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Annals of Oncology 9: 559-564, 1998.
£ 1998 Khmer Academic Publishers. Primed in the Netherlands.
Clinical case
Mandibular pain as the leading clinical symptom for metastatic disease:
Nine cases and review of the literature
M. Pruckmayer,1 C. Glaser,2 C. Marosi3 & T. Leitha1
'University Clinics of Nuclear Medicine, 2Maxillofacial Surgery, 3Internal Medicine I, Division of Oncology, University Vienna. Austria
Summary
Background: Metastases to the jaws are a rare phenomenon.
Nevertheless, the appearance of non-specific symptoms such
as toothache can signal the onset of neoplastic disease in some
patients.
Patients: In this article, we present details of a 74-year-old
patient with a history of breast cancer to illustrate this point.
Retrospectively, covering a time span of one year, we could
identify nine patients (1.2%) with metastatic disease to the
mandible out of a total of 763 patients referred to our Maxillofacial Surgery department with non-specific jaw pain.
Results: Four patients were subsequently diagnosed as having breast cancer, two had lung cancer, one prostate cancer,
one renal cell carcinoma and one adenocarcinoma of unknown
primary site. Only three of these patients had documented
tumor spread to bones before the onset of jaw pain. In the
Introduction
Metastases to the jaws do not constitute a numerically
large group oflesions; however, they are of great clinical
significance since their appearance may be the first
indication of tumor relapse or - spread [1]. As the
clinical presentation of a metastatic lesion to the jaw
may range from slight discomfort or pain to swelling
and numb chin syndrome [2-5], these symptoms usually
do not draw attention to a potential underlying malignancy at the time of the initial presentation. It is estimated that more than 30% of all metastases located in
the jaws derive from breast cancer [6,1).
Long term follow-up of women after potentially curative treatment of breast cancer is a well established
practice. Its purpose is the detection of a second primary
or distant metastatic disease and it may provide psychosocial support to some patients [8-10]. On the other
hand, the influence of intense long term follow-up on
the course of the disease and on quality of life as well as
survival remains a matter of debate [11-14]. Recent data
strongly indicate that frequent laboratory tests and extensive diagnostic procedures after primary treatment
for breast cancer do not improve survival, nor do they
influence health-related quality of life in asymptomatic
patients [15-17].
Despite the fact that the majority of patients relapse
other patients, the dental symptoms were either the first sign of
a generalized neoplastic disease, or indicated relapse of disease
after long term disease free interval. However, further work up
disclosed generalized tumor spread with additional organ- or
bone-lesions in all patients, and the median survival was only
six months (range 3.5-+22) from diagnosis.
Conclusion: Pain of uncertain origin in the jaws should
alert clinicians to the potential of metastatic disease in patients
with a history of cancer and a bone scintigraphy should be be
done to rule out metastatic involvement.
Although metastatic lesions in this area usually herald
generalized neoplastic spread according to our experience,
prompt diagnosis nevertheless can lead to useful palliation
and an enhanced quality of life.
Key words: bone metastasis, mandible, numb lip syndrome
within a few years with the peak hazard at an interval of
1-2 years after primary treatment [18], recurrences can
even occur after decades [19] with a very slow decline in
riskfiveyears after surgery [18]. Breast cancer exhibits a
great propensity for delayed recurrence of local disease
and/or onset of metastatic spread [2] even after long
term disease free survival (DFS). Therefore, the possibility of an underlying recurrence of neoplastic disease
should always be considered with the appearance of nonspecific symptoms, even after a long term DFS.
In nearly 30% of mandibular metastases, the metastatic lesion in the oral region is the first indication of
an undiscovered malignancy at a distant site [6]. Given
these facts, an accurate medical history seems to be of
utmost importance in patients with jaw pain of unclear
origin. We present the case of a 74-year-old woman to
illustrate this point, along with our experience of patients
who presented with mandibular pain at the out patients
clinic of the University Clinic of Maxillofacial surgery
over a period of one year.
Case report
A 74-year-old woman consulted her dentist with pain in
her right mandible in October 1994. A panoramic X-ray
was inconclusive and it was presumed that her dental
c
\
Figure I. Whole body bone scintigraphy with Tc 9 9 m DPD showing multiple hot spots indicative for metastatic bone disease.
prosthesis might not fit well. After about three months
of dental procedures including tooth extractions and
unsuccessful antibiotic and analgesic therapy, she was
transferred to a otolaryngologist where atypical neuralgia of the trigeminal nerve was suspected. Conservative treatment, including carbamazepine, was initiated
without significant relief of symptoms. When additional
swelling of the right mandibular area occured three
weeks later, she was referred to the University Clinic of
Maxillofacial surgery. Clinical investigation five months
after the onset of symptoms disclosed third molar region
pain, swelling and anaesthesia of the lower lip (NLS).
In addition, lower back pain and severe discomfort of
both hips and the occipital skull were present at the time
of referral. A new panoramic X-ray was obtained and
indicated an osteolytic defect in the right mandible.
A careful history revealed the patient's past treatment
for breast cancer. A right radical mastectomy had been
performed eight years previously for an invasive ductal
carcinoma (pT2, pNO, MO, G2). The presence of estrogen
and progesterone receptors had not been determined.
Because of the radical surgery and relatively early tumor
stage, no adjuvant therapy was administered. Intensive
follow-up by means of chest X-ray, bone scan and
abdominal sonography was discontinued by the patient
after a period of two years without any evidence of
recurrence.
After finding the lytic lesion in the right mandible,
whole body scintigraphy was performed. It indicated
multiple sites of increased bone metabolism over the
whole skeleton including a hot spot over the right mandibular ramus (Figures 1 and 2). A bone marrow scan
with 99mTc-labeled murine monoclonal 19-G1 antibody
(Granuloscint*, Behring Werke G) showed decreased
Figure 2. 3D reconstruction of a Tc 9 9 m DPD SPECT of the skull
showing an impressive side difference in volume of the mandibles.
tracer uptake indicating bone marrow replacement suggestive of malignancy. A biopsy of the lesion in the right
mandible confirmed the diagnosis of a breast cancer
metastasis with positive estrogen and progesterone receptors.
After establishing the histologic diagnosis, a complete
staging work-up including chest X-ray and abdominal
CT-scan was initiated. In addition to the multifocal bone
metastases, X-ray also revealed multiple pulmonary
lesions. Chemotherapy with vinorelbine, 1-leucovorin
(L-LV) and 5-fluorouracil (5-FU) was started, along
with 20 mg/d of tamoxifen. The patient was administered 40 mg/m2 vinorelbine (days 1 and 21), 100 mg/m2
L-LV and 370 mg/m2 5-FU (days 1 to 5), respectively. In
order to reduce myelotoxicity, G-CSF was given subcutaneously for five days after chemotherapy. A marked
reduction of pain was achieved after the first cycle of
561
treatment. The patient received a total of five courses
resulting in disease stabilization as judged by radiologic
imaging according to WHO standard criteria. Prolonged
hematologic toxicity with neutropenia despite prophylactic G-CSF application lead to discontinuation of chemotherapy, while tamoxifen-treatment was continued. The
patient showed no evidence of progression for 7.5 months
after discontinuation of cytotoxic treatment.
Upon progression of the bone scan without change of
the pulmonary metastases, second line hormonal treatment with anastrozole was initiated. Despite this change,
further progression of osseous as well as the pulmonary
lesions occured. The patient was put on oral chemotherapy consisting of idarubicin and cyclophosphamide
and received four consecutive cycles. At the time of this
report, the patient is alive 22 months after establishing
the diagnosis of recurrence of her breast cancer.
Experience in 763 patients with jaw pain
Triggered by this experience, we performed a retrospective review of our files including all patients who had
been referred to our department of Maxillofacial Surgery for jaw pain during a one year period. Our search
disclosed a total of 763 patients. Out of these cases, nine
patients (1.2%) with metastatic bone disease to the mandible were identified. Four patients were subsequently
diagnosed with breast cancer, two with lung cancer, one
with prostate, one renal cell cancer and one with adenocarcinoma of unknown origin (Table 1). The median
time span between the onset of symptoms and final
diagnosis was 14 weeks (range 3-27). Five of the 763
patients had a history of cancer; yet, investigations
showed no metastatic disease underlying the non-specific jaw pain.
Of the nine patients with metastatic lesions in our
series, three (two with breast cancer, one with lung
cancer) showed a similiar course of disease as the case
described above. The mandibular metastases in these
patients were the first indication of recurrent disease
after a long term DFS. In one patient with a history of
breast cancer, the DFS had lasted more than 15 years.
Three patients had no history of cancer before bone
scintigraphy indicated systemic neoplastic disease. Biopsy
of the mandibular lesion revealed metastasis of breast
cancer, lung cancer and renal cell cancer, respectively.
Only three patients had an already established diagnosis
of cancer and they developed metastases to the mandible
during ongoing treatment (Table 1). Further investigations disclosed the presence of generalized neoplastic
disease in all nine cases. Two patients had additional
soft tissue lesions including lung and liver metastases,
while the rest had multiple bone metastases. Only two of
the nine patients had a radiolucent defect on conventional X-ray, while all nine subjects showed increased
focal tracer accumulation in 99mTc diphosphonate bone
scintigraphy. As bone scanning provides imaging of the
whole skeletal system, it does not only detect the symptomatic metastatic lesion, but also asymptomatic sites.
Thus, bone scintigraphy indicates generalized disease
prior to its clinical manifestation. In our series, all nine
patients showed multiple hot spots in addition to the
mandibular site, indicative of generalized disease.
Despite palliative treatment administered in all patients, only two patients with breast cancer, including
the case presented above, are still alive at the time of this
analysis. The median survival duration in our patients
from diagnosis of generalized neoplastic disease was six
months (range 3.5-+22 months).
Review of the literature
A computerized literature search (MEDLINE V. 3.1 fl)
of the English-language literature identified 43 papers
on the subject of mandibular metastases published between 1966 and 1997. While reviews including cases of
mandibular metastases were published in 1988 and 1990
[7, 20, 21], the large majority of papers are single case
reports (Table 2). Consistent with our data, breast cancer
constituted the largest group of patients described, but
also prostate, lung, renal cell, transitional cell cancers,
colon cancers, sarcomas, melanomas, neuroblastomas,
and many more have also been reported to metastasize
to the mandible (Table 2). Most authors report a male to
female ratio of approximately 2 : 3 [22, 23], with a peak
incidence between the fourth and seventh decade of life.
In our series, the male to female ratio was 1:2, with a
median age of 66 years (range 38-89). The most common locations for metastases to the mandible are the
molar and premolar region due to a predominance of
red bone marrow in this area [24, 25]. Mandibular
metastases are the first symptom of generalized malignant disease in approximately 30% of cases [6].
Table I. Nine patients diagnosed with mandibular metastasis.
Discussion
No. of
patients
Mandibular metastases are definitely rare [1, 6]. An extensive review of the literature revealed only scarce data
on primary cancers metastasizing to the jaws (Table 2).
According to the literature [4] the combined appearence
of tooth ache, lip anaesthesia and buccal swelling is
highly suggestive for an underlying malignant process.
Thus, the presence of these symptoms should alert clinicians to the possibility of neoplastic disease. In particular,
4
2
1
1
1
Breast cancer
Lung cancer
Prostate cancer
Renal cell
Unknown primary
Actual
cancer
history
Past
cancer
history
cancer
history
1
2
1
1
1
No.
1
1
1
562
Table 2. Review of the literature 1966-1997.
Authors
No.
Primary tumor site
of
cases
Ohba 1975 [38]
Samit 1978 [39]
Draper 1979 [40]
Kaugars 1981 [41]
Cialo 1981 [42]
Bucin 1982 [43]
1
Osguthorpe 1982 [44]
HofTken 1982 [45]
Myall 1983 [46]
Gorsky 1983 [47]
Shankar 1984 [48]
Boraz 1985 [49]
Horie 1985 [50]
Curtin 1985 [51]
Maharaj 1986 [52]
Florine 1988 [53]
Weithman 1988 [54]
Abemayor 1988 [55]
Nardi 1988 [56]
Naylor 1989 [5]
Baumgartner 1989 [57]
Aniceto 1990 [7]
<?
Anderson 1990 [21]
Boyzuk 1991 [58]
Lu 1991 [59]
Marker 1991 [60]
Franklin 1992 [61]
Doval 1992 [62]
Haddad 1992 [63]
Mohandas 1993 [64]
Choukasl993[65]
O Carroll 1993 [66]
Doval 1994 [67]
Bell 1995 [68]
Babu 1996 [69]
Pruckmayer 1996 [3]
Plath 1996 [70]
I
I
I
Osteogenic sarcoma
Melanoma
Follicular thyroid carcinoma
Lung cancer
Prostate cancer
Renal cell cancer, breast cancer,
melanoma
Follicular thyroid carcinoma
Breast cancer
Melanoma
Chordoma
Breast cancer
Neuroblastoma
Hepatocellular carcinoma
Adenocarcinoma of the fallopian
tube
Prostate cancer
Clear cell sarcoma
Transitionsal cell carcinoma
Cystosarcoma phyllodes of the
breast
Angiosarcoma
Colon cancer
Prostate cancer
Breast cancer, melanoma, prostate
cancer, unknown primary, renal cell
cancer
Esophageal adenocarcinoma
Breast cancer
Breast cancer
Hepatocellular cancer
Male breast cancer
Hepatocellular carcinoma
Neuroblastoma
Gastric cancer
Male breast cancer
Adenocarcinoma of the kidney
Transitional cell cancer
Melanoma
Colon cancer
Prostate cancer
Oesophageal squamous cell
carcinoma
these metastatic lesions are the first indication of an
undiscovered malignancy at a distant site in roughly
30% of cases [6]. Mandibular metastases usually indicate generalized disease necessitating histological verification and staging. In 30% of patients, the underlying
malignancy will be defined as breast cancer [1,6], while
other tumor types constitute the minority.
Breast cancer continues to be the most common
cancer in women in most industrialized countries [26].
Most women are diagnosed at an early stage, when
potentially curative treatment strategies are possible;
however, 20% to 85% of these patients will develop
distant metastases within five years of their initial diagnosis [27].
In the adjuvant setting, the heterogeneous behavior
of breast cancer necessitates an individually tailored
strategy for every patient according to established risk
factors [28]. The goals of adjuvant therapy for patients
with breast cancer are prevention of recurrence and in the
long run prolongation of survival [28, 29]. In addition to
adjuvant therapy, intensive follow up after primary
treatment is thought to provide the potential for early
detection of recurrence and may provide extra emotional support [30]. However, recent data question the
usefulness of intensive follow up strategies in terms of
overall survival [11-13, 15, 31, 32]. Nevertheless, these
reports should not provoke diagnostic nihilism in symptomatic patients. In the absence of curative therapies in
case of recurrence, the improvement of quality of life is
the most important treatment objective [29]. In the case
we have presented, physical and emotional help was
achieved, albeit after some months of futile attempts of
pain management.
To our knowledge, our analysis of 763 patients with
jaw pain identifying nine patients with metastases is one
of the largest series published. In accordance with the
literature, we found a predominance of breast cancer.
Lung cancer, prostate cancer, renal cancer and adenocarcinoma of unknown primary site were also documented in our patients. As highlighted in our case
report, a long time span between initial symptoms of
jaw pain and diagnosis of malignancy is common. Consequently, patients usually undergo non-specific treatment for an unnecessary period, leading to an impaired
quality of life. While cost effectiveness has become more
and more crucial in health management, and especially
the common practice of intensive follow-up in cancer
patients has been questioned over the past years [33, 34],
a failure to consider the diagnosis and undertake appropriate investigations postponed the diagnosis and
specific therapy in our patients for a median time of 14
weeks. In addition, our data suggest that the presence of
mandibular metastases are almost always associated
with generalized neoplastic disease. This fact is emphasised by the short median overall survival of six months
from diagnosis in our patients. While such patients are
clearly beyond the scope of curative management, symptomatic relief could be achieved in our patients after
diagnosis of cancer. Thus, the prompt identification of
such individuals offers the potential for major gains in
quality of life, and probably survival.
Despite the widespread availability of conventional
X-ray, radiologic signs are hardly ever diagnostic due to
the absence of pathognomic features of mandibular
metastases. While radiolucency is the most common
feature, only two of the nine patients showed a defect
on conventional X-ray in our series. Bone scintigraphy
usually shows an increased tracer uptake in the affected
area, resulting in a higher sensitivity than conventional
radiography [35-37]. In addition, whole body bone scintigraphy can detect widespread disease. In this analysis,
all of the nine patients showed increased tracer accumulation at the involved site and additional multiple involvement of the whole skeletal system.
In conclusion, we feel that mandibular pain occurring
563
in a patient with a history of malignancy give rise to a
possible diagnosis of bone metastases. While it seems to
be overzealous to suspect the presence of metastatic
disease in every patient with jaw pain, a selected subgroup of individuals, i.e. patients with a history of cancer
or subjects not responding to conventional management
for a prolonged time-span should undergo specific investigations such as bone scintigraphy to rule out a neoplastic basis of complaints.
18.
19.
20.
21.
22.
Acknowledgement
The author wishes to thank Markus Raderer, MD, for
his profound patience and support.
23.
24.
25.
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Received 26 November 1997; accepted 12 January 1998.
Correspondence to:
Martha Pruckmayer, MD
University Clinic of Nuclear Medicine
General Hospital Vienna
Leitstelle 3L
Waehringer Guertel 18-20
A-1090 Vienna
Austria