J. Oral Diag.

2018; 03:e20180010

REVIEW ARTICLE

The role of pleomorphic adenoma stroma on its

neoplastic progression: state of art
Flávia Godinho Costa
Wanderley Rocha 1
Roberto Paulo Correia de
Araújo 2
Gabriela Botelho Martins 3
Alena Ribeiro Alves Peixoto
Medrado 4*
Abstract:
The tumor development is linked to its stroma. The study of tumor stromal cells enables
the understanding of the neoplastic progression. The present narrative literature review
aimed to describe tumor stromal cells, such as endothelial and inflammatory cells, that
may induce the neoplastic progression of pleomorphic adenomas. The Latin American
and Caribbean Center on Health Sciences Information (BIREME) and PubMed electronic
databases were searched for scientific articles on this subject published in Portuguese and
English from 2007 to 2017. The search focused on information about the clinical, imaging,
and anatomopathological characteristics of pleomorphic adenomas and its neoplastic
progression. After analyzing abstracts and reading the cataloged manuscripts, 44 articles
were selected. It was shown that the tumor stroma is important for neoplastic progression
by providing elastic properties to the tumor and by enabling its nutrition. Thus, it is
relevant to study the cellular and molecular mechanisms that occur in extracellular matrix
in order to understand the biological behavior of pleomorphic adenoma.
Keywords: Extracellular Matrix; Neoplasm; Pleomorphic Adenoma

1
MSc. student, Graduate Program in Organs
and Systems Interactive Processes, Federal
University of Bahia (UFBA), Salvador, BA,
Brazil.
2
Professor of Biochemistry, Program in
Organs and Systems Interactive Processes,
Federal University of Bahia (UFBA), Salvador,
BA, Brazil.
3
PhD in Stomatology, Adjunct Teacher,
Program in Organs and Systems Interactive
Processes, Federal University of Bahia (UFBA),
Salvador, BA, Brazil.
4
PhD in Human Pathology, Adjunct Teacher,
Biointeraction Department, Federal University
of Bahia (UFBA), Salvador, BA, Brazil.

Correspondence to:
Alena Ribeiro Alves Peixoto Medrado.
E-mail: alenamedrado@hotmail.com

Article received on June 5, 2018.

Article accepted on July 10, 2018.

DOI: 10.5935/2525-5711.20180010

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1
 INTRODUCTION 8q, 12q, and 17p genes in the DNA of 26 neoplasms
and 13 pleomorphic adenomas. They proposed that
Salivary glands tumors comprise a heterogeneous these chromosomes could be involved in the malignant
group of neoplasms in the maxillofacial region with transformation of the pleomorphic adenoma because
complex morphological characteristics and variable the onset of adenomas with the potential development
clinical behavior. These peculiarities may hinder the of transformation into carcinomas was concomitant to
diagnosis and selection of an adequate clinical approach successive changes in the chromosomal arms of 8q and
by dental surgeons1. Thus, a detailed medical history; /or 12q. Furthermore, they observed many mutations
correlation between clinical, imaging, and morphological in the 17p chromosome arm prior to the malignant
findings; and the anatomopathological analysis of the transformation and progression of pleomorphic
lesion are critical for a reliable diagnosis. adenomas.
Regarding the epidemiological data, tumors of The present narrative literature review highlights
the salivary glands account for approximately 3% to the clinical and histopathological characteristics of
10% of head and neck tumors. Of these, 54% to 79% pleomorphic adenoma, the most prevalent salivary
are benign, while 21% to 46% are malignant2. The gland tumor in the oral cavity. Furthermore, this
parotid gland is the anatomical site most affected by review analyzes how the extracellular matrix of the
these lesions (63.9%), followed by the minor salivary tumor stroma may contribute to the development and
(26.2%), submandibular (9.6%), and sublingual (0.3%) progression of this neoplasm.
glands. Although the parotid is the most frequent site
of onset of salivary gland tumors, the incidence of MATERIAL AND METHODS
malignant neoplasms in this gland is less (15% to 32%)
when compared to the incidence rates of the sublingual This was a narrative literature review study.
(70% to 90%), submandibular (45%), and minor salivary The Latin American and Caribbean Center on Health
(50%) glands2. When the tumor affects the minor salivary Sciences Information (BIREME) and PubMed electronic
glands, it usually develops in the region of the hard databases were searched for scientific articles on the
palate, followed by the upper lip, tongue, floor of the subject and manual searches were performed for citations
mouth, and retromolar space. in the studies identified in the above databases. The
Among benign neoplasms located in the parotid, following health sciences descriptors (DeCS) were used
the most frequent is pleomorphic adenoma, which to perform these searches: “tumor stroma”, “neoplastic
accounts for approximately 53% of all reported tumors, progression”, “pleomorphic adenoma”, and “carcinoma
followed by Warthin’s tumor (7.7%), oncocytoma (1.9%), ex-pleomorphic adenoma”. The Boolean expressions
and basal cell adenoma (1.4%). In general, these tumors “E” or “AND” were used for the associations of words,
grow silently and the increased volume of the anatomical thus allowing for combinations of descriptors. Six
region affected is, most often, the only observed clinical combinations were used with the following descriptors:
manifestation. The mucoepidermoid carcinoma (9.6%) “Tumoral stroma and neoplastic progression”, “Tumoral
stands out among the malignant neoplasms of salivary stroma and pleomorphic adenoma”, “Tumoral stroma
glands, followed by acinar cell adenocarcinoma (8.6%), and e carcinoma ex-pleomorphic adenoma”, “Neoplastic
cystic adenoid carcinoma (3.3%), mixed malignant tumor progression and pleomorphic adenoma”, “Neoplastic
(3.2%), and squamous cell carcinoma (2.1%)1. Such progression and carcinoma ex-pleomorphic adenoma”,
tumors generally show variable symptoms, including and “Pleomorphic adenoma and carcinoma ex-
pain, facial paralysis, and skin ulceration3,4. The rates pleomorphic adenoma”.
of local, regional, and remote recurrence of malignant Two authors individually analyzed the abstracts
tumors are 40%, 15%, and 11%, respectively, and are of the articles to assess which studies were relevant
related to a worse prognosis5. to the subject of this review. Based on the inclusion
Studies on tumor progression have reported criteria, full-length articles in Portuguese and English
cytogenetic evidence on the transformation of available online and published from 2007 to 2017 that
pleomorphic adenomas into ex-pleomorphic adenoma reported the clinical, imaging and anatomopathological
carcinomas. El-Naggar et al.6 suggested that some genes characteristics of pleomorphic adenomas and their
could be related to this malignant transformation. In neoplastic progression were selected. Some relevant
their study, the authors comparatively analyzed the articles published before this period were also included.

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Studies published outside the established criteria and in between the acinar and ductal cells and the basement
databases other than those chosen for the search were membrane and are characterized by an eosinophilic,
excluded. hyaline, and homogeneous cytoplasm, most often with
After analyzing the abstracts and reading the an eccentric nucleus. They may have an epithelioid,
cataloged manuscripts, 40 papers were selected for the polygonal or fusiform pattern10.
present review. The myoepithelial cells of the salivary gland
presumably have a function limited to contractile action,
State of Art helping in the excretion of the glandular contents.
1. Epidemiological profile of pleomorphic adenomas They reportedly also participate in extracellular matrix
Although pleomorphic adenoma may occur in any synthesis, particularly that of the basal membrane,
of the minor salivary glands, the parotid is the major and also play a key role in tumor suppression9. This
salivary gland most frequently affected by this tumor. tumor suppressor role was attributed to myoepithelial
The age group most affected corresponds to the fifth cells because they accumulate large quantities of
decade of life (25.2%), with a higher prevalence among extracellular matrix, and thus promote the onset of a
women (74.5%)1,3. Araya et al.7 when assessing 279 cases mechanical barrier against tumor development. Their
of salivary gland tumors found that 151 were located in potential to secrete high levels of tissue inhibitors of
the parotid and that pleomorphic adenoma was the most metalloproteinases (TIMPs) is linked to their tumor
frequent benign tumor of this gland (53.8%). suppressor role1.
From the clinical standpoint, pleomorphic Tumor dissemination starts with the extracellular
adenoma is a single nodular lesion with well-defined matrix degradation by matrix metalloproteinases
margins and lobulated surface that is hardened, mobile, (MMPs). In addition to these enzymes, neoangiogenesis
and painless on palpation1. Malignant transformation enables tumor growth. The vascular plexus facilitates
primarily occurs after tumor recurrence or in cases of oxygen transport to neoplastic cells. Thus, in the absence
long-term progression. In this situation, the tumor is of vascularization, tumor cells fail to spread, and cell
termed carcinoma ex-pleomorphic adenoma. death occurs due to hypoxia11,12.
Although carcinoma ex-pleomorphic adenoma is a
rare malignant tumor of the salivary gland, Mariano et 3. Relevance of the stroma to tumor development
al.8 reported 38 cases of this neoplasm among Brazilian The tumor stroma plays a key role in the
patients with a mean age of 57.6 years. No gender development of neoplasms. A large quantity of
differences were reported. connective tissue and extracellular matrix (ECM) and
numerous mesenchymal cells such as fibroblasts and
2. Histopathological characterization of the tumor adipocytes, blood and lymphatic vessels, nerves, and
parenchyma and stroma inflammatory and immune cells have also been observed
Pleomorphic adenoma parenchyma is characterized in the tumor stroma13. The ECM consists of fibrous
by a wide variety of cell types, not only between different proteins and glycoproteins. The fibrous proteins include
tumors but also in different parts of the same tumor. collagen and elastin, whereas the glycoproteins include
Thus, epithelial, myoepithelial, and mesenchymal cells fibronectin, proteoglycans, and laminin14.
can be observed forming ductal and cystic structures The tumor stroma is important for neoplastic
as well as nests or islands. The pleomorphic adenoma progression because its composition may vary; for
stroma is eosinophilic and hyalinized, and may have a example, increased collagen biosynthesis may render
mucoid, myxoid, chondroid, or even osteoid matrix1. the tumor elastic15. Furthermore, the tumor stroma
Among the parenchymal cells of the pleomorphic enables neoplasm nutrition through the formation of
adenoma, the myoepithelial cells are the most relevant in blood vessels16. The tumor stroma comprises fibroblasts,
the tumor context because they have a tumor suppressor which are responsible for producing the collagen
role9. In addition to the salivary glands, myoepithelial present in the extracellular matrix17. Fibroblasts play a
cells are present in other exocrine glands such as the key role in tumors because they are the precursors of
mammary, sweat, and lacrimal glands as well as in the myofibroblasts18, which are cells of mesenchymal origin
mucous and seromucous glands of the digestive tract. found in physiological and pathological conditions.
In the salivary glands, the myoepithelial cells are located For example, under physiological conditions, they can

Journal of Oral Diagnosis 2018

3
modulate tissue healing18, whereas they can promote Swelam et al.27 studied VEGF immunostaining
tumor progression under pathological conditions19. in 20 pleomorphic adenomas and seven normal
In addition to fibroblasts, other cell types may act submandibular glands. In normal salivary glands, VEGF
as precursors for myofibroblasts. For example, smooth staining was observed in the serous acini and epithelial
muscle cells, pericytes, endothelial cells, adipocytes, ducts, whereas staining occurred in the ductal formations
and myoepithelial cells can be transdifferentiated and solid areas of pleomorphic adenomas and was
into myofibroblasts. Recent studies have also shown stronger in these areas than that in tumor nests. The
that tissue-resident mesenchymal stem cells can also myxoid areas were also strongly stained by VEGF. Thus,
differentiate into myofibroblasts20. the authors concluded that pleomorphic adenoma is a
In the tumor stroma, myofibroblasts may poorly vascularized tumor because areas with hypoxia
contribute to the deposition of collagen fibers. The were clearly identified in these tumors by VEGF labeling.
increased presence of these fibers renders the stroma The vessels formed in angiogenesis are loosely
desmoplastic20. Clinically, this reaction of the stroma is delimited by solitary cells termed pericytes, a cell group
characterized by the hardening and retraction of several derived from mesenchymal smooth muscle cell lines
malignant tumors. This tumor retraction is attributed that play a key role in the tumor context because they
to the contractile forces generated by myofibroblasts19,20. may contribute to neoplastic progression28. Pericytes
The collagen matrix of the tumor stroma affect the stability of blood vessels by activating or
primarily contains type I and III collagen. Type III producing molecules that promote the differentiation
collagen is most often observed in newly-formed stroma, or quiescence of endothelial cells. Thus, pericytes
whereas type I collagen is most evident in the fibrous contribute to neoplastic progression when they induce
zones of carcinomas and is more related to tumor the differentiation of endothelial cells, allowing the
progression and metastasis21. Picrosirius is a staining formation of new vessels, which favors the nutritional
enables the differentiation of collagen fibers, particularly contribution to neoplastic cells. In addition, studies
between types I and II1,22-24. have also shown that pericytes may be myofibroblast
precursors because pericyte are stem cells capable of
4. Neoangiogenesis and inflammation of the pleomorphic differentiating into a number of different cell lines28,29.
adenoma stroma Although some studies have suggested that
Neoangiogenesis is defined as the formation of pericytes and myofibroblasts may be strategic targets
new blood vessels from pre-existing vessels. It occurs for the treatment of malignant neoplasms1,23,24, studies
under both physiological and pathological conditions that clarify the molecular mechanisms whereby they can
such as embryogenesis, tissue healing, tumor growth, affect the biological behavior of malignant tumors are
and metastasis12,25. still necessary.
The main physiological stimulus of In spite of inflammatory cells, they comprise
neoangiogenesis is hypoxia. This occurs due to the macrophages or tumor-associated macrophages (TAMs),
activation of pro-angiogenic factors such as vascular mast cells, neutrophils, T and B lymphocytes, natural
endothelial growth factor (VEGF), which binds to killer (NK) cells, and invariant T lymphocytes (NKT
receptors on endothelial cells, smooth muscle cells, and cells). Although each inflammatory cell is important in
pericytes. This ligand-receptor interaction activates the the tumor context, TAMs are the most prominent cells
cells and promotes the budding of new capillaries from in the regulation of tumorigenesis30.
pre-existing vessels26. TAMs may be activated by the classical or
VEGF is one of the main neoangiogenesis- alternative pathways. When activated by the classical
inducing growth factors. Although it may directly pathway, they differentiate into M-1 macrophages,
stimulate endothelial cells and fibroblasts to form new whereas they differentiate into M-2 macrophages when
vessels, the underlying molecular mechanism of its activated by the alternative pathway. M-1 macrophages
stimulation remains unknown26. Although the function are usually found in the tumor microenvironment of
of VEGF in neoangiogenesis is well established in the early lesions and are able to eliminate tumor cells by
literature, little is known about its involvement in tumors producing reactive oxygen and nitrogen species (ROS
of the salivary glands, particularly in pleomorphic and RNS, respectively). Furthermore, M-1 macrophages
adenomas. secrete large quantities of interleukin [IL]-12 and

Journal of Oral Diagnosis 2018

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activate CD8+ T lymphocytes, which are responsible for altered in cytogenetic studies of this type of lesion34.
promoting an efficient antitumor response31. Knowing that changes in PLAG1 in pleomorphic
To maintain homeostasis or through the adenomas result from recurrent, balanced chromosomal
mechanisms of tumor cell evasion, macrophages translocations, Voz et al.35 reported that the most
activated by the alternative pathway of the immune frequent chromosomal translocations in the onset of
system differentiate into M-2 macrophages. These altered PLAG1 expression involved the t(3;8)(p21;q12)
macrophages, in turn, secrete IL-10, which negatively and t(5;8)(p13;q12) regions.
regulates the immune response to tumors by impairing Altered PLAG1 expression apparently contributes
the activation of cytotoxic cells and by favoring an to the onset of pleomorphic adenomas. Asp et al.36
immunosuppressive environment that promotes tumor and Kandasamy et al.37 performed cytogenetic and
progression. In addition, M-2 macrophages also produce molecular assays, reporting that the heterogeneity of
growth factors such as VEGF, which contribute to rearrangements in the PLAG1 gene contributes to the
tumor maintenance and facilitate the development of development of pleomorphic adenomas. The recurrence
metastases31. of these lesions may be caused by the increased number
Although some studies have suggested that M-2 of genetic mutations38.
macrophages may contribute to tumor survival31,32, Some factors may significantly affect the
studies that may clarify the molecular mechanisms by malignant transformation of tumors1. Deguchi et al.39
which they are able to influence the biological behavior assessed the expression of c-myc, ras, p21, and p53 in
of the tumor are still required. Similarly, although the pleomorphic adenomas and carcinoma ex-pleomorphic
literature has shown the importance of macrophages adenomas. Although the expression of these proteins
for tumor development, studies about the participation has been observed in pleomorphic adenomas, these
of these cells in tumors of salivary glands, especially oncoproteins were overexpressed in carcinoma ex-
pleomorphic adenomas, are needed to further understand pleomorphic adenomas. Their study showed the
its immunopathogenesis. importance of these oncoproteins for the prognosis of
pleomorphic adenomas, particularly regarding malignant
5. Profiles of the genes involved in the neoplastic transformation. According to Felix et al.40 the activation
progression of pleomorphic adenomas of the oncogenes p53 and c-erbB-2 was implicated in the
Pleomorphic adenoma has well-defined clinical malignant transformation of pleomorphic adenomas.
and histological characteristics1. However, the effect of They observed that p53 was involved in the neoplastic
molecular factors related to its malignant transformation progression of this tumor, whereas c-erbB-2 participated
is still not fully elucidated. Thus, cytogenetic studies in the development of a more aggressive phenotype.
are necessary to assess the biological behavior of this
neoplasm. CONCLUSION
Mitelman et al. 33 constructed a database of
chromosomal changes in cancer. Analysis of 224 The current knowledge regarding the role
pleomorphic adenomas revealed that 30% of these of pleomorphic adenomas stroma in the neoplastic
tumors had a normal karyotype, whereas 70% had some progression is increasing. However, studies that point out
type of chromosomal alteration. The most commonly the molecular profile of these tumors are still necessary
observed changes were balanced, inverted, and in order to elucidate their biological behavior.
unbalanced chromosomal translocations. The balanced
chromosome translocations included the gene regions Conflict of interest
t(3;8)(p21;q12), t(8;9)(q12;p22), and t(5,8)(p13;q12), The authors declare no conflict of interest.
whereas the inversions involved the 12p12-p13 and
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Journal of Oral Diagnosis 2018