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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Granular Cell Ameloblastoma: an Unusual Histological Subtype Report and Review of Literature</title>
<author><name sortKey="Nikitakis, Nikolaos G" sort="Nikitakis, Nikolaos G" uniqKey="Nikitakis N" first="Nikolaos G." last="Nikitakis">Nikolaos G. Nikitakis</name>
<affiliation><nlm:aff id="aff1"><institution>Department of Oral Pathology and Medicine, School of Dentistry, National and Kapodistrian University of Athens</institution>
<country>Greece.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tzerbos, Fotios" sort="Tzerbos, Fotios" uniqKey="Tzerbos F" first="Fotios" last="Tzerbos">Fotios Tzerbos</name>
<affiliation><nlm:aff id="aff2"><institution>Department of Oral and Maxillofacial Surgery, School of Dentistry, National and Kapodistrian University of Athens</institution>
<country>Greece.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Triantafyllou, Kyriaki" sort="Triantafyllou, Kyriaki" uniqKey="Triantafyllou K" first="Kyriaki" last="Triantafyllou">Kyriaki Triantafyllou</name>
<affiliation><nlm:aff id="aff1"><institution>Department of Oral Pathology and Medicine, School of Dentistry, National and Kapodistrian University of Athens</institution>
<country>Greece.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Papadimas, Christos" sort="Papadimas, Christos" uniqKey="Papadimas C" first="Christos" last="Papadimas">Christos Papadimas</name>
<affiliation><nlm:aff id="aff2"><institution>Department of Oral and Maxillofacial Surgery, School of Dentistry, National and Kapodistrian University of Athens</institution>
<country>Greece.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sklavounou, Alexandra" sort="Sklavounou, Alexandra" uniqKey="Sklavounou A" first="Alexandra" last="Sklavounou">Alexandra Sklavounou</name>
<affiliation><nlm:aff id="aff1"><institution>Department of Oral Pathology and Medicine, School of Dentistry, National and Kapodistrian University of Athens</institution>
<country>Greece.</country>
</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">24421980</idno>
<idno type="pmc">3886069</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3886069</idno>
<idno type="RBID">PMC:3886069</idno>
<idno type="doi">10.5037/jomr.2010.1403</idno>
<date when="2011">2011</date>
<idno type="wicri:Area/Pmc/Corpus">000691</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000691</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Granular Cell Ameloblastoma: an Unusual Histological Subtype Report and Review of Literature</title>
<author><name sortKey="Nikitakis, Nikolaos G" sort="Nikitakis, Nikolaos G" uniqKey="Nikitakis N" first="Nikolaos G." last="Nikitakis">Nikolaos G. Nikitakis</name>
<affiliation><nlm:aff id="aff1"><institution>Department of Oral Pathology and Medicine, School of Dentistry, National and Kapodistrian University of Athens</institution>
<country>Greece.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tzerbos, Fotios" sort="Tzerbos, Fotios" uniqKey="Tzerbos F" first="Fotios" last="Tzerbos">Fotios Tzerbos</name>
<affiliation><nlm:aff id="aff2"><institution>Department of Oral and Maxillofacial Surgery, School of Dentistry, National and Kapodistrian University of Athens</institution>
<country>Greece.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Triantafyllou, Kyriaki" sort="Triantafyllou, Kyriaki" uniqKey="Triantafyllou K" first="Kyriaki" last="Triantafyllou">Kyriaki Triantafyllou</name>
<affiliation><nlm:aff id="aff1"><institution>Department of Oral Pathology and Medicine, School of Dentistry, National and Kapodistrian University of Athens</institution>
<country>Greece.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Papadimas, Christos" sort="Papadimas, Christos" uniqKey="Papadimas C" first="Christos" last="Papadimas">Christos Papadimas</name>
<affiliation><nlm:aff id="aff2"><institution>Department of Oral and Maxillofacial Surgery, School of Dentistry, National and Kapodistrian University of Athens</institution>
<country>Greece.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sklavounou, Alexandra" sort="Sklavounou, Alexandra" uniqKey="Sklavounou A" first="Alexandra" last="Sklavounou">Alexandra Sklavounou</name>
<affiliation><nlm:aff id="aff1"><institution>Department of Oral Pathology and Medicine, School of Dentistry, National and Kapodistrian University of Athens</institution>
<country>Greece.</country>
</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Journal of Oral & Maxillofacial Research</title>
<idno type="eISSN">2029-283X</idno>
<imprint><date when="2011">2011</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><title>ABSTRACT</title>
<sec sec-type="background"><title>Background</title>
<p>Granular cell ameloblastoma is a rare histological subtype of ameloblastoma
accounting for less than 5% of the total. The characteristic microscopic
features of granular cells are attributed to the increased presence of
lysosomes in the cytoplasm of the tumour cells.</p>
</sec>
<sec sec-type="methods"><title>Methods</title>
<p>A case of bone expansion in the mandible of 65 year old patient was examined
on the basis of the clinical examination, radiographic imaging and
microscopic features. A complete surgical removal was performed.</p>
</sec>
<sec sec-type="results"><title>Results</title>
<p>The radiographic imaging characteristics were consistent with a locally
aggressive jaw lesion. Histological examination of the tumour revealed
typical features of granular cell ameloblastoma. The specimen margins were
free of tumour and the postoperative course was uneventful. No evidence of
recurrence was noticed during a 1.5 years follow-up period.</p>
</sec>
<sec sec-type="conclusions"><title>Conclusions</title>
<p>The rarity of the granular cell ameloblastoma subtype and the possibility of
confusion with other odontogenic and non-odontogenic lesions with a granular
cell component require an understanding of the salient features of this
locally aggressive neoplasm. A literature review is provided focusing on
emerging molecular parameters in the pathogenesis of these tumours and the
differential diagnosis of oral lesions featuring granular cells.</p>
</sec>
</div>
</front>
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<author><name sortKey="Sauk, Jj" uniqKey="Sauk J">JJ Sauk</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sauk, Jj" uniqKey="Sauk J">JJ Sauk</name>
</author>
<author><name sortKey="Nikitakis, Ng" uniqKey="Nikitakis N">NG Nikitakis</name>
</author>
<author><name sortKey="Scheper, Ma" uniqKey="Scheper M">MA Scheper</name>
</author>
</analytic>
</biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Oral Maxillofac Res</journal-id>
<journal-id journal-id-type="iso-abbrev">J Oral Maxillofac Res</journal-id>
<journal-id journal-id-type="publisher-id">JORM</journal-id>
<journal-title-group><journal-title>Journal of Oral & Maxillofacial Research</journal-title>
</journal-title-group>
<issn pub-type="epub">2029-283X</issn>
<publisher><publisher-name>Stilus Optimus</publisher-name>
<publisher-loc>Kaunas, Lithuania</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">24421980</article-id>
<article-id pub-id-type="pmc">3886069</article-id>
<article-id pub-id-type="publisher-id">v1n4e3ht</article-id>
<article-id pub-id-type="doi">10.5037/jomr.2010.1403</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Case Report</subject>
</subj-group>
</article-categories>
<title-group><article-title>Granular Cell Ameloblastoma: an Unusual Histological Subtype Report and Review of Literature</article-title>
</title-group>
<contrib-group><contrib id="contrib1" contrib-type="author" corresp="yes"><name><surname>Nikitakis</surname>
<given-names>Nikolaos G.</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib id="contrib2" contrib-type="author"><name><surname>Tzerbos</surname>
<given-names>Fotios</given-names>
</name>
<xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib id="contrib3" contrib-type="author"><name><surname>Triantafyllou</surname>
<given-names>Kyriaki</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib id="contrib4" contrib-type="author"><name><surname>Papadimas</surname>
<given-names>Christos</given-names>
</name>
<xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib id="contrib5" contrib-type="author"><name><surname>Sklavounou</surname>
<given-names>Alexandra</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
</contrib>
</contrib-group>
<aff id="aff1" rid="aff1"><sup>1</sup>
<institution>Department of Oral Pathology and Medicine, School of Dentistry, National and Kapodistrian University of Athens</institution>
<country>Greece.</country>
</aff>
<aff id="aff2" rid="aff2"><sup>2</sup>
<institution>Department of Oral and Maxillofacial Surgery, School of Dentistry, National and Kapodistrian University of Athens</institution>
<country>Greece.</country>
</aff>
<author-notes><corresp>Nikolaos G. Nikitakis,
<institution>Department of Oral Pathology and Medicine, School of Dentistry,
University of Athens</institution>
<addr-line>2 Thivon St., Goudi 11527, Athens</addr-line>
<country>Greece</country>
<phone>+30 210 746 1003</phone>
Fax: +30 210 746 1220,
<email>nnikitakis1@yahoo.com</email>
</corresp>
</author-notes>
<pub-date pub-type="collection"><season>Oct-Dec</season>
<year>2010</year>
</pub-date>
<pub-date pub-type="epub"><day>1</day>
<month>1</month>
<year>2011</year>
</pub-date>
<volume>1</volume>
<issue>4</issue>
<elocation-id>e3</elocation-id>
<history><date date-type="received"><day>4</day>
<month>3</month>
<year>2010</year>
</date>
<date date-type="accepted"><day>29</day>
<month>9</month>
<year>2010</year>
</date>
</history>
<permissions><copyright-statement> Copyright © Nikitakis NG, Tzerbos F, Triantafyllou K,
Papadimas C, Sklavounou A. Published in the JOURNAL OF ORAL & MAXILLOFACIAL RESEARCH (http://www.ejomr.org), 1 January 2011.</copyright-statement>
<copyright-year>2010</copyright-year>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><license-p>This is an open-access article, first published in the JOURNAL OF
ORAL & MAXILLOFACIAL RESEARCH, distributed under the terms of the
Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 Unported
License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc-nd/3.0/">http://creativecommons.org/licenses/by-nc-nd/3.0/</ext-link>
), which permits unrestricted non-commercial use, distribution, and
reproduction in any medium, provided the original work and is properly
cited. The copyright, license information and link to the original
publication on <ext-link ext-link-type="uri" xlink:href="http://www.ejomr.org">http://www.ejomr.org</ext-link>
must be included.</license-p>
</license>
</permissions>
<self-uri xlink:type="simple" xlink:href="http://www.ejomr.org/JOMR/archives/2010/4/e3/v1n4e3ht.htm"></self-uri>
<abstract><title>ABSTRACT</title>
<sec sec-type="background"><title>Background</title>
<p>Granular cell ameloblastoma is a rare histological subtype of ameloblastoma
accounting for less than 5% of the total. The characteristic microscopic
features of granular cells are attributed to the increased presence of
lysosomes in the cytoplasm of the tumour cells.</p>
</sec>
<sec sec-type="methods"><title>Methods</title>
<p>A case of bone expansion in the mandible of 65 year old patient was examined
on the basis of the clinical examination, radiographic imaging and
microscopic features. A complete surgical removal was performed.</p>
</sec>
<sec sec-type="results"><title>Results</title>
<p>The radiographic imaging characteristics were consistent with a locally
aggressive jaw lesion. Histological examination of the tumour revealed
typical features of granular cell ameloblastoma. The specimen margins were
free of tumour and the postoperative course was uneventful. No evidence of
recurrence was noticed during a 1.5 years follow-up period.</p>
</sec>
<sec sec-type="conclusions"><title>Conclusions</title>
<p>The rarity of the granular cell ameloblastoma subtype and the possibility of
confusion with other odontogenic and non-odontogenic lesions with a granular
cell component require an understanding of the salient features of this
locally aggressive neoplasm. A literature review is provided focusing on
emerging molecular parameters in the pathogenesis of these tumours and the
differential diagnosis of oral lesions featuring granular cells.</p>
</sec>
</abstract>
<kwd-group><kwd>jaw neoplasms</kwd>
<kwd>ameloblastoma</kwd>
<kwd>odontogenic tumor</kwd>
<kwd>lysosomes.</kwd>
</kwd-group>
</article-meta>
</front>
<body><sec><title>INTRODUCTION</title>
<p>The ameloblastoma is a benign odontogenic tumour located almost exclusively in the
jaws. It has a distinctive microscopic appearance characterized by the presence of
peripheral columnar cells with hyperchromatic, reversely polarized nuclei, arranged
in a palisaded pattern [<xref ref-type="bibr" rid="B1">1</xref>
]. These cells
closely resemble ameloblasts, coining the tumour's name. It has been proved
that these cells are epithelial in origin and can express amelogenin, a precursor of
enamel [<xref ref-type="bibr" rid="B2">2</xref>
,<xref ref-type="bibr" rid="B3">3</xref>
].</p>
<p>Based on clinicopathologic criteria, ameloblastomas are divided into three fairly
distinct types: solid or multicystic (about 86% of all cases), unicystic (about 13%
of all cases) and peripheral (about 1% of all cases) [<xref ref-type="bibr" rid="B1">1</xref>
]. These tumours occur slightly more often between the third to fifth
decades of life, with no significant gender or racial predilection; the most common
location is the mandible, particularly near the angle [<xref ref-type="bibr" rid="B1">1</xref>
]. Although benign, solid or multicystic ameloblastomas (and,
to a lesser extent, unicystic ameloblastomas) are locally aggressive, with a high
recurrence rate after local excision [<xref ref-type="bibr" rid="B1">1</xref>
,<xref ref-type="bibr" rid="B4">4</xref>
].</p>
<p>Ameloblastomas usually manifest as a hard-tissue swellings that may assume very large
dimensions if left untreated. Pain and paresthesia are unusual clinical features
[<xref ref-type="bibr" rid="B1">1</xref>
,<xref ref-type="bibr" rid="B5">5</xref>
]. The usual radiographic appearance of solid or multicystic ameloblastomas
is a multilocular radiolucency with well-defined borders. A unilocular presentation
is also possible for conventional ameloblastomas and is always associated with
unicystic ameloblastomas. Expansion or perforation of the cortical bone, as well as
resorption or divergence of the roots of the adjacent teeth, are frequent [<xref ref-type="bibr" rid="B1">1</xref>
,<xref ref-type="bibr" rid="B5">5</xref>
].</p>
<p>Several microscopic subtypes of the ameloblastoma, especially of its
solid/multicystic variant, are recognized, although these microscopic patterns
generally have little bearing on the behavior of tumour. Large tumours often show a
combination of microscopic patterns. The follicular and plexiform patterns are the
most frequent. Less common histopathologic subtypes include the acanthomathous,
granular cell, desmoplastic, and basal cell [<xref ref-type="bibr" rid="B1">1</xref>
,<xref ref-type="bibr" rid="B5">5</xref>
]. Although the treatment and
prognosis are virtually the same (with the possible exception of more aggressive
desmoplastic variant), knowledge of various histopathologic subtypes is a
prerequisite for accurate diagnosis and management [<xref ref-type="bibr" rid="B1">1</xref>
].</p>
<p>The granular cell subtype of ameloblastoma is characterized by the groups of granular
cells, which have abundant cytoplasm filled with eosinophilic granules that resemble
lysosomes, both ultrastructurally and histochemically [<xref ref-type="bibr" rid="B1">1</xref>
]. The acquisition of granular cell phenotype has been
attributed to an aging or degenerative change in long-standing lesions; however, it
may also affect young patients. When this granular cell change is extensive in an
ameloblastoma, the designation of granular cell ameloblastoma is appropriate [<xref ref-type="bibr" rid="B1">1</xref>
].</p>
<p>The purpose of this paper is to present an unusual case of granular cell
ameloblastoma and to review the pertinent literature highlighting its unique
microscopic features that allow its distinction from other jaw tumours with a
granular cell constituency and discussing the molecular aspects of its
pathogenesis.</p>
</sec>
<sec><title>CASE DESCRIPTION AND RESULTS</title>
<p>A 65 years old male presented with a chief complaint of a painless swelling in his
mandible. Clinical examination revealed a well-circumscribed bone expansion on the
body of left mandible. Panoramic radiograph revealed a large, multilocular
radiolucency with ill-defined borders, located in the body of partial edentulous
left mandible and extending from the first premolar to the second molar area (<xref ref-type="fig" rid="fig1">Figure 1</xref>
). Computed dental tomography showed a
hypodense lesion causing thinning of the buccal and lingual cortical plates (<xref ref-type="fig" rid="fig2">Figure 2</xref>
). During surgical exploration,
perforation of the buccal cortical plate was noticed (<xref ref-type="fig" rid="fig3">Figure 3</xref>
). The lesion was completely removed and the surgical
specimen, which appeared as a lobulated soft tissue mass (<xref ref-type="fig" rid="fig4">Figure 4</xref>
), was submitted for the histological examination.
Sections of the formalin-fixed paraffin-embedded tissue were stained with the
hematoxylin and eosin. The lesion was composed of fibrous stroma with areas of
degenerated myxomatous connective tissue, which was widely infiltrated by the nests
and islands of tumour cells of apparent odontogenic origin (<xref ref-type="fig" rid="fig5">Figure 5A</xref>
). The peripheral layer of tumour aggregates
consisted of a parallel arrangement of tall cylindrical cells with reverse polarity
of their hyperchromatic nuclei and vacuolization of the cytoplasm. Also, the
accumulations of cells rich in eosinophilic granular cytoplasm were found in the
central areas of the majority of the tumour islands (<xref ref-type="fig" rid="fig5">Figure 5B</xref>
). A diagnosis of granular cell ameloblastoma was rendered. The
postoperative course was uneventful and no clinical or radiographic signs of the
recurrence were noticed at the 1.5 year follow-up appointment.</p>
<fig id="fig1" orientation="portrait" position="float"><label>Figure 1</label>
<caption><p>Panoramic radiograph showing large, multilocular radiolucency, located in the
left mandible.</p>
</caption>
<graphic xlink:href="jomr-01-e3-g001"></graphic>
</fig>
<fig id="fig2" orientation="portrait" position="float"><label>Figure 2</label>
<caption><p>Computed tomography showing a hypodense lesion with aggressive imaging
features: it thinned bone margins both on the buccal and lingual sides of
the mandible.</p>
</caption>
<graphic xlink:href="jomr-01-e3-g002"></graphic>
</fig>
<fig id="fig3" orientation="portrait" position="float"><label>Figure 3</label>
<caption><p>Photograph demonstrating intraoperative findings of destruction of the buccal
cortical plate of the mandible.</p>
</caption>
<graphic xlink:href="jomr-01-e3-g003"></graphic>
</fig>
<fig id="fig4" orientation="portrait" position="float"><label>Figure 4</label>
<caption><p>Photograph of surgical specimen appearing as a lobulated soft tissue
mass.</p>
</caption>
<graphic xlink:href="jomr-01-e3-g004"></graphic>
</fig>
<fig id="fig5" orientation="portrait" position="float"><label>Figure 5</label>
<caption><p>Photomicrographs showing tumour islands with a peripheral layer of
ameloblassts and extensive central areas of granular cells with large,
eosinophilic cytoplasmic granules.</p>
<p>A = hematoxylin and eosin stain, original magnification x100.</p>
<p>B = hematoxylin and eosin stain, original magnification x200.</p>
</caption>
<graphic xlink:href="jomr-01-e3-g005"></graphic>
</fig>
</sec>
<sec sec-type="discussion"><title>DISCUSSION</title>
<p>Granular cell ameloblastoma is a rare variant of ameloblastoma. In the
clinicopathologic study of Kameyama et al. [<xref ref-type="bibr" rid="B6">6</xref>
], only 1 out of 77 ameloblastoma cases was classified as the granular cell
subtype. Reichart et al. [<xref ref-type="bibr" rid="B7">7</xref>
] reviewed all
available literature on ameloblastoma of the jaws from 1960 to 1993 and reported
that out of a total of 1593 cases with available data on histologic subtypes, there
were only 56 (3.5%) cases of the granular cell variant. Its age distribution is
considered to be quite similar to the other types of ameloblastomas, for which an
average median age of 35 years old, ranging from 4 to 92 years, is reported [<xref ref-type="bibr" rid="B7">7</xref>
]. Hartman [<xref ref-type="bibr" rid="B8">8</xref>
] reviewed 20 cases of the granular cell ameloblastoma from the files
of Armed Forces Institute of Pathology and reported an average age of 40.7 years
(age range: 21 - 65 years). Interestingly, 40% of the cases occurred in
non-Caucasians, while there was no distinct gender predilection [<xref ref-type="bibr" rid="B8">8</xref>
]. All tumours occurred in the mandible, the
vast majority of which (19 out of 20) affected the posterior regions [<xref ref-type="bibr" rid="B8">8</xref>
]; subsequent reviews confirmed the strong
propensity for involvement of the mandible [<xref ref-type="bibr" rid="B9">9</xref>
]. Jaw swelling and pain were the most frequent presenting symptoms.
Compared to the other ameloblastoma subtypes, no distinguishing radiographic
findings have been reported.</p>
<p>The biological behavior of granular cell ameloblastoma does not seem to differ from
the other histologic subtypes of ameloblastoma; it can be locally aggressive and has
a relatively high chance of recurrence [<xref ref-type="bibr" rid="B10">10</xref>
].
Reichart et al. [<xref ref-type="bibr" rid="B7">7</xref>
] reported a 33.3%
recurrence rate for granular cell ameloblastoma, which was higher, compared to the
more common follicular, plexiform and acanthomatous subtypes. In Hartman's
study [<xref ref-type="bibr" rid="B8">8</xref>
], 11 of 15 patients (73%) developed
recurrent lesions. However, similar to the other types of solid or multicystic
ameloblastoma, the prognosis is more dependent on the method of surgical treatment,
i.e. granular cell ameloblastomas treated by enucleation or curettage exhibit a high
recurrence rate due to the fact that the border of the tumour within cancellous bone
lies beyond the apparent macroscopic surface and the radiographic boundaries of the
lesion. Therefore radical surgical methods are recommended [<xref ref-type="bibr" rid="B10">10</xref>
]. Noteworthy is that granular cell ameloblastomas may rarely
behave in a malignant fashion giving rise to metastasis [<xref ref-type="bibr" rid="B9">9</xref>
].</p>
<p>Granular cell ameloblastoma is diagnosed by the presence of granular cells, which
typically occur within the central area of tumour and progressively replace the
stellate reticulum. Originally they were considered to represent an aging or
degenerative process [<xref ref-type="bibr" rid="B11">11</xref>
,<xref ref-type="bibr" rid="B12">12</xref>
], but recent immunohistochemical studies
suggest that this phenomenon is related with increased apoptotic cell death of the
lesional cells and the phagocytosis by neighbouring neoplastic cells [<xref ref-type="bibr" rid="B13">13</xref>
]. Immunohistochemical investigation proved
that the granular cells are positive for cytokeratin, CD68, lysozyme and
alpha-1-antichymotrypsin, but negative for vimentin, desmin, S-100 protein,
neuron-specific enolase and CD15, indicating epithelial origin and lysosomal
aggregation [<xref ref-type="bibr" rid="B13">13</xref>
]. Dina et al. [<xref ref-type="bibr" rid="B14">14</xref>
] also showed that the granular cells
exhibited membranous positivity for cytokeratin and cytoplasmic positivity for
CD68.</p>
<p>The differential diagnosis of granular cell ameloblastomas includes other oral
lesions with a similar morphology of granular cell accumulation, including granular
cell odontogenic tumour, granular cell tumour and congenital epulis. These lesions
have different biologic behavior and should be discriminated from granular cell
ameloblastomas [<xref ref-type="bibr" rid="B15">15</xref>
].</p>
<p>The granular cell odontogenic tumour is a type of odontogenic tumour featuring a
proliferation of large cells with eosinophilic granular cytoplasm, which appear
similar to the cells of granular cell ameloblastoma. They are very rare lesions
which have been reported in patients of a wide age range with a female predilection
[<xref ref-type="bibr" rid="B1">1</xref>
]. Radiographically, they appear as
multilocular or unilocular radiolucent lesions with occasional radiopacities [<xref ref-type="bibr" rid="B1">1</xref>
]. In contrast to granular cell ameloblastoma,
the granular cells of granular cell odontogenic tumour are not located within
epithelial islands but constitute part of the tumour stroma. Small islands or cords
of the odontogenic epithelium may be seen interspersed among the granular cells,
while small cementum-like deposits and dystrophic calcifications are often found
within the lesion [<xref ref-type="bibr" rid="B1">1</xref>
,<xref ref-type="bibr" rid="B16">16</xref>
]. Ultrastructurally, the granular cells are consistent with
lysosomes, and are immunohistochemically positive for vimentin, CD68, muramidase,
bcl-2, and negative for cytokeratin and S-100 protein [<xref ref-type="bibr" rid="B17">17</xref>
]. The tumour is usually treated with enucleation and
vigorous curettage, rarely recurs and its prognosis is very good.</p>
<p>The granular cell tumour is an uncommon benign soft tissue neoplasm that shows
predilection for the oral cavity. The most common site is the tongue, followed by
the buccal mucosa [<xref ref-type="bibr" rid="B18">18</xref>
]. Differential
diagnosis from a granular cell ameloblastoma is necessary when there is peripheral
localization or cortical perforation and soft tissue extension of the ameloblastoma.
Granular cell tumour usually occurs in the fourth to sixth decades of life and shows
a female predilection. Clinically, it appears as an asymptomatic sessile nodule of
small size [<xref ref-type="bibr" rid="B18">18</xref>
]. Microscopic examination
reveals large polygonal cells with abundant, pale, eosinophilic granular cytoplasm,
with a small vesicular nucleus, arranged into sheets or nests [<xref ref-type="bibr" rid="B18">18</xref>
,<xref ref-type="bibr" rid="B19">19</xref>
].
Immonohistochemical investigation is positive for S-100 protein, which could
indicate neural origin. The occasional presence of pseudoepitheliomatous hyperplasia
of the overlying epithelium, which can result in misdiagnosis of squamous cell
carcinoma, is noteworthy [<xref ref-type="bibr" rid="B18">18</xref>
,<xref ref-type="bibr" rid="B19">19</xref>
]. The granular cell tumour is treated with
conservative local excision and recurrence is uncommon.</p>
<p>Congenital epulis is an uncommon soft tissue tumour which occurs almost exclusively
on the alveolar ridges of newborns or rarely on the tongue. Although this lesion is
also composed of granular cells, the necessity of distinction from a granular cell
ameloblastoma appears unlikely, considering occurrence of the latter in patients of
older age. Interestingly, immunohistochemical investigation is negative for S-100
protein. The lesion is treated with conservative excision and there have been no
reports of the recurrence. Additionally, it appears to stop growing after birth and
may even diminish in size [<xref ref-type="bibr" rid="B18">18</xref>
].</p>
<p>In recent years, research efforts have attempted to elucidate the molecular factors
that govern the pathogenesis and progression of ameloblastoma and its subtypes by
regulating critical cell processes, such as cell proliferation, apoptosis and
differentiation. Numerous signaling pathways and molecules have been investigated
including integrins [<xref ref-type="bibr" rid="B20">20</xref>
], bone morphogenetic
proteins (BMPs) [<xref ref-type="bibr" rid="B21">21</xref>
], telomerase [<xref ref-type="bibr" rid="B22">22</xref>
], angiogenic factors [<xref ref-type="bibr" rid="B23">23</xref>
], matrix metalloproteinases [<xref ref-type="bibr" rid="B24">24</xref>
], and apoptosis regulators [<xref ref-type="bibr" rid="B25">25</xref>
,<xref ref-type="bibr" rid="B26">26</xref>
]. More specifically,
Kumamoto et al. [<xref ref-type="bibr" rid="B27">27</xref>
] studied the role of
p53-MDM2-p14ARF cell cycle regulation system, and the rat sarcoma
(Ras)/mitogen-activated protein kinase (MAPK) signalling pathway [<xref ref-type="bibr" rid="B28">28</xref>
], in the oncogenesis and cytodifferentiation
of odontogenic tumours, including ameloblastomas. Although the molecular components
of the aforementioned systems were found to be expressed in a normal and neoplastic
tissues, the granular cells of all studied granular cell ameloblastomas showed
reduced or no activity. The same investigators explored the role of the p53 homologs
(p63, p73) in odontogenic tumour development and reported significantly lower p63
and p73 expression levels in granular cell ameloblastomas compared to other tumour
subtypes [<xref ref-type="bibr" rid="B29">29</xref>
].</p>
<p>An investigation of the role of the mitochondria-mediated apoptosis signaling pathway
showed decrease or loss of immunoreactivity for the APAF-1 (apoptotic
protease-activating factor-1), caspase-9 and AIF (apoptosis-inducing factor) in the
granular cells of granular cell ameloblastomas [<xref ref-type="bibr" rid="B26">26</xref>
]. Also, Luo et al. [<xref ref-type="bibr" rid="B25">25</xref>
]
evaluated the expression patterns of apoptosis-related proteins, including Fas,
Fas-ligand (FasL), caspase-3 and Bcl-2, in various cellular components of
ameloblastomas; in granular cell ameloblastomas, strong or moderate expression of
Fas antigen, weakly positive expression of FasL and caspase-3, and no expression of
Bcl-2 were found. Moreover, Kumamoto et al. [<xref ref-type="bibr" rid="B30">30</xref>
] studied the immunochemical expression of the apoptosis-related
molecules Bid, Bim, Bad, Noxa and Puma (BH3-only proteins) in tooth germs,
ameloblastomas and ameloblastic tumours, indicating their expression in the
odontogenic epithelial cells near the basement membrane in tooth germs and
ameloblastic tumours. Interestingly, the granular cells in granular cell
ameloblastomas showed immunoreactivity for these BH3-only proteins, while other
subtypes like acanthomatous ameloblastomas showed no reactivity, suggesting a
possible additional role of these proteins in tumour cell differentiation [<xref ref-type="bibr" rid="B30">30</xref>
].</p>
<p>As far as the role of angiogenic factors in the development and progression of
odontogenic tumours is concerned, Kumamoto et al. [<xref ref-type="bibr" rid="B23">23</xref>
] have reported that the expression of platelet-derived endothelial
cell growth factor/thymidine phosphorylase (PD-ECGF/TP) was significantly higher in
ameloblastomas than tooth germs. Immunoreactivity for angiopoietin-1 and -2 was
detected predominantly in the odontogenic epithelial cells near the basement
membrane, in both normal and neoplastic tissues. Granular cell ameloblastomas showed
PD-ECGF/TP reactivity in granular neoplastic cells as well as in stromal cells
[<xref ref-type="bibr" rid="B23">23</xref>
].</p>
<p>It has been proposed that BMPs and their associated molecules may regulate the
cytodifferentiation of normal and neoplastic odontogenic epithelium via
epithelial-mesenchymal interactions [<xref ref-type="bibr" rid="B21">21</xref>
].
Sathi et al. [<xref ref-type="bibr" rid="B31">31</xref>
] focused on the role of BMPs
and the Wnt signaling pathway molecules in granular cell ameloblastomas. Strong
expression of the β-catenin and Wnt-5a was identified within the granular cells
of all studied samples, while BMP-4 expression was weak and Wnt-2 was negative,
suggesting abnormalities in synthesis and secretion of signaling molecules.</p>
<p>The possible contribution of novel signaling pathways such as Notch, sonic hedgehog
(SHH) and PI3K/Akt/mTOR in the pathogenesis of ameloblastomas has recently been in
the center of attention. Kumamoto et al. [<xref ref-type="bibr" rid="B32">32</xref>
]
analyzed the expression of Notch receptors and ligands in ameloblastomas and tooth
germs; mRNA expression of Notch1, Notch2, Notch3, Denta1 and Jagged1 was identified
in all samples of normal and neoplastic odontogenic tissues, but not in keratinizing
cells or granular cells in the corresponding ameloblastoma variants. The detection
of mRNA and protein expression of SHH, PTCH, SMO, and Gli1 in the ameloblastomas
suggests these SHH signaling molecules may play a role in epithelial-mesenchymal
interactions and cell proliferation during growth of these tumours [<xref ref-type="bibr" rid="B33">33</xref>
-<xref ref-type="bibr" rid="B35">35</xref>
].
Also, a number of studies have revealed aberrant signaling in the PI3K/AKT/mTOR
pathway in ameloblastomas [<xref ref-type="bibr" rid="B36">36</xref>
-<xref ref-type="bibr" rid="B38">38</xref>
]. Scheper et al. [<xref ref-type="bibr" rid="B39">39</xref>
] have shown that PTEN was completely absent in 33.3% of
ameloblastomas, while the active, stabilized, phosphorylated form was lacking in
83.3% of cases. In addition, Akt was upregulated in the majority (83.3%) of
ameloblastomas, with overexpression of the p-thr Akt and p-ser Akt seen in 93.3% and
56.6% of cases, respectively. Finally, pS6K, a downstream target of mTOR, was shown
to be upregulated in 86.7% of ameloblastomas with a positive correlation with AKT
upregulation [<xref ref-type="bibr" rid="B39">39</xref>
]. It is hoped that the
evolving understanding of the altered pathways in ameloblastoma may soon provide
non-surgical options for treatment of this condition [<xref ref-type="bibr" rid="B40">40</xref>
].</p>
</sec>
<sec sec-type="conclusions"><title>CONCLUSIONS</title>
<p>The granular cell ameloblastoma is a rare condition with unique histopathologic and
immunohistochemical findings; its treatment and prognosis do not significantly
differ from those of the other subtypes of the solid/multicystic ameloblastoma.
However, it should be differentiated from the other granular cell lesions primarily
because of its higher recurrence rate. A better understanding of the molecular
pathogenesis of ameloblastoma and its subtypes is under way and may provide
diagnostic and therapeutic benefits.</p>
</sec>
</body>
<back><ack><sec sec-type="acknowledgments and disclosure statements"><title>ACKNOWLEDGMENTS AND DISCLOSURE STATEMENTS</title>
<p>The authors report no conflicts of interest related to this study. There was no
external source of funding for the study.</p>
</sec>
</ack>
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