of metastatic foci.
Short-term prognosis generally good corresponding
Treatment and Prognosis to the slow growth leading to prolonged survivals;
Wide local surgical excision is preferred treatment: long-term prognosis is poor
m Problems confronting surgical removal relate m 5-year overall survival ranges from 60% to 90%
to infiltrative nature with tendency to extend m 10-year overall ranges from 29% to 80%
along nerve segments further compounded by m 15-year overall survival ranges from 29% to 55%
their deceptively circumscribed macroscopic Factors affecting prognosis include:

appearance m Location of primary tumor:
Radiosensitive and radiotherapy particularly useful Submandibular gland tumors have worse prog-
(although not curative) in: nosis than parotid gland tumors.
m Controlling microscopic disease after initial Overall, major salivary gland adenoid cystic
surgery carcinomas have a better prognosis than their
m Treating locally recurrent disease minor salivary gland counterparts, although
m Palliation management in unresectable tumors palatal tumors have a better prognosis.
Chemotherapy used as palliation in patients with Sinonasal tract tumors have a poor prognosis.
advanced disease: m Size of the primary tumor:
m Role of chemotherapy in treatment remains Smaller primary neoplasms that are more ame-
unproven. nable to complete resection the better the
m No proven chemotherapeutic protocols prognosis
Tumors measuring greater than 4cm have a duct portions of salivary gland unit (i.e., intercalated
worse prognosis. duct reserve cell).
m Facial nerve paralysis: Terminology of lobular carcinoma was used
Symptoms of facial nerve paralysis may be because of presence of single cellfiling infiltrative
associated with worse prognosis and quicker growth pattern similar to that of lobular carcinoma
demise of patient of breast origin.
m Histologic grade:
Tumors with tubular and cribriform growth Clinical
have better prognosis: More common in women than in men; occurs over
15-year survival rates: a wide age range from the second to tenth decades
Grade I: 39% of life, but most frequently seen in the sixth to eighth
Grade II: 26% decades of life:
Predominantly solid tumors (i.e., more than m Rarely occurs in the pediatric population
30% of overall pattern) have worse prognosis Occurs primarily in minor salivary glands:
associated with earlier and more frequent m Almost exclusively identified in the oral
recurrent tumor. cavity:
Higher incidence of metastasis: Approximately 60% to 70% involve palate
May metastasize even in clinically lower (junction of hard and soft palate)
stage tumors (e.g., T1, T2) Other intraoral locations include buccal
Earlier fatal outcomes: mucosa, upper lip, retromolar region, and base
14% 5-year survival of tongue
5% 15-year survival m Less common locations include parotid gland,
m Clinical stage: lacrimal gland, nasopharynx, nasal cavity, sublin-

Advanced clinical stage associated with poorer gual, and submandibular glands:
outcome May occur in parotid gland as malignant epi-
Stage I: 75% 10-year survival thelial component in a carcinoma ex pleomor-
Stage II: 43% 10-year survival phic adenoma
Stages III-IV: 15% 10-year survival Most common symptom is that of a painless mass
m Positive surgical margins and/or failure of local or swelling occasionally associated with bleeding,
disease control following initial surgery: increase in size or discomfort; other less frequently
Recurrent tumor is generally a sign of identified symptoms include otalgia, odynophagia,
incurability. tinnitus, and airway obstruction
m Adverse prognosis also associated with: m Duration of symptoms is variable, ranging from
Presence of distant metastatic disease (5-year as short as 2 weeks to a 20- to 30-year history of
survival rate of 20%) a mass lesion.
Presence of extranodal extension in nodal Etiology:
metastasis m No predisposing factors known to exist
Presence of osseous invasion

m Higher proliferative index (greater than 10% of Pathology
tumor cells) as determined by Ki67 staining cor- Gross
relates to more aggressive tumors. Polypoid or raised, circumscribed to poorly demar-
cated, round to oval, mucosal-covered masses
ranging in size from 1.0 to 6.0cm in greatest
POLYMORPHOUS LOW-GRADE dimension
ADENOCARCINOMA OF MINOR In general, overlying mucosa remains intact; however,
SALIVARY GLANDS (PLGA) surface ulceration may be present.
(Figs. 20-82 through 20-89)
Definition: Malignant epithelial neoplasm characterized Smears show high cellularity with a population of
by cytologic uniformity, morphologic diversity, infiltra- mixed epithelial and myoepithelial cells.
tive growth pattern, and a low metastatic potential. Sheets and clusters of cells are seen and occasionally
Synonyms: Terminal duct carcinoma; lobular branching papillae may be identified.
carcinoma Epithelial cells appear cuboidal to spindle-shaped
Terminology of terminal duct carcinoma was used with uniform, round to ovoid nuclei with fine nuclear
to emphasize proposed histogenesis of the tumor, chromatin; absent or inconspicuous nucleoli; and a
thought to be progenitor cell of the distal or terminal moderate amount of dense cytoplasm.
A B
C D
Fig. 20-82. High-grade transformation (dedifferentiation) of adenoid cystic carcinoma.

A, Transitional areas from differentiated adenoid cystic carcinoma characterized by cribriform growth and more uniform
appearing cells (left of center) and areas of more disorganized growth (right). B, Higher magnification of the differentiated
adenoid cystic carcinoma foci. C, Higher magnification of the histologically higher grade malignant component representing
a high-grade adenocarcinoma. In relationship to the differentiated carcinoma there was (D) perineural invasion and
(E) cervical lymph node metastasis.
Main microscopic patterns are:

m Tubular (glandular, ductular):
Identifiable central lumens

Seen individually or in clusters
Complex tubuloglandular structures common
Seen throughout the lesion but may be promi-
nent at periphery where they are seen infiltrat-
ing adjacent tissues
m Trabecular:
May appear in streaming pattern with identifi-

able lumens
m Targetoid swirls:
A Best appreciated at lower magnification(s)

Often located at peripheral aspects of
neoplasm
Swirls, concentric whorls or targetoid arrange-
ments
Characteristic although not pathognomonic
May envelop blood vessels or surround nerves
m Solid or lobular:
Often seen in the central portions of the

tumor
Sometimes seen with peripheral palisading of
columnar cells
m Cribriform and/or microcystic:
B Similar to adenoid cystic carcinoma

m Single cell filing:
Refers to pattern of cell growth in which the

Fig. 20-83. Polymorphous low-grade cells are arranged in a single row
adenocarcinoma.
Not a consistently common finding
A and B, At low magnification these tumors are Often located at periphery of tumor
unencapsulated and infiltrative, composed of more than m Papillary or papillary-cystic foci:
one growth pattern (i.e., polymorphous). B, A characteristic Usually not a predominant feature
feature is the presence of a swirling pattern often located Consists of dilated cystic spaces with or without
at peripheral aspects of neoplasm. intraluminal papillary projections
m Less common patterns include fascicular and
Occasionally cells form spheric structures containing canalicular

hyaline globules. Lesional cells characteristically:
Myxoid matrix either dispersed in the background m Small to medium-sized cuboidal to columnar iso-
or interspersed with the cellular elements can also be morphic cells with indistinct cell borders and
seen. uniform ovoid to spindle-shaped nuclei with
vesicular to stippled to minimally hyperchromatic
Histology (basophilic) nuclear chromatin, small to incon-
At low magnification appears well circumscribed, spicuous nucleoli, scant to moderate amounts of
but unencapsulated and infiltrative growth may be eosinophilic to amphophilic cytoplasm, and
appreciated. indistinct cell borders
Multiple growth patterns (i.e., polymorphism) iden- m Spindle-shaped cells may be identified.
tified, including tubular (glandular, ductular), tra- m Minimal to absent nuclear pleomorphism
becular, solid nests, targetoid swirls, cribriform, m Absent to low mitotic activity
fascicular, single cell filing, cystic, and/or papillary: Atypical mitoses uncommon
m These patterns may be identified between tumors m Necrosis is not a typical feature.
and within an individual tumor. m Occasionally other cell types may be seen,
m Many salivary gland tumors are polymorphous including:
so the presence of polymorphism is not diagnostic Clear cells and mucinous cells
for PLGA or for that matter any other salivary Less often oncocytic, squamous, or acinic cells
gland tumor. may be found.
Presence of myoepithelial cells is controversial: Tumor stroma varies from mucoid to hyaline to
m Some reports document myoepithelial cells as mucohyaline:
integral component m Often has a slate gray appearance
m Some reports document absence of myoepithelial m In some cases tumor nests are separated by a
cells or very focal presence of myoepithelial cells. fibrovascular stroma.
A B
C D
Fig. 20-84. Polymorphous low-grade adenocarcinoma.

A variety of growth patterns may be seen from case to case and even within a single case, including (A) tubular with focal
cribriform (arrowhead); (B) microcystic; (C) solid; (D) single cell filing; (E) papillary;
Continued
F G
Fig. 20-84, contd

(F) fascicular; and (G) canalicular.
A B

A and B, Irrespective of growth pattern, the neoplastic cells are rather uniform (isomorphic), with limited variation in size
and shape, vesicular-appearing nuclei, inconspicuous to small nucleoli, and absence of mitotic activity or necrosis.
C, Mitotic figures (arrowhead) may occasionally be identified.
A B

A and B, The stroma tends to be myxoid or chondroid with a grayish appearance. C, Tyrosine-like crystals may be
identified.
A B

Immunohistochemical staining is not typically required in diagnosing polymorphous low-grade adenocarcinoma. Among the
markers seen include (A) haphazard p63 immunoreactivity including focal positive areas adjacent to negative areas;
typically other myoepithelial markers are negative (not shown); (B) CD117 immunoreactivity may be present and is not a
stain that consistently differentiates polymorphous low-grade adenocarcinoma from adenoid cystic carcinoma. A consistent
marker seen in polymorphous low-grade adenocarcinoma is S100 protein (see next image).
A B
C D

Invasive growth is a required feature in diagnosing polymorphous low-grade adenocarcinoma, which may include
(A) perineural invasion (arrowhead) that may be readily identified by light microscopy but may require (B) S100 protein
staining to confirm the presence of a peripheral nerve (arrowhead); note the tumor cells are diffusely and strong S100
protein positive. In addition to neurotropism, infiltrative growth may include invasion into (C) skeletal muscle or fat (not
shown). D, Another characteristic although not pathognomonic finding is entrapment rather than effacement of residual
minor salivary glands. Although not shown here, extension and involvement of the surface epithelium are not indications
of invasion and should not be used as evidence of malignancy.
m Areas of hemorrhage may be present. Invasion of mature adipose tissue and/or skeletal
m
Despite the innocuous cytologic appearance, neo- muscle

plasm always invasive: m Invasion of bone:
m Neurotropism (peri- and intraneural) found in May be seen in tumors of palate or

majority of tumors usually involving small to mandible
medium-sized nerves m Extension and involvement of surface (squamous)
m Perivascular invasion can also be seen with tumor epithelium may be present, but this finding is not
nests often arranged in concentric fashion around considered evidence of invasive growth or diag-
these structures. nostic for malignancy
m Invasion of seromucous glands: Other changes that may be identified include:
Envelopment but not effacement typical infil- m Tyrosine-type crystalloids and psammoma bodies
trative pattern can be seen in some cases.

Rather characteristic although not pathogno- m Pseudoepitheliomatous hyperplasia of surface
monic (squamous) epithelium
phic adenoma (PA) from polymorphous low-

grade adenocarcinoma (PLGA) and adenoid
cystic carcinoma (AdCC) include:
PA: p63+/p40+
Cellular PA: concordant p63+/p40+ or

p63/p40
PLGA: consistent p63+/p40
AdCC: p63+/p40+
CAUTIONARY NOTE: While p63/p40 IHC

panel can be a valuable tool for making distinc-
tion between PA, PLGA, and AdCC it is not
infallible and any given example may demon-
A strate divergence from the reported p63/p40
immunophenotype.
m Usually negative for other markers of myoepithe-
lial cells including calponin, actins, smooth

muscle myosin heavy chain
m GFAP typically negative
m May be reactive for mammaglobin and/or

GCDFP15
m May occasionally be PLAG1 positive
m Variable c-kit (CD117), bcl-2, and galectin 3
m Low proliferative rate indices (less than 5%) by
Ki67 staining
Electron microscopy:
m Glandular or duct-like structures, junctional
B
complexes (desmosomes, tight junctions), lumina,
and microvilli
Fig. 20-89. PLGA. Cytogenetics and molecular genetics:
Rarely, transition to a higher histologic grade tumor may m Somatic PRKD1 hotspot mutations encoding
be seen in PLGA. A, PLGA with typical histology is p.Glu710Asp found in 73% of PLGAs but not in
seen on right transitioning to an area with greater nuclear other salivary gland tumors emerging as a new
pleomorphism and mitotic activity (center and left). cancer-related gene likely constituting a driver of
B, Higher magnification of the higher histologic grade PLGA:
(less differentiated) component of the tumor. Morphologic and molecular overlap with crib-
riform adenocarcinoma of minor salivary
glands (see below) including the fact that these
Squamous metaplasia:
m two tumors are driven by genes in the same
A feature that can be seen following fine-needle family suggests they are closely related
aspiration biopsy or incisional biopsy m CGH analysis revealed:
Histochemistry: PLGA genome is genetically stable, containing

m Intraluminal mucin can be identified by diastase- comparatively few copy number alterations
resistant, PAS-positive material (CNAs)
m Intracytoplasmic mucin if present is focal and In line with clinical observation that PLGA is
weakly stained by mucicarmine or PAS with a slow-growing, low-grade carcinoma with low
diastase. metastatic potential
Immunohistochemistry: m Absence of MYB-NFIB by RT-PCR analysis
m Cytokeratins, EMA, S100 protein, vimentin Single reported case expressing MYB-NFIB
positive m Absence of ETV6 translocation
m Variable reactivity for CEA and muscle-specific
actin (MSA) High-Grade Transformation

m p63 and p40: (Dedifferentiation) in PLGA
Variable p63 reactivity but usually at least Rare occurrence of a histologically typical PLGA
focally present with high-grade carcinoma component characterized
p40 usually negative by:
IHC findings including pairing p63 and p40 m Nuclear atypia
reported to assist in differentiating pleomor- m Markedly increased mitotic activity

m Increased proliferation indices (Ki67 or MIB1 Due to its slow growth rate, local recurrence
index) typically occurs several years following initial
m Prominent zones of necrosis treatment.
m High-grade component may resemble salivary m Regional metastatic rate from 9% to 15%:
duct carcinoma including immunoreactivity for Similar to local recurrence, may occur several
androgen receptor years following initial treatment
Recent identification of high-grade tumor with mor- m Distant metastases seldom reported
phologic, immunohistochemical and molecular fea- m Death attributed to tumor is unusual and occurs
tures of PLGA and cribriform adenocarcinoma of after prolonged periods

minor salivary glands (referred to as high-grade Papillary architecture may be associated with more
polymorphous/cribriform adenocarcinomas) identi- aggressive behavior:
fied characterized by greater nuclear pleomorphism, m Increased incidence of recurrence
increased mitotic activity, solid growth and necrosis m Increased incidence of regional (cervical nodal)
with more aggressive behavior and distant metastasis

m No increase in mortality
Differential Diagnosis (Table 20-9) m Such neoplasms may in fact be cribriform

Pleomorphic adenoma: adenocarcinomas of minor salivary glands (see
m In minor salivary gland sites is unencapsu below)
lated similar to PLGA but noninvasive unlike PLGA may occur as malignant component in carci-
PLGA noma ex pleomorphic adenoma:
Monomorphic adenoma m In setting of carcinoma ex pleomorphic adenoma:
Adenoid cystic carcinoma: Better prognosis than other types of carcino-

m Differentiation is predicated on light microscopic mas arising in pleomorphic adenoma
features because both tumors may show neuro More aggressive than de novo PLGA
tropism and have overlapping immunohisto- Histologic high-grade transformation of an other-
chemical findings. wise typical PLGA may rarely occur:
m Presence of isomorphic cells composed of small m See previous discussion.
angulated hyperchromatic nuclei that character- Some consider polymorphous low-grade adenocarci-
ize adenoid cystic carcinoma contrast to the noma the low-grade variant of adenoid cystic carci-
isomorphic round to oval, vesicular nuclei of noma based on the morphologic similarities as
PLGA. well as common derivation from intercalated duct
m More pronounced cribriform component region; however, there is no support for this
m Presence of MYB-NFIB fusion would support consideration.
diagnosis of adenoid cystic carcinoma. Cribriform adenocarcinoma of minor salivary glands
Cribriform adenocarcinoma (see below): previously considered a variant of PLGA but now
m Based on differences in morphology and, more recognized as a separate tumor type (see below)
importantly, biologic behavior (local recurrence,
cervical lymph node and distant metastases, and
mortalities directly related to neoplasm) should
be considered a distinct and separate entity from
CRIBRIFORM
PLGA. ADENOCARCINOMA
OF MINOR SALIVARY
Treatment and Prognosis GLANDS (CAMSG) (Fig. 20-90)
Treatment includes complete surgical excision in as
conservative a manner as to ensure tumor-free Definition: Submucosal invasive adenocarcinoma with
margins: cribriform, tubular/glandular, and papillary growth,
m Invasion of bone may necessitate more extensive nuclear features reminiscent of thyroid papillary carci-
surgical resection that may include maxillectomy noma, and tendency to be associated in a high percent-
or en bloc resection of mandible. age of cases with nodal metastasis.
Limited (if any) utility for radiation or chemotherapy Synonyms: Cribriform adenocarcinoma of the tongue
Neck dissection is not indicated unless there is evi- and minor salivary glands (CATSMG)
dence of cervical adenopathy.
Overall prognosis is excellent: Clinical
m Indolent behavior Slightly more common in women than in men; occurs
m 95% 10-year survival in adults over a wide age range from 21 to 85 years
m Local recurrence rate between 9% and 17%: with a mean of 56.8 years
TABLE 20-9 PLGA and Other Intraoral Salivary Glands Neoplasms: Selective Differential Diagnosis
Capsule,
Tumor Invasion Growth Patterns Cytomorphology Stroma IHC Cytogenetic
PLGA Absent and Polymorphic, Isomorphic cells with Slate gray Positive for None known
infiltrative including minimal myxoid; epithelial and although
tubular/ductules, pleomorphism; no crystalloids may myoepithelial PRKD2
cribriform, solid, necrosis or increased be present markers: CKs, p63, rearrangement
linear single mitotic activity; S100 protein, reported in a
cell, intercellular hyaline others; p40 single case
streaming material may be negative*; low
along periphery, present proliferation
papillary indices
PA Absent but Polymorphic, Dual cell population: Chondromyxoid; Positive for PLAG1
well including ducts/glands and crystalloids may epithelial and HMGA2
circumscribed tubules, ribbons, myoepithelial cells; no be present myoepithelial
sheets, cords, necrosis or increased markers: CKs, p63,
cysts, trabeculae mitotic activity; p40, S100 protein,
intercellular hyaline others; low
material may be proliferation
present indices
CPA (E or Absent but Polymorphic, Dual cell population: Scanty but Positive for PLAG1
M) well including ducts/glands and identifiable epithelial and HMGA2
circumscribed tubules, ribbons, myoepithelial cells; for chondromyxoid myoepithelial
sheets, cords, myoepithelial stroma; markers: CKs, p63,
cysts, predominant tumors crystalloids may S100 protein,
trabecular, lesional cells include be present others; low
fascicular, spindle-shaped and proliferation
anastomosing plasmacytoid cells but indices
cords ducts/glands focally
seen; no necrosis or
increased mitotic
activity; intercellular
hyaline material may
be present
AdCC, Absent and Polymorphic, Basaloid cells with Myxoid-hyaline Positive for MYB-NFIB
tubular, infiltrative including uniform, angulated, stroma epithelial and
cribriform cribriform, hyperchromatic nuclei, myoepithelial
tubular/ductules, scanty cytoplasm; no markers: CK, p63,
islands, cysts, necrosis or increased p40, S100 protein,
nests, cords, mitotic activity; others; increased
solid intercellular hyaline proliferation
material present indices
CAM Absent and Cribriform, Lesional cells include No specific Strong reactivity Recurrent
SG infiltrative tubular/ round to oval to stromal for cytokeratins PRKD1-3
glandular elongated nuclei with component; (AE1/AE3, CAM5.2, rearrangement
papillary and irregularities in size calcifications CK7, CK8, CK18),
solid growth and shape, clear to including S100 protein, and
patterns; often very fine-appearing psammomatoid vimentin; variable
divided into nuclear chromatin; concretions may reactivity for p63,
lobules by nuclear grooves and be present calponin, CK14,
fibrous septa nuclear smooth muscle
pseudoinclusions actin, CK5/6;
(reminiscent nuclei in negative for
papillary thyroid thyroglobulin and
carcinoma); mild to TTF1; significant
focally moderate reactivity for
nuclear pleomorphism CD117
may be present but no (cytoplasmic and
substantial increase in membranous); low
mitotic activity and no proliferation
necrosis
*p40 not necessarily consistently negative in PLGA or positive in the other neoplasms.
Increased proliferation indices may not be present in all cases of AdCC and by itself does not definitively differentiate it from PA, cellular
PA, and PLGA.
AdCC, Adenoid cystic carcinoma; CAMSG, cribriform adenocarcinoma of minor salivary glands; CKs, cytokeratins; CPA, cellular
pleomorphic adenoma; E, epithelial predominant; M, myoepithelial predominant; PA, pleomorphic adenoma; PLGA, polymorphous
low-grade adenocarcinoma.
A B
C D
Fig. 20-90. Cribriform adenocarcinoma of minor salivary glands.

A, Submucosal unencapsulated and invasive neoplastic proliferation; intact squamous epithelium is present (extreme left).
B, Neoplastic proliferation comprised of lobules separated by fibrous septa showing cribriform and solid growth patterns;
intraluminal eosinophilic secretions are seen. C, Lesional cells show nuclear features reminiscent of those seen in papillary
thyroid carcinoma (solid variant) including round to oval to elongated nuclei with irregularities in size and shape, clear to
very fine-appearing nuclear chromatin. D, Tumor nests detached from surrounding fibrous stroma by clefts imparting a
glomeruloid appearance.
Most common site of occurrence is tongue: Fine-Needle Aspiration Biopsy

m Base of tongue a frequent location Aspirates contain polymorphic fragments of epithe-
m Other intraoral sites of occurrence include soft lial cells arranged in monolayer sheets, papillary
palate, buccal mucosa, tonsil, lip fronds and tips, and occasional cribriform
m May occur outside the oral cavity including major configurations.
salivary glands Metachromatic stromal fragments may be identified
Presentation may include: and may be misinterpreted as colloid.
m Intraoral mass Background myxoid/mucoid material reminiscent of
m Not infrequently may present with enlarged colloid may be prominent.
lateral neck mass
Etiology: Histology
m No known associated causes Submucosal unencapsulated and invasive adenocar-
cinoma with cribriform, tubular/glandular, papillary,
Pathology and solid growth patterns:
Gross m Often divided into lobules by fibrous septa
Unencapsulated lesion with tan-gray to white color In solid areas, tumor nests may be detached from
and firm to hard consistency surrounding fibrous stroma by clefts (presumably
artifactual) imparting a somewhat glomeruloid Cytogenetics and molecular genetics:

appearance: m Novel and recurrent gene rearrangements in
m Peripheral layer of such solid tumor nests often PRKD1-3 identified, suggesting possible pathoge-
displays hyperchromatic nuclei in a vaguely pali- netic dichotomy from PLGA
saded pattern Presence of cases with similar genetic findings
Lesional cells include round to oval to elongated considered indeterminate for CAMSG and
nuclei with irregularities in size and shape, clear to PLGA as well as activated E710D hotspot
very fine-appearing nuclear chromatin, and nuclear mutation in PRKD1 in 73% of PLGAs suggests
grooves: shared pathogenesis between CASMG and
m Nuclear features somewhat reminiscent of PLGA
those seen in papillary thyroid carcinoma (solid m No mutations of RET, BRAF, KRAS, HRAS,
variant) NRAS, c-kit, and PDGFRa genes

m Intranuclear inclusions may be identified. m Negative for high-risk/low-risk HPV types:
Mild to focally moderate nuclear pleomorphism may In one reported case high-risk HPV type 33
be present but with no substantial increase in mitotic detected (this case also showed weak positivity
activity and no necrosis. of HPV type 18)
Calcifications, including psammomatoid concre-
tions, may be present. Differential Diagnosis
Intraluminal mucinous-appearing secretions may be Polymorphous low-grade adenocarcinoma
present. Adenoid cystic carcinoma
Infiltrative growth may include perineural invasion, Metastatic thyroid papillary carcinoma
lymph-vascular invasion, and invasion into soft
tissues including skeletal muscle. Treatment and Prognosis
Intact overlying squamous epithelium often Complete surgical resection to include tumor-free
identified: margins is indicated.
m Typically no ulceration present Regional (cervical) lymph node metastasis:
m Pseudoepitheliomatous hyperplasia may be m High frequency (65%) at presentation
present. m Should necessitate neck dissection as part of
m No evidence of intraepithelial dysplasia and/or initial treatment protocol

carcinoma in situ Highly favorable prognosis:
Histochemistry: m Majority of patients alive without disease or alive
m Intraluminal secretions diastase-resistant, PAS- with recurrent disease over periods ranging from
positive, and weakly mucicarmine positive 2 months to 13 years (median follow-up of 6
Immunohistochemistry years 5 months)
m Strong reactivity for cytokeratins (AE1/AE3, m Prognosis does not appear to be altered by pres-
CAM5.2, CK7, CK8, CK18), S100 protein, and ence of nodal metastasis.
vimentin
m Variable reactivity for basal/myoepithelial cell
markers including p63, calponin, CK14, smooth MALIGNANT MIXED TUMORS

muscle actin, CK5/6 OF SALIVARY GLANDS
m May be reactive for galectin-3, CK19, and
HBME-1 but negative for thyroglobulin and Following lesions are grouped within this category:
thyroid transcription factor 1 (TTF1) m Carcinoma ex pleomorphic adenoma
m Significant reactivity for c-kit (CD117), including m Noninvasive or intracapsular carcinoma ex pleo-
strong cytoplasmic and membranous expression, morphic adenoma

may be present in from 10% to 80% of lesional m True malignant mixed tumor or carcinosarcoma
cells. m Metastasizing pleomorphic adenoma
m p16 staining (cytoplasmic and nuclear) may be
present but typically with patchy pattern in Carcinoma Ex Pleomorphic

majority of cases considered nonreactive; rare Adenoma (CEPA) (Figs. 20-91
cases reported as diffusely reactive
through 20-94)
m Negative for EMA, epidermal growth factor
receptor, HER-2/neu, estrogen receptor, and pro- Definition: Malignant transformation of a pre- or coex-
gesterone receptor negative isting pleomorphic adenoma with infiltrative growth:
m Negative mammaglobin and c-kit m By definition this tumor type lacks evidence of a
m Low proliferation indices (less than 5%) by Ki67 co-existing mesenchymal malignancy (i.e.,
staining sarcoma)
(especially in patients with recurrent tumors), and

regional lymphadenopathy.
Time period for malignant transformation of pleo-
morphic adenoma (initial or recurrent) may be from
2 to 50 years but on average is approximately 20
years:
m Risk of malignant transformation increases with
duration of tumor:
1.6% for tumors less than 5 years
9.5% for tumor present for more than 15
years
Pathology
Gross
Appearance may depend on histologic grade:
Fig. 20-91. Carcinoma ex pleomorphic adenoma.
m Most are histologically high grade and appear as
Carcinoma ex pleomorphic adenoma, high-grade, appearing poorly circumscribed to overtly infiltrative masses
as a huge, fungating mass completely obliterating and with tan-white appearance and firm to hard
distorting the patients normal facial structures. consistency:
Areas of hemorrhage, necrosis, cystic change,
and softening of the tissue may be present.
m May be identified in association with histologic m Occasionally high-grade CEPA may be circum-
evidence of a pleomorphic adenoma scribed and/or encapsulated (see intracapsular

m Arises in a site previously involved by a pleomor- CEPA below)
phic adenoma m Histologically low-grade CEPAs may appear
Synonym: Carcinoma ex mixed tumor poorly circumscribed to overtly infiltrative or
may show similarities to pleomorphic adenoma,
Clinical including circumscription or encapsulation.
Accounts for approximately 12% of all malignant May range in size from 1 to 17cm in greatest
salivary gland neoplasms, 4% to 6% of all pleomor- dimension
phic adenomas, and 2% to 4% of all salivary gland Residual foci of pleomorphic adenoma may be iden-
neoplasms tified, appearing as glistening to fibrotic (nodular)
m Of entities included under the designation malig- foci
nant mixed tumors of salivary glands, more than
90% are (invasive) carcinoma ex pleomorphic Fine-Needle Aspiration Biopsy
adenomas. Unequivocal malignant epithelial cells admixed
No gender predilection; may be seen over a wide age with benign epithelial and stromal components of
range but most frequently occurs in the sixth to pleomorphic adenoma are considered diagnostic by
seventh decades of life: FNAB:
m Occur approximately one decade older than m In most aspirates epithelial cells predominate
patients with pleomorphic adenomas over stromal components.

m Extraordinarily rare in infants and young m Necrosis and mitotic figures, including atypical
children forms, may be seen.

Sites of occurrence: Aspirates may be cellular and include epithelial cells
m Most commonly occurs in major salivary glands: with atypia characterized by mild to moderate degree
Parotid gland > submandibular gland of pleomorphism, absence of unequivocal malignant
May occur less often in minor salivary glands cells, and a variable proportion of benign epithelial
Palate most commonly involved minor salivary and stromal components.
gland site Sampling error is important cause of diagnostic
m Rarely occurs in sublingual gland pitfalls:
Typical clinical presentation includes sudden or m Correlation with clinical findings is essential in
rapid enlargement of a long-standing painless, non- FNAB diagnosis.

enlarging or slowly enlarging mass over a short time m In appropriate clinical setting (i.e., rapid enlarge-
period (e.g., 3- to 6-month period) ment of a long-standing salivary gland tumor),

m Associated symptoms may include pain, facial any degree of nuclear atypia should be docu-
nerve paresis or paralysis, soft tissue fixation mented and should raise concern for a possible
A B
Fig. 20-92. Carcinoma ex pleomorphic adenoma, high-grade.

A, Transition between residual pleomorphic adenoma (top) characterized by benign glandular structures and
chondromyxoid stroma to areas with more complex glandular growth pattern and marked nuclear pleomorphism (lower).
B, Area of residual pleomorphic adenoma characterized by acellular hyalinization with benign tubules. C and D, The
malignant component often is a high-grade adenocarcinoma with features similar to those of salivary duct carcinoma
including cribriform growth with comedotype necrosis and cells with marked nuclear pleomorphism and increased mitotic
activity; lesional cells were androgen receptor positive (not shown). Typically there is extensive invasive growth including
(E) into adjacent salivary gland parenchyma, Continued
Fig. 20-92, contd

(F) perineural invasion, and (G) lymph-vascular invasion (note the features of squamous cell carcinoma).
Fig. 20-93. Carcinoma ex pleomorphic adenoma, low-grade.

A, This man had previous excision of a pleomorphic adenoma (note scar anterior to the ear) with recurrence and recent
enlargement of the recurrent tumor. B and C, The recurrence was a myxoid-predominant pleomorphic adenoma within
which was another type of neoplastic proliferation characterized by tubular growth and cells with prominent basophilic
cytoplasmic granules and vacuolated cells; these cells were DOG1 positive (not shown). The findings are those of an
acinic cell carcinoma ex pleomorphic adenoma.
B
A
D
C
Fig. 20-94. Carcinoma ex pleomorphic adenoma, low to intermediate grade.

A, This patient had multiple recurrences of a palatal mass most recently with rapid increase in size and evidence of bone
invasion by radiologic imaging; a biopsy (not shown) confirmed the presence of tumor in bone, necessitating radical
excision. B, At low magnification the tumor is extensively infiltrative into palatal bone. C, Residual foci of a myoepithelial-
predominant (plasmacytoid) pleomorphic adenoma were present. D, Areas of the tumor showed increased nuclear
pleomorphism with prominent nucleoli, scattered mitoses, and stromal hyalinization. Immunohistochemical staining
showed the neoplastic cells to be reactive for (E) cytokeratin (AE1/AE3), (F) calponin,
Continued
Fig. 20-94, contd

(G) p63, and (H) S100 protein. The findings in this case are those of a myoepithelial carcinoma ex pleomorphic adenoma.
diagnosis that may necessitate additional tissue (e.g., skeletal muscle, adipose tissue, others),
FNAB. neurotropism (peri- and intraneural), and lymph-
vascular angioinvasion.
Histology Evidence of pleomorphic adenoma:
Carcinomatous component may be histologically m Proportion of pleomorphic adenoma in any
high grade or lower grade: given case varies from being readily identifiable
m Carcinoma in most cases is histologically high to cases in which it is difficult to identify
grade, characterized by enlarged cells with marked appearing hypocellular or hyalinized without
nuclear pleomorphism, nuclear hyperchromasia, cellularity.
prominent nucleoli, increased mitotic activity m Foci of pleomorphic adenoma and carcinoma
with atypical mitoses and necrosis. may be demarcated from one another or two
High-grade carcinomas are most often: components may be intimately admixed.
Salivary duct carcinoma or high-grade ade- m Transition areas between benign and malignant
nocarcinoma, not otherwise specified foci may be present.

Less often tumor types include undifferenti- m Evidence of (residual) pleomorphic adenoma may
ated carcinoma, squamous cell carcinoma, include presence of:

adenosquamous carcinoma, sarcomatoid Classic foci including combination of benign
carcinoma, small cell carcinoma, oncocytic tubular or ductular structures, myoepithelial
carcinoma cells, and chondromyxoid stroma
m In a significant minority of cases the carcinoma Hyalinized (nodular) stroma:
is histologically low grade with carcinoma defined May contain identifiable benign tubular or
on basis of recognition into a specific type of sali- ductular structures with bland cytomorphol-
vary gland carcinoma and/or evidence of infiltra- ogy and dual cell (epithelial and myoepithe-
tive growth. lial) differentiation by light microscopy and/
Histologically lower-grade carcinomas include: or immunohistochemical staining
Low- to intermediate-grade adenocarci- May be acellular:
noma, NOS, myoepithelial carcinoma, Extensive hyalinization in a pleomorphic
mucoepidermoid carcinoma, polymorphous adenoma has been shown to be associated

low-grade adenocarcinoma, acinic cell ade- with increased risk for malignant transfor-
nocarcinoma, epithelial-myoepithelial carci- mation, and presence of hyalinized focus/
noma, adenoid cystic carcinoma nodule near to a malignancy is evidence of
m Rare example of melanoma arising in carcinoma residual pleomorphic adenoma supporting
ex pleomorphic adenoma reported diagnosis of CEPA.
Invasive growth is present, including invasion into m Numerous sections may be required to identify
adjacent salivary gland parenchyma, fibroconnective foci of residual pleomorphic adenoma.

Immunohistochemistry: Major glands:

m HER-2 expression, p53 expression, androgen Usually radical extirpation with sacrifice of
receptor, and Ki67 labeling index higher in carci- facial nerve

nomatous component Minor glands:
m S100 protein overexpression reported to be sig- Complete excision with tumor-free margins,
nificantly more prevalent in carcinomatous com- which may necessitate removal of a portion
ponent than in pleomorphic adenoma with or of the mandible or maxilla.
without atypical features m Due to a high rate of nodal metastasis, cervical
Results suggest that S100 protein immunohis- lymph node dissection usually performed
tochemical staining may be useful diagnostic m Adjunctive radiotherapy used for extensively
marker for identifying the early phase of carci- invasive tumors, as well as in conjunction with
noma ex pleomorphic adenoma in combina- surgery:
tion with HER-2, p53, androgen receptor, and Radiotherapy in conjunction with surgery
Ki67 plays a beneficial role in preventing local
m PLAG1 staining may be present but FISH appears recurrence.
to be mores sensitive than IHC staining in detect- m Chemotherapy is of questionable benefit.
ing PLAG1 abnormalities. m Associated with high recurrence and metastatic
Cytogenetics and molecular genetics: rates:

m Most CEPAs regardless of morphologic subtype Recurrence rates (one or more) vary from 23%
carry altered PLAG1 or HMGA2 genes to 53%
m FISH for PLAG1 and HMGA2: Majority of recurrences develop within 5
CEPAs reported positive for PLAG1 or years from the diagnosis, although recur-
HMGA2 rearrangements/amplifications rences decades later may occur.
Represent the most common genetic events in Palatal CEPA tends to recur less often than
CEPA regardless of histologic subtype CEPA of major salivary glands.

Rearrangements of PLAG1/HMGA2 identified Metastatic rates (local and metastatic) vary and
in most hypocellular PAs but only in a small have been reported as high as 70%.
subset of cellular PAs Metastases most frequently occur to regional
De novo carcinomas reported negative for lymph nodes, lungs, brain, and bone (verte-
PLAG1 and HMGA2 bral column).
m HER2 gene amplification found in up to 82% of m In general, prognosis is poor especially in patients
cases with local recurrence, regional metastasis, or

More common in presence of cases with distant metastasis:
extracapsular invasion than without in Following the discovery of metastatic disease,
vasion death usually follows within 1 year.
m Alterations in TP53 gene and p53 protein over- m Survival rates include:
expression identified in up to 67% and 75% of 5-year range from 25% to 65%
cases, respectively: 10-year range from 24% to 50%
Involved in the early stages of malignant trans- 15-year range from 10% to 35%
formation of PA 20-year range from 0 to 38%
m LOH at microsatellite loci on 8q and 12q in Low-grade CEPA:
benign and malignant components and 17p in the m Wide surgical excision is the preferred
malignant component treatment.
m Rearrangements of 8q12 and 12q13-15 fre- m Unless there is clinical evidence supporting nodal
quently identified metastases, then neck dissection may not be

necessary.
Differential Diagnosis m Adjunctive radiotherapy in combination with
Cellular pleomorphic adenoma surgery may be beneficial if the tumor is exten-

Atypical pleomorphic adenoma sively invasive.
Intracapsular CEPA (see below) m Prognosis for these tumors is considered to be
Salivary duct carcinoma much better than for histologically high-grade

True malignant mixed tumor (see below) CEPA.
Factors adversely affecting prognosis include:
Treatment and Prognosis m Origin in major salivary gland
For high-grade CEPA: m Recurrent and/or metastatic disease (locoregional,
m Wide surgical excision is the preferred treatment: distant)

m Higher T stage m Findings akin to ductal carcinoma in situ (DCIS)

m Presence of neurotropism of the breast
m Histologic grade:
High-grade CEPAs have worse prognosis than Clinical

low-grade CEPAs. Uncommon lesion with greater recognition in
m Presence of HER-2 gene amplification literature
m Surgical margins: Demographics, including gender and age, are similar
Presence of tumor-positive margins associated to pleomorphic adenoma.
with higher recurrence rates and tumor- Clinical features at the initial diagnosis that may
associated mortality rates than tumor-free indicate a greater likelihood of malignant transfor-
margins; presence of tumor-free margins does mation include:
not exclude the possibility of recurrence, metas- m Occurrence in the submandibular gland
tasis, or tumor-related death. m Older patient age
m Extent of invasion: m Larger tumor size
Arguably most important prognostic factor Generally thought to represent early stage develop-
Discrepant findings in literature relative to dis- ment in malignant transformation of a pleomorphic
tance defining better or worse prognosis adenoma
including:
Invasion beyond 8mm from the capsule Pathology
associated with a poor outcome (i.e., died of Gross
disease) Similar to pleomorphic adenoma
Invasion greater than 1.5mm portended
worse outcome (e.g., shorter survival) than Histology

invasion less than 1.5mm from capsule Residual foci indicative of a pleomorphic adenoma
Threshold for distinguishing minor extracap- are present, which may include benign glands or
sular invasion with good prognosis from ducts, myoepithelial cells, chondromyxoid stroma,
wide extracapsular invasion with poor prog- and/or hyalinized areas.
nosis is 5mm Carcinomatous element composed of overtly
Patients with minimally invasive tumor have malignant cells with enlarged, pleomorphic, and
more favorable outcome than patients with hyperchromatic nuclei with increased nuclear-to-
widely invasive neoplasm. cytoplasmic ratio, prominent nucleoli, and high
Minimally invasive carcinoma ex pleomor- mitotic rate.
phic adenoma can recur and can cause m To date, no reported instances of low-grade intra-
death. capsular CEPA

m Presence of myoepithelial carcinoma subtype m In theory such tumor types may occur composed
reported to increase risk of recurrence in carci- of residual pleomorphic adenoma and identifiable
noma ex pleomorphic adenoma, especially within malignancy purely based on cell type(s); examples
the group of minimally invasive tumors could include:
Adenoid cystic carcinoma, acinic cell carci-
noma, low-grade mucoepidermoid carcinoma,
Noninvasive or Intracapsular epithelial-myoepithelial carcinoma
Carcinoma Ex Pleomorphic May also include examples of carcinoma
in situ
Adenoma (Fig. 20-95) By definition there is no evidence of invasion beyond
Definition: Salivary gland tumor showing histologic the capsule of the tumor.
evidence of pleomorphic adenoma with unequivocal Extensive sampling of the tumor, which may require
evidence of cytologic malignancy entirely confined to submission of the entire tumor, should be performed
within the capsule without invasive growth. to ensure that extracapsular involvement has not
Synonyms: Early carcinoma ex pleomorphic adenoma; occurred.
intratubular carcinoma ex pleomorphic adenoma; car- Immunohistochemistry:
cinoma in situ ex pleomorphic adenoma m Carcinomatous component strongly positive for
m Carcinoma in situ represents earliest phase of HER-2

malignant transformation, characterized by car- Cells of the maternal PA negative for HER-2
cinoma within ductal luminal cells, retention of Cytogenetics and molecular biology
myoepithelial cell layer, and absence of stromal m Amplification of HER-2/neu gene signals in non-
invasion. invasive carcinoma cells:

A B
C D
Fig. 20-95. Noninvasive carcinoma ex pleomorphic adenoma.

Noninvasive (intracapsular) carcinoma ex pleomorphic adenoma. A and B, Areas of this encapsulated parotid tumor
showed foci of pleomorphic adenoma characterized by benign tubules with dual cell population within a variable appearing
stroma including acellular hyalinization (A) and chondromyxoid appearing (B). C and D, Elsewhere in this neoplasm there
were foci of high-grade carcinoma with features of salivary duct carcinoma (C) and squamous cell carcinoma (D). E, The
entire tumor was submitted for histologic evaluation, showing it to be completely encapsulated without evidence of
invasive growth.
Less common than in cases with extracapsular

invasion Differential Diagnosis
m Alterations in TP53 gene and p53 protein Atypical pleomorphic adenoma:
overexpression Recurrent pleomorphic adenoma:
Involved in the early stages of malignant trans- m May be multinodular and/or include one or more
formation of PA nodules in the soft tissues of the neck

Fig. 20-96. Carcinosarcoma.

Carcinosarcoma appearing as huge parotid tumor
completely distorting this patients face.
Nodules usually discrete and circumscribed

without cytologic atypia

B
Treatment includes complete surgical excision.
Adjunctive therapy likely unnecessary.
Prognosis appears to be good. Fig. 20-97. Carcinosarcoma.
m Typically without metastatic potential
A, At low magnification there are two histologically distinct
m Single reported case with cervical lymph node
areas including solid-appearing (left) and more lightly
metastasis staining nodular/lobular area (right). B, At higher
m Another case reported of parotid gland neoplasm magnification there is an admixture of carcinomatous and
that recurred after interval of 8 years composed sarcomatous components, including carcinoma with
solely of pleomorphic adenoma that 5 years later squamous and glandular features (left and bottom) and
recurred in the same site as myoepithelial carci- chondrosarcoma (center and upper right).
noma without evidence of ductal carcinoma as
was reported in the initial intracapsular carci-
noma ex pleomorphic adenoma Among minor salivary glands, palate is most
frequent site of occurrence
Most common symptoms relate to an enlarging mass
Carcinosarcoma (Figs. 20-96 and 20-97) with recent increase in size with or without associ-
Definition: Malignant salivary gland neoplasm consist- ated pain and/or facial nerve paralysis.
ing of an admixture of malignant epithelial (carcinoma- In general, these tumors arise de novo; however,
tous) and malignant mesenchymal (sarcomatous) some arise in association with a pleomorphic
components. adenoma and are termed carcinosarcoma ex pleo-
Synonym: True malignant mixed tumor morphic adenoma:
m In association with a pleomorphic adenoma, clin-
Clinical ical situation may include a long-standing mass

Rare salivary gland neoplasm lesion with recent/sudden rapid increase in
No gender predilection; most commonly seen in the growth.
sixth decade of life m May develop decades following radiation therapy
May occur in major and minor salivary glands: for benign pleomorphic adenoma, but no clear
m Majority (two thirds of cases) occurs in parotid link between radiotherapy and development of
gland carcinosarcoma
m Remainder of cases arise in submandibular gland Histogenesis subject of controversy, but most au
and minor salivary glands: thorities consider it to be of epithelial cell and
myoepithelial cell origin, the latter giving rise to the Myoepithelial differentiation:
sarcomatous component: p63, calponin, S100 protein, vimentin, smooth
m Pleomorphic adenomas consisting of an admix- muscle actin, glial fibrillary acidic protein
ture of epithelial and mesenchymal-appearing
tissue originate from epithelial and myoepithelial Differential Diagnosis
cells. Carcinoma ex pleomorphic adenoma
m Sarcomatous component derived from modula- Spindle cell squamous carcinoma
tion of modified myoepithelial cells in similar Salivary duct carcinoma, sarcomatous variant
manner to modulation of myoepithelial cells in Synovial sarcoma
benign pleomorphic adenomas producing chon- Sarcoma, primary or metastatic
dromyxoid stroma
Pathology Complete surgical excision is preferred treatment:
Gross m Due to locally infiltrative and destructive growth
Unencapsulated to poorly circumscribed to infiltra- radical surgery is usually necessary.

tive lesion measuring from 2 to 13cm in greatest Lymph node dissection is used for palpable disease.
dimension Adjunct radiotherapy is used to control local disease.
Cut section may show a tan-gray to yellow, predomi- Role of chemotherapy unproven but used in cases
nantly solid lesion with hemorrhage, necrosis, and with metastatic disease
calcification; cystic areas may be present. Prognosis is poor:
m Highly lethal neoplasms with mean survival of
Histology less than 30 months

Biphasic appearance composed of carcinomatous m Majority of patients die from disease.
and sarcomatous elements; sarcomatous component m Recurrent disease occurs in a majority of patients:
usually is dominant component Recurrences include both histologic com

Sarcomatous component: ponents.
m Usually chondrosarcoma m Metastases occur in half the patients:
m Other malignant mesenchymal elements may Metastases including both histologic compo-
include osteosarcoma, fibrosarcoma, malignant nents or may be restricted to the carcinomatous
fibrous histiocytoma, leiomyosarcoma, liposar- or sarcomatous component
coma, rhabdomyosarcoma, myxosarcoma, and Hematogenous spread most common with
malignant giant cell tumor. metastases most frequently to the lungs; other
m Rarely, nonmalignant osteoid may be seen. sites of metastases occur to liver, bone, brain,
Carcinomatous component: and lymph nodes (cervical and hilar)
m Epithelial component is usually adenocarcinoma
or squamous cell carcinoma. Metastasizing Pleomorphic

m Other malignant epithelial elements may include
salivary duct carcinoma, undifferentiated carci-

Adenoma (Fig. 20-98)
noma, adenoid cystic carcinoma, epithelial- Definition: Salivary gland neoplasm with histomorpho-
myoepithelial carcinoma, and papillary logic features of a pleomorphic adenoma but that
cystadenocarcinoma. metastasizes:
Cases occurring in association with a pleomorphic m Metastatic foci are histologically similar (i.e.,
adenoma or in a site of previously excised pleomor- benign) to the primary and/or recurrent
phic adenoma show histologic evidence of coexisting neoplasms
pleomorphic adenoma or evidence of a pleomorphic m Due to potential for increased mortality designa-
adenoma in prior resection material. tion benign has been eliminated.

m Sarcomatous components: Clinical
Vimentin reactivity Extremely rare
Depending on the cell type, immunoreactivity No gender predilection; wide age range but the age
may be present for: at the time of primary tumor is in the third decade
Myogenic markers (desmin, myoglobin, and in the seventh decade for metastatic tumor
myogenin, actins) for tumors with muscle Primary neoplasm most frequently originates in
(skeletal or smooth muscle) differentiation parotid gland:
S100 protein in chondrosarcoma m Other sites include the submandibular gland,
m Carcinomatous components: intraoral minor salivary glands (most often the

Cytokeratin positive palate), and sinonasal seromucous glands.
A B
C D
E F
Fig. 20-98. Metastasizing pleomorphic adenoma.

All these examples occurred in different patients all with tumor recurrence (at least one but usually multiple) of major or
minor salivary gland pleomorphic adenomas, in which the primary tumor, recurrent tumor, and metastatic foci retained
histologic features of usual pleomorphic adenoma without cytomorphologic evidence of malignant transformation. A and
B, Cervical lymph node metastasis; C and D, metastasis to the lung; E through G, metastasis to the humerus,
G
H
I
J
K
L
Fig. 20-98, contd

H and I, metastasis to the skull; and J through L, metastasis to the kidney.
Clinical presentation of primary salivary gland Rarely metastatic foci may represent initial clini-
m
tumor is that associated with pleomorphic cal manifestation.

adenomas: Clinical presentation of metastasis dependent on site
m Absence of clinical presentation/scenario associ- of metastatic disease and may include:
ated with carcinoma ex pleomorphic adenoma m Neck mass or swelling, pain, pathologic fracture,
(i.e., rapid enlargement in tumor size, pain, space-occupying lesion

neuropathies) m Metastasis may occur at the time of initial sali-
Typically, multiple recurrent pleomorphic adenomas vary gland tumor, but more often occur at the
are seen within the area of the primary tumor prior time of the recurrent tumor(s) and/or from years
to development of metastases: to decades later.
m Metastatic spread is by hematogenous and lym- absence of anaplasia, increased mitotic activity with
phatic routes with metastatic foci seen in bone atypical mitoses, necrosis, invasive growth; the pres-
(femur, humerus, pelvis, ribs, calvarium), lung, ence of these features would exclude the diagnosis
kidney, retroperitoneum, skin, and lymph nodes. of metastasizing pleomorphic adenoma:
Reasons for metastases remains unproven, but m Rare examples reported of carcinoma developing
repeated surgical manipulation(s) may represent a in:

primary factor in introducing neoplastic foci into Primary pleomorphic adenoma at some point
vascular channels (iatrogenic implantation) resulting subsequent to metastases
in metastatic disease; however, arguments against Metastatic pleomorphic adenoma
this postulation include: Immunohistochemistry:
m Intravascular tumor foci not identified in reported m Primary and metastatic foci share similar immu-
cases of metastasizing pleomorphic adenoma nostaining as nonmetastasizing pleomorphic

m Vascular permeation in pleomorphic adenomas adenoma (see previous discussion on pleomor-
does not result in metastasis. phic adenoma).
Pathology m No difference in DNA ploidy analysis between
Fine-Needle Aspiration Biopsy primary, recurrent, or metastatic tumors

Identical to the aspiration of a nonmetastasizing m FISH analysis in a small number of cases has
pleomorphic adenoma (see previous): identified the presence of two related hypodiploid
m Metastatic lesions contained benign epithelial, clones in skeletal metastases that differ from
myoepithelial, and stromal components. cytogenetic profile of conventional pleomor-
Cells may be slightly atypical but the cytologic find- phic adenoma, suggesting presence of tumor
ings are not those of a carcinoma. suppressor genes in metastasizing pleomorphic
adenoma.
Gross
Primary tumors are conventional pleomorphic Differential Diagnosis
adenoma including well-circumscribed to encapsu- Other categories of malignant mixed tumors
lated solitary mass. In osseous and less so in nonosseous locations, diag-
Recurrent tumors may be a single mass or, as often nostic considerations may include primary chon-
occurs in recurrent pleomorphic adenomas, may be droid and chondroid-related tumors, including
multinodular. chondrosarcoma and chordoma.
Metastatic tumors may be a single mass lesion or Chondroid hamartoma of the lung:
multiple lesions and often appear well circumscribed m Cartilaginous nests surrounded by cellular
or delineated and may even be encapsulated. fibrous tissue and presence of adjacent alveoli
Cut surface, particularly in recurrent tumor but also and bronchioles assist in identifying chondroid
in primary or metastatic tumor, may show a promi- hamartoma.
nently glistening appearance due to predominant
chondromyxoid stroma. Treatment and Prognosis
Tumor size, whether primary, recurrent, or meta- Preferred treatment is complete surgical excision of
static tumor, ranges from less than 1cm to as large all tumor foci (primary, recurrent, metastases).
as 15cm. Adjunct radiotherapy has been used, but its
efficacy in treatment of metastatic tumor is
Histology questionable.
Identical to that of pleomorphic adenoma including High recurrence rate with approximately 90%
admixture of epithelial, myoepithelial, and chondro- of patients experiencing one or more recurrence of
myxoid stroma: their pleomorphic adenoma at primary site of
m In any given tumor any of these histologic com- occurrence
ponents may predominate such that the histologic Prognosis is generally good even with metastatic
spectrum includes: disease; however, death may occur from metastatic
Epithelial predominant disease:
Myoepithelial predominant m Mortality rates range from 20% to 37%.
Stromal predominant m Death reported from as early as 6 months after
Metastatic foci histologically similar to primary and/ discovery of metastasis to years later
or recurrent tumor(s) m More aggressive clinical course reported in
All tumor foci whether primary, recurrent, or metas- immunocompromised patients (e.g., cardiac
tasis lack evidence of malignancy, including an transplantation)
BASAL CELL Clinical

ADENOCARCINOMA Uncommon salivary gland neoplasm
(Figs. 20-99 and 20-100) No gender predilection; occurs over a wide age range
but most frequently seen in fourth to ninth decades
Definition: Low-grade malignant epithelial salivary of life; rarely occurs in children
glands neoplasm with features of basal cell adenoma but Most commonly occurs in parotid gland (superficial
with infiltrative growth and potential for metastatic lobe):
disease m Approximately 90% occur in parotid gland
m Considered malignant counterpart of basal cell m Less common sites of occurrence include subman-
adenoma. dibular gland and minor salivary glands.

Synonyms: Malignant basal cell adenoma; basal cell Symptoms relate to mass with or without associated
carcinoma; basaloid salivary carcinoma; carcinoma ex pain or tenderness; duration of symptoms may be
monomorphic adenoma from months to years.
A B
C D
Fig. 20-99. Basal cell adenocarcinoma of the parotid gland.

A, At low magnification the tumor is unencapsulated, infiltrative into the parotid parenchyma (top), and composed of solid
and trabecular growth. B, Higher magnification shows tumor nests infiltrating parotid parenchyma. C, Basaloid cell
proliferation composed of pleomorphic nuclei and increased mitotic activity. D, Perineural and perivascular invasion. The
cytologic atypia contrast to basal cell adenoma, which typically are composed of cytomorphologically bland-appearing
nuclei. In some examples of basal cell adenocarcinoma there may be an absence of cytologic atypia (see next illustration).
Fig. 20-100. Basal cell adenocarcinoma of minor salivary glands.

A, Submucosal infiltrative tumor characterized by trabecular and lobular growth; note the intact surface epithelium to the
extreme left. B, Neoplastic cells include admixture of smaller cells with hyperchromatic nuclei and larger cells with
vesicular nuclei; note the bland-appearing cells lacking significant nuclear pleomorphism and mitotic activity. C, Solid area
composed of uniform basaloid-appearing cells. The cytomorphologic features seen in B and C could be those of a basal
cell adenoma. However, in contrast to basal cell adenoma, there is infiltrative growth in basal cell adenocarcinoma,
including (D) peri- and intraneural invasion (arrow) and lymph-vascular invasion (arrowhead). Although not illustrated here
invasion of salivary gland parenchyma would also support a diagnosis of basal cell adenocarcinoma rather than basal cell
adenoma in those cases with shared bland cytomorphologic findings.
Most arise de novo but may occur in asso In infants presence of hybrid basal cell adenoma and
ciation with or develop from a basal cell adenoid cystic carcinoma represents sialoblastoma
adenoma: (see Sialoblastoma).
m Most often membranous type of basal cell
adenoma Pathology
m Reported to occur in 23% of cases Gross
Concomitant dermal eccrine cylindroma may be Circumscribed but unencapsulated, solid, tan-white
identified, suggesting a salivary gland-skin adnexal mass varying in size from 0.7 to 4cm in diameter;
diathesis. cystic foci may be focally identified.
Suggestion that basal cell adenocarcinoma represents
the solid variant of adenoid cystic carcinoma, but Fine-Needle Aspiration Biopsy
differences in histology and biology support separate Aspiration findings are essentially identical to those
classification. of basal cell adenoma (see previous).
Histology of many basal cell adenocarcinomas is m Invasion of adjacent structures (e.g., salivary
similar to basal cell adenoma but features of malig- gland parenchyma, soft tissue structures)
nancy may be present and identifiable by FNAB, m Lymph-vascular invasion
including: m Neurotropism (e.g., perineural or intraneural
m Marked nuclear pleomorphism with increased invasion)

nuclear-to-cytoplasmic ratio Histochemistry:
m Increased mitotic activity m In general, PAS- and mucicarmine-positive mate-
m Necrosis rial is absent or minimally present within the

basal cell adenocarcinoma; PAS-positive material
Histology may be seen within tubular lumens.
Morphologic similarity to basal cell adenoma Immunohistochemistry:
including: m Consistent and diffuse pan-cytokeratin (AE1/
m Variably sized nodules or islands of tumor cells AE3) positive

growing in solid, trabecular, membranous, and/ m Most are reactive for CK14 with variable reactiv-
or tubular patterns ity for CK7, 8, 18, 19

m Variety of morphologic patterns can be seen in m Vimentin positive
any given neoplasm. m Focal reactivity for S100 protein, smooth muscle
m Solid growth with tumor nests separated by actin (usually peripherally located cells), carcino-
eosinophilic basal lamina (i.e., membranous embryonic antigen, epithelial membrane antigen
pattern) or trabecular pattern is most frequent m c-kit (CD117) immunoreactivity reported
Lesional cells composed of uniform, basaloid epithe- m Low proliferation rate (<5%) as seen by Ki67
lial cells consisting of two cell types: staining

m Large round to polygonal to elongated cell with Electron microscopy:
pale staining basophilic nuclei, eosinophilic to m Similar to basal cell adenoma with evidence of
amphophilic cytoplasm, and indistinct cell differentiation along basal, myoepithelial, and
borders ductal cell lines:
m Small, round cell with dark (basophilic) nuclei, Basal cells: rough endoplasmic reticulum, mito-
scant cytoplasm and indistinct cell borders: chondria, tonofilaments, and desmosomes
Tend to be located peripheral to the larger cells Myoepithelial cells: cytoplasmic myofilaments,
Peripheral palisading of nuclei may be seen but plasmalemmal extensions, and desmosomes
tends to be less prominent as compared with Ductal cells: microvilli, tight junctions, and
basal cell adenoma. desmosomes
m Of the two cellular components larger cells tend Cytogenetics and molecular genetics:
to be more common, although in any given tumor m Chromosomal gains and losses, including:
they may be seen in equal proportion. Gains: 9p21.1-pter, 18q21.1-q22.3, 22q11.23-

m Overall cytomorphology may be predominantly q13.31
bland, lacking significant nuclear pleomorphism, Losses: 2q24.2, 4q25-q27
increased mitotic activity, or necrosis. m Loss of heterozygosity with high frequency at
Nuclear pleomorphism, increased mitotic 16q12-13 regions:

activity, and necrosis may be seen but not Seen in sporadic cases and in cases of familial
consistently identified or diagnostic for basaloid tumors and dermal cylindroma
carcinoma. cases
Eosinophilic, hyalinized, PAS-positive basal lamina m Absence of MYB-NFIB fusion transcript
can be seen either as intercellular droplets or peri- Hybrid tumor:

nodule membranes. m May occur as part of a hybrid salivary gland
Additional findings may include presence of: tumor in association with other salivary gland
m Tubular structures may focally be present. tumors (e.g., adenoid cystic carcinoma)
m Squamous differentiation:
Identified in approximately 25% of cases Differential Diagnosis

m Spindle-shaped cells Basal cell adenoma:
m Cystic or cribriform patterns may be present. m Presence of invasive growth distinguishes basal
A stromal benign lymphoplasmacytic cell infiltrate cell adenocarcinoma from basal cell adenoma
may be present. Cellular pleomorphic adenoma
Histologic hallmark for diagnosis of basal cell ade- Adenoid cystic carcinoma:
nocarcinoma rests on the identification of infiltration m In contrast to basal cell adenocarcinoma, adenoid
as manifested by: cystic carcinomas:

Have prominent cribriform pattern of growth

with pseudocyst formation (features usually EPITHELIAL-MYOEPITHELIAL
not present in basal cell adenocarcinoma) CARCINOMA (EMC)
Lack dual cell population (mixture of small (Figs. 20-101 through 20-105)
and large cells seen in basal cell adenocar
cinoma) Definition: Low-grade malignant epithelial salivary
Lack peripheral nuclear palisading gland neoplasm characterized by presence of ductal
Lack squamous differentiation structures composed of two cell types, including inner
Presence of MYB-NFIB fusion transcript (luminal) epithelial cells and outer (abluminal) myoepi-
Myoepithelial carcinoma thelial cells.
Basaloid squamous cell carcinoma Synonyms: Clear cell adenoma/carcinoma; glycogen-
Adamantinoma-like Ewing sarcoma (AES): rich clear cell adenoma/carcinoma; clear cell carcinoma;
m Rare variant of the Ewing family of tumors that tubular carcinoma; adenomyoepithelioma
resembles classic adamantinoma of bone
m AES shows epithelial differentiation and complex Clinical
immunohistochemical expression profile with Uncommon salivary gland neoplasm
keratin and basal marker immunoreactivity and Slightly more common in women than in men; may
can resemble a variety of carcinomas. occur over a wide age range but is most frequently
m May rarely occur in parotid gland histologically encountered in the sixth to seventh decades of life
simulating basal cell adenocarcinoma including: Approximately 75% to 80% occur in parotid gland:
Nested basaloid proliferation with peripheral m Other sites of involvement include submandibu-
palisading in tumor nests lar gland and minor salivary glands throughout
Basaloid epithelial differentiation by cyto- the upper aerodigestive tract including:
keratin (AE1/AE3) and p40 positivity Oral cavity (palate)
Unlike most basal cell adenocarcinomas, AES Sinonasal tract
demonstrate: Symptoms usually relate to asymptomatic, slow-
High grade morphology growing mass:
Absence of true ductal or myoepithelial m Associated pain and/or facial nerve paralysis
component occur infrequently

Tendency toward neuroectodermal pheno- m Ulceration of a mucosal-based lesion may be
type with focal rosette formation, CD99, and present

weak synaptophysin immunoreactivity m Duration of symptoms ranges from months to
Presence of EWSR1 and FLI1 fluorescence in years

situ hybridization confirms presence of translo-
cation supporting diagnosis. Pathology
Gross
Treatment and Prognosis Well-circumscribed but unencapsulated, solid, firm,
Complete surgical excision is the preferred tan-white to yellow mass measuring from 1 to 12cm
treatment: in greatest dimension
m For parotid gland, superficial parotidectomy Hemorrhage and necrosis may occasionally be
m For submandibular gland, complete glandectomy identified.
m For minor salivary gland, wide excision to include Minor salivary gland involvement may be associated
tumor-free margins with mucosal ulceration.
Unless lymph node involvement is clinically evident,
neck dissection would not appear warranted. Fine-Needle Aspiration Biopsy
Local recurrences frequent especially for tumors of Smears generally cellular with no specific architec-
minor salivary glands: tural pattern
m 71% for minor salivary gland tumors Biphasic pattern including epithelial (small cell) and
m 37% for major salivary gland tumors myoepithelial (large/clear cell) may be identified:
Metastatic disease is uncommon: m Epithelial cells are small.
m Occurs in 21% of minor salivary gland cases m Myoepithelial cells are large with abundant clear
m Occurs in 11% of minor salivary gland cases cytoplasm, distinct cell borders, and uniform,
m Involves regional lymph nodes and rarely small nuclei.
lungs m Biphasic pattern may be subtle or absent since the
Prognosis is generally excellent: clear cells have a fragile cytoplasm and often
m Death due to disease is uncommon. appear as naked nuclei.
Fig. 20-101. Epithelial-myoepithelial carcinoma.

Epithelial-myoepithelial carcinoma of the parotid gland. A, Unencapsulated tumor invading into the parotid gland
parenchyma (lower left). B, Characteristic tubular growth composed of a dual cell population with luminal or inner epithelial
cell layer appearing as dark staining cuboidal to columnar cells with central or basally placed nuclei and eosinophilic
cytoplasm and outer abluminal or outer myoepithelial cell layer appearing as polyhedral-shaped cells with eccentrically
placed nuclei, abundant clear cytoplasm, and distinct cell borders; C through E, cytokeratin (CAM5.2) shows dedicated
reactivity of the luminal cells while dedicated staining of the outer myoepithelial cells by (D) p63 (nuclear) and (E) S100
protein (nuclear and cytoplasmic).
Single cells and naked nuclei were prominent in all

cases.
Globules of hyalinized basal lamina may occasion-
ally be seen.
Histology
Circumscribed but unencapsulated tumors:
m Often multinodular or multilobulated
Infiltration present and includes invasion into

adjacent/surrounding salivary gland parenchyma,
neurotropism, perivascular invasion, angioinvasion,
and osseous invasion.
Tumor nests frequently have an organoid arrange-
ment but may also have a cystic, papillary, and/or
solid growth.
Fig. 20-102. Epithelial-myoepithelial carcinoma. Histologic hallmark is presence of two cell types
Often these tumors are infiltrative including neurotropism identified in varying proportions in any given tumor:
(left) and invasion into adipose tissue (right). m Luminal or inner epithelial cell layer:
Dark staining cuboidal to columnar cells with

central or basally placed nuclei and scant eosin-
ophilic cytoplasm
A B C D
E F

Variant growth patterns and cell types may include (A) solid and trabecular; (B) cribriform; (C) small tubules; (D) cordlike;
(E) solid; and (F) fascicular composed of spindle-shaped cells. In some of these examples there is overgrowth of the
myoepithelial cell component obscuring the epithelial cell component.
A
Prominent hyalinization may be present.
Verocay-like nuclear palisading may be

identified
Spindle shaped or elongated
Lesional cells show mild to moderate pleomorphism

but marked cytomorphologic atypia not typically
seen:
m Mitotic activity is absent to low (2 mitoses or
fewer per 10 high-power fields)

m Necrosis usually absent but may be present within
the center of tumor lobules

B m Ancient changes in form of focal marked
nuclear pleomorphism (similar to monster

cells in pleomorphic adenomas) may be
Fig. 20-104. Epithelial-myoepithelial carcinoma. present
Additional variant findings in epithelial-myoepithelial Tumor nests variably separated by thin fibrovascular
carcinoma may include (A) tumors with myoepithelial cell stroma to loose myxoid stroma to basement
overgrowth predominated by cells with clear cytoplasm membrane-like material that may be thickened
with limited but identifiable epithelial component appearing as eosinophilic, hyalinized membrane that
characterized by tubular growth composed of luminal cells is PAS positive.
with eosinophilic cytoplasm; (B) double clear cell variant in Histologic variants include:
which both luminal and abluminal cells are composed of m Oncocytic variant
cells with clear cytoplasm.
Uncommon variant constitute up to 8% of all
EMCs
Oncocytic EMC:
Surround small lumens, which may appear Occurs in patients decades older than con-
cystic and contain eosinophilic proteinaceous ventional EMC

material Often papillary with calcification and associ-
m Abluminal or outer myoepithelial cell layer: ated sebaceous components

Polygonal cells with eccentrically placed nuclei, Apocrine variant
abundant clear cytoplasm, and distinct cell Named for its apocrine ductal component
borders May be mistaken for salivary duct

Variant myoepithelial morphologies may carcinoma.
include: Epithelial component often shows over-
Predominance of myoepithelial cells espe- growth in a cribriform or even solid
cially in tumors with solid growth that pattern.
may obscure epithelial cell layer: referred to Immunophenotypically defined by androgen
as EMC with myoepithelial overgrowth; receptor and gross cystic disease fluid protein
15 positivity. The most important aspect of Mucicarmine negative but rarely may be
differentiating oncocytic and apocrine EMC positive
from other salivary oncocytic tumors is rec- Immunohistochemistry:
ognition of the biphasic nature of these vari- m Luminal or inner epithelial cells:
ants and confirmation that the abluminal Cytokeratins and EMA:

outer layer consists of plump, activated Strongly positive
myoepithelial cells, regardless of tinctorial Dedicated CAM5.2 staining
characteristics. S100 protein and SOX10 variably immunore-

Oncocytic and apocrine variants have indolent active
biology. Absence of myoepithelial markers
m Double clear cell variant: m Abluminal or outer (myoepithelial) cells:
Luminal and abluminal cells composed of cells p63, S100 protein, calponin, smooth muscle
with clear cytoplasm actin, smooth muscle myosin heavy chain,
Usually predominated by clear-appearing epi- muscle-specific actin and SOX10 positive
thelial cells often columnar and stratified con- Cytokeratin and EMA variably and often
taining large-caliber tubules weakly reactive:
Surrounding myoepithelial cells also typically Absence of CAM5.2
clear appearing GFAP occasionally reactive

m Sebaceous variant: Low proliferation rate (<5%) as seen by Ki67
Rare occurrence staining
Histologically show areas of sebaceous differ- bcl-2 and c-kit frequently positive
entiation admixed with features of bilayered DOG1 may be positive, showing combined
ductal structures typical of EMC apical ductal and membranous/cytoplasmic
Sebaceous differentiation may be diffusely or myoepithelial staining profile
focally identified. Renal cell carcinoma marker, CD10, PAX2,
Generally lack cytologic atypia PAX8, and CAIX negative
Positive immunoreactivity for EMA confirmed Electron microscopy:
sebaceous differentiation m Luminal or inner epithelial cells:
Low-grade malignancy similar to conventional Lumina, microvilli, junctional complexes,

EMC desmosomes
m EMC ex pleomorphic adenoma Golgi complexes, dilated endoplasmic reticu-
May be malignant component in carcinoma ex lum, dense core secretory granules, tonofila-
pleomorphic adenoma (EMC ex pleomorphic ments
adenoma) m Abluminal or outer (myoepithelial) cells:
m EMC with myoepithelial anaplasia Intracytoplasmic microfilaments with focal

Represents progression to histologically higher- densities, subplasmalemmal plaques, and mul-
grade EMC tilayered basal lamina
Characterized by solid growth, increased Fewer organelles as compared with epithelial
nuclear atypia in more than 20% of myoepi- cells
thelial cells, and increased mitotic activity Cytogenetics and molecular genetics:
Transition to severe nuclear atypia in myoepi- m To date, no translocation has been identified but
thelial cells gradual rather than abrupt with a limited number of cases evaluated found HRAS
intervening areas of moderate nuclear atypia exon 3, codon 61 mutation.
Anaplastic component may include transi- m Classic (low-grade) EMC lack MYB translocation
tion to squamous cell carcinoma. Hybrid tumor:

Associated with worse prognosis m May occur as part of a hybrid salivary gland
Histochemistry: tumor in association with other salivary gland

m Luminal or inner epithelial cells: tumors (e.g., adenoid cystic carcinoma [AdCC],
May show diastase-resistant, PAS-positive salivary duct carcinoma, others)
intracytoplasmic material m Hybrid EMC-AdCC may harbor MYB
Mucicarmine negative translocation.
Luminal eosinophilic material is PAS positive High-grade transformation (dedifferentiation)
and mucicarmine negative of EMC:
m Abluminal or outer (myoepithelial) cells: m Rare occurrence
May show diastase-sensitive, PAS-positive m Transition from foci of EMC to histologic high-
intracytoplasmic material grade carcinoma characterized by nuclear

pleomorphism, increased mitotic activity, and Absence of biphasic cell pattern, prominent
necrosis fibrovascular stroma, and presence of CD10,
m Ki67 labeling index significantly increased in renal cell carcinoma marker, PAX2, PAX8, and
high-grade carcinoma component as compared CAIX immunoreactivity
with foci of EMC m Thyroid carcinoma:
m Associated with worse prognosis Absence of biphasic cell pattern and presence
m May harbor MYB translocation suggesting close of thyroglobulin and thyroid transcription
relationship (or possibly a variant) to adenoid factor 1 (TTF-1) immunoreactivity
cystic carcinoma
Complete surgical excision is preferred treatment.
Differential Diagnosis Adjunctive radiotherapy used in cases in patients
(Table 20-10) whose tumors cannot be completely excised or when
Clear cell oncocytoma there is doubt as to the completeness of surgical
Clear cell myoepithelioma resection
Mucoepidermoid carcinoma, clear cell variant Local recurrence is frequent occurrence seen in 30%
Acinic cell adenocarcinoma, clear cell variant to 50% of patients:
Primary salivary gland clear cell carcinoma m Most recurrences within 5 years of the initial
Metastatic tumors composed of clear cells, a rare resection but may also occur many years or
phenomenon, including: decades after initial surgery
m Renal cell carcinoma: m Multiple recurrences may occur
TABLE 20-10 Salivary Gland Tumors with Clear Cells: Differential Diagnosis
Tumor Histology Histochemistry IHC Cytogenetics
EMC Dual cell population: (1) Epithelial cells: diastase- Epithelial cells: Limited number of
luminal or inner epithelial resistant, PAS-positive cytokeratin (AE1/AE3, cases positive for
cell layer composed of dark intracytoplasmic CAM5.2) and EMA HRAS exons 3,
staining cuboidal to material, mucicarmine positive. Myoepithelial codon 61 mutations
columnar cells with negative. Myoepithelial cells: S100 protein, p63,
eosinophilic cytoplasm (clear) cells: diastase- calponin, SMA positive
surrounding small lumens sensitive, PAS-positive
and (2) abluminal or outer intracytoplasmic
myoepithelial cell layer material; mucicarmine
polyhedral cells with negative. Intraluminal
eccentrically placed nuclei, eosinophilic material:
abundant clear cytoplasm PAS-positive and
and distinct cell borders mucicarmine negative
CCC (hyalinizing Dominated by cells with Diastase-sensitive, Cytokeratin and EMA EWSR1-ATF1
and non- clear cytoplasm; cells with PAS-positive; positive; limited to (hyalinizing CCC)
hyalinizing) slightly eosinophilic mucicarmine negative absent reactivity for
appearing cytoplasm may myoepithelial cell
be seen scattered markers including S100
throughout the tumor; protein, p63, calponin,
stromal hyalinization may or SMA
may not be present
MEC, clear cell Pure clear cell variant of Diastase-resistant, Cytokeratin positive; CRTC1-MAML2
type MEC likely nonexistent; PAS-positive; p63 positive but other
clear cells are round to oval mucicarmine positive myoepithelial cell
cells with clear cytoplasm, markers negative,
distinct cell borders, including S100 protein,
peripherally-placed, small, calponin, SMA
dark nuclei; clear cells may
be seen and infrequently
may predominate but areas
of residual MEC including
admixture of mucocytes,
epidermoid cells and
intermediate cells present
Continued
TABLE 20-10 Salivary Gland Tumors with Clear Cells: Differential Diagnosiscontd
Tumor Histology Histochemistry IHC Cytogenetics
ACC, clear cell Clear cells round to oval, Diastase-resistant, Cytokeratin, DOG1 None known
type distinct cell borders, small PAS-positive; positive; myoepithelial
peripherally placed dark mucicarmine negative cell markers negative,
nuclei; clear cells result including S100 protein,
from fixation and/or tissue p63, calponin, SMA
processing; pure clear cell
variant likely does not exist
Oncocytoma, Partial or complete Diastase-sensitive, Cytokeratin, EMA None known
clear cell type replacement of granular PAS-positive granules; positive; myoepithelial
eosinophilic cytoplasm by oncocytes show cell markers negative,
cells with clear, intracytoplasmic including S100 protein,
nongranular-appearing blue-black granules by p63, calponin, SMA
cytoplasm; transition areas PTAH staining
of typical oncocytes to clear
cells may be present; other
than the cytoplasmic
appearance, the histology
and histochemical staining
is similar to the more
conventional type of
oncocytoma; clear
cytoplasm is due in part to
fixation and tissue
processing artifact, and to
accumulation of glycogen
within the cytoplasm
displacing the mitochondria
to the periphery of the cells
Myoepithelioma Clear cells have defined cell Clear cells are diastase- Cytokeratins, EMA, p63, EWSR1-ATF1
and membranes; one cell type sensitive, PAS-positive; calponin, S100 protein, reported in clear
myoepithelial among several different mucicarmine negative SMA, vimentin positive cell type of
carcinoma, clear cell types seen in myoepithelial
cell type myoepithelioma with carcinoma
transition areas of typical
myoepithelial cells to clear
cells present
RCC Cell nests separated by thin Clear cells are diastase- Cytokeratins (AE1/AE3, Partial or complete
fibrovascular cores; clear sensitive, PAS-positive; CAM5.2), EMA, CD10, chromosome 3 loss
cells have sharp cell mucicarmine negative renal cell marker, PAX2, or mutation on
membranes; red cells PAX8, CAIX, vimentin short arm
characteristically seen within positive; HMWCK, CK7 chromosome 3p;
luminal spaces and CK20 negative; alterations in
myoepithelial cell chromosomes 14,
markers, GATA3 8, and 9
negative
TC, papillary or Metastasis from thyroid in Clear cells are typically Cytokeratins, RET/PTC and BRAF
follicular types general is rare and one PAS and mucicarmine thyroglobulin, TTF1, mutations for
entirely comprised of clear negative; colloid is positive; myoepithelial more usual
cells unlikely; in this diastase-resistant, cell markers negative types of papillary
scenario clear cells PAS-positive carcinomas; RAS
represent part of metastatic mutation for
cellular composition that follicular variant
includes follicular epithelial papillary thyroid
cells with or without carcinoma, follicular
identifiable colloid, and with adenoma, follicular
or without nuclear features carcinoma
of thyroid papillary
carcinoma; clear cells have
abundant clear to slightly
granular appearance
ACA, Acinic cell adenocarcinoma; CAIX, carbonic anhydrase 9; CCC, clear cell carcinoma (nonhyalinizing and hyalinizing); EMA, epithelial
membrane antigen; EMC, epithelial myoepithelial carcinoma; MEC, mucoepidermoid carcinoma; PAS, periodic acid Schiff; PTAH,
phosphotungstic acid hematoxylin; RCC, renal cell carcinoma; TC, thyroid carcinoma; SMA, smooth muscle actin; TTF1, thyroid
transcription factor 1.
Metastatic tumor: m Connection to surface mucosa in many cases

m Metastases occur most often to regional (cervical m Presence of consistent diffuse p63 immunoreac-
and periparotid) lymph nodes: tivity
Reported in up to 20% of cases m Ultrastructural presence of tonofilaments, well-
m Less common, distant metastases occur primarily formed desmosomes, and hemidesmosomes
to lungs, kidney, and brain: m Presence of squamous and mucinous differentia-
Reported in less than 10% of cases tion may indicate HCCC is a low-grade scleros-
m Metastases may occur 10 years or more after the ing adenosquamous carcinoma
initial resection. m Other evidence show similarities to clear cell
In general, the prognosis is excellent: odontogenic carcinoma (CCOC) except by loca-

m 5-year survival rate reported to be 80% tion including similar:
m 10-year survival rate reported to be 72% Histology
m Death may occur restricted to but not always seen EWSR1-ATF1 rearrangements (a finding not
in cases with metastatic tumor present in other clear cell neoplasms in the dif-
Factors associated with adverse prognosis include: ferential diagnosis)
m Large tumor size Until more clearly defined as being separate from
m Rapid growth CCC, both types of clear cell neoplasms are included
m Occurrence in minor salivary glands (likely under a single category with the possibility that
related to incomplete surgical resection) future classification may separate these two
m Solid growth pattern entities.
m Nuclear atypia in greater than 20% of the tumor
m DNA aneuploidy Clinical

m High proliferative activity Uncommon tumor
Factors affecting disease-free survival include: No gender predilection; primarily identified in the
m Positive margin status fifth through eighth decades of life; rare in children
m Presence of angiolymphatic invasion Most frequently occur in intraoral sites:
m Presence of necrosis m Palate and base of tongue most common sites of
m Presence of myoepithelial anaplasia occurrence

Other intraoral sites include buccal mucosa,
floor of mouth, tongue, lip, retromolar area,
and tonsillar region
CLEAR CELL CARCINOMA m Other less common sites of occurrence include:
(CCC) AND HYALINIZING Major salivary glands: parotid gland sub-
VARIANT (HCCC) mandibular gland
(Figs. 20-106 through 20-108) Nasopharynx, hypopharynx, larynx, lacrimal
gland
Definition: Malignant epithelial salivary gland tumor Most commonly present as an asymptomatic
composed exclusively of monomorphic population of swelling
cells characterized by their clear-appearing cytoplasm m Pain and mucosal ulceration may be present;
(with or without stromal hyalinization) without evi- osseous invasion and fixation to surrounding
dence of myoepithelial differentiation and lacking his- tissues may occur.
tomorphologic features of other salivary gland neoplasms
that may be dominated by a prominent population of Pathology
clear cells (e.g., mucoepidermoid carcinoma, acinic cell Gross
adenocarcinoma, epithelial-myoepithelial carcinoma, Poorly circumscribed, solid mass with a gray-white
myoepithelial carcinoma, others). appearance usually measuring 3cm or less in great-
Synonyms: Clear cell adenocarcinoma; hyalinizing est dimension
clear cell adenocarcinoma; glycogen-rich clear cell Prominent hyalinization may be grossly appreciated,
carcinoma imparting a scar-like/fibrotic appearance.
Infiltration of adjacent tissues may be identified.
Classification Fine-Needle Aspiration Biopsy

Evidence suggests that HCCC may represent a squa- Aspirates contain numerous groups and sheets of
mous mucosal-derived neoplasm rather than a neo- cohesive small and large epithelial cells:
plasm of seromucous gland origin; such evidence m Groups and sheets, which had sharp outlines and
includes: showed focal nuclear overlapping

A B
C D
Fig. 20-106. Clear cell carcinoma of minor (oral cavity) salivary glands.
A, Submucosal unencapsulated and infiltrative tumor with trabecular solid, nested growth; the tumor is infiltrative into
seromucous glands (lower right). B, Another example characterized by diffuse proliferation of cells exclusively composed
of cells with clear cytoplasm. C, At higher magnification the entire neoplasm is comprised of cells with clear-appearing
cytoplasm, distinct cell membranes, and rather bland-appearing nuclei lacking significant nuclear pleomorphism and
increased mitotic activity. D, The lesional cells are p63 negative.
Cells have uniform, round to ovoid nuclei, granular- m Lesional cells characterized by presence of abun-
appearing chromatin, small nucleoli, and abundant, dant clear-appearing cytoplasm:
well-defined clear-appearing cytoplasm. May predominate in any given lesion
Myoepithelial cells or hyaline globules are absent. Cells with slightly eosinophilic-appearing cyto-
plasm may be admixed with clear-appearing
Histology cells.
Clear cell carcinoma (CCC) Nuclei are oval to round with finely granular-
m Unencapsulated infiltrative submucosal neoplasm appearing chromatin, centrally to eccentrically
with solid sheets, nests, cords, trabeculae, and located and inconspicuous to small nucleoli.
single-cell growth patterns: Cell borders/membranes are distinct.
Ducts and gland-like spaces typically not m Cytomorphologically, cells are uniform in appear-
identified ance with mild nuclear pleomorphism, although

But may focally be seen although such struc- moderate pleomorphism may be present, scarce
tures may represent entrapped non-neoplastic to absent mitotic figures; necrosis is not usually
ducts identified.
m Lesional cells may extend and involve overlying m Stromal findings include minimal collagen depo-
surface (squamous) epithelium. sition, appearing as interconnecting fibrous septa.

A B
C D
Fig. 20-107. Hyalinizing clear cell carcinoma of minor (oral cavity) salivary glands.
A, The tumor is characterized by the presence of markedly thickened bands of sclerotic or hyalinized collagen in which
nests and cords of lesional cells are seen. B, In contrast to clear cell carcinoma without hyalinization, which is exclusively
composed of clear cells, in this tumor there is an admixture of cells with pale eosinophilic cytoplasm with clear cells rather
than exclusively composed of clear-appearing cells. C, However, a predominance of clear cells may be seen in a minority
of cases. Irrespective of the nature of the cytoplasm the cells are rather uniform with round to oval nuclei lacking
significant pleomorphism and distinct cell membranes. D, The lesional cells are diffusely p63 immunoreactive.
m Histochemistry: m Electron microscopy:

Intracytoplasmic diastase-sensitive, PAS- Features of duct cell differentiation including
positive material indicative of glycogen microvilli, tight junctions, desmosomes, tono-
Mucicarmine staining usually negative filaments, and basal lamina
m Immunohistochemistry Absence of myoepithelial differentiation
Cytokeratins including high molecular weight m Cytogenetics and molecular genetics:
focally to diffusely positive No specific findings

CEA positive Hyalinizing clear cell carcinoma (HCCC)
Myoepithelial markers typically negative m Unencapsulated infiltrative submucosal neoplasm
including S100 protein, p63, actins, calponin, characterized by presence of markedly thickened
and GFAP bands of sclerotic or hyalinized collagen:
Renal cell carcinoma (RCC) antibody, CD10, Hyalinized stroma may be intimately admixed
PAX2, PAX8, and CAIX negative with lesional cells, creating a somewhat
cribriform arrangement that may simulate

other more common salivary gland tumors
In addition, a fibrocellular stroma that may
appear myxoid (similar to pleomorphic
adenoma) may be seen.
Juxtaposition of two stroma types within the
tumor essentially pathognomonic seen in most
but not all cases

m Predominance of clear cells seen in a minority of
cases:
Often cells with pale eosinophilic cytoplasm
rather than clear cytoplasm are seen or there is
A an admixture of both cell types.
Nuclei are oval to round with finely granular-
appearing chromatin, centrally to eccentri
cally located and inconspicuous to small
nucleoli.
Cell borders/membranes are distinct.
Raisinoid or popcorn-appearing nuclear
membrane irregularities may be seen.
Occasional pseudonuclear inclusions may be
present.

m Cytomorphologically, cells are rather uniform in
appearance with mild nuclear pleomorphism
scarce to absent mitotic figures; necrosis is not
usually identified.

m Cells are arranged in small nests, short and long
B cords, interconnecting thin trabecular structures,
and single cells.
Tendency for cells in center of mass to be sur-
rounded by or admixed with a hyalinized base-
ment membranelike material
Cells often sharply demarcated from desmo-
plastic or fibrocellular stroma
Cells at periphery have greater tendency for
nest formation and for infiltration without
stromal deposition or desmoplastic response.
May appear in short thin cords
Owing to absence of desmoplasia such cells at
periphery may be difficult to appreciate by light
microscopy

m Tumors often connect to surface mucosal epithe-
lium either abruptly or as pagetoid-like growth
C of single cells and may be accompanied by pseu-
doepitheliomatous hyperplasia.
Fig. 20-108. Clear cell carcinoma of minor (oral
m Other findings may include:
cavity) salivary glands. Occasional presence of focal squamous
differentiation
The tumor is infiltrative, including (A) invading into and
Occasional duct formation, which may be true
through palatal bone and (B) perineural invasion, the latter
confirmed by (C) S100 protein staining. ductal differentiation in the neoplasm or more
likely represents entrapped ducts:
Particularly common in parotid gland cases
and absent in oral cavity cases

m Histochemistry:
Intracytoplasmic diastase-sensitive, PAS-
positive material indicative of glycogen
Mucicarmine staining may show dot-like or m Thyroid carcinoma:

frank intracytoplasmic positive material in a Presence of thyroglobulin and thyroid tran-
high proportion of cases. scription factor 1 (TTF-1) immunoreactivity
Congo red staining for amyloid is negative.
m Immunohistochemistry Treatment and Prognosis
Majority diffusely positive for pancyto Complete surgical resection is preferred treatment.
keratin Considered to be a low-grade malignancy associated
In addition, most cases positive for high molec- with a good prognosis following complete surgical
ular weight cytokeratins, p63 (suggestive of excision
squamous differentiation), and CK14 Overall prognosis considered to be excellent:
Many cases focally or diffusely positive for m Local recurrence may occur in up to 17% of
EMA, CK7, CK19, and CAM5.2 cases.

Negative for myoepithelial-related markers m May occasionally metastasize to regional lymph
including S100 protein, actins, calponin, and nodes or metastasize distantly (e.g., lungs):
GFAP Although usually very low rates of metastatic
Renal cell carcinoma antibody, CD10, PAX2, disease, nodal metastasis at presentation
PAX8, and CAIX negative reported in 25% of cases
m Electron microscopy: m Death due to disease rarely may occur.
Shown to have tonofilaments, well-formed des- Rare example of high-grade transformation of

mosomes, and hemidesmosomes: HCCC reported, raising the possibility that HCCC
These features suggestive of squamous may represent yet another tumor type that can
differentiation transform to a histologically higher grade neoplasm
Additional findings include basal lamina. with potential for more aggressive biologic
m Cytogenetics and molecular genetics: behavior
Consistent EWSR1-ATF1 gene fusion:
Represents another lesion type associated
with EWSR1-ATF1 gene fusion (see Table SALIVARY DUCT

20-2) CARCINOMA (SDC)
This molecular signature not present in other
(Figs. 20-109 through 20-112)
clear cell neoplasms that may share features
with HCCC; notable exception is clear cell Definition: High-grade malignant epithelial salivary
odontogenic carcinoma gland neoplasm arising from the excretory ducts histo-
Infiltration often present for CCC and HCCC includ- logically resembling ductal carcinoma of breast.
ing invasion: Synonym: Cribriform salivary gland carcinoma of excre-
m Into (minor) salivary gland parenchyma tory ducts
m Neurotropism (perineural and intraneural)
m Lymph-vascular invasion Clinical

m Invasion into muscle and bone Represents less than 10% of all salivary gland
malignancies
More common in men than in women; most fre-
Differential Diagnosis (Table 20-10) quently identified in the sixth through eighth decades
Clear cell oncocytoma of life and tends to be uncommon in patients under
Clear cell myoepithelioma the age of 50
Mucoepidermoid carcinoma, clear cell variant Parotid gland (related to Stensen duct) is most
Acinic cell adenocarcinoma, clear cell variant common site of occurrence:
Epithelial-myoepithelial carcinoma m Other sites of involvement may include:
Clear cell odontogenic carcinoma: Submandibular gland

m Shown to have EWSR1-ATF1 translocation sup- Minor salivary glands, most often related to
porting link with HCCC palate
Squamous cell carcinoma with prominent clear cells Rare sites of involvement include sublingual
(clear cell variant) gland, paranasal sinuses, larynx.
Metastatic tumors composed of clear cells, a rare Symptoms include a (parotid) mass often with asso-
phenomenon including: ciated rapid enlargement with or without pain or
m Renal cell carcinoma: facial nerve paralysis:
Presence of RCC antibody, CD10, PAX2, m At presentation, cervical lymphadenopathy may
PAX8, and CAIX immunoreactivity be present.


Characteristic cytomorphologic features include
presence of three-dimensional cohesive clusters and
flat sheets of epithelial cells:
m Cribriform and papillary pattern of growth
m Tumor cells are large polygonal and spindle
shaped.
m Eccentrically located, hyperchromatic, pleomor-
phic round to oval nuclei with indistinct to prom-

inent nucleoli
m Abundant finely granular cytoplasm or vacuo-
A lated cytoplasm
m Increased mitotic activity
m Necrosis in the smear background
Histology
Intraductal and infiltrating neoplasm with a variety
of growth patterns including cell nests, nodules or
lobules with central comedo-type necrosis, cribri-
form, solid, cystic, and papillary:
m Multiple growth patterns can be seen in any given
tumor.
m Comedotype necrosis is a characteristic but not
pathognomonic finding.
m Larger nodules tend to be cystic and irregular in
B shape.
m Appearance may suggest growth confined to
Fig. 20-109. Salivary duct carcinoma, fine-needle within ducts (intraductal) but features of invasive
aspiration biopsy. growth include:
Absence of myoepithelial layer
A, B, Aspirate of parotid gland lesion showing cohesive Much larger size of cystic foci as compared
sheets of epithelial cells with hyperchromatic, pleomorphic
with normal ducts (intralobular and
round to oval nuclei, prominent nucleoli, and granular
interlobular)
cytoplasm. Following resection the tumor proved to be a
salivary duct carcinoma. Presence of stromal fibrosis
Absence of normal (non-neoplastic) salivary
gland parenchyma within neoplastic foci
Neoplastic cells are large, cuboidal to polygonal
Majority arise de novo but may also occur as malig- with round often centrally situated hyperchromatic
nant component in carcinoma ex pleomorphic nuclei, prominent eosinophilic nucleoli, and abun-
adenoma: dant eosinophilic cytoplasm; apocrine features
m Clinical scenario in the setting of a carcinoma including decapitation secretion are commonly
ex pleomorphic adenoma is that of rapid enlarge- present.
ment of a long-standing salivary gland mass m Moderate to marked nuclear pleomorphism
lesion. present
m Significant increase in mitotic activity that may
Pathology include atypical mitoses
Gross Cribriform pattern reminiscent of intraductal
Majority are poorly circumscribed and infiltrative mammary carcinoma and includes so-called Roman
but may occasionally appear circumscribed. bridge pattern characterized by bands of neoplastic
Cut section reveals a tan-white to gray-yellow epithelium arched over luminal spaces:
solid mass ranging in size from 1 to 10cm in greatest m This pattern contrasts with the cribriform pattern
dimension; on average these tumors measure seen in adenoid cystic carcinoma, which lacks
3.5cm. Roman bridge appearance.
Cystic spaces filled with necrotic material may be m In addition, adenoid cystic carcinoma demon-
identified. strates an admixture of abluminal cells lining

A B
C D
E F
Fig. 20-110. Salivary duct carcinoma.

A and B, Infiltrative parotid gland tumor characterized by varied growth, including cystic, cribriform, and solid with foci of
comedotype necrosis. C and D, The cytologic features include large cells with pleomorphic vesicular nuclei, eosinophilic
nucleoli, and abundant eosinophilic cytoplasm; C, mitotic activity and D, apocrine features are commonly seen. E, Diffuse
and strong nuclear staining for androgen receptor is a characteristic although not pathognomonic finding. F, Diffuse
GATA-3 (nuclear) staining is another marker seen in salivary duct carcinoma.
A B
C D

Sarcomatoid variant of salivary duct carcinoma characterized by (A) fascicular to storiform growth and (B) spindle-shaped
cells with marked nuclear pleomorphism and increased mitotic activity. There is an absence of identifiable ductal
component. C, Focally a ductal component is seen in association with the malignant spindle-shaped cells. D, Diffuse
cytokeratin immunoreactivity confirms the epithelial nature of the malignant spindle cells.
pseudocysts and scattered epithelial cells lining parenchyma and surrounding soft tissue structures,
small duct-like spaces, a pattern not seen in sali- including adipose tissue, skeletal muscle, and overly-
vary duct carcinoma. ing skin:
Papillary pattern includes projections of neoplastic m Often there is extraglandular extension.
epithelium with fibrovascular cores. Histologic variants include:

Additional findings may include: m SDC, sarcomatoid variant:
m Apocrine-like apical globules (apocrine SDC) Characterized by SDC with associated

m Oncocytic cytoplasmic changes may be present. malignant spindle-shaped and pleomorphic cell
m Squamous differentiation/metaplasia in form of infiltrate
keratinization and intercellular bridges Sarcomatoid proliferation may predominate
m Psammoma-like bodies may be present. with only limited evidence of ductular
Stromal changes include the presence of fibrosis, component.
often dense or sclerotic, as well as a mixed lympho- Heterologous elements such as osteosarcoma-
plasmacytic cell infiltrate. tous foci may be present; similar findings can
Invasive growth includes angioinvasion, neural inva- be seen in spindle cell squamous carcinoma and
sion, and invasion of adjacent salivary gland is not indicative of a carcinosarcoma
A B
C D

Other variants of salivary duct carcinoma include (A and B) micropapillary characterized by clusters of morula-like epithelial
cells with fibrovascular cores; (C and D) mucin-rich characterized by presence of lakes of extracellular mucin within which
are nests or islands of neoplastic epithelium.
m SDC, micropapillary variant: m SDC, osteoclast-like giant cell variant:

Characterized by SDC with associated clusters Characterized by conventional SDC with asso-
of morula-like epithelial cells with fibrovascu- ciated osteoclast-like giant cells, latter resem-
lar cores bling cells seen in giant cell tumor of bone
Reported to be more aggressive than conven- In contrast to cells in a giant cell tumor,
tional salivary duct carcinoma osteoclast-like giant cells in SDC are immuno-
m SDC, mucin-rich variant: reactive for epithelial markers and androgen
Characterized by conventional SDC with asso- receptor.
ciated lakes of extracellular mucin within m High-grade SDC in situ (SDCIS)
which are nests or islands of neoplastic Rare variant that may occur in major and
epithelium minor glands
m SDC, oncocytic variant: Characterized by intraductal proliferation of
Characterized by conventional SDC with onco- high-grade malignant cells similar to ductal
cytic cells, the latter showing abundant eosino- carcinoma in situ of the breast:
philic cytoplasm Variable degrees of nuclear pleomorphism,
At least 50% of the neoplasm should be com- prominent central nucleoli, eosinophilic to
posed of oncocytic cells to invoke a diagnosis vacuolated cytoplasm, some with apocrine
of this variant. snouts
Absence of mucocytes m Diffuse GATA-3 (nuclear) staining

High mitotic rate m Estrogen and progesterone receptor markers
Comprised of ducts and cysts often containing usually negative but 1q or both may be positive
comedo-like necrotic debris sometimes with in minority of cases
calcification m GCDFP-15 (BRST-2) may be focally positive.
Lumina are lined throughout by atypical cells m HER-2 (membranous staining) and EGFR posi-
varying in thickness from one to several tive in high proportion of cases

layers. m CK5/6 and p63 focal to absent staining
In smaller ducts proliferation can fill whole m S100 protein and markers indicative of myoepi-
lumen. thelial differentiation, including calponin, p63,

In larger cysts a variety of architectural pat- smooth muscle actin, and vimentin are typically
terns can be seen, including Roman bridges, negative:
papillary, cribriform. Similar to its use in ductal carcinomas of the
Lining cells display variable degrees of nuclear breast, myoepithelial markers have been used
pleomorphism, and central nucleoli may be to identify a peripheral non-neoplastic myoepi-
prominent. thelial layer that, if identified, may indicate a
Cancerization of acini can be identified. tumor confined to within a duct (intraductal
Strict criteria required for diagnosis including: carcinoma) as opposed to absent staining that
Absence of local invasion determined by may indicate an infiltrative process.
adequate sampling of the whole lesion and However, similar cells can be seen in metastatic
presence of an intact myoepithelial layer foci and reactivity with stromal myofibroblasts
around all tumor islands ideally confirmed may suggest myoepithelial layering and there-
by immunohistochemistry for basal- fore an intraductal process, when in fact the
myoepithelial markers (e.g., CK5/6, CK14, carcinoma is invasive.
p63, calponin, smooth muscle myosin heavy m Rare documentation of neuroendocrine differen-
chain) tiation as evidenced by presence of chromogranin

Too few cases to determine with certainty and synaptophysin reactivity
natural history of pure SDCIS but limited cases m Prostate-specific antigen and prostatic acid phos-
with adequate follow-up have survived for phatase may be positive.

years following complete excision with no m High proliferative index ranging from 25% to
recurrence or progression of disease 80% by Ki-1 (MIB1) staining

Relationship of SDCIS to low-grade cribri NOTE: Molecular classification of SDC similar to
form cystadenocarcinoma (LGCCC) remains breast cancer proposed but clinical relevance remains
unclear: uncertain; such suggested classification includes (see
May represent separate entities below):
May represent extreme low-grade end of m Luminal AR-positive SDC
spectrum of SDCIS m HER-2-positive SDC
m Rare examples reported in: m Basal-like SDC
Setting of carcinoma ex pleomorphic adenoma Electron microscopy:

described with rhabdoid features m Desmosomes, tight junctions, rough endoplasmic
In association with IgG4-related salivary gland reticulum, mitochondria, basal lamina, and
disease luminal cells with microvilli
Histochemistry: Cytogenetics and molecular genetics:
m Intracytoplasmic diastase-sensitive, PAS-positive m Loss of heterozygosity in chromosome 9p21, 6q,
material can be seen. 16q, 17p, 17q regions

m Intracytoplasmic mucicarmine staining is usually m ERBB2 (HER-2) gene amplification in up to 36%
negative. of cases and protein expression from 26% to

m Intraluminal mucicarminophilic material may be 100%
present. m EGFR gene mutation may be present in minority
Immunohistochemistry: (fewer than 10%) of cases.

m Cytokeratins (low and high molecular weight), m Frequent TP53 gene mutation and protein
CK7, EMA, and CEA overexpression
m Androgen receptor (AR): m Deletion of PTEN tumor suppressor in majority
Most cases AR positive of cases

Represents characteristic although not pathog- m Apoptosis-related genes CASP10 and MMP11
nomonic finding overexpressed

CDKN2a/p16 gene inactivation

m
PIK3CA and HRAS mutations recently reported

m Treatment and Prognosis
in 33% and 34% of cases analyzed, respectively, Aggressive management requiring combination com-
and BRAF mutation identified in a minority of plete (radical) surgical extirpation with radical neck
cases. dissection and postoperative radiotherapy represent
m Absence of MECT1-MAML2 fusion preferred treatment.
Molecular classification of SDC Recurrent disease occurs from approximately one
m Proposal made to classify SDC into three molecu- third to two thirds of patients.
lar subtypes analogous to breast cancer Lymphatic and hematogenous spread occurs:
m Luminal androgen receptorpositive subtype m Regional nodal metastases occur in approxi-
(most common): mately 66% of patients:

Androgen receptor positive, HER-2 negative, Nodal metastases may occur at the initial pre-
CK5/6 negative sentation or subsequent
m HER-2 subtype: m Distant metastasis occurs in from 50% to 70%
HER-2 immunohistochemical expression 3+, of patients:

HER-2/neu gene amplified Most common sites for distant spread include
Basal phenotype (least common): the lungs, bone, and brain.
Androgen receptor negative, HER-2 negative, May metastasize to skin
CK5/6 positive Mortality rates attributed to this neoplasm are high:
m Unclassifiable group also identified from 60% to 80% of patients die from disease within
5 years from the diagnosis.
Hybrid Tumors Adverse prognostic features include:
Hybrid tumors represent the occurrence of a neo- m Tumors greater than 3cm in diameter
plasm composed of two or more histologic distinct m Distant metastasis
types, each of which conforms with an exactly m HER-2 overexpression
defined tumor category having an identical origin m Micropapillary pattern
within same topographic area m CDKN2a/p16 gene inactivation
Most common tumor types include: Frequent expression of HER-2, EGFR, and AR in
m Adenoid cystic carcinoma SDC suggest that these receptors can be suitable
m Salivary duct carcinoma molecular targets of systemic therapy for patients
m Epithelial-myoepithelial carcinoma with SDC:
Prognosis predicated on highest histologic grade m Treatment may include trastuzumab, lapatinib,
malignancy (e.g., salivary duct carcinoma) and bevacizumab individually or in combination.

m Efficacy of anti-HER-2 and anti-androgen ther
apy for receptor-positive SDC yet to be fully

Differential Diagnosis proven but preliminarily has shown favorable
Mucoepidermoid carcinoma, high grade: response
m Consistent CK5/6 and p63 staining that contrasts
to SDC showing limited to absent reactivity for

these markers
Adenoid cystic carcinoma LOW-GRADE INTRADUCTAL
Acinic cell adenocarcinoma CARCINOMA (Figs. 20-113
Cribriform cystadenocarcinoma (low-grade salivary and 20-114)
duct carcinoma); see below
Oncocytic carcinoma Definition: Cystic epithelial salivary gland neoplasm
Papillary cystadenocarcinoma characterized by intraductal epithelial proliferation sur-
Metastatic mammary carcinoma: rounded by myoepithelial cells composed of histologi-
m Overlapping histologic and immunohistochemically low-grade nuclei, absence of infiltrative growth,
cal features but rarity of breast cancer metastasiz- and overall indolent biologic behavior.
ing to salivary glands essentially excludes the m Likely represents preinvasive phase of an invasive
diagnosis carcinoma (e.g., salivary duct carcinoma,

Metastatic prostatic adenocarcinoma: cystadenocarcinoma)
m Although SDC may be reactive with prostatic- m Strict criteria required for diagnosis, including:
specific immunomarkers, rarity of prostate cancer Absence of local invasion determined by ade-
metastasizing to salivary glands essentially quate sampling of the whole lesion and pres-
excludes the diagnosis. ence of an intact myoepithelial layer around all
A B
Fig. 20-113. Low-grade intraductal carcinoma of the parotid gland.

A, Unencapsulated multicystic proliferation with cribriform growth. B and C, Cribriform growth composed of cells with
apocrine-like features. The cellular proliferation is rather bland composed of relatively uniform-appearing epithelial cells
with round nuclei, fine-stippled chromatin and small nucleoli; nuclear pleomorphism is limited and there is no appreciable
increase in mitotic activity; necrosis is absent.
tumor islands confirmed by immunohisto- m May exceptionally occur in oral cavity (e.g.,
chemical staining palate, tongue)
Synonyms: Low-grade salivary duct carcinoma; low- m Rarely reported as arising within a periparotid
grade cribriform cystadenocarcinoma (LGCCC); in situ lymph node

carcinoma Presentation that of slow-growing, asymptomatic
NOTE: mass or swelling
m Classification of this tumor type is controversial
and evolving: Pathology

Initially, considered to represent low-grade Gross
variant of salivary duct carcinoma May show nodular and cystic appearance
Clinical Fine-Needle Aspiration Biopsy

Rare tumor Smears reveal tumor cells arranged in irregular over-
Slightly more common in women than in men; tumor lapping and show inconspicuous nuclear atypia with
of elderly adults variable-sized and irregularly shaped cytoplasmic
Almost exclusively a tumor of parotid gland: vacuoles
A B
C D
Fig. 20-114. Low-grade intraductal carcinoma of the oral cavity.

A, Dilated duct with cystic, micropapillary, cribriform, and solid growth. B, Cells show moderate nuclear pleomorphism.
C, Areas showing similar features to atypical ductal hyperplasia of the breast may be identified. D, p63 immunoreactivity
highlights the myoepithelial cells confirming the proliferation is intraductal.
Histology by light microscopy requiring immunohistochemical

Unencapsulated tumor composed of dominant cyst staining for identification (see below).
or multiple variably sized cysts In addition to cystic foci, separate ductal epithelial
Cystic epithelial proliferation shows cribriform and proliferation identified composed of small ducts with
papillary growth patterns with fibrovascular cores: cribriform, micropapillary, and solid growth consist-
m Roman arches similar to those seen in relation ing of cells cytomorphologically similar to those seen
to mammary lesions in cystic foci.
Cellular proliferation includes: Transition from low nuclear grade to higher nuclear
m Relatively uniform-appearing epithelial cells with grade (i.e., intermediate and high grade)
round nuclei, fine stippled chromatin, and small Invasive carcinoma or micro-invasion reported in up
nucleoli to 23% of cases
m Apocrine-appearing cells may represent domi- Invasive carcinoma may rarely occur and may be
nant cell type or may focally be present. identified in recurrent lesions:
m Nuclear pleomorphism is limited. m Invasion may be in the form of microinvasive
m No appreciable increase in mitotic activity carcinoma.

m Comedotype necrosis may or may not be present. m Less often, includes presence of solid nests of
Myoepithelial cells present and may appear mono- tumor within adjacent salivary gland parenchyma
layered and attenuated but may not be identifiable or connective tissue
Stromal fibrosis/sclerosis and mixed chronic inflam-

matory infiltrate may be present, especially in areas
of invasive carcinoma.
Neurotropism and angioinvasion not typically
present
Cells may contain:
m Apical apocrine-like microvacuoles/globules
which are diastase resistant, PAS positive
m Yellow- to brown-appearing intracytoplasmic
pigment resembling lipofuscin
m Lesional cells:
Cytokeratin, EMA, S100 protein positive

Calponin, smooth muscle actin, vimentin
usually negative
Androgen receptor, HER-2, and GCDFP15
(BRST-2) may be positive
Estrogen receptor, progesterone receptor
usually negative
GATA-3 (nuclear) staining may be focally
positive.
Low proliferative activity (<5%) seen by
Ki-67
m Myoepithelial cell layer:
Reactive for p63, CK14, actins (smooth muscle,

muscle specific), calponin Fig. 20-115. Cystadenocarcinoma.
Differential Diagnosis Cystadenocarcinoma of the parotid gland appearing as a
Sclerosing polycystic adenosis predominantly cystic and focally solid lesion.
Cystadenoma
Cystadenocarcinoma
Acinic cell adenocarcinoma, papillary-cystic variant Tend to be tumors of major salivary glands, in par-
High-grade salivary duct carcinoma in situ ticular the parotid gland
m Less often occurs in the sublingual gland and
Treatment and Prognosis minor salivary glands, including buccal mucosa,

Surgical excision is preferred treatment. palate, lips, floor of mouth, and tongue
Excellent prognosis with no reported metastasis or Presentation that of slow-growing, asymptomatic
mortality over 2- to 12-year follow up mass or swelling; erosion of bone particularly related
to palate tumors may occur:
m Rarely associated with pain and facial paralysis
CYSTADENOCARCINOMA
Pathology
(Figs. 20-115 through 20-118)
Gross
Definition: Malignant epithelial salivary gland tumor Delineated or partially circumscribed cystic or mul-
characterized by predominant cystic and papillary ticystic mass ranging in size from 0.4 to 6cm in
growth and lacking defining histomorphologic features greatest dimension
of another type of salivary gland malignancy.
Synonyms: Papillary cystadenocarcinoma; malignant Histology
papillary cystadenoma; low-grade papillary adenocarci- Circumscribed but unencapsulated cystic or multi-
noma of the palate cystic proliferation separated by fibroconnective
tissue or approximating one another
Clinical Cysts haphazardly arranged varying in size and
Rare tumor shape
No gender predilection; occurs over a wide age range Lumens may contain mucinous material as well as
but the majority of patients are older than the sixth calcifications; latter may also be present outside the
decade of life cysts in stroma.
A A
Fig. 20-116. Cystadenocarcinoma, low grade. B
A, Cystic and predominantly papillary architecture with

fibrovascular cores. B, At high magnification the cells are Fig. 20-117. Cystadenocarcinoma,
rather uniform with bland-appearing nuclei. The findings intermediate grade.
could be those of a papillary cystadenoma but invasion A, Unencapsulated, multicystic and infiltrative parotid gland
was present (not shown), allowing for a diagnosis of a tumor in which the cysts are haphazardly arranged, vary in
low-grade (papillary) cystadenocarcinoma. size and shape, and show a variable epithelial pattern of
growth, including macrocystic, cribriform, and papillary.
B, At high magnification the cells show greater
Small duct-like structures and solid epithelial islands disorganization and nuclear pleomorphism as compared
with or without lumens may be identified between with low-grade neoplasms but not as significant as seen
in higher grade neoplasms.
cysts:
m Duct-like structures and solid islands may be
infiltrative into non-neoplastic salivary gland Most often cell type is small cuboidal, less often
m
parenchyma and/or surrounding fibroconnective larger cuboidal or tall columnar cells

tissues. m Other cell type that may be identified include
Epithelial cell proliferation varies in growth and cell mucous, oncocytic, clear, and epidermoid cells.
type: Majority histologically low grade, characterized by:
m Papillary architecture is present in the majority of m Cytomorphologic uniformity with minimal pleo-
cases, varying from simple/single papillary pro- morphism, although moderate pleomorphism
jection to multiple papillae and creating a complex may be present.
papillary to solid appearance that may fill involved m Prominent nucleoli may be identified.
lumen. m Low to absent mitotic activity
m Cribriform growth may be seen especially in m Necrosis usually absent
cases in which epithelial lining cells become m Cytomorphologically high-grade nuclear features
thickened. may be present.

m Cystic epithelial lining cells may form a single Histologically higher-grade lesions may occur, includ-
layer or multiple layers in thickness. ing intermediate and high grade:
Intermediate grade:
m
As compared with low grade, greater degree of

nuclear pleomorphism and increased mitotic
activity but not reaching levels associated with
histologically high-grade neoplasms
m High grade:
Marked nuclear pleomorphism, increased

mitotic activity, atypical mitoses, and necrosis
Invasive growth is prerequisite for diagnosis:
m Invasion may be limited in extent requiring liberal
sampling of the resection specimen.

m Neurotropism may be present in minority of
cases (<10%).
Stromal findings may include:
A m Lymphoplasmacytic cell infiltrate that occasion-
ally may be dense.

m Ruptured cysts may result in stromal hemor-
rhage, hemosiderin-laden macrophages, and

granulation tissue.
Histochemistry:
m Mucin stains are usually negative.
Cystadenoma
Warthin tumor
Acinic cell adenocarcinoma, papillary-cystic variant
Mucoepidermoid carcinoma, low grade
Low-grade intraductal carcinoma
B Polymorphous low-grade adenocarcinoma

Complete surgical resection is preferred treatment:
m Parotid gland: superficial parotidectomy with
sparing of facial nerve unless involved by tumor

m Submandibular and sublingual glands: glan
dectomy
m Minor salivary glands: wide excision to include
tumor-free margins:
In presence of osseous invasion that can be
seen in palatal lesion, more radical excision
is required.
In absence of clinical evidence of neck disease, neck
dissection would not appear to be warranted.
Recurrence and metastasis (regional and distant) are
C
uncommon, occurring in less than 8% and 10% of
patients, respectively.
Fig. 20-118. Cystadenocarcinoma, high grade. To date, no reported tumor-related death
A, Cystic and papillary neoplasm. B, Focally intracystic
mucinous material may be present. C, At high
magnification there is marked nuclear pleomorphism MYOEPITHELIAL CARCINOMA
and increased mitotic activity. (Figs. 20-119 through 20-123)
Definition: Malignant salivary gland tumor composed
exclusively of cells with myoepithelial differentiation as
determined by light microscopic, immunohistochemical,
m Pain, dysphagia, and hoarseness uncommonly

may occur.
m Invasion of bone with bone destruction may
occur in association palatal tumors.

May arise:
m As de novo neoplasm
m From preexisting pleomorphic adenoma (myoepi-
thelial carcinoma ex pleomorphic adenoma) or

myoepithelioma
Clinical presentation may be that of a long-
standing mass with recent rapid increase
in size
A Alternatively, develops following multiple
recurrences
No known etiologic factors
Pathology
Aspirates show similar findings to those seen in myo-
epithelioma (see previous) but with cytologic fea-
tures indicative of a malignancy, including:
m Marked nuclear pleomorphism, increased mitotic
activity, atypical mitoses, and necrosis
Gross
Unencapsulated, nodular tumor that on cut section
is gray-white and firm, measuring from 2 to approxi-
B mately 6cm, although examples can be larger
Cystic areas and necrosis may be identified.
Fig. 20-119. Myoepithelial carcinoma. Histology

A, Large floor of mouth solid mass with deviation of the Unencapsulated tumor that may be circumscribed
tongue. B, On imaging the mass is large and infiltrative. characteristically with nodular or multinodular
appearance:
m Growth patterns include sheets, nests, trabeculae,
and/or ultrastructural findings, and with invasive growth fascicular, storiform, or cord-like (also referred to
and metastatic potential: as reticular)
m Represents malignant counterpart of myoepithe- Cellular components similar to those seen in myo-
lioma. epithelial predominant pleomorphic adenomas or in
Synonym: Malignant myoepithelioma myoepithelioma, including:
m Spindle-shaped, plasmacytoid (hyaline), epitheli-
Clinical oid, and clear cells:

Uncommon tumor Combination of cell types is usually present,
No gender predilection; tumor of adults with occur- although a given tumor may be predominantly
rence over wide age range from second to ninth or exclusively composed of a single cell type.
decades of life; mean age at presentation in mid-sixth Epithelioid cell type reported to be most
decade common
Most common site of occurrence is parotid gland Nuclear pleomorphism varies from case to case and
m Less common sites of occurrence include: may be mild, moderate, or severe; mitotic activity
Submandibular gland varies from scarce or few in number to examples
Minor salivary glands: with high mitotic rate; necrosis may be present.
Palate most common Metaplastic changes, including squamous and seba-
Presentation usually that of asymptomatic mass or ceous cells, may be identified.
swelling: Stroma varies from copious amount of mucoid or
m Duration of symptoms usually from months to myxoid-appearing stroma to sparse stromal tissue in
years markedly cellular tumors:
Fig. 20-120. Myoepithelial carcinoma.

Multiple growth patterns can be seen in myoepithelial carcinomas including (A) large solid nest; (B) fascicular and
storiform; (C) trabecular; (D) cordlike/reticular; and (E) microcystic. A variable stroma is present from sparse to fibrous to
mucinous appearing.

The cell types in myoepithelial carcinoma include (A and B) spindle-shaped; (C) plasmacytoid; (D, E) epithelioid; and
(F) clear. The degree of nuclear pleomorphism varies from case to case. In panels A and D there is limited nuclear
pleomorphism, whereas in panels C and E nuclear pleomorphism is present; note the mitotic figure in panel
E (arrowhead). Continued
m Limited to abundant reduplicated basement

membrane-like material appearing as eosinophilic
hyaline material may be present.
m Cystic degeneration may be present.
Although cytomorphologic evidence of malignancy

may be readily identified, these findings may not be
present and an unequivocal diagnosis is predicated
on infiltrative growth, including:
m Invasion into nonneoplastic salivary gland
parenchyma
m Adjacent fibroconnective tissues
m Neurotropism
G m Angioinvasion
By definition, ductal differentiation is not a compo-

Fig. 20-121, contd
nent except in cases arising in association with a
pleomorphic adenoma:
G, Areas of necrosis in a comedotype pattern may m Presence of duct differentiation would confer a
be present. different designation (e.g., epithelial-myoepithelial
carcinoma, others)
m Presence of duct differentiation in this tumor type
is the subject of debate with some authorities

allowing for limited ductal differentiation.
m Pancytokeratin (e.g., AE1/AE3) is consistently
reactive.
Other cytokeratins including CAM5.2, CK903
(34BE12), CK5/6, CK7, and CK14 are variably
expressed.
m Vimentin positive
m Immunoreactivity for a marker associated with
myoepithelial differentiation should be identified

for diagnosis, including:
p63, calponin, S100 protein, smooth muscle
actin, smooth muscle myosin heavy chain:
Smooth muscle actin is seen in spindle-
A shaped myoepithelial cells but not in plasma-

cytoid myoepithelial cells.
m Desmin and c-kit (CD117) reactivity are uncom-
monly seen.
m Myogenin, melanocytic markers negative.
m Variable identification of cytoplasmic microfila-
ments with focal dense bodies, pinocytotic vesi-

cles, desmosomes, basal lamina, and intermediate
filaments
m Not known to have EWSR1 rearrangement(s)
with one exception

m Clear cell variant of myoepithelial carcinoma of
major and minor salivary glands (de novo and ex

B pleomorphic adenoma) shown to harbor EWSR1
rearrangement:
Prognosis of clear cell type of myoepithelial
Fig. 20-122. Myoepithelial carcinoma. carcinoma with EWSR1 rearrangement appears
Immunoreactivity in myoepithelial carcinomas includes to be aggressive with poor clinical outcomes,
(A) cytokeratin (AE1/AE3); (B) p63 (nuclear staining). including:
A B

An unequivocal diagnosis of a malignant tumor is predicated on infiltrative growth that may include (A) invasion into
parotid gland parenchyma; (B) (left and right) angioinvasion; (C) osseous invasion.
Increased incidence of nodal metastasis and Mucicarmine-positive vacuolated/signet ring

distant metastasis cells embedded in myxoid stroma
Increased incidence of disease-associated At least focal p63 staining and/or calponin
mortality due to disseminated disease reactivity
Membranous E-cadherin positive
Hybrid Tumors FISH negative for ETV6, EWSR1, and ALK1
Uncommonly may be a tumor type occurring as a rearrangements
hybrid tumor representing occurrence of neoplasm Fairly indolent fashion
composed of two or more histologic distinct types,
each of which conforms with an exactly defined Differential Diagnosis
tumor category having an identical origin within Myoepithelioma:
same topographic area m Differentiation may be possible on basis of cyto-
Prognosis predicated on highest histologic grade morphologic features in cases of myoepithelial

malignancy (e.g., salivary duct carcinoma) carcinoma with:
High-grade transformation (dedifferentiation) of Marked cellular pleomorphism
myoepithelial carcinoma Increased mitotic activity
m Rare examples of transition to histologically High proliferation indices (>10%) by Ki67
higher-grade neoplasm reported staining
Secretory myoepithelial carcinoma: m However, as previously noted, in any given
m Recently described example of myoepithelial carcinoma there may

m Dual secretory and myoepithelial phenotype not be significant cytomorphologic findings to
allow differentiation on such features alone and Clinical symptoms usually include a mass with
in such scenarios presence of infiltrative growth or without associated pain.
differentiates myoepithelial carcinoma from m Pathology:
myoepithelioma. Most tumors are circumscribed; however, they

Epithelial-myoepithelial carcinoma may have infiltrative margins.
Clear cell carcinoma Histologically, at low magnification a multi-
Sarcoma (in those cases dominated by a spindle- nodular or lobular architecture is evident; at
shaped cellular component): periphery of lobules lesion is hypercellular
m Synovial sarcoma arranged in reticular, trabecular, nests, or solid
m Malignant peripheral nerve sheath tumor patterns.
m Leiomyosarcoma Lesional cells may be epithelioid, clear, spindle,
m Sclerosing rhabdomyosarcoma: or plasmacytoid:
May occur in parotid gland simulating myoepi- Characterized by cytomorphologic het
thelial carcinoma erogeneity; although epithelioid type pre-
Presence of desmin and myogenin and absence dominates, majority of cases are composed
of cytokeratin, p63, and S100 protein of more than one myoepithelial cell
Spindle cell squamous carcinoma (sarcomatoid type
carcinoma): Cytologic atypia of at least moderate degree
m Cytokeratins and p63 immunoreactivity may be is present, including nuclear enlargement,

present in spindle cell squamous carcinoma, but vesicular to coarse-appearing nuclei, and
typically such tumors lack evidence of other myo- variably prominent nucleoli.
epithelial markers, including calponin. Increased mitotic activity, tumor necrosis,
Metastatic malignant melanoma and lymph-vascular invasion may be

Plasmacytoma present.
Soft tissue myoepithelial carcinoma: Rare examples with rhabdoid morphology
m Primary myoepithelial tumors of soft tissues are described

uncommon. Stromal component includes myxoid change
m Classification includes: and/or hyalinization.
Benign neoplasm (myoepithelioma) (see under Cartilaginous differentiation and metaplastic
myoepithelioma) ossification may be present.

Malignant neoplasms (myoepithelial carci- Immunohistochemical staining:
noma) Lesional cells reactive for cytokeratins (AE1/
m As compared with their salivary gland AE3, CAM5.2, PAN-K), EMA, S100 protein,
counterpart: calponin, p63, SMA, MSA, GFAP, CD10,
A higher proportion of myoepithelial tumors and vimentin
of soft tissues are malignant. CD99 immunoreactivity may be present.
Unlike salivary gland myoepithelial carcinoma, Desmin, CD34, and brachyury typically
in which a majority arise in association with a negative
pleomorphic adenoma (i.e., myoepithelial car- Nuclear expression of INI-1 may be lost in a
cinoma ex pleomorphic adenoma), this occur- minority of cases; loss of INI1 may be seen
rence is rare relative to soft tissue myoepithelial in cases with rhabdoid morphology, making
carcinoma, the majority of which occur as a de distinction from other INI1-negative rhab-
novo malignancy. doid tumors difficult
m Clinical: Well established that myoepithelial carcinomas
Sites of involvement: demonstrate EWSR1 gene rearrangement,
Majority occur in soft tissues outside head making them genetically distinct from salivary
and neck most commonly arising in limbs gland counterpart:
(upper and lower) and girdle with involve- Identification of EWSR1-POU5F1 or
ment of the subcutis and deep soft tissues EWSR1-PBX1 gene fusion
Among more common sites of occurrence in Differential diagnosis rather broad and may
head and neck is neck (See Section 4) and include:
craniofacial region Extraskeletal myxoid chondrosarcoma, epi-
Demographics: thelioid malignant peripheral nerve sheath

Occur over a wide age range with many tumor, synovial sarcoma (poorly differenti-
cases affecting pediatric ages but develop in ated), undifferentiated carcinoma, and Ewing
adult populations as well sarcoma/PNET
Treatment and prognosis:

Protocols include wide surgical resection for
localized tumors and adjuvant radiotherapy

with or without nodal dissection.
Potential for local recurrence and/or metas-
tases (nodal and viscera).

More aggressive behavior occurs in pediatric
ages than in adult population, including

death from disease.
Use of chemotherapy is unproven and appears
in limited studies to offer no added benefit.

Complete surgical resection is preferred treatment,
which includes:
m Parotid gland: superficial parotidectomy
m Submandibular gland: glandectomy
m Minor salivary glands: wide excision to include
tumor-free margins
m In presence of osseous invasion a more radical Fig. 20-124. Parotid squamous cell carcinoma.
excision is required. Primary squamous cell carcinoma of the parotid presenting
In absence of clinical evidence of neck disease, a as an ulcerated and necrotic, firm mass extending behind
neck dissection would not appear to be warranted. the ear, with separate tumor nodules just anterior to the
Radiotherapy used in select situations with mixed gland, and associated with facial nerve invasion and
outcomes paralysis. From this appearance and obvious cutaneous
Efficacy of chemotherapy not proven involvement, a primary cutaneous carcinoma cannot be
Behavior of these tumors is variable: ruled out and is clinically the most likely origin rather than
m Some behave in indolent/low-grade manner.
originating in the parotid gland. The majority of squamous
m Others behaving more aggressively (intermediate
cell carcinomas of the parotid gland represents secondary
involvement from a separate primary cancer rather than
to high grade)
being a primary parotid squamous cell carcinoma.
From 50% to 67% develop recurrent tumor; often
multiple recurrences
Approximately 50% of patients develop metastatic inability to exclude a mucosal squamous cell car-
disease: cinoma secondarily involving minor salivary
m Lung most common site of metastasis glands
m Distant metastasis more frequent than regional
(nodal) metastasis Clinical

Approximately 30% of patients die of disease. Rare tumor
More common in men than in women; occurs over
a wide age range but most frequently identified in
PRIMARY SQUAMOUS the seventh to eighth decades of life; rarely may
CELL CARCINOMA (SCC) occur in pediatric ages
(Figs. 20-124 and 20-125) Primarily identified in parotid gland but may also be
seen in submandibular gland:
Definition: Malignant epithelial neoplasm of major sali- m In parotid gland nearly all cases identified in
vary glands composed of squamous cells characterized superficial lobe

by presence of keratinization and/or intercellular Most common symptom is mass lesion with or
bridges: without pain and/or cranial nerve paralysis:
m Diagnosis predicated on absence of clinical or m Rapid enlargement of the mass may be a present-
historical evidence of a squamous cell carcinoma ing complaint.

in another (head and neck) site that has metasta- m Fixation to adjacent structures and associated
sized to the salivary gland or invaded directly into ulceration may be present.
the salivary gland from a mucosal or cutaneous m Duration of symptoms is usually relatively short
primary squamous cell carcinoma (within 1 year).

m Diagnosis of primary SCC relative to minor sali- m Due to high frequency of regional (nodal)
vary glands not considered appropriate due to the metastases at the initial presentation, patients
may also present with cervical lymphade

nopathy.
Cause may be related to prior radiotherapy to head
and neck, included for treatment of:
m Neoplasms
m Acne
m Glandular (tonsillar, thyroid, thymic) enlarge-
ment
m Median time frame of 15 2 years from radiation
1
exposure to development of carcinoma, with

range of 7 to 32 years
m Not all reported cases of salivary gland squamous
A cell carcinoma associated with prior radiation

exposure
Pathology
Gross
Unencapsulated, firm to hard, gray to white mass
usually measuring more than 3cm in greatest
dimension
Ulcerated and fixation to adjacent tissues is com-
monly present.
Histology
Infiltrating well to moderately differentiated squa-
B mous cell carcinoma similar to those occurring in
other head and neck sites:
m Invasive tumor has variable growth patterns
including trabecular, nested, or anastomosing

cords
m Intracellular keratin, keratin pearl formation, and
intercellular bridges are seen.

m Presence of keratinization and intercellular
bridges confers the designation of squamous
rather than epidermoid although these terms have
been used interchangeably.
m Less often, carcinoma is poorly differentiated
and/or spindle cell squamous carcinoma but still

retains histologic evidence of squamous cell dif-
ferentiation allowing for classification in this cat-
egory of tumor rather than another tumor
C
category (e.g., salivary duct carcinoma, undiffer-
entiated carcinoma).
Fig. 20-125. Parotid squamous cell carcinoma. m Increased mitotic activity and necrosis may be
present.
A, Although the tumor appears circumscribed and separate
from the parotid gland parenchyma (left), it was infiltrative
Invasive tumor includes:
m Infiltration of adjacent salivary gland paren
with an associated desmoplastic stroma; B, trabecular and
anastomosing cordlike growth; C, keratinizing squamous chyma
cell carcinoma histologically similar to squamous m Invasion into surrounding fibroconnective tissues
carcinomas occurring in more usual sites. Prior to m Neurotropism
rendering a diagnosis of a primary parotid squamous cell m Angioinvasion
carcinoma, a primary carcinoma of another site (e.g., skin) m Osseous invasion (e.g., mandible, temporoman-
either with direct invasion of the parotid gland or dibular point)
metastasis to the parotid gland must be excluded. Tissue invasion often (but not always) produces a
desmoplastic response in and around the neoplastic
infiltrate.
A marked chronic inflammatory cell infiltrate occa- Salivary duct carcinoma:

sionally may be associated with the invasive tumor m Generally not problematic in differentiating from
nests. squamous cell carcinoma but occasional cases

Salivary duct changes, including squamous metapla- may show squamous differentiation or predomi-
sia and/or dysplasia, may be identified: nance of spindle-shaped cells (i.e., sarcomatoid
m Transition from normal to dysplastic duct epithe- variant) that in conjunction with high-grade cyto-
lium to squamous cell carcinoma may occasion- morphology and perhaps absence of ductal dif-
ally (and fortuitously) be identified. ferentiation may create problems in differentiating
In patients exposed to radiation, the non-neoplastic from squamous cell carcinoma:
salivary gland may show radiation-induced changes, Presence of reactivity for androgen receptor,
including atrophy and fibrosis. GATA3 and to a lesser extent HER-2 should
May be the malignant component or one of the allow for differentiating salivary duct carci-
malignant components of: noma or a variant thereof from SCC
m Carcinoma ex pleomorphic adenoma Ductal squamous metaplasia
m Malignant transformation of Warthin tumor Necrotizing sialometaplasia
Histochemistry: Keratocystoma:
m Special stains for epithelial mucin are negative m Histologically characterized by presence of mul-
but should be performed to rule out the presence ticystic spaces lined by stratified squamous cells
of high-grade mucoepidermoid carcinoma. lacking cytomorphologic evidence of malignancy
Immunohistochemistry: or invasive growth
m Diffuse and strong reactivity for cytokeratins m Transformation from parotid ductal epithelium
(AE1/AE3, CAM5.2, CK5/6, others) and p63 to tumor may be identified.

m Absence of reactivity for androgen receptor, m Foreign body giant cell reaction to keratin can be
GATA3, HER-2 seen.

Cytogenetics and molecular genetics: m Immunoreactivity for cytokeratin but not for
m No reported MECT1-MAML2 translocation S100 protein or smooth muscle actin; low prolif-
erative rate as determined by Ki-67 (MIB1)
Hybrid Tumors staining
Uncommonly may be a tumor type occurring as a
hybrid tumor, representing occurrence of neoplasm
composed of two or more histologic distinct types, Treatment and Prognosis
each of which conforms with an exactly defined Complete surgical excision (e.g., parotidectomy, sub-
tumor category having an identical origin within mandibular glandectomy) is preferred treatment:
same topographic area m Direct involvement of facial nerve is not uncom-
mon, often necessitating facial nerve resection.

Differential Diagnosis Neck dissection:
Nonprimary salivary gland squamous cell carci- m Owing to high rate of nodal metastases routine
noma: neck dissection advocated

m More often than not, presence of squamous cell High rate of microscopic nodal metastases in
carcinoma in salivary glands represents a nonpri- patients with no palpable cervical lymphade-
mary salivary gland malignancy, either metastatic nopathy (clinical N0 neck)
from a separate primary site or direct invasion Adjunctive radiotherapy may be beneficial in
from a cutaneous or mucosal-based squamous controlling local disease and/or may improve
cell carcinoma survival.
Detailed clinical history indicated to determine Treatment failure as manifested by local recurrence
if the patient has history (current or remote) of and/or metastatic disease common
a squamous cell carcinoma of another site Survival rates include:
either within or outside head and neck area m 5-year of 24%
Mucoepidermoid carcinoma, high grade m 10-year of 18%
Adenosquamous carcinoma (see Section 5, Larynx, m 15-year of 17%
for full description): m 20-year of 17%
m Represents a mucosal-based carcinoma arising Adverse prognostic findings include:

from surface epithelium composed of an admix- m Presence of ulceration or fixation
ture of squamous cell carcinoma and adeno m Older-aged patients (greater than 60 years)
carcinoma m Larger tumors (T3 or greater)
m Rarely if ever develops in major salivary glands m Higher-stage tumor

Most patients with salivary gland squamous m Possibility that presence of LESA represent reac-
cell carcinoma present with higher clinical tive process and not precursor lesion
stage tumors m No known association with other autoimmune
Facial paralysis disorders (e.g., Sjgren disease)

Deep tissue fixation Etiology:
Prognosis does not correlate to the histology. m Linked to Epstein-Barr virus:
Near 100% association in patients from

endemic areas
LYMPHOEPITHELIAL-LIKE In non-endemic areas EBV is usually absent,
CARCINOMA (LEC) but may rarely be identified

(Figs. 20-126 and 20-127) Presence of EBV in clonal episomal form sug-
gests role in tumor development
Definition: Undifferentiated carcinoma with associated Elevated serologic titers of anti-EBV viral
prominent non-neoplastic lymphoplasmacytic cell capsid antigen IgA, anti-EBV nuclear antigen
infiltrate: IgG seen in the majority of patients from
m Histologic features similar to nasopharyngeal endemic regions.
carcinoma, nonkeratinizing undifferentiated
type Pathology
Synonyms: Undifferentiated carcinoma; lymphoepi Gross
thelioma-like carcinoma; lymphoepithelial-like carci- Circumscribed but unencapsulated, lobulated, firm,
noma; undifferentiated carcinoma with lymphoid tan-white mass measuring from 1 to 10cm in great-
stroma; malignant lymphoepithelial lesion; carcinoma est dimension
ex lymphoepithelial lesion
Clinical Carcinoma cells variably seen in smears in cohesive
Rare salivary gland tumor aggregates or individual cells and include medium to
Unique ethnic and demographic features: large size cells with large vesicular-appearing nuclei,
m Predilection for Arctic region natives (Eskimos/ one or more prominent nucleoli, high nuclear-to-
Inuits from Alaska, Canada, Greenland), South- cytoplasmic ratio
eastern Chinese and Japanese Associated mature lymphocytes and plasma cells are
m Highest incidence worldwide of salivary gland typically numerous.
lymphoepithelial carcinoma is in Eskimo/Inuit
population Histology
m Familial predisposition reported: m Infiltrative tumor characterized by presence of
Inherited trichoepitheliomas also reported in lobules, sheets, nests, islands, trabeculae, or cords
this setting, suggesting hereditary predis of neoplastic cells separated by or overrun by
position lymphoid stroma
m In Eskimos/Inuits: m Neoplastic cells are polygonal to spindle-shaped
More common in women with large round to oval, basophilic to vesicular-

Predilects to the parotid gland appearing nuclei, one or more prominent
More aggressive clinical course presents with nucleoli, and abundant amphophilic to lightly
higher clinical stage disease. eosinophilic cytoplasm
In general, occurs over a wide age range with most m Cells have indistinct cell borders and syncytial
patients in the fifth decade of life growth is usually evident.

Most common site of occurrence is in the parotid m Moderate to marked nuclear pleomorphism
gland (80%) followed by the submandibular gland present
with rare occurrence in minor salivary glands m Increased mitotic activity and necrosis seen
throughout the upper aerodigestive tract. m Squamous differentiation may be present.
Presentation is usually that of a mass swelling with Prominent basaloid morphology may be seen (basa-
or without associated pain and/or facial nerve loid LEC):
paralysis: m Identified in Inuit population
m Fixation to skin and/or underlying structures seen m Associated with EBV
in advanced tumors A dense non-neoplastic lymphoplasmacytic cell infil-

m High frequency (10% to 40%) of concurrent cer- trate with or without germinal centers is present:
vical lymphadenopathy m Identified between and around tumor nests or
Most develop de novo but may arise in association may overrun and obscure presence of epithelial
with lymphoepithelial sialadenitis (LESA): component
A B
C D
E F
Fig. 20-126. Lymphoepithelial-like carcinoma of the parotid gland.

A and B, Infiltrative but circumscribed cellular proliferation separated from the adjacent parotid gland parenchyma (left) that
includes clusters of lighter staining neoplastic foci in a background of dense lymphocytic cell infiltrate including germinal
centers. Note the absence of an associated desmoplastic reaction to the infiltrative neoplasm. C, Cohesive cluster of
neoplastic cells characterized by cells with enlarged vesicular nuclei, prominent eosinophilic nucleoli, and indistinct borders
creating a syncytial growth. These histologic features are similar to nasopharyngeal carcinoma, nonkeratinizing
undifferentiated type. The lesional cells are (D) cytokeratin positive; (E) p63 positive (nuclear staining); and (F) positive by
in situ hybridization for Epstein-Barr encoded RNA (EBER).
A B
C D
Fig. 20-127. Lymphoepithelial-like carcinoma of the parotid gland.

Variant histologic features may include (A) fascicular growth with spindle-shaped neoplastic cells that were cytokeratin and
p63 reactive (not shown) and also (B) EBER positive; (C) basaloid cell features that were cytokeratin and p63 reactive (not
shown); and also (D) EBER positive.
m Abundant histiocytes may be seen creating a m Epstein-Barr virus:

starry sky appearance In-situ hybridization for Epstein-Barr encoded
m Noncaseating granulomatous inflammation may RNA (EBER) consistently positive in cases
be identified. from endemic regions
An amyloid stroma may also be present. Usually negative but can occasionally be posi-
Invasion is present, including into non-neoplastic tive in cases from nonendemic regions
salivary gland parenchyma, surrounding connective Electron microscopy:
tissues, neurotropism, and angioinvasion. m Epidermoid cell features, including desmosomes,
Immunohistochemistry: tonofilaments, and cytoplasmic microfilaments

m Epithelial cells:
Cytokeratins and EMA positive Differential Diagnosis

p63 positive but variable reactivity may be Metastatic EBV-associated carcinoma
present from case to case and even within the m Overlapping histologic, immunohistochemical,
same case and molecular features
c-kit (CD117) reactivity may be present m Differentiation predicated on detailed clinical
p16 negative evaluation to exclude primary nasopharyngeal or

m Lymphoid cells: less commonly oropharyngeal carcinoma
Reactive for B-cell (CD20) and T-cell (CD3) Metastatic HPV-associated oropharyngeal carci-
markers noma:
m Presence of p16 and/or identification of high-risk

HPV by molecular testing (PCR, ISH) and absence Clinical
of EBV would allow for differentiation. Rare primary salivary gland tumor
Malignant lymphoma Slightly more common in men than women; occur
Lymphoepithelial sialadenitis over a wide age range but most common in the fifth
Malignant melanoma to seventh decades of life
Nonsebaceous lymphadenoma Most common site of occurrence is the parotid gland
(80% of cases); less common sites include the sub-
Treatment and Prognosis mandibular gland, sublingual gland, and minor sali-
Combined (multimodality) therapy, including surgi- vary glands:
cal resection, neck dissection, and radiation therapy m Minor salivary gland involvement includes intra-
preferred treatment: oral sites, as well as throughout the upper aerodi-

m Up to 40% of patients may present with regional gestive tract.
lymph node metastasis. Presentation usually that of rapidly enlarging and
Local recurrence and distant metastasis may occur. painless mass
5-year survival rate reported to be 75% to 86% m Facial nerve paralysis commonly present
Prognosis linked to clinical stage (60%)
m Duration of symptoms is typically short, occur-
ring over several months

NEUROENDOCRINE m Cervical lymphadenopathy fairly common finding
CARCINOMAS at presentation
Neuroendocrine cells originating from the neural
Represent group of malignant neoplasms with epi- crest migrate to a variety of sites including to salivary
thelial and neuroendocrine differentiation glands (major and minor salivary glands):
Classification includes: m Neuroendocrine cells identified in intercalated
m Typical carcinoid (well-differentiated neuroendo- ducts and seromucous acini

crine carcinoma) Rarely, patients present or have an associated para-
m Atypical carcinoid (moderately differentiated neoplastic syndrome.
neuroendocrine carcinoma)
m Small cell neuroendocrine carcinoma (poorly dif-
Pathology
ferentiated neuroendocrine carcinoma) Gross
m Large cell neuroendocrine carcinoma (poorly dif- Poorly circumscribed, multilobulated, firm, gray-
ferentiated neuroendocrine carcinoma) white mass; infiltration into adjacent structures may
Rare tumor type in salivary glands: be evident.
m In salivary glands, primarily involve parotid and Hemorrhage and necrosis may be identified.
much less often submandibular gland
m Most common type is small cell neuroendocrine Histology
carcinoma. Infiltrative tumor growing in diffuse sheets, cord,
m Rarely, atypical carcinoid and large cell neuroen- trabeculae, ribbons, or irregular nests:
docrine carcinoma may arise in salivary m Associated fibrous and/or fibrovascular stroma
glands with or without hyalinization may be present.

Histologically may be classified into:
m Pulmonary subtype:
Small Cell Undifferentiated Absence of CK20 reactivity

(Neuroendocrine) Carcinoma m Merkel cell subtype:
Presence of CK20 reactivity

(Figs. 20-128 and 20-129) May or may not show expression of Merkel
Definition: Malignant salivary gland tumor composed cell polyoma virus (MCPyV)
of undifferentiated small cells showing epithelial
and neuroendocrine differentiation: Pulmonary Subtype
m Histologically similar to pulmonary counterpart Infiltrative neoplasm with diffuse, cord-like, trabecu-
m May in fact be better considered as neuroendo- lar growth and variable fibrovascular stroma
crine carcinoma, Merkel cell type (see below) Lesional cells are rather uniform composed of round
Synonyms: Small cell carcinoma; extrapulmonary oat to oval nuclei with dispersed (stippled) appearing
cell carcinoma; neuroendocrine carcinoma; poorly dif- nuclear chromatin, inconspicuous to small nucleoli,
ferentiated neuroendocrine carcinoma minimal cytoplasm, and indistinct cell borders:
A B
C D
E F
Fig. 20-128. Small cell (neuroendocrine) carcinoma, pulmonary type, of the parotid gland.
A, Hypercellular tumor (left) infiltrative in the parotid gland (right). B, Growth patterns include diffuse or sheet-like and
trabecular. C, Confluent focus of necrosis. D, Small cells with hyperchromatic nuclei, dispersed (stippled) appearing
nuclear chromatin, inconspicuous nucleoli, minimal cytoplasm, and indistinct cell borders; nuclear molding, mitotic figures
and individual cell necrosis are present. Lesional cells are immunoreactive for (E) cytokeratin (CAM5.2) with dot-like
paranuclear staining and (F) synaptophysin. Staining for CK20 was negative (not shown).
A B
C D
Fig. 20-129. Small cell (neuroendocrine) carcinoma, Merkel cell type, of the parotid gland.
A, Intraparotid infiltrative neoplasm appearing as cohesive clusters and trabeculae; an associated inflammatory cell
infiltrate is present. B, Lesional cells are uniform, composed of round to oval nuclei with pale or washed out chromatin.
The lesional cells are immunoreactive for (C) CK20 with a paranuclear dot-like staining pattern; (D) synaptophysin and
(E) Merkel cell polyoma virus (nuclear staining). In addition to CK20, other cytokeratins including AE1/AE3 and CAM5.2
were positive with paranuclear dot-like staining pattern (not shown).
m Cell are approximately two times larger than Rarely, foci of ductal differentiation and squamous
mature lymphocytes, but occasionally larger differentiation may be seen:
tumor cells may be present. m Tumors with ductal differentiation have been
m Fusiform to polygonal shaped cells may occasion- termed ductal-type of small cell carcinoma.
ally be present. Small cell carcinoma may rarely be the malignant
m Crush artifact resulting in nuclear clumping and component in carcinoma ex pleomorphic adenoma.
diffusion of chromatin material may be identified
m Nuclear molding and peripheral nuclear palisad- Hybrid Tumors
ing may be present. Uncommonly may be a tumor type occurring as a
m Tumor necrosis readily apparent either as conflu- hybrid tumor, representing occurrence of neoplasm
ent foci of necrosis or individual cell necrosis composed of two or more histologic distinct types,
m A high mitotic rate, including atypical mitoses, is each of which conforms with an exactly defined
present. tumor category having an identical origin within
Neural-type rosettes including pseudorosettes same topographic area
(Homer Wrighttype) or true rosettes (Flexner-
Wintersteinertype) may be identified. Other Histologic Types of Salivary Gland
Immunohistochemistry: Neuroendocrine Carcinomas
m Cytokeratins positive, including pancytokeratin In addition to small cell neuroendocrine carcinoma,
(AE1/AE3), CAM 5.2: other types of salivary gland neuroendocrine carci-
Typically shows a punctate or globular para- nomas are rare but may include:
nuclear pattern of staining m Typical carcinoid (well-differentiated neuroendo-
m EMA positive crine carcinoma):

m p63 may be positive and if present tends to be Extraordinarily rare parotid tumor with scat-
focal or scattered positive cells tered reports that appear to indicate parotid
m CK7 and CK20 negative involvement occurred secondary to a primary
m Neuroendocrine marker(s) positive, including at carcinoid of a separate site
least one of the following: m Atypical carcinoid (moderately differentiated
Synaptophysin, chromogranin, CD56 neuroendocrine carcinoma):
m Neuron-specific enolase positive Invasive malignant neoplasm characterized by
m S100 protein is usually negative. trabecular, solid, and focally organoid growth
m No immunoreactivity for Merkel cell polyoma patterns
virus (MCPyV), thyroid transcription factor 1 Lesional cells characterized by round to oval
(TTF-1), melanocytic cell markers (HMB45, nuclei with dispersed (salt and pepper or
melan A, tyrosinase, MITF1), hematolymphoid neuroendocrine type) chromatin and granular
markers (leukocyte common antigen), myogenic eosinophilic-appearing cytoplasm
markers (desmin, actins, myogenin, myoglobin), Mild to moderate nuclear pleomorphism
or vimentin Increased mitotic activity
Electron microscopy: Necrosis (individual cell and confluent

m Membrane-bound neurosecretory granules comedotype)
m Sparse cytoplasmic organelles; well to poorly Neural-type rosettes may be identified.
formed desmosomes Infiltrative growth may include invasion of sali-

vary gland parenchyma, perineural invasion,
Merkel Cell Type lymph-vascular invasion
Sheet-like growth Immunohistochemical staining:
Lesional cells rather uniform composed of round to Lesional cells reactive for:
oval nuclei with pale or washed out chromatin Cytokeratins (AE1/AE3, CAM5.2) with
described as blown up balloons: punctate paranuclear staining,

m Minimal nuclear molding Neuroendocrine markers including chro-
Immunohistochemistry: mogranin, synaptophysin, CD56

m Similar to pulmonary subtype except for the pres- p63 may be positive.
ence of CK20 reactivity Negative for CK20, melanocytic cell

m Merkel cell polyoma virus (MCPyV): markers, S100 protein, CD45, calcitonin,
Discrepant findings in the literature with TTF1, and MCPyV
some reports documenting presence of MCPyV m Large cell neuroendocrine carcinoma:
while other reports document absence of Requisite pathologic criteria include all four of
MCPyV the following:
Tumor cells with moderate to abundant

cytoplasm LARGE CELL
Features of neuroendocrine differentiation UNDIFFERENTIATED
(organoid nesting, trabecular growth, CARCINOMA (Fig. 20-130)
rosettes, and peripheral palisading)
Mitotic activity>10/10hpf (2mm2) Definition: High-grade malignant epithelial salivary
Confirmation of neuroendocrine differentia- gland tumor lacking evidence of glandular, squamous
tion using immunohistochemical staining for or neuroendocrine differentiation and an inability
chromogranin-A, synaptophysin, neuron- to classify in another (more specific) salivary gland
specific enolase, and/or neural cell adhesion carcinoma.
molecule (CD56)
Other typical but not requisite findings Clinical
include: Extraordinarily rare salivary gland tumor type
Nuclei with prominent nucleoli No gender predilection; tumor of adults with patients
Cellular pleomorphism usually in seventh to eighth decades
Large areas of necrosis No ethnic or racial predilection or association with
EBV (unlike lymphoepithelial carcinoma)
Majority of parotid gland origin:
Differential Diagnosis m Submandibular gland, lacrimal gland, and minor
Metastatic small cell (neuroendocrine) carcinoma of salivary glands may rarely be primary sites of
lung (or other) origin occurrence
Metastatic Merkel cell carcinoma Presentation usually that of rapidly enlarging mass
Adenoid cystic carcinoma, solid variant: often with associated facial nerve paralysis and cervi-
m Cribriform growth and rather diffuse reactivity cal lymphadenopathy; fixation to adjacent tissues is
for p63, calponin, and absence of neuroendocrine commonly present.
markers assist in diagnosis.
Malignant lymphoma Pathology
Malignant melanoma Fine-Needle Aspiration Biopsy
Rhabdomyosarcoma Isolated and loosely cohesive large cells with abun-
dant cytoplasm, and variably pleomorphic nuclei
with prominent nucleoli
Treatment and Prognosis Multinucleated tumor giant cells and macrophage
Combined multimodality therapy, including surgical polykaryons may be present.
resection, regional lymph node dissection, and No evidence of squamous, myoepithelial, or wide-
adjunctive radiotherapy, represents preferred spread mucinous differentiation
treatment. Focal rare mucin production may be identified on
Local recurrence and metastasis occur in approxi- special stains.
mately 50% of patients:
m Hematogenous spread is more common than Gross
lymphatic spread. Poorly circumscribed, obviously invasive, firm, solid,
m Distant metastatic sites include liver and brain. gray-white mass measuring from 2 to 10cm in great-
Chemotherapy has been used with questionable effi- est dimension
cacy in patients with recurrence and distant Hemorrhage and necrosis are often identified.
metastases.
Survival rates include: Histology
m 2-year of 70% Widely invasive tumor composed of sheets, nests,
m 5-year of 46% and trabeculae lacking evidence of specific cellular
Adverse prognostic findings include: differentiation and separate by a fibrous stroma.
m Tumor size: Lesional cells:
Tumors greater than 4cm more apt to demon- m Large usually measuring greater than three times
strate neurotropism, invasion of surrounding the size of cells in small cell neuroendocrine
soft tissues, and increased incidence of local carcinoma
failure. m Usually polygonal with enlarged round to oval,
Better prognosis associated with: vesicular nuclei, one or more prominent nucleoli,
m Merkel cell subtype abundant amphophilic to eosinophilic cytoplasm
m Smaller tumor size (<4 cm) and rather distinct cell borders
A B
C D
Fig. 20-130. Large cell undifferentiated carcinoma of the parotid gland.

A, Intraparotid infiltrative neoplasm appearing as a nodular focus with diffuse growth; (B) diffuse (sheet-like) growth; (C) at
high magnification the lesional cells are characterized by markedly enlarged and pleomorphic round to oval nuclei with
vesicular nuclear chromatin, prominent eosinophilic nucleoli, and indistinct eosinophilic cytoplasm. Increased mitotic
activity is present. There is an absence of any type of cellular differentiation (e.g., squamous, glandular, other). The
lesional cells were only reactive for several different cytokeratins including (D) OSCAR.
m Alternative cytoplasmic findings include vacuo- May represent the dedifferentiated cellular compo-
lated to partially clear appearance. nent of a number of differentiated salivary gland
m Nuclear pleomorphism commonly seen but occa- tumors (e.g., acinic cell adenocarcinoma, others) and
sional cases may display nuclear uniformity may be the malignant component or one of the
m Increased mitotic activity including atypical malignant components seen in carcinoma ex pleo-
mitoses and tumor necrosis commonly identified morphic adenoma.
m Multinucleated (osteoclast-like) giant cell may be Histochemistry:
identified. m Stains for epithelial mucin are negative.
Invasion readily apparent including into non- m Intracytoplasmic glycogen (diastase-sensitive,

neoplastic salivary gland parenchyma, surrounding PAS-positive) may be present.
connective tissues, perineural invasion, and lymph- Immunohistochemistry:
vascular invasion. m Cytokeratins positive (pancytokeratin, others)
Desmoplastic stroma that may include benign lym- m CK20 negative
phoplasmacytic cell infiltrate but does not approach m Should be negative for neuroendocrine markers:
the density and/or extent seen in lymphoepithelial Presence of neuroendocrine markers may
carcinoma. result in classification large cell type of
neuroendocrine carcinoma if requisite histo- Occur predominantly but not exclusively in the
logic features are present (see above) parotid gland (80%)
m Melanocytic, hematolymphoid and mesenchymal m Other sites of occurrence may include:
markers negative Submandibular gland and much less often in

m EBV negative (by immunohistochemistry and/or association with minor salivary glands
in situ hybridization) Presents as mass or swelling with or without associ-
m p16 negative ated pain and/or facial nerve paralysis
Cytogenetics and molecular genetics: m Cervical lymphadenopathy at presentation is
m TP53 mutations fairly common.
m Loss of heterozygosity at chromosome 17p May arise as a de novo neoplasm or in association
with a long-standing benign oncocytoma
Differential Diagnosis m Cases occurring in association with oncocytoma
Squamous cell carcinoma, poorly differentiated may present with rapid enlargement of a preexist-
Adenocarcinoma, NOS, poorly differentiated ing mass lesion.
Mucoepidermoid carcinoma, high grade m Rarely occur following radiation treatment
Cystadenocarcinoma, poorly differentiated

Large cell neuroendocrine carcinoma
Malignant lymphoma Pathology
Malignant melanoma Fine-Needle Aspiration Biopsy
Sarcomas Aspirates show similar findings to those seen in
Metastatic carcinoma to salivary glands from sepa- oncocytoma (see Oncocytoma).
rate primary carcinoma Cytologic features indicative of a malignancy, includ-
ing marked nuclear pleomorphism, increased mitotic
activity with atypical mitoses, and necrosis may not
Treatment and Prognosis be present.
Radical surgical extirpation with postoperative
radiotherapy represents preferred treatment. Gross
Chemotherapy has been used in treatment with Unencapsulated single or multinodular, firm mass
varying success. lesion with tan-gray appearance; foci of necrosis may
Aggressively behaving tumor with high rate recur- be present.
rence and metastases (regional and distant).
Prognosis is poor: Histology
m 36% 2-year survival Partially encapsulated or unencapsulated lesion
Factors adversely affecting prognosis include: showing varied growth patterns, including sheets
m Large tumor size (4cm or greater) and nests of neoplastic cells infiltrating surrounding
m Age >50 years tissues with loss of normal lobular architecture
m Metastatic disease Lesional cells characterized by:
m Presence of large, round to oval cells with abun-
dant granular eosinophilic cytoplasm due to the

ONCOCYTIC CARCINOMA absolute increase in the number of cytoplasmic
(Fig. 20-131) mitochondria
m Nuclei tend to be enlarged, centrally located,
Definition: Malignant salivary gland epithelial tumor round to oval, with vesicular chromatin and often
predominantly or exclusively composed of oncocytic with prominent nucleoli.
cells with cytomorphologic features of malignancy (ade- m Ductal differentiation may be present.
nocarcinomatous features) and invasive growth but m Oncocytic cells may form pseudoluminal
lacking findings that might allow classification into spaces.
another tumor type. Nuclear pleomorphism varies from case to case and
Synonyms: Malignant oncocytoma; oncocytic adeno- even within the same case:
carcinoma; malignant oxyphilic adenoma m Any given tumor may demonstrate foci with
absent nuclear pleomorphism adjacent to or

Clinical admixed with cells showing moderate to marked
Exceedingly rare tumor type nuclear pleomorphism.
More common in men than in women; most fre- These features raise possible occurrence of an
quently occurs in the fifth through eighth decades oncocytic carcinoma arising in association with
of life oncocytoma.
A B
C D
E F
Fig. 20-131. Oncocytic carcinoma of the parotid gland.

A, The tumor is unencapsulated and infiltrative into parotid parenchyma, appearing as multiple discrete nodules. A variety
of growth patterns can be seen, including (B) trabecular, cord-like, and solid; (C) complex back-to-back glandular-appearing
(pseudoluminal) spaces and cysts. D and E, The lesional cells are characterized by the presence of cells with prominent
granular eosinophilic-appearing cytoplasm but vary in their degree of pleomorphism from case to case and even within a
given case including (D) limited nuclear pleomorphism and (E) moderate to marked nuclear pleomorphism. Irrespective of
the presence or absence of nuclear pleomorphism these are malignant neoplasms that may include (F) perineural invasion
and/or
fine-needle aspiration biopsy, and such findings

should not be construed as evidence of
malignancy.
m Rare examples of (encapsulated) oncocytoma
with metastatic tumor reported (so-called metas-

tasizing oncocytoma):
Primary tumor showed minimal cytologic
atypia.
Nodal metastasis at presentation
Distant metastases months after diagnosis
Patient died 18 months after diagnosis.
Oncocytosis
Salivary gland tumors with oncocytic cells as either
an admixed cellular component or the predominant
G component, including:
m Mucoepidermoid carcinoma
m Acinic cell adenocarcinoma

Fig. 20-131, contd
(G) nodal metastasis. Metastatic carcinoma with oncocytic features,
including origin from the kidney, pancreas
m Increased mitotic activity, including atypical
mitoses and necrosis (coagulative type), may be Treatment and Prognosis
present. Treatment is complete surgical excision that often
Invasion is present and includes: necessitates total parotidectomy; nodal dissection is
m Infiltration of non-neoplastic salivary gland advocated given the increased incidence of regional
parenchyma (nodal) metastasis.
m Surrounding connective tissues Efficacy of radiotherapy in treatment of these tumors
m Neurotropism and/or lymph-vascular invasion has not been definitively proven.
Histochemistry: Behavior is that of a high-grade malignancy:
m Stains for mitochondria including Novelli and m Tendency to recur (56%)
phosphotungstinic acid hematoxylin (PTAH) m Tendency to metastasis (80%), including regional
show purplish and blue cyotplasmic granules, lymph nodes and distant metastases
respectively. Distant metastases occur to lungs, kidney,
m Stains for epithelial mucin are negative. mediastinum, liver, bone, and thyroid gland.
Immunohistochemistry: Distant metastasis is associated with poor
m Cytokeratin positive, including pancytokeratin prognosis, resulting in tumor-related death
(AE1/AE3), CK7, CK8, and CK19 within 4 years.
m CEA and EMA positive
m S100 protein, p63, calponin, smooth muscle actin
negative MALIGNANT SEBACEOUS

m Antimitochondrial antibodies, used infrequently,
TUMORS
may be of assistance in the diagnosis.
m Increased proliferative activity as determined by
Sebaceous Carcinoma
Ki-67 (MIB1) staining may be present.
(Figs. 20-132 and 20-133)
m Numerous mitochondria that vary in size and Definition: Malignant epithelial salivary gland neoplasm
shape with infiltrative growth composed of islands and sheets
m Desmosomes, nearly continuous basal lamina of atypical cells, including sebaceous cells of varying
and lumina with microvilli, are present. maturity.
Synonym: Sebaceous adenocarcinoma
Differential Diagnosis NOTE: Cells with sebaceous differentiation may be
Oncocytoma: seen in other salivary gland neoplasms including (but
m Generally devoid of nuclear pleomorphism, in not limited to) pleomorphic adenoma, oncocytomas,
creased mitotic activity, and coagulative necrosis Warthin tumors, basal cell adenoma, mucoepidermoid
Necrosis and/or infarction may be present, carcinoma, acinic cell adenocarcinoma, adenoid cystic
especially following traumatic events such as carcinoma.
m Variable degree of sebaceous differentiation:

In some cases very few easily overlooked,
appearing in small clusters of individual
cells
In some cases large islands of sebaceous cells
are seen in association with squamous and
basaloid cells
Sebaceous cells are large with hyperchromatic
nuclei and abundant clear to eosinophilic
cytoplasm.
m Squamous and basaloid cells show cytologic
atypia, including:
Enlarged, moderate to marked pleomorphic
and hyperchromatic nuclei
Increased mitotic activity including atypical
Fig. 20-132. Parotid gland sebaceous carcinoma. forms and necrosis may be present.
Sebaceous carcinoma of the parotid gland appearing as a
Invasive growth including:
m Perineural invasion (20%)
circumscribed, tan-white to yellowish mass.
m Angioinvasion is uncommon.
Oncocytes, mucocytes, and foreign body giant cells

may rarely be identified.
Clinical Histochemistry
Rare neoplasm Immunohistochemistry
No gender predilection; bimodal age distribution m Sebaceous cells:
with peak incidences in third decade and seventh and EMA positive
eighth decades
Majority occur in parotid gland: Differential Diagnosis
m Rare cases identified in oral cavity, vallecula, sub- Sebaceous adenoma
mandibular gland, sublingual gland, and Metastatic sebaceous carcinoma from orbital or
epiglottis. cutaneous sites
Most common symptom is that of a slow-growing
mass or swelling with or without associated pain Treatment and Prognosis
and/or facial nerve paralysis: Surgical excision (subtotal or total parotidectomy) is
m Cutaneous fixation may be present. preferred treatment.
Adjunctive radiotherapy and chemotherapy have
Pathology been used, but of questionable efficacy in controlling
Gross disease
Circumscribed or partially encapsulated, yellow to Appear to behave as low-grade to intermediate-grade
tan-white mass measuring from 0.6 to 8.5cm in neoplasms:
diameter with pushing or infiltrative margins m Local recurrence may occur.
m Metastatic disease (regional lymph node or to
Histology distant sites) may develop late in the disease

Encapsulation may be present but these lesions dem- course.
onstrate at least focally infiltrative margins: m 5-year survival rates are reported to be approxi-
m Infiltration includes into surrounding fibrocon- mately 62%.

nective tissue and/or salivary gland parenchyma m Appears to be a more aggressive neoplasm than
Growth patterns include solid, sheet-like, irregular its counterpart in orbit

islands or nested:
m Coalescence into large solid sheets may occur.
m Numerous and occasionally cystic well-formed

Sebaceous Lymphadenocarcinoma
ductal structures seen: Definition: Malignant counterpart of sebaceous lymph-
Cells lining ducts are cuboidal to low columnar adenoma from which it arises.
with abundant eosinophilic cytoplasm
Neoplastic cells are mostly characterized by squa- Clinical
mous or basaloid cell types both outnumbering seba- Rare tumor with only five reported cases in world
ceous cells: literature to date
A B
Fig. 20-133. Salivary gland sebaceous carcinoma.

Sebaceous carcinoma of the parotid gland. A, At the extreme left is parotid parenchyma from which the tumor originates
and invades as solid cellular nodules with sheet-like growth into skeletal muscle. B through D, Cytologic features include a
predominant basaloid cell proliferation with admixed larger sebaceous cells with abundant clear to eosinophilic-appearing
cytoplasm. E, Lesional cells are EMA positive.
More common in men than woman; majority were

in seventh decade of life with one in sixth decade and MUCINOUS
one in fourth decade ADENOCARCINOMA (Fig. 20-134)
All of parotid origin except one purported to arise
in periparotid lymph node Definition: Salivary gland epithelial malignancy charac-
Most common presentation was that of a painless terized by presence of extracellular mucinous pools or
mass or swelling; one had associated pain on lakes containing neoplastic epithelial cells.
palpation Synonym: Signet ring adenocarcinoma
m Duration of symptoms includes 1 month, 2.5
years, 3 years, 10 years, and 20 years. Clinical

Rare salivary gland tumor
Slightly more common in men than in women; occurs
Pathology over a wide age range but most patients are in
Gross seventh decade of life or older:
Partially encapsulated, yellow-tanappearing lesion m Reported in patient in second decade of life
Occur in minor salivary glands and major salivary

Histology glands:
Histologic features are those of sebaceous lymphad- m In minor salivary glands, most common in oral
enoma characterized by presence of sebaceous cell cavity, particularly palate:

nests admixed with salivary ducts in a lymphoid Other intraoral sites include buccal mucosa,
background (with or without germinal centers) lip, and tongue
sharply demarcated from foci of carcinoma charac- m Among major glands submandibular gland
terized by marked nuclear pleomorphism, increased appears to be most commonly involved.
mitotic activity, atypical mitoses and invasive growth m Presentation includes slow-growing, painless
including into adjacent parotid parenchyma and mass or swelling; occasionally may be associated
perineural invasion: with pain
m Carcinoma may include malignant sebaceous m Mucosal-based lesions may have associated
cells with ductal differentiation, poorly differ ulceration.
entiated carcinoma, adenoid cystic carcinoma,
undifferentiated carcinoma, and epithelial- Pathology
myoepithelial carcinoma Fine-Needle Aspiration Biopsy
m Carcinomatous foci tend to lack lymphoid cell Aspirates may include monomorphic, moderately
stroma. atypical cells, single and clustered, associated with
A foreign body giant reaction may be seen. abundant mucoid material and focal necrosis.
Immunohistochemistry: Tumor cells have eccentric nuclei, prominent nucle-
m Variably staining in carcinomatous component, oli, and occasional cytoplasmic vacuolization.
including: Binucleated and multinucleated tumor cells may be
For EMA, cytokeratins present.
Increased proliferation rate by Ki67 staining
p53 overexpression may be present. Gross
Tend to be soft in consistency due to prominent
mucinous content with a glistening to gelatinous
Differential Diagnosis appearance; tumors range in size from 2.5 to 7cm
Sebaceous lymphadenoma in greatest dimension.
Histology
Treatment and Prognosis Characterized by presence of cystic cavities contain-
Surgical resection is preferred treatment. ing extracellular mucinous pools within which are
Postoperative radiotherapy may be beneficial. epithelial cells appearing in clusters, nests, cords, or
Given the rarity of this tumor with limited available individual cells:
follow-up information prognosis remains uncertain; m Epithelial cells appear to float in mucinous
of the reported cases with ample follow-up: material.

m Three are alive and free of disease at 2, 6, and 14 m Cavities separated by fibroconnective tissue
years, respectively. Lesional (epithelial) cells:

m One patient died of unrelated causes. m Show varying architectural patterns, including
m One patient had pulmonary metastasis. branching cords, papillae, cribriform, solid
clusters and lumens, or incomplete duct-like

structures
m Are cuboidal to polygonal to columnar with
hyperchromatic nuclei and abundant eosinophilic

to clear to vacuolated-appearing cytoplasm:
Nuclear pleomorphism ranges from mild to
moderate
Mitotic activity tends to be few to scarce.
Histochemistry:
m Extracellular mucinous material:
Mucicarmine positive
Diastase resistant, PAS positive
m Intracytoplasmic mucin and diastase-resistant,
PAS-positive material may be identified.

A Immunohistochemistry:
m Cytokeratins including AE1/AE3, CK7, CK8,
CK18, and CK19 positive

m No immunoreactivity for CK20, CDX2, villin
m Absence of myoepithelial, acinar, and neuroendo-
crine cell markers

m Estrogen receptor and progesterone receptor
negative
Mucoepidermoid carcinoma
Salivary duct carcinoma, mucin-rich variant:
m De novo or arising in association with pleomor-
phic adenoma (i.e., mucin-rich salivary duct car-

cinoma ex pleomorphic adenoma)
B Colonic (or intestinal)-type adenocarcinoma of oral
minor salivary glands:
m Rare tumor reported to occur at base of tongue
or anterior tongue occurring in absence of primary

colonic adenocarcinoma:
To date, only four reported cases in the
literature
One patient with 10-month history of occupa-
tional exposure to sawdust while working in
hardware store prior to development of base of
tongue tumor
m Histologically similar to sinonasal intestinal-
type adenocarcinoma (see Section 1, Sinonasal
Tract) including presence of submucosal-based
infiltrative neoplasm composed of admixture
C of well- to moderately differentiated colonic-
type adenocarcinoma characterized by tubular/
glandular structures with an associated mucinous
Fig. 20-134. Mucinous adenocarcinoma of the component
parotid gland.
m Immunohistochemical staining includes:
A and B, This was an intraparotid neoplasm characterized Cytokeratins including AE1/AE3, CAM5.2,
by glands floating in mucous pools. C, Extracellular and CK7
intracytoplasmic mucin positive material is present. CK20, CDX-2 (nuclear staining), and villin
positive
CEA, EMA positive
Nuclear staining for hMLH1, hMSH2, hMSH6,
and hPMS-2 mismatch repair proteins reported
No KRAS mutations of codons 12, 13, and 61 m One case reported in anterior cheek of infant
by DNA sequencing presumptively arising in ectopic salivary gland
m Metastases to cervical lymph nodes (unilateral or tissue
bilateral) Presenting symptom(s) usually that of asymptomatic
m Histogenesis uncertain but possibilities include: parotid or submandibular gland mass:
Origin from transformed minor salivary duct m May include rapid growth
epithelium at this location m Rarely, may be associated with facial paralysis
Development from heterotopic gastrointestinal m May be fixed either to underlying structures or to
tissue skin with or without ulceration

m Tendency to metastasize to regional cervical Radiology:
lymph nodes (unilateral or bilateral) m MRI may show a large facial mass, which is
m One patient with long-term follow-up remained mostly hypointense to the brain and isointense
disease free for 14 months before developing mul- with muscle on T1-weighted images, and mildly
tiple bilateral pulmonary metastatic disease and hyperintense on T2-weighted images and high-
died from his disease 5 years after diagnosis. intermediate signal intensity similar to that of fat
Cystadenocarcinoma, mucinous on T2-weighted images
Cutaneous mucinous (eccrine) carcinoma m Foci of hemorrhage and necrosis may be
Metastatic mucinous (colloid) carcinoma, including present.
gastrointestinal, pancreatic, breast, sinonasal origin m Invasion into adjacent structures such as the
maxilla and adjacent muscles may be present.

Treatment and Prognosis Elevated levels of alpha-fetoprotein may be present.
Surgical resection is preferred treatment. Association with hepatoblastoma and congenital
Local recurrence in approximately 33% nevi reported
Aggressive tumors:
m Most present with advanced clinical stage Pathology
disease Fine-Needle Aspiration Biopsy
m Cervical node metastasis in 63% Cytologic features include presence of variably
m Distant metastases in 29% arranged, tight, solid clusters of atypical-appearing,
m Death from disease in 47% basaloid-like cells in a background of dispersed epi-
thelial and myoepithelial cells.
SIALOBLASTOMA (Fig. 20-135) Clusters contain an admixture of benign ductal cells
and dense, metachromatic, magenta hyaline globular
Definition: Rare congenital/perinatal low-grade malig- material with smooth, rounded outlines.
nant salivary gland tumor composed of basaloid cells Cytologic findings show complete concordance with
and occasional ductal structures recapitulating primitive the histology of sialoblastoma.
salivary gland anlage with unpredictable biologic
behavior. Gross
Synonyms: Embryoma; congenital basal cell adenoma; Circumscribed to partially encapsulated, nodular or
congenital carcinoma; low-grade basaloid adenocarci- lobulated, solid lesion with a tan-gray to yellow
noma; hybrid basal cell adenoma-adenoid cystic appearance, usually firm, measuring from 1.5 to
carcinoma 15cm.
Hemorrhage and necrosis may be present.
Clinical
Very rare salivary gland tumor that to date number Histology
less than 50 cases reported in the world literature May vary from being well circumscribed/
More common in males than in females; majority semiencapsulated and noninfiltrative to infiltrative,
occurs in newborns or shortly after birth; less often, which may include:
can occur in children over 2 years of age: m Infiltration into adjacent structures such as sali-
m Rare purported cases reported in adults (see vary gland parenchyma

below under Differential Diagnosis with adenoid m Facial nerve invasion
cystic carcinoma) Cellular neoplasm composed of a combination of

Essentially limited to parotid gland and subman- solid islands of basaloid cells as well as ductal struc-
dibular gland: tures, which recapitulate appearance of the develop-
m Parotid gland >> submandibular gland ing fetal salivary gland.
m One case of eyelid in infant presumptively arising m Hypercellular islands separated by fibrous or
from lacrimal gland (palpebral lobe) reported fibromyxomatous stroma

A B
C D
Fig. 20-135. Sialoblastoma.

A, Intraparotid infiltrative tumor characterized by lobular and nodular growth separated by varying degrees of
fibroconnective tissue. B and C, The combination of solid islands of basaloid cells with admixed ductal structures
recapitulate the appearance of the developing fetal salivary gland and is characteristic for sialoblastoma. D, At higher
magnification the basaloid cells are primitive appearing with large round to ovoid vesicular to hyperchromatic nuclei; the
ductal component includes small ducts with identifiable lumina lined by cuboidal to low columnar-appearing cells with
eosinophilic cytoplasm; intraluminal secretory material is present.
Islands may be tightly packed (i.e., solid Favorable and unfavorable histologic patterns iden-
growth) with little intervening (fibrovascular) tified, including:
stroma or may be loosely arranged with abun- m Favorable:
dant intervening stroma. Semiencapsulation with cytologically bland

Basaloid cells: basaloid tumor cells showing mild nuclear
m Primitive-appearing with large round to ovoid pleomorphism, identifiable mitoses but absent
vesicular nuclei, ample eosinophilic cytoplasm, atypical mitoses, absent necrosis, and presence
one or more nucleoli, and indistinct cell borders of intervening stroma:
m Vague peripheral nuclear palisading may be seen. m Unfavorable:
Ductal component: Presence of anaplastic tumor cells, increased

Small ducts have distinct lumina. mitotic activity including atypical mitoses,
Lined by cuboidal to low columnar cells with necrosis, minimal stroma, and presence of
eosinophilic cytoplasm can be present broad pushing infiltrative periphery
Ductal lumina may contain basophilic secre- Cribriform growth similar in pattern to that seen in
tory material. adenoid cystic carcinoma may be present.
Other cell types that may occasionally be present Adenoid cystic carcinoma:
include sebaceous, squamous, and acinar cells; calci- m Diagnosis of adenoid cystic carcinoma rare in
fication may also be seen. neonates and infants:

Malignant spindle cell (sarcomatoid) component Tumor with hallmark features of sialoblastoma
rarely identified: but with cribriform growth in neonates or
m Spindle cells cytokeratin and S100 protein infants should be diagnosed as sialoblastoma.
positive m Sialoblastoma in adults rarely if ever occurs, and
m Considered sarcomatoid transformation of basa- in adults any degree of cribriform growth would
loid (myoepithelial) cell component result in classification of a tumor with features of
Immunohistochemistry: sialoblastoma as an adenoid cystic carcinoma;
m Basaloid cells: however:
Diffuse reactivity for CK903 (34BE12); vari- Three adult tumors with primitive histopatho-
able to absent expression of other keratins and logic findings characteristic for sialoblastoma
EMA including cribriform growth reported:
Diffuse p63 reactivity Included 46-year-old female, 55-year-old
Positive staining often focal for S100 protein, male, and 83-year-old male
calponin, smooth muscle actin Two cases of palate and one of parotid
GFAP negative Differences in clinical behavior in these cases

Alpha-fetoprotein expression may be present from adenoid cystic carcinoma cited as evi-
(reported in cases with unfavorable histology) dence to support diagnosis as sialoblastoma
m Ductal cells: rather than adenoid cystic carcinoma including
Reactivity for cytokeratins including diffuse or prolonged disease-free interval over long-term
focal luminal staining for pancytokeratin, follow-up
CAM5.2, CK5/6, CK7, and CK903 (34BE12), Nevertheless, if confronted with such a lesion
as well as EMA in adults, diagnosis of sialoblastoma in lieu
Focal S100 protein may be present. of adenoid cystic carcinoma cannot be ren-
Negative for CK20, p63, smooth muscle actin, dered with complete confidence, and treatment
calponin, and GFAP should follow that for adenoid cystic
Proliferative indices may vary from low levels carcinoma.
(<5% cases with favorable histology) to markedly
increased levels (50% to >90% with unfavorable Treatment and Prognosis
histology) Surgical resection with negative resection margins is
p53 (nuclear) staining may be focal or diffuse in both preferred treatment:
cellular components m In majority of cases results in cure
Electron microscopy: Local recurrence reported in approximately 25% of

m Cell junctions present between ductal and sur- patients:
rounding tumor cells m Occur from months to a few years after resection
m Basaloid cells have well-developed endoplasmic m Local recurrences have been associated with
reticulum, free ribosomes, and surrounding basal increased nuclear pleomorphism, increased
lamina mitotic activity, necrosis, and increased prolifera-
m Intracytoplasmic thin filaments and subplasma- tion indices.
lemmal densities can be seen in peripheral Regional nodal metastasis infrequently occurs.
cells: Chemotherapy (vincristine, actinomycin D, and
Based on presence of actin immunoreactivity cyclophosphamide) considered effective adjuvant or
and intracytoplasmic thin filaments, cells sur- neoadjuvant treatment option for unresectable,
rounding ductal cells are believed to be of myo- recurrent or metastatic tumor
epithelial origin. Biologic behavior (presence or absence of recurrence
and/or metastatic disease) may correlate to:
Differential Diagnosis m Histologic features:
Basal cell adenoma: Tumors with unfavorable histology (see above)

m Basal cell adenomas in contrast to sialoblastoma associated with more aggressive biologic
occur in adults (rare prior to age 20) and are behavior
noninvasive and composed of less primitive cells, m Proliferation indices and p53:
greater peripheral nuclear palisading, less cyto- Increase proliferation rate and diffuse p53
morphologic atypia, and less mitotic activity. staining associated with more aggressive bio-
Basal cell adenocarcinoma logic behavior
Fig. 20-136. Parotid malignant lymphoma.

MALT lymphoma of the parotid gland diffusely involving the
gland with nodular and tan (fish-flesh) appearance.
NONEPITHELIAL MALIGNANT
SALIVARY GLAND TUMORS
Primary Malignant Lymphoma
(PML) of Salivary Glands
(Figs. 20-136 through 20-141)
B
Definition: Malignant neoplastic proliferation of lym-
phoid cells arising in salivary glands with involvement
of glandular epithelium.
m Diagnosis predicated on absence of malignant
lymphoma (ML) of noncontiguous site

m If ML of noncontiguous site identified by clinical
staging and bulk of tumor is not in the salivary

gland, then the salivary gland involvement is con-
sidered secondary.
m Complicating issue is presence of intraparotid
lymph nodes, which may give rise to ML and

therefore are nodal based.
m The distinction between a nodal-based ML sec-
ondarily involving parotid glandular epithelium

from an ML originating in the parotid gland with
secondary nodal involvement cannot always be C
determined.
Most ML of salivary glands are non-Hodgkin lym- Fig. 20-137. Extranodal marginal zone B-cell
phomas (NHL). lymphoma of mucosa-associated lymphoid
Salivary gland NHL may develop essentially in two tissue type.
settings:
A and B, Lymphomatous cells coalesce around and
m In setting of immune sialadenitis (Sjgren infiltrate into the characteristic lymphoepithelial lesions.
syndrome) with lymphoepithelial sialadenitis C, At higher magnification the neoplastic (monocytoid B)
(LESA ML): cells are monomorphic with abundant, pale to clear
Most often extranodal marginal zone B-cell cytoplasm and uniform-appearing nuclei.
lymphoma (EMZBCL), which is a low-grade
B-cell lymphoma arising in mucosal-associated
lymphoid tissue (MALT) referred to as
Fig. 20-139. Diffuse large B-cell lymphoma of the

parotid gland.
The gland is replaced by a homogeneous tan (fish-flesh)-
appearing proliferation.
Excluded from category of primary extranodal

lymphoma is relapse of nodal-based lymphoma
in an extranodal site.
B m Given the above, prior to rendering a diagnosis
of a primary extranodal lymphoma, detailed clin-

Fig. 20-138. MALT lymphoma.
ical staging evaluation is indicated.
In addition to immune sialadenitis (Sjgren syn-
Extranodal marginal zone B-cell lymphoma of mucosa- drome) ML salivary glands are also closely linked to
associated lymphoid tissue type. Immunohistochemical patients with hepatitis C virus (HCV) infection, sug-
staining includes (A) left panel, leukocyte common antigen gesting a possible role in the pathogenesis of these
in the lymphomatous cells but not epithelial cells; right
lymphomas.
panel, cytokeratin reactivity in the lymphoepithelial lesions
but not lymphomatous cells. B, Lesional cells are CD20
Risk of developing a ML in patients with immune
reactive (left panel) but nonreactive for CD3 (right panel); sialadenitis is markedly increased:
m Risk of developing salivary gland NHL 44 times
scattered CD3 positive T-cells are present.
greater than control groups
m Slightly less than 10% of patients with immune
extranodal marginal zone lymphoma of sialadenitis develop ML of extranodal sites

mucosa-associated lymphoid tissue (MALT including:
lymphoma) Salivary glands, lacrimal gland, lungs
m As a de novo process unrelated to other diseases m Many of these patients develop benign atypical
such as lymphoepithelial sialadenitis (non-LESA lymphoproliferative disorders.

ML)
Most often a diffuse large B-cell lymphoma (DLBCL) MALT Lymphoma
Rare salivary gland tumor:
m Represents less than 5% (range 2.4% to 4.5%) Clinical
of all primary extranodal NHL and approxi- Most common salivary gland lymphoma type
mately 2% of all salivary gland tumors: Decided female predilection; occurs with wide age
Extranodal lymphoma includes those patients distribution but, in general, tends to occur in elderly
with stage IE or IIE disease. people with mean age in mid-seventh decade of life:
Lymphomas of extranodal sites in patients with m 5% or less of patients with salivary gland NHL
stage IIIE and IV disease are considered to rep- are younger than fifth decade of life.
resent disseminated (systemic) disease rather m Rarely, salivary gland NHL may occur in pediat-
than primary extranodal lymphoma. ric ages.

Fig. 20-141. Diffuse large B-cell lymphoma of the

parotid gland.
Immunohistochemical staining shows the neoplastic cells
to be left panel, CD45 (leukocyte common antigen)
positive and right panel CD20 positive. The neoplastic cells
were nonreactive for cytokeratins and T-cell markers (not
shown).
syndrome) but without signs of pre-existing

lymphoma may be possible by labial salivary
gland biopsies as a routine part of screening for
Sjgren syndrome
B In approximately 25% serum monoclonal compo-
nent (IgG or IgM) may be identified.
Occurs in association with immune sialadenitis
Fig. 20-140. Diffuse large B-cell lymphoma of the (Sjgren syndrome):
parotid gland. m Less often may occur with other associated dis-
A, Diffuse cellular proliferation effacing the parotid eases, including:

parenchyma with infiltration into the adjacent parotid Rheumatoid arthritis, systemic lupus erythe-
parenchyma (lower right of center). B, Diffuse dyscohesive matosus, hypothyroiditis
cellular proliferation composed of large cells with m In addition to immune sialadenitis also closely
pleomorphic, vesicular nuclei, and eosinophilic nucleoli. linked to patients with hepatitis C virus (HCV)
infection, suggesting a possible role in the patho-
genesis of these lymphomas:
Most often occurs in parotid gland, including HCV characterized by sialotropism and ability
approximately 75% of all cases to replicate in salivary glands as well as by
m Less often, submandibular gland involvement lymphotropism
occurs (from 17% to 20% of cases). Patients with HVC but without Sjgren syn-
Usual presentation includes slow growing salivary drome not known to have increased risk of
gland mass: lymphoma in salivary glands
m Cervical lymphadenopathy may be present at pre- Overall importance of HCV in pathogenesis of
sentation in approximately 30% of patients. ML arising in Sjgren syndrome remains
Presentation may also include ocular, oral, and uncertain
extraglandular signs, including keratoconjunctivitis Risk of developing an ML in patients with immune
sicca and xerostomia: sialadenitis markedly increased:
m Approximately one third have bilateral enlarge- m Risk of developing salivary gland NHL 44 times
ment of affected salivary glands. greater than control groups

m Salivary gland enlargement may be episodic or m Slightly less than 10% of patients with immune
chronic. sialadenitis develop ML of extranodal sites

Early diagnosis of MALT lymphomas in including:
patients with immune sialadenitis (Sjgren Salivary glands, lacrimal gland, lungs
m Many of these patients develop benign atypical m Immunophenotype (recapitulates that of mar-
lymphoproliferative disorders. ginal zone cells)
Chlamydophila psittaci (Cp) implicated in ocular Express CD20, CD79a, CD21, and CD35
adnexa MALT lymphoma: CD5, CD23, CD10, and cyclin D1 negative
m Cp infection identified in small percentage of Aberrant coexpression of CD43 may be present
patients with Sjgren syndrome developing lym- in approximately 50% of cases:
phoma, suggesting its possible role in develop- Indicative of neoplastic phenotype
ment of salivary gland lymphoma in patients with Immunoglobulin light chain restriction:
Sjgren syndrome Typically IgM; less often IgA or IgG; IgD
negative
Pathology Expressed by lymphocytes and monocytoid
Characteristics include: B cells, and usually plasma cells

m Occurs in setting of LESA with residual histologic Bcl-2 positive (but absent in reactive germinal
evidence of LESA, including lymphoepithelial center cells)
lesions Nonreactive for T-cell markers
m Nodular or diffuse (confluent) cellular infiltrate Cytokeratin immunoreactivity limited to lym-
with partial or total effacement of normal lobular phoepithelial lesions:
architecture: May be of assistance in cases where lympho-
Separate tumor foci may be seen. epithelial lesions are overrun and obscured
m Presence of halo formation surrounding lym- by lymphoid cells.
phoepithelial lesions distorting or effacing sali- m Cytogenetic and molecular genetics:
vary gland parenchyma: Of chromosomal translocations strongly asso-

Monocytoid and centrocyte-like cells coalesce ciated with marginal zone lymphoma, only
and surround lymphoepithelial lesions t(14;18) involving IgH and MALT1 fusion
Represents early change present in proportion of cases ranging from 0
May link several or multiple lymphoepithelial to 18%
lesions Other translocations strongly associated
Normal lobular architecture altered with with marginal zone lymphoma not seen in
replacement of acini and ducts and invasion of salivary gland include:
the neoplastic cells into surrounding structures t(11;18) involving AP1 and MALT1; trans-
m Heterogeneous B-cell infiltrate present including: location most frequently present in gastric
Sheets of lymphoid cells, monomorphic, (and lung) MALT lymphoma
medium-sized cells with abundant, pale cyto- t(1;14) involving BCL10 and IGH
plasm and bland, uniform nuclei, and distinct t(3;14) involving FOXP1 and IGH
cell membranes Clonality by itself is insufficient to diagnose

Atypical small lymphocytes lymphoma in setting of LESA as monoclonality
Centrocyte-like (cleaved) cells in LESA does not necessarily predict clinical or
Monocytoid B-cells morphologic evidence of lymphoma
Immunoblasts Nonlymphomatous monoclonal lesions might
Lymphoplasmacytic cells be considered borderline lesions.
Plasma cells: Chromosomal abnormalities, including triso-
May be numerous mies 3 and 18
May show intranuclear inclusions (Dutcher
bodies) or intracytoplasmic PAS-positive

immunoglobulin crystals can be seen. Differential Diagnosis
m Reactive germinal centers Lymphoepithelial sialadenitis (LESA):
m Clusters of epithelioid histiocytes may be present m Absence of halo formation formed by coales-
around lymphoepithelial lesions. cence of monocytoid and centrocyte-like cells

m Ductal dilatation creating a cystic or multicystic around lymphoepithelial islands, retention of
appearance not infrequently seen: normal salivary gland lobular architecture,
Presence of cysts vary in size from small to absence of increased plasma cells with or without
greater than 0.5cm. Dutcher bodies assists in differentiating LESA
m Amyloid deposition rarely may be present. from MALT lymphoma
m Transformation to higher grade lymphoma, Chronic sialadenitis
usually DLBCL, may occur. HIV-associated salivary gland disease
Mantle cell lymphoma: Most often occurs in parotid gland (approximately

m Less heterogeneous population of atypical lym- 75% of all cases)
phoid cells as compared with EMZBCL m Less often, submandibular gland involvement
m CD5, CD43, and cyclin D1 immunoreactivity occurs (from 17% to 20% of cases).
contrast immunoreactivity of EMZBCL Majority arise de novo:
Other low-grade lymphomas: m Some patients may have history of Sjgren
m Follicular lymphoma: syndrome.
May present diagnostic difficulties with MALT m Rare patients have history of Sjgren syndrome
lymphoma when there is follicular colonization and hepatitis C (HCV) infection.

CD10, bcl-6, and bcl-2 immunoreactivity Patients present with painless swelling of affected
contrasts with immunoreactivity of MALT gland(s).
lymphoma Mass is nontender, firm, and often fixed to
In presence of follicular colonization marginal adjacent tissues.
zone neoplastic cells are bcl-2 negative. Pain and tenderness uncommonly occur.
Increased incidence in patients with immunodeficient
Treatment and Prognosis conditions:
Local therapy including surgery or radiotherapy m Epstein-Barr virus identified in some of these
Survival rates include: lymphomas

m 5-year survival of 85% to 90%
m 15-year relative survival was 78.4%

Pathology
Relatively indolent behavior usually remains Gross
localized: Circumscribed to ill-defined and infiltrative lesion
m Majority are Ann Arbor stage IE or IIE Cut surface appears tan-white to yellow-tan with a
disease: homogeneous (fish-flesh) appearance and firm
54% IE consistency.
19% IIE
10% IIIE/IV Histology
m Relapses not uncommon and may involve: Characterized by:
Primary site lymph nodes, especially cervical m Diffuse replacement of salivary gland tissue
neck, and extranodal sites with effacement of the normal lobular
Relapses can be treated successfully. architecture:
m Dissemination is slow to occur and may Lymphoma cells infiltrate and replace acini and
involve cervical lymph nodes and other mucosal ducts.
sites. Infiltration into adjacent connective tissue
m Excellent prognosis for low-grade lymphoma structures seen that may include perineural
with localized disease (IE) invasion
m Prognosis for nodal involvement (IIE) is similar Extraglandular spread into surrounding peri-
to that of primary low-grade nodal-based glandular soft tissues occurs.
NHL. m Neoplastic cells are large with round to oval
MALT lymphomas may transform to DLBCL: enlarged nuclei, vesicular chromatin, and promi-
m Occurs in approximately 12% of cases nent eosinophilic nucleoli.
m Tumors tend to follow a more aggressive course, m Lymphoepithelial islands (LELs) not seen
including death, but may have a more favorable m Immunophenotype:
prognosis than comparable nodal disease. Express CD45 and various pan-B markers
including CD20, CD79a, PAX5
CD20 lost in 60% of recurrent tumors
Diffuse Large B-Cell treated with rituximab

Lymphoma (DLBCL) Monotypic surface or cytoplasmic immuno-
globulin frequently seen (IgM > IgG > IgA)
Clinical Melanoma-associated antigen (MIM1) expres-
Represents approximately 10% of salivary gland sion (nuclear staining)
PML BCL6 expression in approximately 60%
Slight female predilection; wide age distribution but, CD10 expression in 20% to 40%
in general, tendency to occur in elderly people with CD5 expression in approximately 10%
mean age in mid-seventh decade of life CD30 expression in approximately 10%
BCL6 expression in approximately 50%

Ki67 index >20% (mean 55%) SARCOMAS OF
May be p63 positive SALIVARY GLANDS
m Cytogenetic and molecular genetics:
Clonal rearranged immunoglobulin heavy- and Clinical

light-chain genes Sarcomas of salivary glands are extremely uncom-
Rearranged germline T-cell receptor (TCR) mon, accounting for less than 2% of all malignant
genes salivary gland tumors and approximately 0.5% of
Small number of cases of DLBCL have a component all salivary gland tumors.
of marginal zone lymphoma This category excludes carcinosarcoma (previously
m Likely represent transformation of MALT lym- discussed under Malignant Mixed Tumors).
phoma to DLBCL Sarcomas of salivary glands tend to occur in older-
m Associated with more aggressive behavior aged patients.
Most sarcomas involve the parotid gland.
Differential Diagnosis Presentation includes mass or swelling with or
Lymphoepithelial sialadenitis (LESA) without pain and/or facial nerve paralysis; a rapidly
IgG-related sialadenitis enlarging mass occurs in a minority of patients.
Sinus histiocytosis with massive lymphadenopathy Virtually all sarcoma types have been reported
(Rosai-Dorfman disease) to occur in salivary glands; more common types
Carcinoma (undifferentiated, others): include:
m Immunoreactivity for epithelial markers (cyto- m Malignant peripheral nerve sheath tumor
keratins, others) and absence of immunoreactiv- m Fibrosarcoma
ity for hematolymphoid markers allow for m Undifferentiated pleomorphic sarcoma
differentiation. m Rhabdomyosarcoma
m Angiosarcoma
Treatment and Prognosis m Synovial sarcoma
Treatment and prognosis similar to histologically m Leiomyosarcoma
identical lymphomas of lymph nodes: m Kaposi sarcoma:
m Treatment may include combination of surgical Often occurs in HIV-positive patients

resection, radiotherapy, and chemotherapy. Develop in the parotid gland or intra- or peri
Most patients have localized disease. parotid lymph nodes
m Liposarcoma
Other Types of Salivary Gland m Alveolar soft part sarcoma
m Others:
Non-Hodgkin Lymphomas Recently rare case of adamantinoma-like
Other types of NHLs may involve salivary glands, Ewing sarcoma reported as primary parotid
including: neoplasm:
m Follicular lymphoma: EWSR1 and FLI1 fluorescence in situ hybrid-
In different studies varies from second most ization confirmed presence of translocation
common (to MALT lymphoma) or third most supporting diagnosis
common (to MALT lymphoma and DLBCL) EWSR1 identified in salivary gland hyalin-
type of salivary gland lymphoma izing clear cell carcinoma

m Mantle cell lymphoma, anaplastic large cell lym- Prior to diagnosis of a primary sarcoma of salivary
phoma, extranodal NK/T cell lymphoma of nasal glands, clinical evaluation indicated to:
type, and peripheral T-cell lymphoma m Exclude a history of a histologically similar
sarcoma of a separate and/or adjacent (e.g, soft

Hodgkin Lymphomas of tissues of neck) primary site
m Exclude metastasis to involved salivary gland
Salivary Glands from a separate primary site or direct invasion
Primary involvement of salivary glands by Hodgkin into the salivary gland from an adjacent primary
lymphoma is rare. site
Classical and nodular lymphocyte predominant m Confirm origin from within the involved salivary
type gland
Majority occurs in parotid gland and likely repre- Diagnosis and differential diagnosis based on light
sents secondary spread from nodal-based microscopic features often requiring adjunct studies,
disease. including histochemistry, immunohistochemistry,
electron microscopy, cytogenetics to confirm the very young (infants and children) and the very old
diagnosis (tenth decade and older).
Depending on tumor type the differential diagnosis Majority of cases involve parotid gland, and to a
may include (but is not limited to) carcinomas (espe- lesser extent submandibular gland:
cially in those sarcomas with epithelioid features) m Metastases may occur to intraparotid lymph
and malignant melanoma. nodes and secondarily involve parotid paren-

Treatment usually requires complete surgical resec- chyma.
tion combined with radiation and chemotherapy. Relative to parotid gland, the majority (80%) of
Because sarcomas are more likely to spread hema- secondary tumors originate from head and neck
togenously rather than via lymphatic channels, neoplasms.
unless there is clinical evidence of neck disease, cervi- Relative to the submandibular gland, the majority
cal (nodal) neck dissection would not appear to be (85%) of secondary tumors originate from distant
warranted. sites.
Prognosis is dependent on a variety of factors Most common secondary tumors involving salivary
including: glands are cutaneous squamous cell carcinoma and
m Stage of disease malignant melanoma.
m Tumor size For primary tumors that originate from distant (non-
m Sarcoma type head and neck) sites, most common tumor types
m Histologic grade metastasizing to salivary glands are of lung (espe-
Recurrence occurs from 40% to 64% of patients: cially small cell neuroendocrine carcinoma), kidney,
m Most recurrences occur within 1 year following and breast origin:
treatment. m In contrast to renal clear cell carcinoma, clear cell
Distant metastases occur in 40% to 64% of patients. carcinomas of salivary glands are:
Tumor-related death ranges from 36% to 64%. Nonreactive for renal cell carcinoma antibody,
Overall 5-year and 10-year survival rates of 42% CD10, PAX2, PAX8, CAIX
and 20%, respectively Demonstrate presence of EWSR1 translo
cation.
SECONDARY TUMORS m In rare examples of simultaneously occurring sali-
vary duct carcinoma and primary mammary duct

Definition: Salivary gland involvement by malignant carcinoma differentiation can be problematic
tumor originating from separate primary site that has given overlapping histologic features and immu-
spread to involved salivary gland by direct invasion nohistochemical staining:
from an adjacent site or via hematogenous or lymphatic Differentiation possible if primary breast
spread from a distant site. cancer is histologically low grade as salivary
duct carcinomas are histologically high
Clinical grade
Metastatic disease to salivary glands uncommon,
representing approximately 5% of all malignant sali-
vary gland tumors. FURTHER READING
Much more common in men than in women; peak
incidence is in the seventh to eighth decades of life References may be accessed online at ExpertConsult
although may occur in any age group including the .com.
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CH 20 Neoplasms of The Salivary Glands

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CH 20 Neoplasms of The Salivary Glands

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Chapter

Neoplasms of the Salivary Glands

salivary gland neoplasm are: adenoma

BOX 20-1 Classification of Neoplasms of the Salivary Glands

Benign Neoplasms Mammary analogue secretory carcinoma

Mesenchymal neoplasms of salivary glands are rare: Acinic cell carcinoma

m Exception is in infants Adenoid cystic carcinoma

Hemangioma and lymphangioma most Carcinoma ex pleomorphic adenoma (CEPA)

common Epithelial-myoepithelial carcinoma

malignant. All are unencapsulated.

m Major salivary gland neoplasms: posed of admixture of epithelial cells and

nostic for malignancy. Immunohistochemical staining (cytokera-

Familial or genetic predisposition immunohistochemical antigenic profile among a

m Exposure to industrial chemicals Transcription factor crucial in development of

m Has a specificity rate reported to be 60% to 75% cystic carcinoma, epithelial-myoepithelial

ocal or inconclusive likely result in intraoperative epidermoid carcinomas, oncocytic carci-

TABLE 20-1 Immunohistochemistry* of Selective Salivary Gland Neoplasms

TABLE 20-2 Salivary Gland Neoplasms: Chromosomal Translocations

morphic adenoma, others). Some tumors occurring in a specific site have a

ex pleomorphic adenoma. Tumor involvement of the facial nerve is associ-

variety of cytomorphologic findings. Tumors occurring in younger patients and in

PLEOMORPHIC ADENOMA (PA) Slightly more common in women than men;

m Considered a pure epithelial neoplasm with dren and adolescents

Clinical exclusively) in the superficial lobe (i.e., superficial

of the parotid, submandibular glands, and minor a parapharyngeal space mass.

TABLE 20-3 TNM Classification of Salivary Gland Carcinomas*

for periods up to several years. ryngeal space (followed by peripheral nerve

Fig. 20-1. Pleomorphic adenoma.

Parapharyngeal space is a potential space between

Despite efforts in localization of key proteins using cases reported to date):

Fig. 20-2. Axial contrast-enhanced CT scans of three different patients.

m Spatial segmentation of MALDI-imaging data m May demonstrate cystic change

Fig. 20-3. CT and MR of pleomorphic adenoma.

Morphologic diversity including: Tyrosine-like crystals appearing as crystalline

m Oncocytic cells and lacking nuclear atypia can be diagnosed as

Fig. 20-4. Parotid pleomorphic adenoma.

plete capsules and there may be juxtaposition of

Nodules may be separate from one another.

not diagnostic feature for malignancy

Fig. 20-6. Pleomorphic adenoma.

Fig. 20-7. Cellular epithelial-predominant pleomorphic adenoma.

Fig. 20-8. Cellular myoepithelial-predominant pleomorphic adenoma.

Fig. 20-8, contd

Fig. 20-9. Chondromyxoid predominant pleomorphic adenoma.

Fig. 20-10. Metaplastic and retrogressive changes following aspiration.

amount of cytoplasm appearing eosinophilic to in the same neoplasm.

Fig. 20-11. Variant histologic findings in pleomorphic adenomas.

Fig. 20-11, contd

Fig. 20-12. Growth characteristics of pleomorphic adenoma.

Fig. 20-12, contd

phic adenoma. Calcification and fat

Fig. 20-13. Potential confounding findings in pleomorphic adenomas.

Postfine-needle aspiration biopsy changes: Necrosis/infarction

manipulation or fine-needle aspiration biopsy the presence of necrosis/infarction in the

Fig. 20-14. Recurrent multinodular and multifocal pleomorphic adenoma.

m Epithelial-predominant pleomorphic adenoma and often relegated to focal areas of the

m Chondromyxoid-predominant pleomorphic ad tumor but often are limited in number.

spillage caused by tumor injury presumably by

Atypical Pleomorphic Adenoma

m Prominent zones of (acellular) hyalinization

Pleomorphic adenomas with prominent zones

Presence of atypical features should prompt exten-

Recurrent Pleomorphic Adenoma