gbm diffusely infiltrates the surrounding brain tissue , but does not typically invade blood vessels and rarely spreads outside the central nervous system ( cns ) .
metastasis to the outside of the cns was accounted for in only 0.2% cases4 ) .
the most common site of extraneural metastasis of the gbm is pleura and the lung10,12 ) .
although the exact mechanism of extraneural metastasis has been poorly understood , the lymphatic drainage , the venous system and the adjacent dura and bone have been suggested as the three possible routes of extraneural spread2 ) .
interestingly , we experienced a rare case of extraneural metastasis of the gbm , presenting as an unusual neck mass .
herein , we report this unusual case , with review of the literature , and we suggest the risk factors of extraneural metastasis .
a 46-year - old man was referred to our neurosurgical unit complaining of progressive right hemiparesis . at admission , he was alert and fully oriented .
neurological examination revealed right hemiparesis ( grade 3/5 ) . in the past medical history , he had undergone a craniotomy in the left fronto - parietal region for brain tumor 10 years ago in another hospital .
although we could not obtain pathological and medical records , he informed that his brain tumor had been diagnosed as low grade glioma , and he had received radiation therapy following craniotomy .
magnetic resonance images ( mri ) and computed tomography ( ct ) scan on admission demonstrated a poorly defined heterogenously enhancing mass with extensive peritumoral edema in the left frontal motor cortex ( fig .
since the mass was located near the previous craniotomy site , we suggested that this tumor might be related with previously diagnosed glioma . under the presumptive diagnosis of secondary tumor , malignant transformation of a low grade glioma or radiation induced glioblastoma
the mri scans taken 2 weeks later showed a remnant mass in the left frontal lobe ( fig .
3 ) . considering his previous history of radiation therapy , we performed gamma knife radiosurgery for the remnant mass , with a marginal dose of 20 gy to the 50% isodose line , followed by 6 cycles of adjuvant chemotherapy with the pcv regimen ( i.e. procarbazine , lomustine , and vincristine ) .
three years later , he presented with progressive weakness of the right extremities and dysarthria .
4a ) . surgical resection was done for the mass lesion and the histopathological findings revealed recurrence of the gbm .
he remained in a stable condition during the 6 cycles of adjuvant chemotherapy with temozolomide . since then , he underwent craniotomy two more times and shunt procedure for the recurrence of the tumor and hydrocephalus for 30 months .
five years after the initial diagnosis , a palpable mass lesion was observed on his left side of the neck .
the neck ct with contrast enhancement revealed a 34 cm sized round mass , with peripheral rim enhancement in the left side of the neck ( fig .
mass was biopsied and the histopathology indicated a metastatic deposit of the gbm . at that time , his condition , including consciousness and motor function , worsened , and the brain mri noted the progression of the gbm .
we performed the surgical resection of the brain tumor and of the neck mass , simultaneously .
the pathological specimens were shown with increased cellularity , with blood vessel proliferation and necrosis ( 30% ) .
all pathological specimens , from both the brain tumor and the neck mass , were confirmed as gbm ( fig .
glioblastoma multiforme is one of the most malignant neoplasms in human beings and the most common primary tumor in the cerebral hemisphere .
the incidence accounts for 2 to 3 cases/100000 per year in both europe and north america , and 75% of the patients die within 18 months from diagnosis13 ) .
gbm commonly spreads by direct extension and infiltration into the adjacent brain tissue and along the white matter tract .
although the tumor is associated with a strong tendency for local invasiveness , the metastatic spread of the gbm outside of the cns is extremely rare .
thus , the spread outside the cns occurs with a frequency of only 0.2%4 ) .
the reason why the gbm rarely metastasizes is still unclear , but some hypotheses have been proposed . the first hypothesis was suggested on the basis of the short life span of patients . the severe aggressiveness of the gbm results in a very short survival period of patients .
the second suggestion has been based on the barrier effect of the basement membrane . in in vitro experiments , the capillary basement membrane played an important role as a physical barrier against migration of the glioma cells into the blood stream in the brain1 ) . as another assumption , the cellular environment of the cns
also might be related to the prevention of metastasis of the gbm , because the cns lacks extracellular the matrix components , such as collagen and fibronectin , which are overexpressed only in the hyperplastic blood vessels . through hyaluronic acid and other glycosaminoglycans which are main components of the extracellular spaces
although the exact mechanism of extraneural metastasis has been poorly understood , cervio et al.2 ) suggested three possible mechanisms of extraneural spread , as follows : 1 ) the lymphatic cerebrospinal fluid drainage into the extraneural tissue ( despite absence of an identifiable lymphatic system in the cns ) ; 2 ) the venous invasion , either via the leptomeningeal sinuses or via the intracerebral vein ; 3 ) direct invasion through the dura and bone or through tumor cell migration along the ventriculoperitoneal shunts .
after the surgical procedure , the tumor cells may access the lymphatic or blood circulation through the damaged blood - brain barrier ( bbb ) .
craniotomy with tumor resection is associated with the opening of the brain vessels and can be associated with the spread of tumor cells , as previously demonstrated in the literature15 ) . in the present case ,
the patient underwent several operations , which might increase the chance of distant metastasis . in the literature , the most common sites of metastases were pleura / lungs , followed by lymph nodes , bones and liver8,11,12 ) . in the report on the extraneural metastases of astrocytoma and glioblastoma ,
the distribution of metastases was , as follows : 43 ( 59.7% ) lung and pleural , 37 ( 51.4% ) lymph node , 22 ( 30.5% ) bone , 16 ( 22.2% ) liver , 5 heart , 3 adrenal gland , 2 each in the kidneys , diaphragm and mediastinum , and 1 each in the pancreas , the thyroid gland , and the peritoneum11 ) . for establishing the presence of extraneural metastasis
, the following 4 criteria should be met16 ) : 1 ) the metastatic lesion must be histologically identified as cns tumor ; 2 ) the clinical history must indicate a cns tumor as the initial neoplasm ; 3 ) a complete autopsy must be performed to exclude the possibility of any other primary tumor ; 4 ) the morphologic features of the primary lesion and of the metastatic lesion must be identical . in this case , the patient fulfilled these criteria . at presentation with extraneural metastasis , this patient developed enlargement of the cervical lymph node . since the patient showed the lymphatic involvement of the gbm as extraneural metastasis , we considered that the main pathway of extraneural metastasis might be the lymphatic spread .
the possibility of hematogenous metastasis to the neck should be included , because the patient had undergone multiple craniotomies .
although it has been well known that surgery could be a risk factor for the extraneural metastasis of the gbm , surgery is not a prerequisite for the extraneural spread of the primary cns tumor .
spontaneous metastases also have been reported in patients who had not experienced previous surgery6 ) .
spontaneous spreading of the tumor was attributed to direct invasion in both the vascular and the lymphatic systems . in summary , this patient survived for 6 years after aggressive treatments including surgery for 5 times , radiotherapy and chemotherapy .
we suggest that the relatively longer lifespan of this patient might have affected the extraneural metastasis of the gbm .
the damage of the cerebral vessels and of the bbb by repeated surgical manipulations could also accelerate the tumor penetration outside of the cns .
although the exact mechanism of the extraneural metastasis is not well understood , the gbm can metastasize to extraneural organs .
multiple craniotomies and longer survival period of the patient could be considered as risk factors of the extraneural metastasis .
this present case provides proof for the possibility of extraneural metastasis of the gbm , especially in patients with longer survival .
the neuro - oncologists should pay attention to the systematic survey for extraneural metastasis of the gbm .
 glioblastoma multiforme ( gbm ) is the most aggressive intracranial tumor and it commonly spreads by direct extension and infiltration into the adjacent brain tissue and along the white matter tract . 
 the metastatic spread of gbm outside of the central nervous system ( cns ) is rare 
 . the possible mechanisms of extraneural metastasis of the gbm have been suggested . 
 they include the lymphatic spread , the venous invasion and the direct invasion through dura and bone . 
 we experienced a 46-year - old man who had extraneural metastasis of the gbm on his left neck . 
 the patient was treated with surgery for 5 times , radiotherapy and chemotherapy . 
 he had survived 6 years since first diagnosed . 
 although the exact mechanism of the extraneural metastasis is not well understood , this present case shows the possibility of extraneural metastasis of the gbm , especially in patients with long survival . 
INTRODUCTION
CASE REPORT
DISCUSSION
CONCLUSION