Oral Oncology (2008) 44, 743– 752

available a t www.sciencedirect.com

journal homepage: http:// intl. elsevierhealth. com/ journals/oron/

Metastatic tumours to the oral cavity –

Pathogenesis and analysis of 673 cases
a,*
Abraham Hirshberg , Anna Shnaiderman-Shapiro a, Ilana Kaplan b,
Rannan Berger c

a
Department of Oral Pathology and Oral Medicine, The Maurice and Gabriela Goldschleger School of Dental Medicine,
Tel Aviv University, Tel Aviv, Israel
b
Institute of Pathology, Rabin Medical Centre, Beilinson Campus, Petah-Tiqva, Israel
c
Institute of Oncology and Radiotherapy, Sheba Medical Center, Tel Hashomer, Israel

Received 2 September 2007; received in revised form 19 September 2007; accepted 19 September 2007
Available online 3 December 2007

KEYWORDS Summary The oral region is an uncommon site for metastatic tumour cell colonization and
Metastases; is usually evidence of a wide spread disease. In 25% of cases, oral metastases were found to
Oral metastases; be the first sign of the metastatic spread and in 23% it was the first indication of an undis-
Oral cancer; covered malignancy at a distant site. The jawbones, particularly the mandible, were more
Mouth metastases frequently affected than the oral soft tissues (2:1). In the oral soft tissues, the attached
gingiva was the most commonly affected site (54%). The major primary sites presenting oral
metastases were the lung, kidney, liver, and prostate for men, breast, female genital organs
(FGO), kidney, and colo-rectum for women. The primary site differs according to oral site
colonization, in men the lung was the most common primary site affecting both the jaw-
bones and oral mucosa (22% and 31.3%, respectively) followed by the prostate gland in
the jawbones (11%) and kidney in the oral soft tissues (14%). In women, the breast was
the most common primary tumour affecting the jawbones and soft tissues (41% and
24.3%, respectively), followed by the adrenal and female genital organs (FGO) in the jaw-
bones (7.7%) and FGO in the soft tissues (14.8%). The clinical presentation of the metastatic
lesions differ between the various sites in the oral region. In the jawbones most patients
complain of swelling, pain and paresthesia which developed in a relative short period. Early
manifestation of the gingival metastases resembled a hyperplastic or reactive lesion, such as
pyogenic granuloma, peripheral giant cell granuloma, or fibrous epulis. Because of its rarity,
the diagnosis of a metastatic lesion in the oral region is challenging, both to the clinician
and to the pathologist, in recognizing that a lesion is metastatic and in determining the site
of origin. The clinical presentation of a metastatic lesion in the oral cavity can be deceiving
leading to a misdiagnosis of a benign process, therefor, in any case where the clinical

* Corresponding author. Tel.: +972 3 5326999; fax: +972 3 6409250.

E-mail address: hirshmd@post.tau.ac.il (A. Hirshberg).

1368-8375/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.oraloncology.2007.09.012
744
presentation is unusual especially in patients with a known malignant disease a biopsy is
mandatory.
ª 2007 Elsevier Ltd. All rights reserved.
Introduction
Cancer is a complex disease in which many basic processes,
such as cell division, apoptosis, and cell migration, are dys-
regulated. It is the process of metastasis that results in mor-
bidity and eventual mortality.
Metastatic tumours to the oral region are uncommon and
may occur in the oral soft tissues or in the jawbones. Be-
cause of its rarity, the diagnosis is challenging and should
be considered in the differential diagnosis of inflammatory
and reactive lesions which are common in the area. Several
reviews have been published in the past concerning the
metastatic process to the oral region.1–3 However, a num-
ber of advances in the understanding of the aetiopathogen-
esis of the metastatic process warrant an update (for
further reading see Refs. 4–10).
The present review explores the role of oncogenic signal-
ling pathways and the complex relationships among the
many factors influencing metastasis, with special emphasis
to the oral region as the metastatic target. In addition,
the English-language literature was searched for all avail-
able information on the topic of malignant metastatic
tumours to the oral cavity (oral mucosa and jawbones).
The metastatic cascade
The metastatic process is a complex biological process,
involving detachment from the surrounding cells, regulation
of cell motility and invasion, survival, proliferation and eva-
sion of the immune system. The metastatic behaviour of
malignant cells is regulated by a repertoire of signalling
pathways, several components of which have been evalu-
ated as therapeutic targets in preclinical models and in clin-
ical trials.1
Initiation of the metastatic process – epithelial to
mesenchymal transition (EMT)
Compared to normal epithelia, carcinoma cells almost
invariably show diminished intercellular adhesiveness, ex-
pressed by the loss of E-cadherin-mediated adhesions as
they progress toward malignancy.11 Following detachment
from the neighbouring cells, tumour cells permeate the ba-
sal lamina barrier and invade the adjacent tissues. At that
stage, cells progressively express mesenchymal molecules
(including vimentin and N-cadherin), and are characterized
by elongated cell morphology with established cell-polarity,
a process called epithelial to mesenchymal transition
(EMT).12,13 The EMT is marked by complex and coordinated
set of molecular changes leading to the motile behaviour of
cancer cell14 which involves dynamic cytoskeletal changes,
cell–matrix interactions, localized proteolysis, actin–myo-
sin contractions, and focal contact disassembly.4,15,16
Stromal cells have also been found to modulate cancer
cell motility by producing growth factors and proteases
A. Hirshberg et al.
which support the survival and proliferation of cancer cells
in a paracrine fashion.17 Tumour-associated macrophages
express epidermal growth factor (EGF) and promote EGF
receptor-dependent carcinoma cell invasion in vivo.18 In
addition, in many tumours, fibroblasts and macrophages
produce matrix metalloproteases (MMPs) degrading the
extracellular matrix (ECM) and hence, promoting cancer cell
motility, which would otherwise hinder movement.
Angiogenesis and tumour dormancy
Tumour progression depends upon the formation of new
blood vessels (angiogenesis) and is a prerequisite for tumour
outgrowth.8,19 It is well established that tumour growth be-
yond the size of 1–2 mm is angiogenesis dependent.20 An in-
crease in microvessel density, together with the presence of
inflammatory response, facilitate tumour cells intravasation
and dissemination through the bloodstream. In general, in-
creased tumour vascularization (e.g., increased microvessel
density) and tumour expression of proangiogenic factors
have been associated with advanced tumour stage and poor
prognosis in a variety of human cancers.21
Hypoxia appears to be a major regulator of angiogenesis,
the transcriptional response to oxygen deprivation is largely
mediated by hypoxia inducible factor 1 (HIF-1).22 A large
number of additional genes are associated with different
steps of angiogenesis, among which are nitric oxide syn-
thases, growth factors such as VEGF, angiopoietine, fibro-
blast growth factors, and their various receptors, and
genes involved in matrix metabolism, including MMPs, plas-
minogen activator receptors and inhibitors, and collagen
prolyl hydroxilase.22 A current model of tumour angiogene-
sis suggests that this process involves recruitment of sprout-
ing vessels from existing blood vessels and incorporation of
endothelial progenitors into the growing vascular bed.23 The
fenestrated, pathologically leaky new vasculature facilitate
the entry of cells into the circulation. The rate of malignant
cell shedding generally increases with tumour size, never-
theless, dissemination can occur in the early stages of tumo-
urigenesis, to the point that some metastases have no
known primary source.
Tumour cells can undergo a period of dormancy followed
by a rapid growth during relapse. Most human tumours arise
in the absence of angiogenic activity and exist in a micro-
scopic dormant state for months to years. Following surgery
or other forms of therapy, local or metastatic recurrences
may occur, probably attributed to the switch to the angio-
genic phenotype in otherwise microscopic dormant tu-
mours.24 It appears that dormant cancer cells can persist
by completely withdrawing from the cell cycle, or by contin-
uing to slowly cycle and die at an equivalent rate.25,26
Apoptosis inhibition
The metastatic process is highly inefficient – only a small
proportion of metastatic cancer cells successfully colonize
Metastatic tumours to the oral cavity – Pathogenesis and analysis of 673 cases
distant sites.6 Recent experimental observations have pro-
vided support for the hypothesis that the induction of
apoptosis is a safeguard system to avoid metastasis. Apop-
tosis is probably involved in all stages of the metastatic
cascade. Apoptosis is triggered as early as the cancer cell
is detached from the ECM in the primary site (a process
called anoikis). ECM-dependent inhibition of apoptosis is
likely to be mediated by the integrin-activated signalling
pathway, which modulates the activity of apoptosis-regu-
latory genes such as members of the BCL2 family or the
caspases.6,27 Active c-Src is involved in the process of
anoikis, recent reports have shown a transient increase
in Src activity upon detachment in both cancer and normal
cells, and that inhibition of this activation increased
apoptosis.28
Entry of cancer cells into the vasculature constitutes an
important barrier to metastasis, circulating cancer cells
have to pass through several stressful steps, including sur-
vival in the bloodstream, arrest in the capillary bed and
resumption of proliferation in distant organs. In the circula-
tion most metastatic cells are destroyed either by mechan-
ical stress or cell death mediated by the immune system.29
In the circulation, metastatic tumour cells response to
mechanical stress, by the production of free radicals and
nitric oxide (NO) which is known to trigger apoptosis. 30
Another important stress sensor is the p53 tumour suppres-
sor which may drive the cell towards apoptosis.31
Site-specific metastatic process
Considerable evidence indicates that metastases of various
cancers to distant organs is not a random event, but is a reg-
ulated, site-specific process.7,32 This non-random process
was first described by Paget in his ‘seed and soil’ hypothe-
sis33; the metastatic ‘seed’ grows preferentially in an organ
environment that, in some way, provides a suitable ‘soil’.
The interaction between specific receptors on the surface
of disseminating tumour cells and the target organ endothe-
lium has been implicated as a contributing factor for the or-
gan-specific metastasis. In several malignancies, the
stromal-derived factor1 (SDF-1/CXCL12)–CXCR4 signalling
pathway induces the metastatic cells to invade and home
specific sites mainly bone marrow.34,35 The Chemokine
receptors CXCR4 and CCR7 have been found to be expressed
in primary breast cancers and metastasis but not in normal
mammary ductal cells, and that their respective ligands
CXCL12 (SDF-1) and CCL21 are preferentially expressed at
principal sites of metastasis such as lung and lymph nodes,
in addition, administration of neutralizing CXCR4 antibody
significantly impaired breast cancer metastasis to the lungs
and regional lymph nodes in mouse xenograft models.36
Recently, a breast cancer surface protein, metadherin,
that interact with the vasculature of the lung, has been
found to be highly expressed in breast cancer, as a func-
tional player in lung-specific metastasis of breast cancer
cells.37
Metastases to the bone
The best characterized example of reciprocal cellular and
molecular adaptations that occur between cancer cells and
their stroma during site-specific metastatic progression
745
comes from the analysis of tumours that metastasize to
bone. What enables metastatic cells to colonize the unique
bone microenvironment, and what determines whether the
lesion will be primarily osteolytic or osteoblastic? Bone
homeostasis is preserved through a balance between osteo-
blasts and osteoclasts. A highly conserved molecular cir-
cuitry maintains this balance under normal conditions and
after acute injury. Cancer cells that successfully metastasize
to bone invariably hijack these conserved physiological
mechanisms. Whereas prostate cancer cells frequently
secrete osteoblast-promoting factors, including BMPs, Wnt-
family ligands, endothelin-1, and PDGF, osteolytic breast-
cancer cells frequently inhibit these pathways by secreting
soluble inhibitors while over-expressing osteoclast-inducing
factors such as PTHrP (parathyroid hormone-related pro-
tein), IL-8, and IL-11.38–40 In addition, there is frequent
dis- ruption of the homeostatic RANK-RANKL loop between
osteoclasts and osteoblasts. Metastatic prostate carcinomas
can secrete high amounts of the RANKL inhibitor osteopro-
tegerin, thereby attenuating osteoclastic reactions during
metastasis.40 Conversely, osteolytic cancer cells can secrete
proteases that cleave RANKL into a more active form, there-
by activating the osteoclasts.41 Moreover, because bone is a
rich source of matrix-embedded growth factors such as IGF
and TGF-b, these cytokines are released upon osteolysis
and act upon the invading tumour cells to promote the induc-
tion of osteoclast-promoting factors.39,42–44
Metastatic tumours to the oral cavity
In the present analysis we searched the English-language lit-
erature between 1992 and 2006 for reports of metastases to
the jawbones and oral soft tissues. Selected were cases in
which the reported data included at least the primary origin
of the tumour, the oral site and histological confirmation.
Cases that were diagnosed as metastatic tumour with pri-
mary unknown were excluded. The collected data was
added to the data published in previous studies in which
the literature was searched up until 1991.1–3
The literature search between 1992 and 2006 disclosed
93 articles reporting 126 cases of metastatic lesions to
the oral cavity (mucosa 61 cases and jawbones 65 cases).45–
137 Most cases were reported as case report and small
series of cases. Several reports were not included be-
cause they did not meet the inclusion criteria. D’Silva
et al.138 reported 114 cases of metastatic tumours to the
jaws retrieved from several hospital archives, however, be-
cause they reported only cases metastasizing to the jaw-
bones, including their data in the present analysis might
cause bias in favour of certain primary sites and of oral site,
and was thus excluded from the analysis.
Results
Table 1 presents the combined data from both sources,
summarizing data of 673 cases reported since 1916.
Age and gender
Most metastatic tumours to the oral region were found in
patients in their fifth to seventh decade (mean age for male
746 A. Hirshberg et al.

Table 1 Correlation between site of origin and gender in oral mucosa and jawbone metastases, summarizing data of 673 cases
reported since 1916 (based on the present study and previous studies1–3)
Primary site Total Total Jawbone Oral mucosa

M F U Total M F U Total M F U
Lung 112 92 14 6 58 50 7 1 54 42 7 5
Breast 111 3 108 91 1 90 20 2 18
Kidney 65 39 25 1 36 21 15 29 19 9 1
Bone 47 27 20 33 20 13 14 7 7
Colo-rectum 40 17 21 2 28 10 16 2 12 7 5
Skin 39 23 12 4 15 7 7 1 24 16 5 3
Adrenal 36 19 17 36 19 17
Liver 34 31 2 1 23 21 1 1 11 10 1
FGO 28 28 17 17 11 11
Prostate 27 27 25 25 2 2
Thyroid 21 5 16 19 4 15 2 1 1
Eye 20 8 10 2 18 7 9 2 2 1 1
Testes 16 16 10 10 6 6
Stomach 15 9 5 1 6 4 2 9 5 3 1
Esophagus 14 13 1 7 7 7 6 1
Brain 13 5 8 11 4 7 2 1 1
Bladder 12 9 3 9 7 2 3 2 1
Other 23 17 5 1 13 10 2 1 10 7 3
Total 673 360 295 18 455 227 220 8 218 134 74 10

cases of pheochromocytoma and neuroblastoma including those from the retroperitoneum and mediastinum.

was 51.1 years and 47.1 years for females). The mean age in
patients with jawbone metastases (52 years) was lower
compare with patients with oral soft tissue metastases (42
years). The differences between the two groups can primar-
ily be attributed to paediatric cases of neuroblastoma,
which have the propensity to metastasize to bones, includ-
ing the jawbones.
There was an almost equal gender distribution in jaw-
bones metastases, whereas, in oral soft tissues there was
2:1 male to female ratio.
Primary site
The most common primary sites for oral metastases were
the lung, kidney, liver and prostate for men, breast, fe-
male genital organs, kidney, and colo-rectum for women.
Differences exist concerning the preference of some pri-
mary tumours to metastasize to specific oral site. Some tu-
mours prefer the jawbone as their metastatic target, for
example, 11% of the jawbone metastases in men originated
from the prostate gland compared with 1.5% in the soft tis-
sues. In women, 40.6% of jawbone metastases originated
from the breast compared with 25% in the soft tissues. In
addition metastatic lesions from the adrenal, thyroid,
and eye exclusively preferred the jawbones as their meta-
static target.
Oral site
The jawbones were more frequently affected than the oral
soft tissues (2:1). In the jawbones, the mandible was the
most common location (372 cases, 82%) with the molar area
being the most frequently involved site. In 24 cases meta-
static deposits were found in both jaws. In the oral soft tis-
sues, the attached gingiva was the most common affected
site (118 cases, 54%), followed by the tongue (49 cases,
22.5%), and with much less frequency by the remaining oral
soft tissues. The primary site differed according to oral site,
in men the lungs were the most common primary site affect-
ing both the jawbones and oral mucosa (22% and 31.3%,
respectively) followed by the prostate gland in the jaw-
bones (11%) and kidney in the oral soft tissues (14%). In fe-
males, the breast was the most common primary tumour
affecting the jawbones and soft tissues (41% and 24.3%,
respectively), followed by the adrenal and female genital
organs in the jawbones (7.7%) and female genital organs in
the soft tissues (14.8%).
Clinical presentation
The clinical presentation of the metastatic lesions differed
between the various oral sites. In the jawbones most pa-
tients complained of rapidly progressing swelling, pain and
paresthesia. Radiographic description was available in 413
cases (58 cases in the new survey and 355 in the previous
analysis2), showing in most cases (86%), a lytic radiolucent
lesion with ill-defined margins. Occasional osteoblastic le-
sions were observed as either pure or mixed radiopacity
(17% of the cases). In approximately 5% of the cases, radio-
graphs did not show any pathological changes. Physical
examination revealed, in most cases, a bony swelling with
tenderness over the affected area. The early manifestation
of the gingival metastases resembled a hyperplastic or reac-
tive lesion, such as pyogenic granuloma, peripheral giant
Metastatic tumours to the oral cavity – Pathogenesis and analysis of 673 cases
cell granuloma, or fibrous epulis. In other locations in the
oral soft tissues the clinical presentation was that of a sub-
mucosal mass. Only in a few cases the lesion appeared as
ulceration. In some cases, especially those of metastatic
hepatocellular carcinoma, severe post-biopsy hemorrhagic
episodes had been reported.62
A peculiar site for metastasis is the post-extraction site.
Analysis of the literature revealed 56 cases in which tooth
extraction preceded the discovery of the metastases.139 In
many of these cases the metastatic tumour was assumed
to be present in the area before extraction.
Prognosis and treatment
In 169 cases (25%, 36 cases from the new survey, 32 and 101
from previous studies, respectively1,2), the metastatic tu-
mour was found before the primary origin was diagnosed,
while in 155 cases (23%, 27 cases from the new survey and
128 from previous study2) oral metastasis was the first sign
of the metastatic disease. The average time between the
diagnosis of the primary tumour and the detection of oral
metastases was about 40 months. Some oral metastases,
however, were reported to appear more than 10 years fol-
lowing the diagnosis of the primary tumour. In most cases
the prognosis was grave with an average survival time of
about 7 months. Therefore, treatment regimen aimed to
improve ‘‘quality of life’’ included local resection, radio-
therapy or chemotherapy even in widespread disease. In
several cases, where the oral tumour was the only meta-
static lesion, resection seemed to result in improved prog-
nosis,87 although the reported follow-up period was
relative short. In neuroblastoma, some cases may benefit
from chemotherapy even in disseminated disease, which
can cause maturation towards ganglioneuroblastoma.74
Discussion
The oral region is an uncommon site for metastatic tumour
cell colonization and is usually the evidence of a wide
spread disease. However, about 25% of oral metastases have
been found to be the first sign of a metastatic spread and in
23% it was the first indication of an undiscovered malignancy
at a distant site. Batson140 proposed the valveless vertebral
venous plexus as a mechanism for bypassing filtration
through the lungs; an increase in intrathoracic pressure di-
rects blood flow into this system from the caval and azygous
venous system and accounts for the increased distribution
of axial skeleton and head and neck metastasis.140,141
An attempt to analyse the information in the literature
regarding metastatic tumours to the oral cavity poses sev-
eral problems. Most of the information is presented in iso-
lated case reports or in a small series of cases. Moreover,
in recent years, mainly unusual cases have been reported,
which could cause bias in the favour of unusual cases regard-
ing the primary site and oral site. D’silva et al.138 has re-
cently published a comprehensive series of 114 cases of
metastasis to the jawbones, and the data obtained in his ser-
ies correlates well with the result of the present study in re-
gard to the primary site, gender, and clinical presentation.
There are more published cases of jawbone metastases
than in the oral soft tissues. A metastatic lesion in the oral
747
soft tissues is easily recognized, in contrast to the jawbone
where a metastatic deposit may not be evident especially in
a wide spread disease, in which the patient may succumb
within several months. The accurate incidence of metasta-
sis to the jawbones is difficult to access and is probably
far more common than is noted. In the skeletal bones, the
frequency of micrometastasis is higher than is found by con-
ventional methods, such as bone scans and radiographs.142
In the mandible, microscopic deposits of metastatic tumour
cells which were not identified in routine radiographic
examination, were found in 16% of autopsied carcinoma
cases.143
Although, the most common malignancies are also the
most frequent tumours that metastasize the oral cavity,
differences still exist, probably reflecting differences in
biologic behaviour of the tumours, degree of aggressive-
ness and possible preference toward oral tissues. For
example, prostatic carcinoma is the most common malig-
nancy affecting males followed by the lung, colo-rectum
and urinary bladder (29%, 15%, 19% and 7%, respec-
tively).144 Nevertheless, in males, the lung was the most
common primary cancer metastasizing the oral region fol-
lowed with much lower incidence by the kidney liver and
prostate. Lung cancer is the most common tumour causing
death among men, followed with much lower incidence by
the prostate, colo-rectum and pancreas (31%, 9%, 9%, and
6%, respectively).144 This may reflect the predominance in
oral metastasis from lung cancer in males. Some tumours
rarely metastasize the oral cavity, for example pancreatic
cancer (six reported cases), which is a highly aggressive tu-
mour accounting for 6% of all cancer mortality; patients
probably die before oral metastases have a chance to be
expressed.144
Differences exist concerning the preference of some pri-
mary tumours to metastasize to specific oral site. Tumours
originate from the prostate, breast and adrenal prefer the
jawbone as their metastatic target, the skeletal bones spe-
cifically those with a significant red marrow component are
frequent sites of metastases of these tumours.145 The path-
ogenesis of the metastatic process in the jawbones is not
clear. Most likely it is not a simple mechanical process be-
cause of the uneven distribution of the metastatic spread
between the jawbones and the oral mucosa, even though
these oral structures share a common blood supply. The
jawbones, especially in the old age, are poor in active mar-
row, which is usually found in the posterior part of the man-
dible. However, remnants of haematopoietic marrow can be
detected in edentulous mandibles, in cases of focal osteo-
porotic bone marrow defects.
The type of interaction between the bone microenviron-
ment and the tumour cells can potentially give rise to oste-
olytic (bone resorbing) or osteoblastic (bone forming)
metastasis. Osteolytic bone metastases are characteristic
for most malignancies, and indeed, over 90% of jawbone
metastases presented as osteolytic lesion. It should be
noted, however, that about 5% of the reported cases of
metastases to the jawbones, lacked any radiographic
change.
In the oral soft tissues the attached gingiva is the most
common site for the metastatic colonization. Inflammation
may play a role in the attraction of metastatic cells towards
the attached gingiva. Malignant cells may be entrapped by
748
the rich capillary network of the chronically inflammed gin-
giva. The microenvironment present in the chronically
inflammed gums may favour the progression of the meta-
static cells. Chronic inflammation has been linked to various
steps involved in tumourigenesis, including cellular transfor-
mation, promotion, survival, proliferation, invasion, angio-
genesis, and metastasis.146,147
Jawbone metastasis is manifested in most patients with
pain, swelling and paresthesia. Pain is a major complaint in
metastatic bone disease. Chemicals derived from tumour
cells, inflammatory cells, and cells derived from bone
appear to be involved simultaneously in driving this
frequently difficult-to-control pain state.148 Special atten-
tion should be given to patients with ‘‘numb chin syn-
drome’’ or mental nerve neuropathy,149 a symptom
which should always raise the suspicion of a metastatic dis-
ease in the mandible. With the progression of the disease,
oral metastatic lesions, especially those located in the soft
tissues, cause progressive discomfort. Pain, bleeding,
superinfection, dysphagia, interference with mastication,
and disfigurement are some of the main complaints of pa-
tients. In some cases, the metastasis is discovered in a re-
cent extraction site.139 A soft tissue mass extruding from a
recent extraction wound accompanied by pain are the
main symptoms. In many of these cases the metastatic tu-
mour is present in the area before the extraction causing
pain, swelling and loosening of teeth. Theses symptoms
lead the clinician to extract the affected tooth. However,
in some cases, metastasis probably develops after extrac-
tion. Tooth extraction can serve as a promoting factor in
the metastatic process.
In patients with a known malignant disease, the clinical
presentation may favour the pre-operative diagnosis of
metastasis. However, in 24% of patients, the metastatic le-
sion in the oral region is the first indication of an undiscov-
ered malignancy at a distant site. Chorost et al. have
recently review the approach in evaluation patients with a
cancer of unknown primary150; a complete history and phys-
ical examination should be performed, with special atten-
tion to the breast, rectal and pelvic examination. The
standard battery of laboratory tests includes a complete
blood count, liver function tests, calcium, urinalysis, and
serum creatinine. A chest radiograph is always indicated,
supplemented with CT in suspected cases. Gender-specific
tests include serum prostate-specific antigen assay and
transrectal ultrasound for male patients, mammography
and cervical Pap smears for female patients. If these tests
fail to find the primary tumour, CT scan of the abdomen
and pelvis can been used to identify primary tumours in
the pancreas, liver, adrenals, kidney, gallbladder, ovaries,
and stomach. Positron electron transmission (PET) scanning
with fluorodeoxyglucose (FDG) is rapidly gaining favour in
the evaluation of unknown primary cancers, particularly in
instances where other imaging modalities have failed to
identify a source.
The histologic diagnosis is a keystone in evaluating pa-
tients with cancer of unknown primary. Attention should
be given to differentiating primary intraoral malignancies
from metastatic tumours. Several primary intraoral malig-
nancies, especially those originating from salivary glands,
have similar histological features to tumours occurring in
distant organs. For example, primary ductal carcinoma of
A. Hirshberg et al.
salivary gland origin versus metastatic breast carcinoma;
primary intraoral clear cell tumour of salivary gland origin
or intraosseous clear cell carcinoma versus metastatic renal
cell carcinoma; and primary squamous cell carcinoma ver-
sus metastatic squamous cell carcinoma from the lung. In
addition, malignant soft tissue tumours may originate
intraorally but, because of their relatively uncommon
occurrence in the oral region, metastatic origin should be
considered. Immunoperoxidase staining, in conjunction
with the histopathology and clinical history, can delineate
specific cell lineages in many cases. Serum markers,
although they lack adequate specificity can be used
alongside the pathological and clinical information, and
may be helpful in diagnosing the origin of the primary
tumour.150
Because of its rarity, the diagnosis of a metastatic lesion
in the oral region is challenging, both to the clinician and to
the pathologist, in recognizing that a lesion is metastatic
and in determining the site of origin. The clinical presenta-
tion of a metastatic lesion in the oral cavity can be deceiv-
ing, leading to a misdiagnosis of a benign process, therefore,
in any case where the clinical presentation is unusual, espe-
cially in patients with a known malignant disease, biopsy is
mandatory. Although the oral cavity is not a common site
for metastatic colonization, it is an interesting site because
of the various and different tissues that may be involved
in the metastatic process. Research is needed, therefore,
to evaluate the importance of the oral cavity in attracting
metastatic tumour cells.
Conflict of Interest Statement
On behalf of the co-authors and myself, we declare that we
do not have any financial and personal relationships with
other people or organizations that could inappropriately
influence (or bias) our work.
Acknowledgements
The authors would like to acknowledge Professor Amos
Buchner for his assistance in editing the manuscript and
his invaluable guidance.
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