CANCER TREATMENT REVIEWS (2005) 31, 247–255

www.elsevierhealth.com/journals/ctrv

TUMOUR REVIEW

Brain metastasis of unknown primary:

A diagnostic and therapeutic dilemma
a, a,1 b,2
Konstantinos S. Polyzoidis *, George Miliaras , Nicholas Pavlidis

a
Department of Neurosurgery, Medical School, University of Ioannina, P.O. Box 1186, Post code 45110,
Ioannina, Greece
b
Department of Medical Oncology, Medical School, University of Ioannina, Post code 45110, Ioannina,
Greece

KEYWORDS Summary The diagnosis of a brain metastasis is usually made during the routine
Brain metastasis; follow up examinations of patients with known cancer, who are under the care of
Unknown primary; oncology departments. The involvement of the neurosurgeon depends on the philos-
Diagnosis; ophy and referral patterns of each oncology group. Patients with brain metastases
Therapy; of unknown primary (BMUP) are much more likely to seek the help of a neurosurgeon
Prognosis or a neurologist before contacting an oncologist, because the presenting clinical
features originate from the brain. BMUPs are almost equal in numbers to brain
primaries and differ from regular cerebral metastases regarding their site of origin,
which will remain unknown in about 50% despite vigorous investigation. The clinical
picture is similar to that of primary brain tumours but they seem to show different
areas of predilection in the brain parenchyma. By reviewing the literature we are
presenting the epidemiology, clinical presentation, diagnostic workup and treat-
ment plan for this group of patients.
c 2005 Elsevier Ltd. All rights reserved.

Introduction

Brain metastasis is a common complication in can-

cer patients. The metastatic dissemination of a so-
lid tumour to the brain is generally associated with
* Corresponding author. Tel.: 0030 26510 97527; fax: 0030 a poor prognosis. Brain metastasis from an unde-
26510 97030. tected primary tumour (BMUP) appears to be a dis-
E-mail addresses: kostapol@otenet.gr (K.S. Polyzoidis), tinct clinical entity. In up to 15% of the patients
milasgrg@hotmail.com (G. Miliaras), npavlid@cc.uoi.gr (N.
Pavlidi.
with brain metastasis, the site of the primary tu-
1
Tel.: 0030 26510 97527; fax: 0030 26510 97030. mour will not be detected despite thorough
2
Tel./fax: 0030 26510 99394. investigation.1


0305-7372/$ - see front matter c 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ctrv.2005.03.006
248
Scanty information is available in the literature,
most of it in the field of oncology. The prognosis
and treatment strategies remain controversial,
and not very familiar to the neurosurgical commu-
nity.2 By reviewing the current literature we will
try to elucidate the particular characteristics of
this neglected group of patients, who are more
likely to seek the attention of a neurologist or neu-
rosurgeon before that of an oncologist in contrast
to the regular cancer population with cerebral
metastases.
Definition
In general oncologic terms the definition of cancer
of unknown primary (CUP) has varied over time
according to the inclusion criteria used as well as
the evolution of diagnostic tools.3 In the early
1970s the diagnosis of CUP could be made only if
the primary tumour was not found at autopsy.4 To-
day the definition of CUP includes patients who
present with histologically confirmed metastatic
cancer in whom a detailed medical history, thor-
ough physical examination, and complete labora-
tory investigation fail to identify the primary
site.5,6 In a general medical oncology service met-
astatic carcinoma of an unknown primary site may
constitute as much as 3–5% of the referred solid
tumour patients.3
Regarding the patients who present with cere-
bral metastases, the time interval for the detec-
tion of the primary site has no generally accepted
definition. It varies from an indefinite period7 to
two 8 or three months.9 Others are in favor of using
the time of initial presentation, suggesting a brief,
but not necessarily thorough, preoperative investi-
gation for the primary lesion in order to remove the
mass in the brain as early as possible.9
The diagnosis of brain metastases is usually
made in the staging evaluation of a newly diagnosed
primary tumour (metachronous presentation). In
BMUP patients brain metastases are diagnosed be-
fore the primary tumour is found (precocious pre-
sentation).1 Very rarely the diagnosis of the brain
metastasis and the lung lesion will be made at the
same time period (synchronous presentation).
Table 1 Estimated incidence of brain tumours in the USA
Primary brain tumours: 18,000–30,000 patients/year
Secondary brain tumours: 10,0000–170,000 patients/year
BMUPs (15% of all brain metastases): 15,000–25,500 patients/year
Refs. [13,16,43].
K.S. Polyzoidis et al.
Epidemiology
Cerebral metastasis occurs in about 15–40% of all
cancer patients representing about 12 patients
per 100,000 of the population per year.10–14 This
proportion has increased in recent years partly
owing to the increased sensitivity of MRI for detect-
ing these tumours and also the longer survival of
these patients.15
Secondary intracranial lesions are estimated to
become symptomatic in about 80,000 patients per
year in the US compared to 18,000 with primary
brain tumours.16 Others have reported that brain
metastases occur ten times more frequently than
primary brain tumours.17 Approximately one-third
to one-half of the brain metastases are single, pos-
ing significant difficulties in the differential diagno-
sis from primary tumours. Brain metastases are
found at autopsy in 10–15% of patients with can-
cer.18–20 As already mentioned, in up to 15% of
the patients with brain metastasis the primary
tumour will not be detected despite thorough
investigation.1 Thus BMUPs are estimated to be al-
most equal in numbers to primary brain tumours
(Table 1).
Although the leptomeninges, cranial nerves,
blood vessels, or the skull can be affected, the
commonest site of metastasis is by far the brain
parenchyma. The brain tissue is involved in about
15% of these patients and is the exclusive location
in about 10%.16
Symptomatic brain metastases in patients with-
out a previously diagnosed malignancy are infre-
quent (5%) in clinical series.1 On the contrary
they represent up to 40% of metastases in neuro-
surgical series21 and 30–40% of operated cerebral
metastases from lung tumours.22 The available
data are obviously heterogenic, since they are de-
rived from retrospective studies from different
eras of imaging technology.
Biology and pathology
The metastatic cascade is the process by which the
primary tumour detaches and forms deposits at a
Brain metastasis of unknown primary
remote site.15 Several steps are required and each
step is controlled by multiple genes. Genetic dif-
ferences between a primary tumour and its metas-
tases often exist.23,24 A certain size is critical in
order for a metastasis to develop, which is esti-
mated experimentally to have a diameter between
0.5 and 1 cm. CUP represents a unique entity in
which a presumed primary tumour is able to metas-
tasize before becoming large enough to be identi-
fied.3 In addition the length of time that the
cancer exists is equally important. Primaries of
BMUPs appear to have the potential to become
malignant early in tumour development.
The biology of BMUPs is similar to that of other
brain metastases, but differs from that of primary
brain tumours. Most of the primary brain tumours
are diffusely infiltrating, whereas metastases are
usually well circumscribed. Hematogenous spread
is by far the most common mechanism, and the
deposition of the lesions tends to occur either
where vessel calibre changes (at points of turbu-
lent flow) or at arterial end points. In the brain
these areas are the interface between the grey
and white matter, and the watershed regions of
borderline vascularization.15
Eventually about 50% of patients with BMUP
will have their primary sites diagnosed.21,25 As
with other series of brain metastases, the lung
is the most frequent primary site (51%).26 This
frequency varies from 33%27 to 78%28 in the liter-
ature. Although the breast is the second most
common primary site in patients with known
malignancy (10–17%), it is underrepresented in
the group of patients with BMUP, because the
metastatic dissemination to the brain occurs later
in its natural course, after the diagnosis has al-
ready been established. Melanoma, with 8% of
metachronous secondaries, is equally reported in
the literature of BMUPs.29–31 Surprisingly, the
pancreas is found in 8%, and the remainder of gas-
trointestinal cancers represent 19%. In comparison,
cerebral metastases from pancreatic neoplasms
are extremely rare in the general cancer popula-
tion (0.1–0.3%),32 while gastrointestinal malig-
nancies appear in 3–10% of patients with brain
metastases.18,29–31 Thus, patients presenting
with BMUP may not have the same primary sites
that would be expected if the primary site had
already been known.26
The majority of cases are adenocarcinomas with
poorly differentiated tumours being the next most
frequent pathology.28 Unfortunately, adenocarci-
nomas metastatic from different locations have al-
most identical microscopic appearances, which
does not facilitate the diagnosing of the site of
origin.33
249
Light microscopic examination can basically
characterize only cell morphology and tumour dif-
ferentiation. Extensive pathological investigation
by immunohistochemistry, electron microscopy or
cytogenetic studies results in the identification of
specific subgroups of CUP patients in almost
20% of the cases in general oncology34 but far fewer
in BMUP. CSF examination is indicated only in
those patients suspected of leptomeningeal
carcinomatosis.35
Clinical presentation
The brain secondary is responsible for the first
symptom in almost one-half of patients operated
on for a cerebral metastasis. The clinical presenta-
tion with brain symptoms may be due to the fact
that thoracic symptoms occur rather late in lung
cancer, while brain lesions give symptoms at a
much earlier stage.
The mean age of BMUP patients ranges from 51
to 55 years, and there is a definite male preponder-
ance. As with any brain mass lesion, symptoms are
focal or general due to the increased intracranial
pressure. Headache is the most common symptom,
followed by focal neurological dysfunction, cogni-
tive and behavioral disturbances, seizures (in about
15–25%) and evidence of elevated intracranial
pressure.26 Cranial nerve involvement is observed
mainly in patients with carcinomatous basal menin-
gitis. The functional status of the patients can be
classified according to the recursive partitioning
analysis (RPA) classes for patients with brain
metastases: Class I includes all patients with a
Karnofsky performance status (KPS) >70, age <65
years, a controlled primary tumour and no extra-
cerebraI metastases, Class III includes all patients
with a KPS <70, and Class II all other patients.2
Intracranial hemorrhage is not an uncommon
presentation of brain metastases (15%), particu-
larly in those from melanomas and choriocarcino-
mas.36 Hemorrhage can also occur in CUP
metastasis to the spinal cord.37
‘‘Miliary’’ metastatic tumours to the brain from
an unknown primary have also been reported.38
These patients present with minimal neurological
deficit, but their survival is poor. The only explana-
tion is that the host’s brain immune response to the
neoplasm is unusually altered.
Paraneoplastic cerebellar degeneration may
precede a potentially curable remote malignancy
by months or years. Periodic reevaluation is
needed when the cancer remains occult.39 Also,
25% of cases of metastatic meningoradiculitis
250
(metastases to nerve roots) remain with unde-
tected origin.40
Sites of predilection
The location of the BMUP lesions is of great interest
and probably reflects the biologic dissemination of
the metastatic seeds in areas of borderline vascular
supply. Thus a preponderance are found in the
parietal lobe,8,41,42 followed by frontal, occipital
and cerebellar localizations in about equal per-
centages. This appears to be different from the dis-
tribution of primary brain tumours.43 About 85% of
brain metastases are found in the cerebral hemi-
spheres, usually at the watershed areas between
the middle and posterior cerebral arteries. Very
rarely BMUPs may be located in the basal ganglia
or the thalamus.
About 10–15% of metastases are found in the
cerebellum and only about 3% are found in the
brainstem. Certain primary tumours such as those
from the kidney and colon are more likely to
metastasize to the cerebellum than are lung can-
cers or those arising elsewhere in the body. Besides
the arterial spread to the posterior fossa, the
Batson’s plexus in the spinal canal may also facili-
tate such dissemination.44
Rare sites of BMUP that have been reported
include: metastatic invasion of both optic nerves
by a non-detectable primary tumour (simulating
optic neuritis)45; pituitary lesion representing the
initial symptoms of an otherwise unknown malig-
nancy46; metastatic carcinoma of unknown origin
in the suprasellar region in a patient with known
Wegener’s granulomatosis47; metastatic adenocar-
cinoma masquerading as basal pontine tubercu-
loma, treated with antituberculous drugs,48 and
metastasis of an occult gastric carcinoma to an exist-
ing prolactinoma (neoplasm to neoplasm metasta-
sis); the progressive growth of a pituitary mass
accompanied by a decrease in hormonal overpro-
duction should be considered suggestive of this
possibility.49 Finally, disseminated melanomatosis
of the CNS and other organs was reported in a case
with extensive postmortem examination, that was
inconclusive as to whether the widespread CNS
involvement with melanoma was primary or
secondary.50
Diagnosis
Diagnostic categories should include the diagnosis
of the brain metastasis and that of the primary
lesion.
K.S. Polyzoidis et al.
Diagnosis of brain metastases
The diagnosis of brain metastasis in a patient with a
known systemic cancer is a simple matter. How-
ever, the diagnosis in a patient with BMUP is diffi-
cult. Multiple intracranial lesions are highly
suspicious. Voorhies et al.51 reported that solitary
intracranial lesions may prove to be metastatic in
15% of patients with no known systemic cancer.
The most sensitive imaging modality for brain
metastases is MRI; patients should therefore be
screened by the use of MR imaging. Its multiplanar
imaging capabilities, superior tissue contrast, elim-
ination of bony artifacts and versatile parameters
are extremely effective in the evaluation of such
patients.42 Triple dose gadolinium injection has
been suggested for the detection of multiple met-
astatic lesions.52 Subcortical low intensity on MRI
may be found in meningitis, viral encephalitis,
and leptomeningeal metastasis.53 Nowadays CT
scan should be used only when MRI is not available.
Some authors have reported a correlation between
CT and MRI features and histopathological mor-
phology of the tumour, but it has not gained gen-
eral acceptance.42
In carcinomatous meningitis the leptomeninges
are diffusely infiltrated by neoplastic cells. Although
nerve root irritation is common, the diagnosis is
still difficult because CSF cytology and radiological
investigations (such as MRI) are negative in many
cases. The brain may appear grossly edematous in
the absence of macroscopic cerebral secondary
tumours.15
Diagnosis of primary tumours
Physicians have always looked for ways to identify
the occult primary. Nevertheless, this practice
has been criticized for the low yield and the lack
of impact on patient prognosis.54,55 The early man-
agement of the brain lesion is of primary impor-
tance without wasting valuable time for a
thorough investigation. A two-to three-month win-
dow is usually acceptable for the detection of the
primary neoplasm, because the initial workup is
occasionally delayed by attention to the brain
tumour.2,41
Imaging techniques
Routine chest radiography has always been a part
of the initial evaluation of the patient with BMUP.
CT of the chest has not been adequately evaluated
and is reserved for patients with chest X-ray abnor-
malities. The usefulness of CT scanning of the
abdomen and pelvis is very well documented, and
Brain metastasis of unknown primary
results in the detection of a primary site in 30–35%
of CUP patients. CT can also provide guidance in
selecting the optimal site for biopsy.56,57 Mammog-
raphy and other breast imaging tests are of little
value in BMUP patients, because breast carcinoma
is unlikely to present as BMUP.28,58
The clinical relevance of positron emission
tomography (PET) for detecting the primary tu-
mour in addition to conventional procedures is lim-
ited.59 Sengupta et al.60 state that PET might be
a more accurate and cost-effective method for
detecting unknown primary tumours than a conven-
tional diagnostic approach. However, it needs to
replace all conventional diagnostics to be so. The
combination of PET/CT could also be a useful
tool.61
Serum tumour markers
The serum tumour markers CA 125, CA 19-9 and CA
15-3 show no correlation with the histology, site of
primary disease, or number of metastases. More-
over they do not offer any diagnostic, or predictive
value in patients with BMUP. CEA has been found to
have possible predictive value only for survival.28 It
is postulated that patients with CUP have a nonspe-
cific overexpression of serum tumour markers and
that routine use of these markers does not offer
diagnostic assistance.3 However late metastases
of lung cancers have a different immunophenotype
from precocious metastases: the immunopositivity
for CEA is 3/23 vs. 16/17, respectively; K-ras
immunopositivity is 30.4% vs. 47%,62 respectively.
The frequency of p53 mutations is relatively low,
suggesting that p53 mutations may not play a major
role in the development and progression of this un-
ique tumour type.63
Endoscopy
Fiberoptic endoscopy is advisable in patients with
thoracic indications or abdominal symptoms.64
How often can the primary site be
identified?
A primary tumour may remain unknown and asymp-
tomatic throughout the treatment of brain metas-
tasis. Further follow-up until the patient’s death
and even an autopsy sometimes fails to reveal
it.65 Unfortunately, as already mentioned, the al-
most identical microscopic appearances of adeno-
carcinomas from different locations offer little
assistance in detecting the site of origin.33
In a large number of operated BMUPs (13–48%)
the primary tumour remains undetected.21,22,25 In
autopsy series the primary tumour was not found
251
in 13.7% of cases. Out of 181 cases of operated
cerebral metastases 99 were BMUPs. From this last
group 35 patients (35.4%) had their primary neo-
plasm diagnosed during the initial evaluation and
treatment for the brain metastasis, that is, within
2 months after the neurosurgical operation. In 14
additional cases (14.1%) the primary site was de-
tected later than 2 months after surgery.62 Modern
imaging and pathology techniques seem to provide
a higher rate of detection of primary sites.27
Differential diagnosis
The differential diagnosis of brain metastasis
should include: primary intracranial tumour (gli-
oma, meningioma, and lymphoma), infection
(brain abscess and viral encephalitis), demyelinat-
ing disease (multiple sclerosis or chemotherapy
induced), cerebral infarction, and cerebral hemor-
rhage.35 Most of the above lesions can be solitary or
multiple (5% of gliomas are multifocal). Therefore,
tissue diagnosis is mandatory. Even in the presence
of systemic cancer, about 11% of the patients in
one study proved to harbor a single enhancing but
non-metastatic brain lesion.66
Treatment
In patients with known primary tumours the deci-
sion on the treatment method is relatively straight-
forward; it depends on site, histology, location,
and consequential operability of brain metastasis,
as well as the patient’s general condition (perfor-
mance status, age, and other concomitant dis-
ease), all of which may influence the survival.65
Management of BMUP patients usually requires
immediate treatment of the brain tumour followed
by periodic reevaluation for a primary tumour.8
Several reports have described the clinical out-
come in these patients, but the authors derived
conflicting conclusions from the results.1,21,41,65
Deficiencies in study design, differences in inclu-
sion criteria and the complex presentation of pa-
tients with BMUP render it difficult to draw
definitive statistics with regards to survival rates
and appropriate management.67
The treatment of brain metastases is classified
as supportive (corticosteroids, anticonvulsants,
antibiotics, anticoagulants, antidepressants) and
definitive (surgery, radiation therapy-whole brain
radiation, radiosurgery or both, and chemother-
apy-systemic or local).
252
Antiepileptics
The recommendation of the Subcommittee of the
American Academy of Neurology (AAN)68 is that
in patients with newly diagnosed brain tumours
prophylactic anticonvulsants should not be
used routinely. This remains to be addressed in
patients with a high risk of seizure: metastatic
melanoma, hemorrhagic lesions and multiple
metastases. For patients who undergo an opera-
tion the efficacy of prophylaxis has not been pro-
ven.69 AAN recommends tapering them in one
week postoperatively.
Surgery
Young patients with single metastasis, good KPS
and no progression of the systemic disease should
have surgery or radiosurgery to achieve local tu-
mour control, in combination with whole brain
radiation therapy (WBRT) for sterilization of the
other areas. Otherwise, as in multiple brain metas-
tases, radiation therapy is the main treatment. Sur-
gery also offers the benefit of tissue diagnosis.14,70
If only one lesion is present in an accessible site,
and it is larger than 3 cm (not amenable to radio-
surgery), surgery followed by radiation therapy is
the treatment of choice for patients in good clini-
cal condition.17,71 Unfortunately, nearly half of pa-
tients with single metastasis are not candidates for
surgery because of the inaccessibility of the tu-
mour, the presence of extensive systemic disease,
or other factors.66
Stereotactic radiosurgery
Radiosurgery is attractive because of its minimal
invasiveness, but has a size limit of 3 cm and
does not provide tissue diagnosis. The results
with surgery or stereotactic radiosurgery (SRS)
are the same.14 SRS provides a high rate of tu-
mour control, regardless of tumour location or
histology.8 The true tolerance of the brain stem
for SRS remains unclear,72 while the most fre-
quent complications are significant edema with
mass effect, necrosis, and hemorrhage.73 Frac-
tionated stereotactic radiotherapy (2–3 fractions)
is more comfortable, less costly than SRS, and
can be combined with novel radiosensitizers (gad-
olinium texaphyrin).35
Whole brain radiation treatment
Retrospective data indicate that following surgery
survival figures improve if WBRT is added.66 The
K.S. Polyzoidis et al.
Radiation Therapy Oncology Group (RTOG) study
has established recommended radiation treatment
schedules in patients treated with WBRT for unre-
sectable brain metastases. WBRT and stereotactic
radiosurgery should be the standard treatment for
patients with a single unresectable brain metasta-
sis and considered for patients with two or three
brain metastases.74 The risk of late neurotoxicity
(memory loss, dementia) is reported in up to 5.1%
of patients.75
Chemotherapy
Chemotherapy has a relatively small role in the set-
ting of BMUP. After the tissue diagnosis has been
established it may be considered in brain metasta-
sis from breast cancer or small cell carcinoma of
the lung, particularly in patients with minimal clin-
ical signs or with a recurrent brain metastasis,
although agents that have proven effective against
the primary sites of cancer have been ineffective
against cerebral metastases from the same cell
population.70,76
Survival rates
In a prospective study, the survival pattern of pa-
tients with a single brain metastasis, who re-
ceived WBRT preceded by surgical resection
whenever possible, was the same as compared
with patients with known primary cancer from
other studies27 In a retrospective study the med-
ian overall survival (OS) for patients with BMUP
was 4.8 months and showed no significant differ-
ence compared to the OS of 3.4 months for
patients with brain metastases and a known pri-
mary (p = 0.45). Patients with a KPS >70 had a
statistically significant better OS than patients
with a KPS <70. Within the RPA-class II, median
survival for patients with and without extracereb-
ral metastases showed no statistically significant
difference (9.5 and 6.5 months, respectively,
p = 0.75). The median OS for patients with a sol-
itary metastasis was 7.3 months vs. 3.9 months
for patients with multiple metastases (p = 0.05).
Patients who underwent resection of brain metas-
tases before WBRT had a significant better OS
than patients who underwent WBRT alone (9.5
vs. 3.6 months median survival, respectively,
p = 0.0022).2
The majority of these patients die from the
extracranial disease, and a minority (those with
solitary brain lesion and in good overall condition)
will live more than five years.41
Brain metastasis of unknown primary
Management algorithm
Based on the available data the following algorithm
(modified from 43) is proposed for the management
of patients with BMUP (Table 2).
Prognostic and predictive factors
Tumours that are small enough to elude high reso-
lution imaging, endoscopy, or serologic tests
should have a smaller extracranial tumour burden
despite the presence of a brain metastasis.25,59,77
Others believe that the prognosis is poor compared
with patients with a known primary, because proper
management of the extracranial tumour is
delayed.65
The classification and regression tree (CART)
analysis, which is a simple method for sorting out
complex clinical issues such as those presented by
BMUP patients, has been used for the evaluation
of various potential prognostic factors (Table
3).67 The rare location of the metastasis in the
brainstem is also significant.8 As already mentioned
the detection of the primary site does not alter the
prognosis.54,78
Table 2 Management algorithm of BMUPs
No known cancer
CT chest, abdomen, pelvis, biochemical markers
Cancer found No Cancer
Resect brain lesion Surgically accessible
(if accessible) or
biopsy primary Resect
Metastasis
Lesion resected Lesion not resected
WBRT >3 cm <3 cm
WBRT +/- RS+WBRT
Local boost
253
Table 3 Factors with statistically significant influ-
ence on the outcome of BMUP patients
Age (<65 years)
Number of brain metastases (single vs. multiple)
Karnofsky performance status (>70)
Method of therapy used (see Table 2)
Absence of extracranial disease
The identification of chromosomal abnormalities
associated with neoplasms is becoming increas-
ingly important in predicting prognosis. The use
of tumour-specific chromosomal abnormalities
in diagnosis is still limited, but it is likely that
future research will identify specific genetic
abnormalities.79
Summary and conclusion
BMUPs are more frequent than generally thought.
The most common pathology is adenocarcinoma,
and the primary site, when detected, is the lung
in the majority of cases. The oncologic manage-
ment of BMUP patients mandates the resection of
an accessible single brain metastasis: diagnosis is
established and the symptoms are alleviated. Inac-
cessible tumours need a stereotactic biopsy, and if
<3 cm, they are treated with SRS. WBRT is either an
adjunct in both these categories, or is the primary
treatment modality if the previous two conditions
are not met. The detection of the primary tumour
by an elaborate paraclinical survey, or the knowl-
edge of its histopathology do not influence the
prognosis. On the contrary prognosis depends
mainly on age, the KPS, the number of metastases,
the treatment modality, and the extent of the
extracranial disease.
Not surgically accessible
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