Adenoid Cystic Carcinoma of Salivary Glands

Hindawi
International Journal of Otolaryngology

Volume 2023, Article ID 7401458, 16 pages
https://doi.org/10.1155/2023/7401458
Review Article
Adenoid Cystic Carcinoma of Salivary Glands: A Ten-Year Review
and an Assessment of the Current Management, Surgery,
Radiotherapy, and Chemotherapy
Eyad Saleh and Abdouldaim Ukwas

Eastman Dental Institute, University College London, London, UK
Correspondence should be addressed to Abdouldaim Ukwas; [email protected]
Received 2 January 2023; Revised 14 February 2023; Accepted 18 February 2023; Published 29 April 2023
Academic Editor: Francesco Gazia
Copyright © 2023 Eyad Saleh and Abdouldaim Ukwas. Tis is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Adenoid cystic carcinoma (ACC) is a rare cancer that arises from the salivary glands and other sites in the body, such as the lung
and breast. Although the tumor accounts for 10% of all salivary gland malignancies, it only accounts for 1% of head and neck
malignancies. It can afect both major and minor salivary glands; here, it is called salivary gland adenoid cystic carcinoma or
SACC, with a slight predilection to the latter, and commonly manifests between the 6th and 7th decades of life. Te disease also
shows a slight female predilection, with a reported female to male ratio of 3 : 2. Lesions of SACC are often insidious and slow-
growing, and symptoms such as pain and altered sensation are frequently associated with advanced stages of the disease. Salivary
adenoid cystic carcinoma is characterized by perineural invasion (PNI), a distinctive feature that potentially plays a signifcant role
in the tumor’s relapse and recurrence, which is approximately 50%. Te disease is not prevalent, and its etiopathogenesis is poorly
understood, although several genetic patterns and biomarkers have been linked to its initiation and/or progression. Te discovery
of these mutations and biomarkers has encouraged several clinical studies to use therapeutic agents to target the specifc receptors
on the cancer cells to potentially prevent further proliferation of the tumor cells and metastasis of the disease. Diagnosis of SACC
is often challenging and frequently requires a combination of clinical examination, imaging, and histopathology. Management of
SACC is primarily surgical excision, while radiotherapy has shown to be efective in improving local control in cases with
microscopic residual disease. However, treatment of recurrent or metastatic tumors by radiotherapy with or without chemo-
therapy has so far shown limited success. Te aim of this thesis is to provide an update of literature on SACC with a particular
focus on the latest management approaches and future trends.
1. Introduction early stages, while pain and altered sensation are frequently
associated with advanced stages of the disease. Adenoid
Adenoid cystic carcinoma (ACC) is a rare malignancy that cystic carcinoma is characterized by per neural invasion
originates from the salivary glands and other sites in the (PNI), a distinctive feature that facilitates its local and
body, such as the lung and breast. Te tumor afects both systematic spread and potentially plays a signifcant role in
major and minor salivary glands, with a slight predilection to the tumor’s relapse and recurrence, which is approximately
the latter. It accounts for 10% of all salivary gland neoplasms 50%. Te accurate etiology of SACC is poorly understood,
and approximately 1% of head and neck malignancies. but several studies have identifed a number of genetic
Although SACC can afect all age groups, it commonly mutations which could potentially be involved in its car-
manifests between the sixth and seventh decades of life. cinogenesis. Te discovery of these mutations has encour-
Moreover, SACC shows a slight predilection for women, aged several clinical studies to use therapeutic agents such as
with a reported female-to-male ratio of 3 : 2. Lesions are multitargeted tyrosine kinase inhibitors (TKIs) to target the
often slow-growing and asymptomatic, especially in the same receptors on the cancer cells to potentially prevent
2 International Journal of Otolaryngology
further proliferation of the tumor cells and metastasis of the also afect the major salivary glands, where the parotid gland
disease. Management of SACC is primarily surgical, with is involved in most cases, followed by the submandibular.
wide excision still considering the treatment of choice, while Salivary adenoid cystic carcinoma is a rare disease that
neck dissection is often indicated with positive lymph nodes. accounts for approximately 1% of head and neck malig-
Treatment of recurrent or metastatic tumors by radiotherapy nancies and around 10% of salivary glands neoplasms,
with or without chemotherapy has so far shown limited making it one of the most common salivary gland cancers
success. Nevertheless, radiotherapy has shown to be efective [2, 3]. Tere are no reports of a geographical area where the
in improving local control in cases with microscopic residual disease is prevalent. A retrospective study, undertaken in the
disease. US and analyzed 30 years of data from the National Cancer
Institute, showed that SACC has a predilection to the white
2. Methodology Caucasian population and a female-to-male ratio of 3 : 2 [2].
However, some small-sample and unicentric studies have
Two databases were searched: PubMed/National Library of reported a male-to-female ratio of 1.6 : 1 [3]. Te neoplasm
Medicine (NLM) and Cochrane Library. Tese databases can afect any age group, but it predominantly manifests
were searched from August 01st, 2011 to August 31st, 2021, between the 6th and 7th decades of life which has estimated
using the search terms “adenoid cystic carcinoma and sal- that there are between 1,450 and 1,660 new SACC cases per
ivary glands,” “salivary adenoid cystic carcinoma,” and year in the USA [2, 4]. However, the incidence of the disease
“adenoid cystic carcinoma of salivary glands.” Exclusion showed a signifcant decline between 1973 and 2007 [2],
criteria included titles which include one term without the which could be attributed to the early recognition resulting
other, and ACC of sites out of the scope of this review, i.e., from the advances in the diagnostic and treatment pro-
only salivary glands lesions were included. Te following visions. SACC is considered a variant of salivary gland
fowchart shows the search strategy Figure 1. malignancies, and the rarity of the disease made the research
into its incidence alone difcult and often included in sal-
3. Results ivary gland cancer studies. A recent systemic review of 141
multicentric, multicountry clinical studies that included
PubMed results included literature reviews, systemic re- more than 25,800 patients found that adenoid cystic car-
views, case reports, case series, and retrospective studies, and cinoma was the second most common tumor after pleo-
they were as follows: 640 articles for the search terms morphic adenoma and the most common malignancy in the
“adenoid cystic carcinoma and salivary glands,” 191 articles salivary gland [5].
for “salivary adenoid cystic carcinoma,” and 82 articles for
“adenoid cystic carcinoma of salivary glands.” Results from
the Cochrane Library search were 22 articles, of which 9 3.3. Clinical Features. Te clinical behavior of SACC is
were clinical trials. A total number of 278 duplicate records similar to other malignancies that afect the salivary glands,
and 323 ineligible reports were removed. Te initial records with no detectable clinical signs or symptoms for lengthy
of 312 were assessed primarily, and further 129 studies were periods, sometimes years [2]. Salivary adenoid cystic car-
excluded as they focused on the ACC in general, not SACC cinoma is an insidious tumor that grows very slowly and can
specifcally. Similar case reports were removed, and un- remain unrecognized until it reaches advanced stages. Tis is
fnished clinical trials were also excluded. precisely accurate for ACC of the minor salivary glands,
Te eligible studies for review were 163, including 157 which commonly takes longer to be diagnosed [6]. Salivary
from PubMed and six clinical trials from Cochrane Library. adenoid cystic carcinoma most commonly afects minor
salivary glands, particularly the palate, where it manifests as
3.1. Data Extraction. All results were evaluated, and in- a lump and is associated with difculty in chewing or
formation relevant to this study (i.e., epidemiology, clinical swallowing but can also afect the tongue and the foor of the
features including features of metastasis, histopathology, mouth [3, 7, 8]. If the primary SACC lesion involves minor
etiology, diagnostic processes, management; surgery, ra- salivary glands of the upper aero digestive tract, it can
diotherapy, chemotherapy, prognosis, novel therapies, and present as dysphagia or less frequently as dyspnea, cough,
the possible future trends) was extracted. wheezing, hoarseness, or hemoptysis. [9]. Te parotid gland
is the most commonly afected major salivary gland, fol-
lowed by the submandibular [2]. Te tumor generally causes
3.2. Epidemiology. Adenoid cystic carcinoma (ACC) is enlargement of the involved gland in the form of a lump or
a histopathological subtype of the epithelial malignancies nodule in the periauricular and/or infra-auricular areas, or
that afects the exocrine glands in the head and neck area signifcant swelling of the afected side of the face sometimes
and, to a lesser extent, other organs in the body such as the can reach an extensive size if neglected [10]. Furthermore,
esophagus, uterine cervix, lung, and breast [1, 2]. Salivary SACC of the parotid has been reportedly associated with an
gland adenoid cystic carcinoma (SACC) (also known as odontogenic-like pain referring to the maxillary sinus and
adenoid cystic carcinoma of salivary glands or ACCSG) is sialolithiasis [11, 12]. Salivary adenoid cystic carcinoma of
a tumor that originates from both major and minor salivary the submandibular gland can present as a slow-growing
glands. It primarily afects the minor salivary glands, with swelling in the foor of the mouth, often interfering with
the palate being reportedly the most common site, but it can speech and mastication thus readily detectable or in the form
International Journal of Otolaryngology 3
Identifcation of new studies via databases and registers
Records removed before screening:

Identifcation
Duplicate records (n = 278)

Records identifed from:
Records marked as ineligible by automation
Registers (n = 933)
tools (n = 323)
Records removed for other reasons (n = 13)
Records screened Records excluded

(n = 312) (n = 129)
Screening
Reports sought for retrieval Reports not retrieved

(n = 183) (n = 0)
Reports excluded:
Reports assessed for eligibility Study is not focusing on SACC (n = 13)
(n = 183) Similar case reports (n = 7)
Unfnished clinical trials (n = 6)
New studies included in review

Included
(n = 157)
Reports of new included studies
(n = 6)
Figure 1: SACC search strategy.
of a lump afecting the submandibular area or presenting in reportedly associated with poor disease prognosis regardless
the posterior lower border of the mandible on the afected of the age group [18]. Other factors which may increase the
side [13]. Other clinical features which have been linked to likelihood of distant metastasis include solid histology, tu-
SACC of the submandibular gland include hyposalivation mor size of >3 cm, and the involvement of the regional
due to sublingual gland obstruction [14] and frst bite lymph nodes [1]. It has been hypothesized that SACC cells
syndrome, a sequela of parapharyngeal space surgery his- may diferentiate into Schwann-like cells, which facilitates
torically linked to the denervation of the parotid gland, not their travel along nerves without triggering a host response,
the submandibular [15]. Other clinical features which are thus remaining undetectable for a prolonged time [19].
frequently associated with SACC include dull pain, altered Moreover, SACC can spread via the conventional peri-
sensation of the tongue, palate maxilla or face, and/or facial vascular route, most commonly to the lungs, followed by
nerve palsy [16], indicating perineural invasion (PNI) of the bone, liver, skin, and breasts, and rarely intracranially.
local nerves, a sign mainly encountered in the advanced However, intracranial metastasis is likely to occur in other
stages of the disease [1, 17]. Furthermore, some reports have ways, such as PNI, or via direct invasion of the base of the
interestingly linked SACC to ectopic Cushing syndrome. skull by an adjacent primary lesion [20].
Despite the slow development of the SACC, it is considered
an aggressive tumor that can easily invade the surrounding
structures. Perineural invasion (PNI) is a distinctive feature 3.3.1. Metastatic Features. Salivary adenoid cystic carci-
of SACC by which the tumor cells travel along the nerves noma is well known for its locoregional aggressive behavior
causing distant metastasis, especially intracranially. In and distant metastasis. Te tumor can spread via the con-
a systemic review of 22 studies, PNI was discovered in more ventional route of perivascular perfusion or distinctively by
than 40% of 1,332 patients diagnosed with SACC and was perineural invasion (PNI), a unique mechanism that
diferentiates this cancer from other similar malignancies lymph nodes reportedly afects 5% to 10% of the SACC cases.
that afect the same sites. Several studies have investigated A large, retrospective Chinese study (n = 798) identifed
the association between SACC and PNI, and they have cervical lymph node metastasis in 10% of SACC cases [30].
reported that approximately 40% to 60% of SACC cases Te liver was reported in several studies as a single site of the
showed evidence of PNI [21]. Although intracranial me- systemic spread of the disease. Organs with less common
tastasis of SACC has been frequently linked to its PNI metastasis include the breast and larynx, and those which are
feature, it is extremely rare for the tumor to result in brain rarely involved in SACC metastasis include the pituitary
metastasis. However, Nair et al. reported a case of SACC of gland, the sternum, the dorsal spine [31], the choroid, the toe
the palate, which presented as an ipsilateral palsy of the 6th bones, and the pericardium [31–38].
cranial nerve and suggested that the tumor may have spread Furthermore, it has been reported that SACC of the
through the cavernous sinus [22], which highlights the submandibular gland had a higher tendency to metastasize
importance of using neuroimaging in cases with non- than the parotid, which could be attributed to the ability of
traumatic abducent nerve palsy. Another means of spread the submandibular tumor to generate more tumor-
that SACC has frequently shown is the dissemination via the associated blood vessels and tumor-induced
lymphovascular route. In a preliminary study investigating angiogenesis [39].
cervical lymph node metastasis in SACC cases, about 10% of
the sample (n � 62) had lymph node metastasis at the time of
3.4. Etiology. Te etiology of SACC has insufciently been
surgery or thereafter [23]. A primary SACC can also spread
reported in the literature, and there is no sound evidence to
via the perivascular route to other sites, such as the base of
precisely describe the factors that trigger the tumor. In
the skull, extradural spaces, brain, and scalp [24, 25]. Al-
addition, the precise pathogenesis of the disease is not fully
though PNI is a well-known clinical and histopathological
understood. However, the sequence of the disease devel-
feature of SACC that signifcantly impacts SACC prognosis,
opment has been studied widely using the same approach
the specifc mechanism underlying its pathological devel-
used to study other types of cancers, but SACC studies were
opment is still unclear [26]. Many in vivo and in vitro studies
explicitly exploring the potential factors underlying the
have been conducted to investigate the biological and
disease progress and metastasis. Areas that have been ex-
pathological mechanisms of SACC metastasis and have
tensively reported include genetics, the role of biological
linked some biomarkers to the development of the meta-
biomarkers, the spreading features, and to a lesser extent, the
static uniqueness of the disease and how these biomarkers
involvement of viruses and bacterial bioflm in the SACC
may infuence the spread of SACC through the nerves or via
disease process.
the lymphovascular route [27]. Tis fnding can result in
a new approach that can potentially be applied to tumor
diagnosis and treatment. An in vitro study conducted on 3.4.1. Genetics. Te research into the potential genetic in-
mice has established that overexpression of the transcrip- volvement of SACC has been focusing on examining the
tional activator MYB, an oncogenic protein from the human same genetic mutations that have already been proven to
myleoblastosis transcriptional family, plays a role in the play a role in the pathogenesis of other cancers. Most of the
metastasis of the SACC, especially to the lungs [28]. Te reported fndings have confrmed that genetic factors are
study has demonstrated that MYB is aberrantly overex- potential initiators of SACC. However, there have not been
pressed in SACC tissues, which could promote SACC cell frm fndings on which specifc gene type or mutation causes
proliferation and metastasis, and has concluded that MYB SACC. Dai et al. [40] have investigated the possible link
may potentially be a novel therapeutic target for SACC between beta-calcitonin gene-related peptide β CGRP of
treatment [8]. Furthermore, the fndings of Fu et al. [29] rs2839222 T/T genotype and SACC occurrence, and the
suggest that miR-103a-3p may act as a tumorigenesis factor study fndings have concluded that this gene could be a high-
that promotes the distant spread of SACC to the lungs, and risk factor for SACC because the serum levels of CGRP and β
the authors have concluded that this biomarker could CGRP peptides were signifcantly high in SACC patients. It
contribute to the understanding of SACC pathogenesis and has also been reported that the gene mutation KDM6A could
provide a new prospect for potential therapeutic targets. play a role in the SACC disease process [41]. Te study has
Another study has identifed that signifcantly elevated also reported a new gene mutation KRAS in two cases of
CCR5 levels, a gene-encoded protein that is known to be SACC of Bartholin’s salivary glands in the lip. Xie et al. [42]
involved in some human cancers, in SACC tissues were have detected evidence of upregulation of the NOTCH
associated with distant metastasis, thus blocking these signaling cascade, a well-known signaling pathway that has
markers in the primary lesion could potentially help limit the been proven to contribute to the development of some
tumor metastasis [21]. human cancers, and its genetic receptor NOTCH1, as well as
its downstream gene HES1, in the carcinogenesis, invasion,
and metastasis of SACC, potentially by promoting the
3.3.2. Organs with SACC Metastasis. Salivary adenoid cystic epithelial-mesenchymal transition (EMT)-related genes
carcinoma is an aggressive tumor that spreads both locally [42]. While the aforementioned studies have directly in-
and systemically to several organs. In a retrospective study of vestigated specifc genes and pathways to ascertain their role
74 patients with distant metastasis, the lungs were the single in the etiopathogenesis of SACC, a study by Liu et al. has
site of metastasis in 50 cases [20]. Metastasis to cervical studied the gene expression profles of the GSE88804 dataset
from Gene Expression Omnibus on 22 cases of SACC and all 15 serine proteases of the KLKs were detected in both
normal salivary gland tissues, to investigate and identify the samples, but KLK1, KLK8, KLK11, and KLK14 were
key genes in the development of SACC [43]. Although the underexpressed in the SACC samples [49]. Te study
study fndings were inconclusive on which type of genes concluded that these biomarkers might play an essential role
and/or genetic mutations were involved in the occurrence in the early detection of the disease and its prognosis. An
and progression of the disease, they have confrmed the immunohistochemistry study investigated the potential role
upregulation of 119 and the downregulation of 263 difer- of the hypoxia-induced proteins in the oncogenesis and
entially expressed genes (DEGs) in SACC samples compared metastasis of SACC, and 25 samples from both SACC and
to the normal salivary gland tissues, which strongly suggests normal salivary glands tissues were examined [50]. Te study
clear genetic links of SACC development. Tis suggestion indicated that these proteins were produced intratumorally
can be supported by studies of the etiopathogenesis of ACC in a microenvironment that lacked a sufcient oxygen
in other parts of the body. Pei et al. [44] reported that MYB supply and were overexpressed in the SACC samples, in-
or MYBL1 genes were detected in all samples of trachea- ferring that they have a potential contribution to the pro-
bronchial ACC and concluded that these genes could serve gression of the disease. Using the same technique, a positive
as a hallmark in the occurrence of the tumor. In 2017, contribution to the tumor invasion and metastasis was
Channir published a case report presenting a genetic in- evident for the extracellular matrix metalloproteinase in-
volvement of (MYB-NFIB fusion) in two cases of ACC of ducer (EMMPRIN), which stimulated the matrix metal-
minor salivary glands from a daughter and her father and loproteinase (MMP) expression in highly invasive cancer
suggested that SACC patients may have a family history of cells [51]. In a systemic review investigating the potential
the disease, especially in frst-degree relatives [45]. Fur- role of the proteoglycans (PGs) produced by the myoepi-
thermore, samples of SACC and normal salivary glands thelial cells in SACCs, Wang et al. [52] reported a positive
tissues were compared using immunohistochemistry (IHC) contribution of PGs in the proliferation and migration of the
staining to determine the role of the inhibitor of DNA tumor cells [53]. When the PG synthesis was inhibited, the
binding 1 (ID1) and the gene expression levels of known ID1 metastasis and perineural growth of the cancer cells were
target genes, including S100A9, CDKN2A, and matrix signifcantly reduced, highlighting the PGs’ potential role in
metalloproteinase 1 (MMP1) [46]. Te results identifed ACC development and pathogenesis. In a comparative
overexpression of ID1 and all target genes in SACC samples study, Jiang et al. studied the infuence of the beta tumor
compared to the normal tissues. Te study concluded that growth factor (TGF-β) on EMT and reported that TGF
ID1 has a signifcant contribution to SACC oncogenesis, induced EMT through a mediator redox protein thioredoxin
invasion, and metastasis. Te results were further confrmed 1 TXN [54]. Te overexpressed TXN in the SACC cells
by blocking ID1 activities in SACC cells using target genes, indicated that it could be a potential marker in detecting and
resulting in decreased cell proliferation, local invasion, and treating SACC.
migration. Some genes were negatively afecting the tu-
morigenicity of SACC by suppressing tumor cell activity, 3.4.3. Disease Spread. Since SACC is an aggressive tumor
proliferation, and migration, such as the cadherin-4 gene both locally and systemically, many studies have been
(CDH4), which encoded nonepithelial R-cadherin (R- conducted to investigate the pathogenesis behind such
CAD). In a study of 107 samples of SACC and normal tissues properties. Tese studies have shown that various elements
surrounding the tumors, Xie et al. [47] found that R-CAD contribute to the invasion, metastasizing, and spreading
was overexpressed in all paraneoplastic tissues but only in process of SACC, and based on their fndings, clinical trials
less than two-thirds of the SACC samples. Moreover, the of target chemotherapeutic agents were granted to suppress
inhibition of CDH4 in vitro increased cell activity, and in the disease spread. Many elements were proven to be in-
vivo induced the SACC tumorigenicity. Tese fndings volved in promoting the invasiveness of SACC. Some of
confrmed the tumor suppressing role of CDH4 in the these elements were investigated clinically on samples from
pathogenesis of SACC. patients who underwent surgical resection of SACC lesions.
Zhang et al. studied 158 SACC specimens, exploring the
3.4.2. Biomarkers. Several studies have investigated the potential role of CXCR5 in SACC metastasis [55]. CXCR5 is
involvement of specifc peptides and proteins in the SACC a protein that has been linked to many human cancers,
etiology. In a quantitative spectrometry-based study to especially breast cancers with lymph node metastasis. Te
analyze the protein expression profle in SACC and peri- study identifed a signifcant positive association between the
tumoral tissue samples [48], more than 40,000 specifc CXCR5 and PNI of the samples. Te overexpression of
peptides and 4,454 diferentially expressed proteins (DEPs) CXCR5 was accompanied by a remarkable increase in the
were identifed [48]. Of which, HAPLN1 was the most proliferation and migration of the tumor cells. Tis fnding
upregulated protein and BPIFB1 was the most down- was confrmed by blocking the CXCR5 overexpression,
regulated. Te study emphasized the importance of in- which subsequently suppressed the tumor cells’ migration
vestigating the efects of these biomarkers on the SACC activity and metastasis. Te role of the fatty acid synthase
occurrence and progression. Kerr et al. [49] compared the (FASN), a known factor in developing cancer, in the de-
expression of Kallikrein-related peptidases (KLKs) in SACC velopment of SACC was investigated in an in vitro study
and normal salivary gland tissue samples and reported that [56], which confrmed that FASN promotes the epithelial-
mesenchymal transition (EMT), invasion, and metastasis of 3.5. Diagnosis

SACC cells. Blocking FASN resulted in an apparent re-
duction in the migration and EMT activities of the 3.5.1. Diagnosis of SACC. Te defnitive diagnosis of SACC
tumor cells. usually requires clinical examination, radiographic in-
Chen et al. reported that a specifc molecule, called long vestigations, and histopathology.
noncoding RNA (lncRNA) MRPL23 antisense RNA 1
(MRPL23-AS1), could induce lung metastasis from SACC [57]. 3.5.2. Clinical Examination of SACC. Salivary adenoid cystic
Notably, plasma levels of this molecule were markedly elevated carcinoma generally presents as a slow-growing lesion of the
in the blood samples taken from patients with SACC, and this afected salivary gland. But this feature is not distinctive, and
was associated with increased EMT and microvascular per- most of the lesions show unsuspicious clinical appearance.
meability. Furthermore, many signaling pathways have been In rare cases, however, the clinical presentation does raise
identifed as potential infuencers in developing various human the suspicion of malignancy, but the presentation is not
cancers. Ji et al. investigated the role of Claudin-7 CLDN7 in specifc for SACC.
SACC progression [58]. Claudin-7 CLDN7 is a known Clinical assessment of the site is usually the frst step in
membrane protein that has been shown to be involved in the diagnosis. When the overlying mucosa shows no ab-
several signaling pathways that promote some cancers, but its normal properties, the clinical signifcance of any underlying
role in SACC is still unclear. Tis study reported that the clinicopathological feature of the SACC will be obscured;
protein levels were lower in SACC patients and were associated hence, the diagnosis based on the physical examination will
with an increased level of oncogenic activities of SACC cells. be challenging. If the clinical presentation suggests a ma-
Both EMT and cell migration were attenuated with the lignancy due to abnormal soft tissue presentation, bleeding,
overexpression of CLDN7 and were restored when inhibited, and necrosis in the mouth or PNI-related symptoms, SACC
highlighting the importance of this molecule in suppressing should always be included in the diferential diagnosis until
SACC progression and metastasis. In a similar approach, the proven otherwise.
role of NR2F1, a protein encoded by the NR2F1 gene which is
also involved in many human cancers, was investigated [59].
Te study concluded that NR2F1 might be underlying a po- 3.6. Radiographic Assessment
tential mechanism of the recurrence and metastasis of SACC
3.6.1. Ultrasound. Te frst line of imaging when suspecting
because its lower expression in SACC samples compared to the
neoplastic growth in a major salivary gland is ultrasound
normal salivary gland tissues was associated with cancer cell
[61], which is a noninvasive technique that can help identify
dormancy as well as cell migration and metastasis. An in vitro
the nature of any lump, its approximate borders, and its
study, that investigated the potential efect of the intertumoral
contents [62]. Additionally, ultrasound can be used in some
pressure on the oncogenic activities of SACC cells using
diagnostic or interventional procedures as a 3D guidance
a simulation of interstitial fuid pressure (IFP), concluded that
when performing fne needle aspiration biopsy (FNA) or
there was a positive link between an increased level of inter-
cytology screening for SACC as an initial biopsy technique.
tumoral pressure and increased levels of proliferation and
migration activities of the tumor cells.
Te lack of information reported in the literature re- 3.6.2. Computed Tomography CT and MRI. Computed to-
garding the etiology of SACC necessitates further clinical mography (CT) (or contrast-enhanced cervical computed
and immunohistochemical studies to understand the exact tomography-CECCT) is crucial for detecting any bone in-
or potential etiological mechanisms of the disease. volvement and accurately determining the tumor borders.
Te reported CT features of SACC are variable, usually
dependent on the site, the stage of the disease, and the grade
3.4.4. Bacterial and Viral Involvement. Te available liter- of the bone involvement. In a study of 102 cases of SACC of
ature lacks studies that have examined any potential role of the palate, Ju et al. [63] reported that tumors showed bone
bacteria in the etiology of the SACC. However, one study destruction including palatine, maxillary, and nasal bones,
compared the oral bacterial bioflm from 13 SACC patients enlargement of the greater palatine foramen (GPF), and
with samples from a control group of 10 healthy patients and involvement of the pterygopalatine fossa, foramen rotun-
concluded that there is a clear diference in the composition dum, and cavernous sinus. Magnetic resonance imaging
of the microbial fora between the two groups. However, (MRI), contrast-enhanced cervical computed tomography
there was no evidence to support any theory underlying the (CECCT), and/or contrast-enhanced MRI (CEMRI) are all
bacterial initiation of SACC [60]. essential techniques for diagnosing SACC. Tey greatly help
Tree studies explored the potential involvement of determine the tumor features accurately, including their
certain viruses in the development of SACC. Two studies efects on the surrounding structures, bone, and soft tissues.
attempted the detection of the viruses in SACC samples and Wang reported using contrast-enhanced CT to examine the
patients, and the third study explored the role of some vi- resection margin after surgery, Wang et al. [64], while
ruses in the disease development. Viruses investigated were Shimamo reported to use CECCT and CEMRI to study the
a polyomaviruses group of three viruses (SV40, JCPyV, and perineural invasion PNI of ACCs in the oral and maxillo-
BKPyV), human papillomaviruses HPV, and Pim-1 siRNA. facial region [65]. His fndings confrmed the usefulness of
Table 1 summarizes the fndings of the three studies. using both techniques in detecting SACC spreading features
International Journal of Otolaryngology
Table 1: Viral and bacterial involvement in SACC.

Virus Study (author) Aim Etiological signifcance
Polyomaviruses, SV40, JCPyV, and BKPyV Hanna Hämetoja et al. 2019 Detection of virus in SACC: only JCPyV is detected No
Human papilloma virus (HPV) Hong-Xia Liu et al. 2017 Detection of virus in SACC: not detected No
No etiological contribution but can be a target of a new
Pim-1 siRNA Xin Zhu et al. 2014 Potential negative efect on SACC development
therapy
7
with a slight superior accuracy for the MRI. However, he two types of cell diferentiation: glandular and myoepithelial,
concluded that both techniques are equally valuable for with the latter tending to be more dominant. Cells in all
detecting SACC. Te use of PET-MRI and/or PET-CT is also histologic patterns show hyperchromatic nuclei and mini-
critical when looking for metastasis of SACC in the whole mal cytoplasm. Te histopathological pattern of the crib-
body. For instance, Shah reported a case of SACC that had riform subtype consists of islands of basaloid cells
metastasized to the kidney and was subsequently recognized surrounded by spaces that imitate cystic formations. Mul-
by the PET-MRI scan [66]. Moreover, there seems no sig- tiple cyst-like formations with various sizes create a histo-
nifcant diference in the diagnostic accuracy between the logic picture that resembles a unique shape of the “Swiss
two techniques, as reported by Ruhlmann et al. [67], who cheese.” Despite the shape of a cyst, these formations are not
concluded that PET-CT and PET-MRI had an equal accu- true glandular cysts and have no lumina. However, true
racy of 94% in detecting local lesions. glandular lumina with cuboidal cells can be seen difused
throughout the tumor as microcystic spaces, usually flled
with pink and bluish materials that include basement
3.6.3. Fine Needle Aspiration (FNA) Biopsy. It is a limited
membrane constituents, such as proteoglycans that are
diagnostic tool used as an initial, relatively noninvasive
usually produced by the glandular epithelium [73]. Te
procedure when the clinical and radiographic features do
histologic picture is nearly the same for the tubular pattern,
not suggest an advanced disease [68]. Te technique aims to
with a slight increase in the hyalinized extracellular stroma
examine the nature and origin of the cells inside the lumen of
and a formation of nests of the cancer cells rather than cyst-
the cystic lesion and can either be performed as a simple
like lesions. In the solid pattern, the cancer cells form
biopsy under local anesthesia when the cystic lesion is su-
random isles with no tubular or cystic formations and the
perfcial or easy to access or under regional or general
stroma is predominant [73]. Te traditional histopatho-
anesthesia with ultrasound guidance, ultrasound-guided
logical examination of SACC samples may not be sufcient
FNAC [69]. Tummidi et al. [70] reported a case of sino-
to reach a defnitive diagnosis in some cases; thus, the use of
nasal adenoid cystic carcinoma (SNACC) that was suc-
other techniques such as immunohistochemistry may
cessfully diagnosed using FNA cytology alone. Te collected
sometimes be necessary. Immunohistochemistry is a histo-
specimen showed cell block and positive immunohisto-
pathological staining technique that uses specifc tissue
chemistry for CD-117, a feature of SACC.
biomarkers to detect neoplastic activities. Despite the in-
sufcient data reported in the literature regarding this di-
3.6.4. Histopathology. Salivary adenoid cystic carcinoma is agnostic tool, it has been reported that the expression of
a histopathological subtype of the basaloid malignancies that biomarkers such as CD-117, P-53, and Ki-67 in a suspected
afect the exocrine glands in the head and neck, mainly the SACC biopsy can precisely diferentiate the cancer from its
salivary glands. Te cancer was previously known as closest imitators [74]. Goulart-Filho et al. [75] used im-
“cylindroma” due to its histologic pattern that consists of munohistochemistry to investigate the role of the patho-
cylinders of glandular epithelial cells immersed in a dense logical formation of new blood vessels as a potential
hyaline stroma [10]. Tere are three main histopathological mechanism of SACC progression and metastasis and con-
patterns for this tumor: cribriform, tubular, and solid. All cluded that SACC development is unrelated to neo-
these subtypes can be identifed based on the dominant angiogenesis. Both immunohistochemistry and histopath-
shape and arrangement of the epithelial secreting cells, the ological examinations of SACC specimens show biphasic
myoepithelial cells, and the extracellular matrix. Tere is no elements in the development of the tumor, which are
proper protocol to distinguish between these subtypes, but myoepithelial cells and glandular/secreting epithelial cells,
a recent study has suggested that the histologic subtype can with the former being predominant in most of the SACC
be considered to be solid when the solid pattern accounts for cases. A study based on immunohistochemistry labelling
more than 30% of the tumor [71]. A retrospective study of 87 indicated that myoepithelial cell proliferation and difer-
SACC cases indicated that the cribriform subtype was the entiation in SACC contributed to the disease’s carcino-
most encountered histologic pattern of SACC and that the genesis progress more than its epithelial/secreting
solid was the least common [72]. Te study authors used counterpart [76]. Furthermore, because submandibular
these histopathological patterns to compare the clinico- ACC often demonstrates more proliferation of the myoe-
pathological and prognostic features associated with each pithelial cells and less diferentiation than that of the parotid
subtype and concluded that the solid pattern had the least gland, the study concluded that this could potentially explain
diferentiated cells and the richest extracellular stroma, the aggressive clinical behavior of the submandibular ACC.
which was the most locally aggressive, with the highest
occurrence of PNI, and that it had the poorest prognosis.
Belulescu et al. [3] reported that the solid pattern was en- 3.6.5. Te Diferential Diagnosis of SACC. Te diferential
countered in 46% of the cases, which contradicts observa- diagnosis of SACC requires clinical examination, histo-
tions from other studies, in which the solid pattern was the pathological investigation, and sometimes immunohisto-
least common. But these discrepancies can be attributed to chemistry staining [77]. Clinically, the spectrum of
several factors, including the study sample and/or design diferential diagnosis of SACC is narrow. However, the
and the population type. Te electron microscope and manifestation of a swelling in a suspected site necessitates
immunohistochemistry studies of SACC specimens showed the application of a surgical sieve to rule out any other
pathology that may present as a lump. Lesions that SACC in each ACC case.” It is a simple yet efective prognostic tool
needs to be distinguished from vary between common and that can predict the overall survival (OS), disease-free sur-
rare and often include neoplasms such as pleomorphic vival (DFS), and disease metastasis-free survival (DMFS) in
adenoma, mucoepidermoid carcinoma, adenoid basal cell SACC cases based on a simple measurement using a mi-
carcinoma, polymorphous adenocarcinoma, acinic cell croscope equipped with a micrometer to measure the solid
carcinomas, and myoepithelial carcinomas. Furthermore, component of the tumor’s samples. It showed an excellent
a case report found increased plasma levels of IgG in ACC reproducibility with a cut of of 0.20 mm, lower than any
patients and concluded that there might be a link between other system used before with a Kappa coefcient of 0.81
IgG4-related disease (IgG4-RD) and ACC; thus, the ma- higher than any previous system. However, the system has
lignancy should be included in the diferential diagnosis some drawbacks, such as it is not helpful in small-sized
when encountering IgG4-RD cases [78]. lesions, and it is not considering other components of the
SACC specimen apart from the solid components.
3.6.6. SACC and Pleomorphic Adenoma (PA). Clinically,
there are no specifc features that can distinctively difer- 3.7. Management and Prognosis
entiate the two neoplasms. Both tumors can demonstrate
a similar clinical picture of a painless, slow-developing mass 3.7.1. Treatment of SACC. Until today, there is no stan-
of diferent sizes, although PA can reach extensively large dardized comprehensive treatment that can be used in
sizes, which, on examination, tends to be frm, unilateral, managing all SACC cases. Te available literature lacks high-
well defned, and relatively mobile [79]. Histologically, the quality reviews of the current management approaches,
primary diference between PA and SACC is the rich outcomes, and long-term follow-up. Generally, management
plasmacytoid appearance of individual tumor cells in the of SACC depends on the size of the primary lesion, me-
former, which is considered a reliable feature to diferentiate tastasis and the grade of the disease, and the patient’s general
between the two neoplasms [79]. Histologic examination is health, and it often consists of a combination of surgery,
crucial to diferentiate between the two neoplasms as this postoperative radiotherapy (PORT), and, occasionally,
will eventually afect their prognosis and management; PA is chemotherapy.
benign, while SACC is an aggressive malignancy.
3.7.2. Surgery. Te current surgical regime still comprises
3.6.7. SACC and Mucoepidermoid Carcinoma (MC). tumor resection with safe margins, with or without re-
Mucoepidermoid carcinoma is a rare malignancy that construction. Surgery should be planned according to the
commonly afects the parotid gland. Te clinical pre- size and the site of the lesion, and the surgeon should ensure
sentation of MC is similar to its imitators, including SACC. that the tumor is both accessible and resectable. Surgery is
It can present as a solitary lesion of a cystic nature, and its still the frst line of treatment when the tumor is resectable,
diagnosis is often challenging even on the cytomorphology but postoperative radiotherapy is required in some cases,
level [80]. When the histological picture of MC contains the such as large lesions, lesions with postoperative positive or
typical cytomorphology of islands of bi-layered epithelium close margins, and nonresectable lesions. However, the ef-
with oncocytic and basal cells, squamous cells showing fectiveness of PORT for smaller tumors is still controversial.
atypical nuclei, and necrotic stroma, the diagnosis is often In a retrospective study of 58 SACC cases in which surgery
straightforward. However, in most cases, these typical fea- was the primary treatment in more than two-thirds of the
tures are unclear, which necessitates the use of other cases, the 10-, 20-, and 25-year survival rates were 63.7%,
techniques such as immunohistochemistry, CT imaging 27.3%, and 20.0%, respectively [84]. Many case reports and
[77], and molecular profling to reach a defnitive diagnosis retrospective studies have indicated that surgery is the most
[81]. All other neoplasms in the diferential diagnosis of efective treatment approach compared to other treatment
SACC require a comprehensive diagnostic approach using options such as radiotherapy and chemotherapy. However,
clinical assessment, histopathology, imaging, immunohis- surgery has some limitations that can reduce its efective-
tochemistry, and molecular profling to reach an accurate ness, as its application and efectiveness often depend on the
diagnosis, which is often challenging and requires a multi- location and size of the tumor, the experience of the surgeon,
disciplinary approach. and the provisions at their disposal [85]. Although negative
margins are associated with better overall survival rates and
disease-free progression [85], complete tumor resection with
3.6.8. Grading of SACC. Tere is no specifc system to grade negative margins is not always possible. Terefore, PORT is
and classify SACC, but a general system (Milan system) is sometimes needed to compensate for the incomplete re-
used to report and stratify all salivary gland neoplasms [82]. moval of the tumor. High rates of postoperative positive
For the staging and grading of SACC, the TNM system is still margins have frequently been linked to poor prognosis and
used. A recently published study has suggested a more increased likelihood of recurrence, especially in patients who
objective system to evaluate the solid components of SACC, do not receive a PORT [86]. It seems that, in many cases,
a system called minAmax (minor axis maximum) [83]. Tey standalone surgery is insufcient to establish a better
identifed minAmax as “the length of the minor axis of the prognosis and survival rate and that surgery with PORT can
maximum estimated oval ftting the largest solid tumor nest achieve better outcomes [87]. In a recently published
systemic review of the current treatment approaches for brachytherapy was used for a locally recurrent case of ACC
SACC, Ran et al. have reported that surgery was the sole of the tongue, and the technique successfully eliminated the
module of treatment in over 40% of the sample, surgery with recurrent lesion. Ha et al. [95] and Lee et al. [96] indicated
PORT in 35%, while standalone radiotherapy was used in that conjoined radiotherapy and chemotherapy in patients
19% of the cases [9]. Te study has investigated the outcomes with unresectable SACC efectively achieved complete re-
of the two most used modules in the treatment of SACC, i.e., mission in 80% of the cases [97]. Similarly, Hsieh et al.
surgery alone and surgery with PORT, and has reported that investigated the use of concurrent chemoradiotherapy fol-
the 5- and 10-year survival was better in the second module: lowing surgery and reported that this approach was efective
86.4%, 55.6% and 97.3%, 44.4%, respectively. In a systemic in controlling local recurrence but was inefective in im-
review of SACCs with metastasis to the lungs, the surgical proving the overall survival rate. Te reported therapeutic
removal of the metastatic lesions proved to reduce disease dose of the radiotherapy ranges between 30Gy to 70GY, with
progression and increase the overall survival rate [88]. doses above 60Gy linked to better outcomes in terms of
Nevertheless, the procedure was widely dependent on the a more prolonged disease-free survival (DFS) when com-
condition of the lungs, the size of metastasis, and the pa- pared to doses of less than 60Gy: 40 + 18.87 months for the
tient’s general health. Another systemic review which former, and only 13 + 3.4 months for the latter [91]. Re-
studied the infuence of elective neck dissection (END) on cently, the application of heavy ion therapy has shown [103]
the topical spread of the disease and metastasis-free period promising results in nonresectable cases and primary tumors
when conducted together with the surgery concluded that near the skull base [102].
patients who underwent surgery with END showed a better
metastasis-free period but recommended that this procedure 3.7.4. Chemotherapy. Chemotherapy alone has little or no
should be limited to levels I to III of the lymph nodes [89]. infuence on the treatment of SACC. Many clinical trials
have tested some chemical agents as potential systemic drugs
to treat the unresectable SACC, advanced stages, recurrent
3.7.3. Radiotherapy. Radiotherapy alone is seldom used to lesions, or when the other treatment modules have failed to
treat SACC as it has been shown to be insufcient, and it is produce any clinical benefts. Te results were not consis-
only indicated in advanced stages and nonresectable cases of tent, and the efectiveness of this treatment module needs
SACC [90]. However, the use of postoperative radiotherapy further research with new approaches and novel agents.
(PORT) as an adjunct modality with surgery is reportedly Some clinical trials are still ongoing, but the available trials
efective and has become widely used in the management of are phase I and II only, and they investigated mainly
SACC [91]. Indeed, it has been reported that patients who antiangiogenic agents from diferent generations. Te fol-
did not undergo PORT were 13 times more likely to develop lowing table summarizes these studies.
local recurrence than patients who received the treatment Several studies have investigated the exact mechanism of
[86]. Nevertheless, a large retrospective study that analyzed action of some therapeutic agents. Wang et al. investigated
data from more than 4000 SACC cases has indicated that the the efect of erlotinib on SACC tumorigenesis and concluded
use of PORT in ACC of the submandibular gland was only that while the drug inhibited some tumor cells’ activities, it
helpful in stage III tumors and had no beneft in the early encouraged others such as cell aggregation and regeneration
stages [92]. Te study has also reported that ACC of the by promoting stem cell-like potential [53]. Chemotherapy in
submandibular gland had the worst prognosis compared to SACC management has limited use, and the current evi-
SACC of the other salivary glands. Tere are four techniques dence does not indicate a substantial clinical beneft from
reportedly used in delivering the radiation dose to the tissues using the most common agents. Despite achieving a stable
afected by SACC: 3D conformal radiation therapy (3D- disease in many cases, the overall results are not satisfying.
CRT), image-guided radiotherapy (IGRT), brachytherapy, Generally, an efective systematic therapy to manage
and intensity-modulated radiotherapy (IMRT). All these SACC is lacking, especially in late stages and unresectable
types are used in PORT, but there is a lack of evidence on tumors; hence, the need for more clinical, pathological, and
which modalities provide the best results when treating genetic studies to understand the carcinogenesis and
SACC, although they have all been linked to improved pathogenesis of SACC, and potentially provide new treat-
treatment outcomes and prognosis. A retrospective analysis ments that target its aetiological mechanisms.
of 40 cases of SACC reported that the use of both IGRT and
IMRT techniques showed no better outcomes than 3D-CRT
[90]. Lang et al. [93] studied the application of IMRT with 3.7.5. Prognosis of SACC. Both the topical/regional invasion
carbon ions as a booster following surgery and reported and PNI properties of the disease have been linked to the
reasonable control of the local disease and an improved high rate of recurrences and resistance to treatment. Re-
overall disease-free survival (DFS) rate. In a single institute currence of SACC is common, and the risk of this happening
experience of ACC of the parotid gland, iodine-125 in- after the initial treatment is believed to be as high as 50% in
terstitial brachytherapy was used as a PORT technique in 86 some cases [104]. Such a high risk of recurrence, together
patients [94]. Te results showed promising outcomes: the 5- with the lack of adequate, comprehensive treatment, con-
and 10-year DFS rates were 74.8% and 66.6%, respectively, tributes to the poor prognosis. Furthermore, recurrent and
highlighting the efectiveness and safety of iodine-125 in- metastasized adenoid cystic carcinoma (R/M ACC) can
terstitial brachytherapy as a PORT. Moreover, resist the treatment for more extended periods and make
Table 2: A list of recent studies of potential diagnostic and therapeutic agents.

Study/author Investigated target Potential use Comment
(Nightingale et al.) [97] Prostate-specifc membrane antigen (PSMA) Terapeutic target
(Qiao et al.) [98] MiR-140-5p Terapeutic target
(Wang et al.) [52] Globularifolin Terapeutic treatment Target/systemic
(Liu et al.) [99] Te synergistic efect of both JQ1 and PI3K Novel treatment combination
(Cai et al.) [100] Simvastatin Terapeutic target
(Huang et al., 2018) HES1 Terapeutic target
(Chen et al.) [101] Regorafenib Systemic drug
(Ma et al., 2017) AGR2 Terapeutic target
(Yang et al.) [102] SOX10 Diagnostic marker
Table 3: Update of the novel and potential therapies used in treating ACC in areas diferent from salivary glands.
Study/author Investigated target Potential use Comments
(Doddapaneni et al.) Terapeutic
Fibroblast growth factor receptor 1 (FGFR1) Used for ACC of lacrimal glands
[116] target
Terapeutic Used for ACC of salivary glands, thymus
(Udagawa et al.) [117] Liposomal formulation of eribulin (E7389-LF)
agent gland, and other sites
Targeting the oncogenic transcriptional
(Andersson et al.) Terapeutic Used for ACC of salivary glands, ACC lacrimal
regulator MYB by inhibition of IGF1R/AKT
[118] target glands, and other sites
signaling
Used for ACC of salivary glands, lacrimal
(Tchekmedyian et al.) Te multitargeted tyrosine kinase inhibitor Terapeutic
glands, breast, bronchi, and the external
[109] lenvatinib agent
auditory canal
disease management challenging. Some studies reported including SACC [55]. Te study results have highlighted the
a better prognosis in females and younger patients with 5-, efectiveness of these agents in reducing lung metastasis and
10-, and 15-year survival rates of 90.34%, 79.88%, and improving disease stability. Another study that used three
69.22%, respectively [76]. A recent study published in 2020 drugs together vorinostat, pindolol, and tofacitinib [107] to
reported a lower overall survival rate for 5 and 10 that vary treat an advanced case of SACC has reported an improve-
between 68% to 80% and 52% to 65%, respectively, but the ment in the disease stability but only a partial response to
study sample was small (N � 49] [102]. Te study also in- treatment. Terefore, surgery and postoperative radiother-
dicated that the long-term survival rate was between 23% apy will remain the mainstay of treatment in most SACC
and 40%. cases for the foreseeable future because most of the novel
It has been indicated that PNI and other factors, in- chemotherapeutic agents have demonstrated limited efec-
cluding locoregional invasion, are risk factors for recurrence tiveness in the management of SACC [108–115].
and resistance to treatment and that the risk signifcantly
increases when these factors coexist [104]. Recurrent and
3.8.2. Future Trends in Diagnosis and Treatment. Many
metastasized salivary gland adenoid cystic carcinoma (R/M
studies have investigated the viability of using specifc bi-
SACC) resulting from PNI and typical spread is often
ological markers, proteins, and signaling pathways that have
challenging in terms of management and prognosis, and
been shown to promote or suppress SACC as a potential
patients may need to undergo several surgeries and post-
target therapy or as an early hallmark for the diagnosis of
resection radiotherapy [105]. Moreover, recurrence and
SACC. Tables 2 and 3 summarize these studies
metastasis are often associated with poor long-term prog-
[97–102, 109, 116–118].
nosis and disease-free survival [21].
4. Conclusion
3.8. Novel Terapies and Future Trends
Salivary adenoid cystic carcinoma is a rare cancer but is one
3.8.1. Novel Terapy. Until today there is no novel chemo- of the most common salivary gland malignancies. Te
or radiotherapy that has been approved or applied in the disease is not prevalent, and its etiopathogenesis is poorly
management of SACC, with the exception of some novel understood, although several genetic patterns and bio-
approaches that used conventional agents such as concur- markers have been linked to its initiation and/or
rent chemoradiotherapy [95, 106], which have previously progression.
been discussed in section 3.7.3 of this thesis. However, Te diagnosis is complex and, in many cases, requires
a novel approach that combines a traditional antiangiogenic special investigations to reach a defnitive diagnosis. Man-
drug with immune checkpoint inhibitors, toripalimab and agement is often challenging, and the disease frequently
anlotinib, has been shown to be helpful in human cancers, shows recurrence.
Metastasis surgery and adjuvant radiotherapy are still the References

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Hindawi

International Journal of Otolaryngology

Eyad Saleh and Abdouldaim Ukwas

Correspondence should be addressed to Abdouldaim Ukwas; [email protected]

Academic Editor: Francesco Gazia

Identifcation of new studies via databases and registers

Records removed before screening:

Duplicate records (n = 278)

Records screened Records excluded

Reports sought for retrieval Reports not retrieved

New studies included in review

Figure 1: SACC search strategy.

mesenchymal transition (EMT), invasion, and metastasis of 3.5. Diagnosis

Table 1: Viral and bacterial involvement in SACC.

Table 2: A list of recent studies of potential diagnostic and therapeutic agents.

Metastasis surgery and adjuvant radiotherapy are still the References

retrospective single institute analysis,” American Journal of

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