Resident Short Reviews
Adenoid Cystic Carcinoma
Jesse Jaso, MD; Reenu Malhotra, MD
Ndeceptively
Adenoid cystic carcinoma is a malignant tumor with a
benign histologic appearance characterized by
indolent, locally invasive growth with high propensity for
local recurrence and distant metastasis. The tumor is
composed of basaloid cells with small, angulated, and
hyperchromatic nuclei and scant cytoplasm arranged into
3 prognostically significant patterns: cribriform, tubular,
and solid. Some tumors undergo dedifferentiation into a
high-grade form. Numerous studies have attempted to
elucidate accurate histologic prognostic features but have
often yielded conflicting results. Microarray analysis and
gene expression profiling have provided new potential
diagnostic and prognostic markers. However, tumor grade,
stage, lymph node metastasis, invasion of major nerves,
and margin status remain the most consistent predictors of
prognosis. The combination of surgery and postoperative
radiation therapy has improved locoregional control of the
disease. Despite this achievement, late local recurrence
and distant metastasis rates remain high and may occur
decades after initial diagnosis.
(Arch Pathol Lab Med. 2011;135:511–515)
O verall, adenoid cystic carcinoma (ACC) is a rare
tumor, accounting for only 1% of all malignant
1
tumors of the oral and maxillofacial region. It accounts for
22% of all salivary gland malignancies and is one of the
most common malignant tumors of the minor salivary and
seromucinous glands.1,2 The most common site is the
minor salivary glands of the oral cavity.2 However,
involvement can occur in almost any site with a secretory
gland component and has been reported in sites such as
the lacrimal gland, breasts, uterine cervix, esophagus,
lungs, and prostate.2
First described in 1853, this neoplasm underwent
numerous name changes before being given its current
name by Spies in 1930.3 Adenoid cystic carcinoma is well
known for its prolonged clinical course and tendency for
delayed onset of distant metastases. The tumor has a well-
described histologic appearance with certain features that
Accepted for publication March 26, 2010.
From the Department of Pathology and Laboratory Medicine,
University of Texas Health Science Center at Houston Medical School
and University of Texas Medical Center-Houston (Dr Jaso); and the
Department of Pathology and Laboratory Medicine, University of Texas
Health Science Center at Houston Medical School, Houston, Texas (Dr
Malhotra). Dr Malhotra is now with Caris Diagnostics, Irving, Texas.
The authors have no relevant financial interest in the products or
companies described in this article.
Reprints: Jesse Jaso, MD, Department of Pathology, University of
Texas Medical Center-Houston, 6431 Fannin St, Houston, TX 770030-
1501 (e-mail: jesse.jaso@uth.tmc.edu).
Arch Pathol Lab Med—Vol 135, April 2011
may predict prognosis. Surgical removal is often difficult
given the tumor’s propensity for invasion into adjacent
structures and completely negative margins may not be
attainable. Radical surgery has not been shown to improve
survival or reduce local recurrence when compared with a
conservative surgical approach and postoperative radia-
tion.3 Currently, the prevention and prediction of late local
and distant recurrence remains difficult and there is a lack
of prospective randomized multicentric trials to guide
optimal treatment and surveillance.
CLINICAL FEATURES
Adenoid cystic carcinoma is most common in the fifth
and sixth decades of life. However, it can appear at
virtually any age. The patient population in 1 recent
review was reported to range from 10 to 96 years.4 Gender
predilection is an inconsistent feature in the literature with
some authors reporting a male predominance and others
finding a female or no gender predilection.1,5–7 In
decreasing order, the most common sites of ACC appear
to be the minor salivary glands of the oral cavity, the major
salivary glands, and the extraoral seromucinous glands.4
The clinical course is characterized by an initial period of
slow and indolent growth that is usually asymptomatic. In
most cases the tumor goes unnoticed until it has invaded
local nerves and structures causing varying symptoms
depending on location.4 Thus, most patients will present
with locally invasive disease. In a recent review of ACC of
the nasopharynx, 74.3% of patients showed advanced
disease at the time of initial evaluation.8 Despite this,
cervical lymph node metastasis is a rare event. Instead, the
tumor spreads through a hematogenous route with
distant metastasis appearing years, even decades, after
initial diagnosis.4,9 In 1 recent series, rate of distant
metastasis was reported as 47.8% with mean time to
distant metastasis reported as approximately 5 years.10
Yet, the disease-free intervals in this study ranged from 8
to 150 months, highlighting the need for close long-term
surveillance. The most common site of distant metastasis
is the lung, followed by bone with other common sites
including the liver and the brain.4,5,7–10 Unlike lung
metastasis, the course of disease is usually fulminant if
metastases occur in bone, especially the spine.5
Most patients will undergo extensive resection followed
by postoperative radiation regardless of margin status.
With this treatment modality, disease-free survival rates at
5 years are generally high. Consistent use of postoperative
radiation therapy has been associated with a local control
rate of 95% at 5 years.11 Unfortunately, despite improved
local control, disease-free survival rates decline signifi-
cantly at 10 and 15 years.4,5,7–9 Additionally, 1 recent series
Adenoid Cystic Carcinoma—Jaso & Malhotra 511
found no difference in survival, rate of recurrence, and
time to recurrence between patients treated with surgery
and postoperative radiation and those treated with
surgery alone.12 Furthermore, distant and local recurrence
can occur concurrently and despite initial local control,
leading several authors to consider distant and local
recurrence as separate diseases.1,10 Guidelines regarding
management of metastatic disease are still not fully
established. However, prolonged survival, even in the
presence of multiple lung metastases, is not unusual.6,9,10
Fordice et al5 suggest that there may be 2 patient
populations in ACC: One ‘‘doomed to rapid death from
aggressive tumor’’ and another doomed to a prolonged
course measured in decades.
GROSS PATHOLOGY
The tumor is typically a firm, poorly circumscribed, and
unencapsulated mass. Tumor size typically averages from
1 to 8 cm in maximum dimension. Tumor size greater than
3 cm has been associated with increased rates of distant
metastasis.9 The cut surface is white to gray-white with a
solid appearance. Hemorrhage and necrosis are rare
features and should raise the suspicion of high-grade
transformation into dedifferentiated ACC.13
HISTOPATHOLOGY
The microscopic appearance of the tumor is heteroge-
neous, consisting of varying amounts of 3 distinct growth
patterns; however, the cytology of the tumor cells
themselves is relatively uniform. The cells of the tumor
display a basaloid appearance with angulated, hyper-
chromatic nuclei and scant, clear to eosinophilic cyto-
plasm.14,15 Electron microscopy and immunohistochemical
analysis have shown that the tumor cells represent 2
populations of cells showing either myoepithelial or
intercalated duct cell differentiation.16
Three growth patterns for ACC have been described:
cribriform, tubular, and solid. The cribriform subtype is
the most frequent.14 It is composed of islands of basaloid
cells surrounding variably sized cystlike spaces forming a
‘‘Swiss cheese’’ or sievelike pattern (Figure 1). The cystlike
spaces are referred to as ‘‘pseudocysts’’ because they do
not represent true glandular lumina and are contiguous
with the surrounding stroma.14 The pseudocysts contain
basophilic glycosaminoglycans and/or eosinophilic, peri-
odic acid-Schiff–positive basal lamina material.14–16 Rare,
true glandular lumina composed of cuboidal cells show-
ing ductal differentiation can also be found scattered
throughout and their presence greatly aids in diagnosis
(Figure 2).
The tubular pattern shows similar cytology with the
tumor cells arranged in nests surrounded by variable
amounts of eosinophilic, often hyalinized stroma. Occa-
sionally, the stroma component is increased, compressing
the tumor cells into thin strands, forming a ‘‘trabecular’’
pattern. Well-formed ducts with recognizable inner
epithelial and outer myoepithelial layers are more
prominent than in the cribriform pattern. The continuity
of the pseudocysts with the surrounding stroma is also
more prominent.
The solid pattern contains aggregates of basaloid cells
without tubular or cystic formation. Although the basa-
loid cytology of the tumor cells is retained, the tumor cells
may be larger and nuclear pleomorphism may be more
pronounced. Mitotic figures and comedonecrosis may
512 Arch Pathol Lab Med—Vol 135, April 2011
also be seen.14 As in the cribriform pattern, true ducts will
occasionally be seen scattered among the sheets of cells.
This feature, along with accompanying areas of cribriform
or tubular growth, can aid in differentiation from other
basaloid neoplasms.
The percentages of each pattern form the basis of the
grading system composed by Szanto et al.17 Grade I
tumors contain only the tubular or cribriform growth
pattern, grade II tumors contain cribriform or tubular
growth with less than 30% solid component, and grade III
tumors contain more than 30% solid component. Al-
though the prognostic significance of this grading system
has been questioned,1 the presence of a solid component
has been a consistent predictor of poor prognosis in
several series.4,5,7 However, a recent series of 23 patients
with ACC found no statistically significant associations
between histologic grade and local recurrence, distant
metastasis, or overall survival.10 In addition, grading can
be difficult as 1 tumor may show varying degrees of more
than 1 subtype. Instead, several authors have reported that
staging using the American Joint Committee on Cancer
tumor stage is more predictive of prognosis and distant
metastasis.1,7,12 Careful documentation of perineural inva-
sion during staging is especially important as identifica-
tion of invasion of major (ie, cranial) nerves has been
shown to be of greater prognostic significance than minor
nerve invasion.5,6,11
High-grade or ‘‘dedifferentiated’’ ACC contains 2
histologic components: an area of conventional ACC of
any grade and an area of high-grade undifferentiated
carcinoma or poorly differentiated adenocarcinoma.13,14
The most common histologic appearance of the dediffer-
entiated component in 1 recent series was poorly
differentiated cribriform adenocarcinoma.13 The high-
grade areas do not display any histologic features of
ACC and most importantly display loss of ductal-
myoepithelial differentiation.13 Other findings include
increased (.5 per high-power field) mitotic activity,
comedonecrosis, micropapillary and squamoid growth
patterns, and fibrocellular desmoplasia.13
IMMUNOHISTOCHEMICAL FINDINGS
Use of immunohistochemical stains such as smooth
muscle actin, S100, and smooth muscle myosin heavy
chain will highlight cells showing myoepithelial differen-
tiation surrounding the pseudocysts (Figure 3). The
lumens of the pseudocysts will stain positively for
basement membrane components such as type IV collagen
and laminin.15 Adenoid cystic carcinoma of the salivary
gland has also been shown to be strongly positive for c-
KIT (CD117) regardless of grade.18,19 Strong c-KIT expres-
sion will be seen in almost all neoplastic cells in the solid
pattern, all cells surrounding pseudocysts in the cribri-
form pattern, and all luminal cells in the tubular pattern18
(Figure 4).
Many markers have been studied as potential prognos-
tic indicators in ACC. Increased expression of the cellular
proliferation marker Ki-67 is seen with increasing
amounts of solid (grade III) component and has been
shown to correlate with worse prognosis.6,20 Thus, it may
be a useful adjunct in assignment of tumor grade and
prognosis. Ki-67 and p53 may show increased staining in
areas of high-grade transformation.13 Increased p53
expression may also be an independent marker of poor
prognosis.2,4
Adenoid Cystic Carcinoma—Jaso & Malhotra
Figure 1. Cribriform growth pattern displaying several prominent pseudocysts surrounded by basaloid cells with hyperchromatic angulated nuclei
(hematoxylin-eosin, original magnification 3200).
Figure 2. High-power view displaying the characteristic eosinophilic basement membrane material in pseudocysts. Several true glands lined by
cuboidal epithelium are visible in the center (hematoxylin-eosin, original magnification 3400).
Figure 3. Immunohistochemical stain for smooth muscle actin as a marker for myoepithelial differentiation (original magnification 3400).
Figure 4. Immunohistochemical stain for CD117 (c-KIT) showing strong staining around pseudocysts (original magnification 3400).

MOLECULAR/ANCILLARY STUDIES Because of the poor response of ACC to chemotherapy,

Past studies have shown that tumor aneuploidy
correlates with more aggressive disease and a poor
prognosis.21 A recent study of 52 cases of ACC showed
that deletion of 1p-32-36 was the most common genetic
change in ACC and was significantly associated with solid
tumor phenotype and decreased overall survival.22
Arch Pathol Lab Med—Vol 135, April 2011
newer studies have attempted to use molecular techniques
to define potential future therapeutic targets. A recent
large-scale microarray analysis of 15 cases of ACC found
the transcription factor–encoding gene SOX4 was signif-
icantly overexpressed in ACC relative to normal salivary
gland tissue.23 Genes encoding AP-2a and AP-2g as well as
genes highly involved in the Wnt/b-catenin signaling
Adenoid Cystic Carcinoma—Jaso & Malhotra 513
pathway were also overexpressed. The study also con-
firmed increased expression of genes indicative of
myoepithelial differentiation as well as those involved in
the production of basement membrane and extracellular
matrix. As previously mentioned, ACC of the salivary
gland has been shown to strongly express c-KIT. A recent
study found multiple heterogeneous point mutations of
the c-kit gene in 8 of 14 cases of ACC of the salivary
gland.19 The application of these findings regarding
therapeutic targets remains to be defined.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of ACC includes tumors that
also exhibit tubular and cribriform structures such as
polymorphous low-grade adenocarcinoma, tumors with
basaloid cellular morphology such as basal cell adenoma
and basal cell adenocarcinoma, and tumors with a dual
population of ductal and myoepithelial cells such as
pleomorphic adenoma.
Pleomorphic adenoma can be identified by the presence
of mesenchymal, especially cartilaginous, differentiation
in the stroma. The differential diagnosis may be more
difficult on fine-needle aspiration biopsy, especially in
cases of cellular pleomorphic adenoma with scant stroma.
A recent study found that expression of glial fibrillary
acidic protein and CD57 could be reliably used in cell
block preparations to differentiate pleomorphic adenoma
from ACC.24 In this study of 10 cases, 100% of cases
diagnosed as pleomorphic adenoma expressed glial
fibrillary acidic protein and 80% expressed CD57. None
of the cases of ACC were positive for either marker.
Basal cell adenoma can be identified by the presence of a
capsule and lack of stromal and perineural invasion. Basal
cell adenocarcinoma may be more difficult to differentiate
with solid ACC; however, lack of clear cytoplasm and
hyperchromatic, angulated nuclei with the presence of
peripheral palisaded nuclei in the former may aid in
diagnosis.14 Also, most tumors displaying a solid compo-
nent of ACC will often display areas of cribriform or
tubular growth.
Polymorphous low-grade adenocarcinoma occurs al-
most exclusively in the minor salivary glands and may
contain overlapping histopathologic features with ACC
such as ductal, tubular, and even cribriform growth.
Perineural invasion is also common. However, the
presence of cuboidal or columnar cells containing pale
and ovoid nuclei with eosinophilic cytoplasm is in
contrast with the hyperchromatic and angulated cells of
ACC.25 In addition, polymorphous low-grade adenocarci-
noma lacks a dual population of ductal and myoepithelial
cells and typically has negative or low (less than 50% of
cells) expression of c-KIT compared with the high c-KIT
expression of ACC.18
CURRENT TREATMENT, COMMENT,
AND RECOMMENDATIONS
Optimal treatment of ACC has not yet been fully
established. Although most authors advocate the use of
surgical excision and postoperative radiotherapy,3,6,11
some series have found no statistically significant differ-
ence between patients treated with combination therapy
and those treated with surgery alone.4,12 Careful tumor
staging and grading with documentation of perineural
invasion and margin status continue to be important
prognostic tools. Additional prognostic information can
514 Arch Pathol Lab Med—Vol 135, April 2011
be obtained using Ki-67 and p53 staining. There may be an
increasing role for cytogenetic and gene expression
analysis as additional prognostic factors. However,
studies evaluating the efficacy of chemotherapeutic and
molecular therapies remain disappointing.2 Close follow-
up and surveillance of all patients for recurrence and
metastasis is essential, although no formal guidelines exist
regarding the most appropriate mode and duration of
surveillance. Once metastatic disease has occurred,
especially in the lungs, many patients can survive for
long periods. Despite this, ACC is currently incurable and
most patients will eventually succumb to local recurrence,
distant metastasis, or both. The clinical course of the
disease can be surprisingly heterogeneous with some
patients surviving decades and others surviving only
months. In 1 series, survival in patients with initial
recurrence presenting as distant metastasis ranged from
5 months to 12K years.8 Clearly more accurate measures
of prognosis are needed, along with studies examining the
use of molecular and genetic changes as therapeutic
targets. Therefore, proper physical examination followed
by surgery and radiation with close surveillance and
careful attention to quality of life issues are the corner-
stones of management of this disease.
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