gastrointestinal stromal tumours ( gists ) are the most frequent mesenchymal tumours of the digestive tract , derived from the cajal interstitial cells .
they are characterised by the presence of a gain - of - function mutation of the kit or pdgfra oncogenes .
their incidence remains low , around 520 per million in different population - based studies , but their prevalence has been increasing during the last decade thanks to the therapeutic progress related to the use of tyrosine kinase inhibitors ( tkis ; imatinib , sunitinib , and regorafenib ) .
gists can occur anywhere along the gastrointestinal tract , but the most frequent anatomical locations are the stomach ( 60% ) , jejunum , and ileum ( 30% ) , followed by the duodenum ( 5% ) , colorectum ( < 5% ) , and more rarely the oesophagus ( 12% ) and the omentum .
about 40% of patients with gists will develop metastases , most commonly in the liver ( 65% ) or the peritoneum ( 50% ) , and less frequently in the lung .
bone metastases of gists are a very rare event . in the small series in the literature , their proportion is low ( < 5% ) when compared with all secondary locations [ 5 , 6 , 7 , 8 ] . biologically , little
is known about bone metastases of gists , as these metastatic sites are rarely biopsied .
particularly , it is still unknown whether bone metastases keep the same kit / pdgfra mutations as the primary tumour or acquire new mutations . here ,
we present a case of gastric gist with synchronous liver and bone metastases that were fully documented by pathological and molecular analysis .
a 66-year - old man , a retired oenologist with histories of asthma , non - insulin - dependent diabetes mellitus , and bilateral genu valgum consulted his general practitioner in november 2015 for asthenia lasting more than 6 months and left posterior intercostal pain . a thoraco - abdomino - pelvic ct scan ( fig .
1a ) revealed a 16-cm abdominal tumour lesion above the pancreas , associated with several suspect hepatic nodules , and multiple osteolytic lesions of the spine and pelvis .
clinically , the patient 's weight was stable , and his who performance status was equal to 0 .
the left posterior intercostal pain was imperfectly controlled by 3 g / day of paracetamol , and the patient had no digestive symptoms .
physical examination found a painless voluminous tumour of the left hypochondrium ; neurological examination was normal .
laboratory tests were normal , with the exception of a grade 1 increase in gt .
gastric endoscopic ultrasound revealed a voluminous intra - abdominal 17-cm tumour , in contact with the stomach , mainly necrotic , as well as multiple suspect hepatic lesions , all enhanced after injection
. pathological analysis of endoscopic ultrasound - guided fine - needle aspiration biopsies of the gastric tumour and 1 hepatic lesion revealed an epithelioid - cell gastric tumour and a spindle - cell liver tumour ( fig .
, tumour cells were characterised by few mitoses ( < 5/50 high - power fields ) , no necrosis , and an immunohistochemistry ( ihc ) staining strongly positive for cd117 and dog1 , weakly positive for aml , and negative for desmin and ps100 .
the gastric tumour was cd34-negative , whereas the hepatic lesion was cd34-positive ( table 1 ) .
no kit or pdgfra mutation was found in the hepatic metastasis , whereas the gastric tumour harboured a kit exon 11 mutation ( c.1676_1714del , p.val559_ile571del ) , further confirming the diagnosis of gastric gist with hepatic metastasis .
ct scan showed an increase in size of both the abdominal tumour ( 19 cm ) and the hepatic metastases as well as multiple osteolytic lesions involving notably the spine and the pelvis .
3 ) showed several bone uptakes located on the cervico - dorso - lumbar spine , sternum , scapula , pelvis ( sacrum and left sacroiliac joint ) , rib cage ( k5k7 ) , left femur , and right humerus .
1b , c ) confirmed the vertebral bone lesions , and notably identified a t1 and t9 epiduritis and a mild medullar compression in c7 , t1 , and t9 without intramedullary lesion . a ct scan - guided biopsy of a lesion of the right posterior iliac bone confirmed the diagnosis of bone metastasis by a spindle - cell gist showing the same morphological and ihc profile ( fig .
2c ) as the hepatic metastasis , and the same kit exon 11 mutation as the primary gastric tumour .
the diagnosis of voluminous gastric gist with synchronous liver and bone metastases was retained . in february 2016 ,
no local treatment was initiated for the vertebral bone lesions because of the absence of any neurological symptoms , the expected efficacy of imatinib , and the control of dorsal pain by small doses of oxycodone . in may 2016 , after 3 months of treatment , ct scan showed a regression of both the primary tumour ( 14 cm ) and the hepatic and bone metastases . in august 2016 , after 6 months of treatment , ct scan showed further regression of the primary tumour ( 12 cm ) and the hepatic metastases ( recist 1.1 partial response with 33% decrease in target lesions when compared to baseline ) and stabilisation of bone metastases . in november 2016 , after 9 months of imatinib , ct scan confirmed the partial response of the primary and hepatic lesions , which had become more necrotic , and stabilisation of the bone lesions .
currently , the patient continues imatinib , which is perfectly tolerated , without any digestive , bone , or neurological symptoms related to the tumour lesions .
the classical metastatic locations of gists are the liver and peritoneum , whereas bone metastases are rare .
we report here a case of gastric gist with synchronous hepatic and bone metastases at diagnosis , documented in all sites with respect to histology and molecular biology . in epidemiologic terms
, the true incidence of bone metastases remains unknown , but was reported to be between 3.2 and 5.5% in 4 retrospective series of 53309 patients with metastatic gists [ 5 , 6 , 7 , 8 ] . to our knowledge , 37 cases , including the present case , have been reported in the english - language literature during the last decade , including 31 since 2011 .
the incidence seems to be growing thanks to the longer survival of metastatic patients due to the increasing use of tkis , as observed in other cancers responding to medical therapies in their advanced stages .
bone metastases mainly occurred in men ( n = 31/37 ) and patients older than 50 years ( n = 29/37 ) . like in our case ,
the location of the primary gist was mainly the stomach ( n = 12/36 informative cases ) , followed by the ileo - jejunum ( n = 10 ) , the rectum ( n = 8) , the duodenum ( n = 4 ) , the mesentery ( n = 1 ) , and the oesophagus ( n = 1 ) . of note , rectal gists were overrepresented in that population of bone metastases , with 8/36 patients ( 22% ) , whereas their frequency in overall gists is around 5% . a likely explanation might be the haematogenous spread via the non - portal vein drainage from the rectum . regarding the pathological characteristics , most of the primary tumours were spindle ( 11/20 informative cases ) or mixed ( 7/20 ) , and only 2 cases , including the present one , were purely epithelioid ( 2/20 ) .
interestingly , contrary to our patient , most of the informative cases described a high number of mitoses of over 5/50 high - power fields ( n = 20/25 ) , suggestive of intermediate or high risk of relapse .
the mutational status of the primary tumour was documented for only 5/37 cases and showed an exon 11 kit mutation , which is the most frequent mutation found in gists before any treatment . regarding the bone metastases , they occurred in 23/31 informative cases during the follow - up of treated primary gists , within a median delay of 48 months ( range , 4120 months ) after the diagnosis of the primary tumour . in 8 patients , including ours , the diagnoses of primary tumour and bone metastasis were synchronous , whereas 1 case corresponded to a prevalent bone metastasis .
these rare observations suggest that bone metastasis can be the initial metastatic manifestation . like in our patient ,
the bone metastases mainly occurred concomitantly with or after other metastatic sites like the liver ( n = 27 ) , peritoneum ( n = 8) , lung ( n = 4 ) , or soft tissues ( n = 2 ) , likely through haematogenous spread via vein drainage from these metastatic sites .
their topography was mainly the spine ( n = 17 ) , especially thoracic and lumbar , followed by the pelvis ( n = 11 ) , the ribs ( n = 11 ) , the femur ( n = 7 ) , and less frequently the shoulder ( n = 3 ) or the humerus ( n = 2 ) .
interestingly , skull or face metastases were numerous ( n = 9 ) , including the temporal bone , clivus , or mandible , and led to complex diagnostic investigations and surgical procedures . the discovery of bone metastases was often based on clinical symptoms or was done incidentally during diagnostic or staging thoraco - abdomino - pelvic ct scan .
the bone metastases in gist patients are classically lytic and well - defined lesions . with an expanded access to magnetic resonance imaging
, it is likely that more bone metastases of gists will be diagnosed in the future .
furthermore , bone metastases have an intense fluorodeoxyglucose uptake ; in case of response to tkis , the standardised uptake value decreases very early after the beginning of treatment , which makes pet scanning an interesting option for follow - up .
the pathological type was spindle cells in all 10 informative cases , similar to our case ; all tested cases were kit - positive by ihc , and only 3 cases were sequenced , showing kit exon 11 mutation .
comparison between the primary tumour and the bone metastasis was possible for some pairs ; the concordance was perfect for kit ihc ( 12/12 pairs ) and mutational analysis ( 2/2 pairs ) , suggesting clonal origin , whereas only 1 case ( ours ) showed discordant pathological type , with epithelioid type in the primary and spindle cells in the metastasis .
the absence of mutation documented in the liver metastasis in our patient may reflect intratumour heterogeneity .
because of the scarcity of data , it remains unclear whether a particular mutational status is associated with these unusual metastases .
the systemic treatment was based on tkis , mainly imatinib ( n = 22 ) used in 1st line , sunitinib used in 2nd line ( n = 8) , and less frequently nilotinib ( n = 2 ) or sorafenib ( n = 1 ) , with several 
attitudes due to toxicity or long - term disease stabilisation , although not recommended today . regarding the local treatment of bone metastases
, the literature review showed that surgery ( n = 8) was realised for oligometastatic patients for different skeletal localisations , or patients with functional impairment , sometimes associated with graft or prosthesis .
some of these patients who underwent complex surgical bone resections with r0 margins benefitted from long - term disease - free survival [ 12 , 13 ] .
even if gists , like soft tissue sarcomas , are often considered radio - resistant , external beam radiotherapy was associated with a significant improvement of bone pain in most of the cases .
interestingly , 1 case report described the concomitant use of imatinib during radiotherapy , with good tolerance .
bisphosphonates were used in 5 patients ( zoledronic acid ) , and 1 case of jaw osteonecrosis was described after imatinib and zoledronic combination . the clinical outcome after the diagnosis of bone metastasis was available in 26/37 patients : 9 patients died after a median time of 11 months ( range , 1103 ) , whereas 17 remained alive with a median follow - up of 19 months ( range , 2187 ) .
thus , although bone metastases occurred preferentially in high - risk metastatic gists , their prognosis was not particularly dreadful . in conclusion ,
bone metastases of gist are rare but likely underdiagnosed , and their frequency is increasing because of the improvement of imaging techniques and of patients survival .
physicians in charge of gist patients should be aware of this unusual metastatic site during the prolonged natural history of gists in the tki era .
we recommend attention notably in case of gists > 5 cm , with a high mitotic index or with a rectal location . if bone metastasis remains a palliative disease , multiple therapeutics options ( like surgery , radiotherapy , tkis , and bisphosphonates ) are available to improve symptoms and prolong survival .
 gastrointestinal stromal tumours ( gists ) are mesenchymal tumours of the digestive tract , derived from cajal interstitial cells . 
 bone metastases are very rare , and there is no consensus regarding their treatment . here , we present the unusual case of a 66-year - old man with a gastric gist with synchronous bone and liver metastases , fully documented at the pathological and molecular levels with a kit exon 11 mutation . after 9 months of imatinib , 
 the scanner showed a 33% partial response of target lesions . 
 we also review the literature and describe the characteristics , treatment , and outcome of all cases previously reported . 
Introduction
Case Report
Discussion
Statement of Ethics
Disclosure Statement