Beruflich Dokumente
Kultur Dokumente
www.elsevierhealth.com/journals/ctrv
TUMOUR REVIEW
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
0305-7372/$ - see front matter c 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ctrv.2005.03.006
248 K.S. Polyzoidis et al.
remote site.15 Several steps are required and each Light microscopic examination can basically
step is controlled by multiple genes. Genetic dif- characterize only cell morphology and tumour dif-
ferences between a primary tumour and its metas- ferentiation. Extensive pathological investigation
tases often exist.23,24 A certain size is critical in by immunohistochemistry, electron microscopy or
order for a metastasis to develop, which is esti- cytogenetic studies results in the identification of
mated experimentally to have a diameter between specific subgroups of CUP patients in almost
0.5 and 1 cm. CUP represents a unique entity in 20% of the cases in general oncology34 but far fewer
which a presumed primary tumour is able to metas- in BMUP. CSF examination is indicated only in
tasize before becoming large enough to be identi- those patients suspected of leptomeningeal
fied.3 In addition the length of time that the carcinomatosis.35
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 Clinical presentation
brain metastases, but differs from that of primary
brain tumours. Most of the primary brain tumours The brain secondary is responsible for the first
are diffusely infiltrating, whereas metastases are symptom in almost one-half of patients operated
usually well circumscribed. Hematogenous spread on for a cerebral metastasis. The clinical presenta-
is by far the most common mechanism, and the tion with brain symptoms may be due to the fact
deposition of the lesions tends to occur either that thoracic symptoms occur rather late in lung
where vessel calibre changes (at points of turbu- cancer, while brain lesions give symptoms at a
lent flow) or at arterial end points. In the brain much earlier stage.
these areas are the interface between the grey The mean age of BMUP patients ranges from 51
and white matter, and the watershed regions of to 55 years, and there is a definite male preponder-
borderline vascularization.15 ance. As with any brain mass lesion, symptoms are
Eventually about 50% of patients with BMUP focal or general due to the increased intracranial
will have their primary sites diagnosed.21,25 As pressure. Headache is the most common symptom,
with other series of brain metastases, the lung followed by focal neurological dysfunction, cogni-
is the most frequent primary site (51%).26 This tive and behavioral disturbances, seizures (in about
frequency varies from 33%27 to 78%28 in the liter- 15–25%) and evidence of elevated intracranial
ature. Although the breast is the second most pressure.26 Cranial nerve involvement is observed
common primary site in patients with known mainly in patients with carcinomatous basal menin-
malignancy (10–17%), it is underrepresented in gitis. The functional status of the patients can be
the group of patients with BMUP, because the classified according to the recursive partitioning
metastatic dissemination to the brain occurs later analysis (RPA) classes for patients with brain
in its natural course, after the diagnosis has al- metastases: Class I includes all patients with a
ready been established. Melanoma, with 8% of Karnofsky performance status (KPS) >70, age <65
metachronous secondaries, is equally reported in years, a controlled primary tumour and no extra-
the literature of BMUPs.29–31 Surprisingly, the cerebraI metastases, Class III includes all patients
pancreas is found in 8%, and the remainder of gas- with a KPS <70, and Class II all other patients.2
trointestinal cancers represent 19%. In comparison, Intracranial hemorrhage is not an uncommon
cerebral metastases from pancreatic neoplasms presentation of brain metastases (15%), particu-
are extremely rare in the general cancer popula- larly in those from melanomas and choriocarcino-
tion (0.1–0.3%),32 while gastrointestinal malig- mas.36 Hemorrhage can also occur in CUP
nancies appear in 3–10% of patients with brain metastasis to the spinal cord.37
metastases.18,29–31 Thus, patients presenting ‘‘Miliary’’ metastatic tumours to the brain from
with BMUP may not have the same primary sites an unknown primary have also been reported.38
that would be expected if the primary site had These patients present with minimal neurological
already been known.26 deficit, but their survival is poor. The only explana-
The majority of cases are adenocarcinomas with tion is that the host’s brain immune response to the
poorly differentiated tumours being the next most neoplasm is unusually altered.
frequent pathology.28 Unfortunately, adenocarci- Paraneoplastic cerebellar degeneration may
nomas metastatic from different locations have al- precede a potentially curable remote malignancy
most identical microscopic appearances, which by months or years. Periodic reevaluation is
does not facilitate the diagnosing of the site of needed when the cancer remains occult.39 Also,
origin.33 25% of cases of metastatic meningoradiculitis
250 K.S. Polyzoidis et al.
results in the detection of a primary site in 30–35% in 13.7% of cases. Out of 181 cases of operated
of CUP patients. CT can also provide guidance in cerebral metastases 99 were BMUPs. From this last
selecting the optimal site for biopsy.56,57 Mammog- group 35 patients (35.4%) had their primary neo-
raphy and other breast imaging tests are of little plasm diagnosed during the initial evaluation and
value in BMUP patients, because breast carcinoma treatment for the brain metastasis, that is, within
is unlikely to present as BMUP.28,58 2 months after the neurosurgical operation. In 14
The clinical relevance of positron emission additional cases (14.1%) the primary site was de-
tomography (PET) for detecting the primary tu- tected later than 2 months after surgery.62 Modern
mour in addition to conventional procedures is lim- imaging and pathology techniques seem to provide
ited.59 Sengupta et al.60 state that PET might be a higher rate of detection of primary sites.27
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 Differential diagnosis
combination of PET/CT could also be a useful
tool.61 The differential diagnosis of brain metastasis
should include: primary intracranial tumour (gli-
Serum tumour markers oma, meningioma, and lymphoma), infection
The serum tumour markers CA 125, CA 19-9 and CA (brain abscess and viral encephalitis), demyelinat-
15-3 show no correlation with the histology, site of ing disease (multiple sclerosis or chemotherapy
primary disease, or number of metastases. More- induced), cerebral infarction, and cerebral hemor-
over they do not offer any diagnostic, or predictive rhage.35 Most of the above lesions can be solitary or
value in patients with BMUP. CEA has been found to multiple (5% of gliomas are multifocal). Therefore,
have possible predictive value only for survival.28 It tissue diagnosis is mandatory. Even in the presence
is postulated that patients with CUP have a nonspe- of systemic cancer, about 11% of the patients in
cific overexpression of serum tumour markers and one study proved to harbor a single enhancing but
that routine use of these markers does not offer non-metastatic brain lesion.66
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 Treatment
immunopositivity is 30.4% vs. 47%,62 respectively.
The frequency of p53 mutations is relatively low, In patients with known primary tumours the deci-
suggesting that p53 mutations may not play a major sion on the treatment method is relatively straight-
role in the development and progression of this un- forward; it depends on site, histology, location,
ique tumour type.63 and consequential operability of brain metastasis,
as well as the patient’s general condition (perfor-
Endoscopy mance status, age, and other concomitant dis-
Fiberoptic endoscopy is advisable in patients with ease), all of which may influence the survival.65
thoracic indications or abdominal symptoms.64 Management of BMUP patients usually requires
immediate treatment of the brain tumour followed
by periodic reevaluation for a primary tumour.8
How often can the primary site be Several reports have described the clinical out-
identified? come in these patients, but the authors derived
conflicting conclusions from the results.1,21,41,65
A primary tumour may remain unknown and asymp- Deficiencies in study design, differences in inclu-
tomatic throughout the treatment of brain metas- sion criteria and the complex presentation of pa-
tasis. Further follow-up until the patient’s death tients with BMUP render it difficult to draw
and even an autopsy sometimes fails to reveal definitive statistics with regards to survival rates
it.65 Unfortunately, as already mentioned, the al- and appropriate management.67
most identical microscopic appearances of adeno- The treatment of brain metastases is classified
carcinomas from different locations offer little as supportive (corticosteroids, anticonvulsants,
assistance in detecting the site of origin.33 antibiotics, anticoagulants, antidepressants) and
In a large number of operated BMUPs (13–48%) definitive (surgery, radiation therapy-whole brain
the primary tumour remains undetected.21,22,25 In radiation, radiosurgery or both, and chemother-
autopsy series the primary tumour was not found apy-systemic or local).
252 K.S. Polyzoidis et al.
(if accessible) or
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