
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)11983-4
10.1016/j.heliyon.2024.e35952
e35952
Review Article
Intracranial metastasis of gastrointestinal stromal tumors: A literature review of published case reports and case presentation
Lee Zhiquan Damian a
Loh Daniel De-Liang a
Yang Valerie Shiwen b
Bin Harunal Rashid Mohamad Farid b
Chen Min Wei chen.min.wei@singhealth.com.sg
a⁎
a Department of Neurosurgery, National Neuroscience Institute, Singapore 11 Jalan Tan Tock Seng, Singapore, 308433
b Division of Medical Oncology, National Cancer Centre Singapore, Singapore 11 Hospital Crescent, Singapore, 169610
⁎ Corresponding author. chen.min.wei@singhealth.com.sg
14 8 2024
30 8 2024
14 8 2024
10 16 e3595230 3 2024
30 7 2024
6 8 2024
© 2024 The Authors. Published by Elsevier Ltd.
2024

https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Background

Intracranial metastasis of gastrointestinal stromal tumors (GISTs) is uncommon and the optimal management for these patients remains undefined. The introduction of selective tyrosine kinase inhibitors (TKI) has drastically improved survival in patients with GISTs. However, its efficacy in patients with intracranial metastasis of GISTs is uncertain due to poor penetration of the blood brain barrier. The role of surgery and radiotherapy in these patients has also not been established. No large-scale studies exist, and the literature is limited to case reports. We report a case treated at our institution, conducted a literature review of existing case reports, and discussed the optimal management of patients with intracranial metastasis of GISTs.

Methods

A literature review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All studies with intracranial metastasis of GISTs were included, with data extracted and analyzed in totality.

Results

26 cases were included in the review. The median time to diagnosis of intracranial metastasis in patients with previously known GISTs was 66 months. Solitary metastasis was seen in 16 cases (59.3 %). 18 patients (69.72 %) underwent surgical resection; 14 had additive therapy with 9 receiving TKI. The mean duration of follow up was 11 months. Clinical response was seen in 3 patients in the non-surgical group, all 3 were treated with TKI alone.

Conclusion

The effectiveness of TKI in intracranial GISTs metastasis is seen both as first-line therapy for asymptomatic lesions and as an additive treatment post-surgery. Surgery retains a key role in establishing histological and molecular diagnosis and for symptomatic relief of mass effect.

Highlights

• Intracranial metastasis from GIST is rare with limited evidence to guide management.

• TKIs remain widely used as first line or adjuvant therapy with reasonable results.

• Surgery plays a key role in relief of mass effect and histological/molecular diagnosis.

• Multimodal therapy in appropriately selected patients appears safe and effective.

Keywords

Gastrointestinal stromal tumors
Intracranial metastasis
Intracerebral metastasis
Central nervous system metastasis
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pmc1 Statements and declarations

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. The authors have no relevant financial or non-financial interests to disclose.

2 Introduction

GISTs originate from the interstitial cells of Cajal. These tumors express CD117 antigen (C-Kit), a gain of function mutation responsible for the activation of growth in these tumors. Although GISTs account for 1–2% of all gastrointestinal tumors, they are the most common non-epithelial neoplasms in the gastrointestinal tract. GISTs most commonly arise in the stomach (56 %), followed by the small bowel (32 %), and the colon and rectum (6 %).10–42 % have been found to have malignant potential [1,2]. Common sites of metastasis include the liver and peritoneum.

Intracranial metastasis from GISTs is a rare phenomenon with less than 4 % of intracranial metastasis arising from gastrointestinal cancers [3]. There is limited evidence to guide treatment decisions for these patients. No large-scale studies exist, and the literature is limited to case reports. Conventional chemotherapy and radiation have poor rates of control. And while the introduction of selective TKI such as Imatinib has led to improved survival in patients with GISTs [4], there is conflicting evidence as to the effectiveness of TKIs for metastatic intracranial GISTs due to poor penetration across the blood brain barrier [5,6]. No evidence-based guidelines exist, and there is also no consensus as to the optimal management of such patients.

This article is a review of the published case reports on intracranial metastasis of GISTs while also reporting a case of our experience with a patient with a similar condition to illustrate the various treatment strategies and discuss the optimal management.

3 Methods

Literature Review The literature review was conducted according to the PRISMA guidelines. A search was conducted using PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE) and Scopus through 14 August 2022. The keywords used were “Gastrointestinal Stromal Tumors”, “Intracranial Metastasis”, “Intracerebral Metastasis” and “Central Nervous System Metastasis”. Inclusion criteria were all studies with patients diagnosed with GISTs with intracranial metastasis. Articles were excluded if the intracranial metastasis was attributed to other causes in the study, if they were not in the English language or if the full text was unavailable.

The articles were selected in two stages. Firstly, the abstracts of all citations identified by the above searches were downloaded, and the list was narrowed using the inclusion or exclusion criteria. Secondly, the full texts of this short list were retrieved and similarly evaluated for eligibility. The reference lists of the identified publications were hand-searched for additional relevant studies. Fig. 1 illustrates the selection process.Fig. 1 Flow diagram of the review and selection of cases.

Fig. 1

Each patient's data was then retrieved individually from the case reports. Demographic variables noted were age and gender. Clinical information such as duration from time of GISTs diagnosis to intracranial metastasis, use of TKI and prior gastrointestinal surgical resection, immunohistochemical properties of tumor and presenting symptoms were recorded. Number of intracranial metastasis, treatment for intracranial metastasis and use of further systemic treatment such as TKI, chemotherapy or radiotherapy were also noted. Lastly, duration of survival was also reviewed. Two authors extracted the data independently, and any doubts were resolved with discussion.

4 Case presentation

A 49-year-old Chinese gentleman presented to our hospital with acute onset of left sided weakness and unsteady gait for a month's duration. Physical examination revealed left upper limb hemiparesis of power grade 3 with associated fine motor deficits and dysmetria. The patient was diagnosed 6 years ago with localized high risk gastric GIST with KIT exon 11 deletion. He had undergone microscopically margin negative (R0) gastric wedge resection and completed 3 years of additive Imatinib (400 mg per day).

Magnetic resonance imaging (MRI) of the brain was performed which revealed a 6.2× 3.1 × 3.3 cm heterogeneously enhancing intraparenchymal lesion in the right superior parietal lobe with associated internal haemorrhage and vasogenic oedema. There were 2 other sub-centimeter lesions in the left cingulate gyrus and left hemipons (Fig. 2).Fig. 2 MRI Brain with contrast with evidence of intracerebral lesions in the right superior parietal lobe, left posterior cingulate gyrus and left hemipons.

Fig. 2

The patient underwent right craniotomy and excision of the right parietal tumor and recovered uneventfully. MRI performed the day after surgery revealed gross total resection of the tumor. Histological examination showed infiltration of glial tissue by malignant spindled to epithelioid cells, with moderate nuclear pleomorphism, occasional intranuclear pseudoinclusions and rhabdoid morphology. Focal necrosis was seen and with an increased mitotic activity of up to 9 mitoses per 10 high powered fields, or 14 mitoses per 5 mm2. Immunohistochemical studies showed that the malignant cells were strongly positive for CD34, CD117, and DOG1 with weak focal positivity for EMA and GFAP, which confirms the diagnosis of metastatic GIST. This was also corroborated with similar pathological features in the previous gastric wedge resection six years ago. The Ki67 proliferative index was approximated to be 10–20 %. These cells were also negative for SSTR2.

Mutational analysis and molecular profiling of the resected metastatic tumour revealed a 24-nucleotide deletion at KIT exon 11, from position c. 1668 to position c. 1691, resulting in a small deletion-insertion involving the amino acids at codons 556–564. This finding was the same mutation pattern seen in the patient's previously resected primary gastric GIST, confirming the diagnosis of intracranial GIST metastasis.

He commenced on imatinib 400 mg OM as additive therapy and a multidisciplinary board decision was made to hold off radiotherapy unless interval MRI brain showed progression of residual lesions despite imatinib. MRI brain after 6 weeks of imatinib showed significant reduction in size of residual brain lesions and MRI brain at 10 months from commencement of imatinib showed complete resolution of residual brain lesions (Fig. 3). At the time of writing, the patient is 16 months post -surgical resection and continues to be on Imatinib with no evidence of systemic or intracranial recurrence.Fig. 3 MRI brain with contrast at 10 months post-surgery with complete resolution of residual lesions.

Fig. 3

5 Results

A total of 25 publications were identified and included in this review. The data is summarized in Table 1. Data from our case report was also included in the analysis of results.Table 1 Reports of intracranial metastasis of GISTs.

Table 1Author, year	Age	Sex	Presentation	Location of intracranial disease	Location of primary GIST	Presence of extra-cranial metastasis	Interval from GIST diagnosis	Surgical resection	Extent of resection	Mutational analysis	Additive therapy	Outcome	Length of follow-up	
Akiyama et al., 2004 [23]	67	M	Visual loss	Left cavernous sinus	Small intestine	Yes	84 months	No	NA	NR	RT	Tumour progression; Died	7 months	
Badri et al., 2017 [24]	66	M	Headache, vomiting	Right cerebellum	Small intestine	No	NA	Yes	Total	NR	WBRT + chemotherapy	No recurrence	12 months	
Baeg et al., 2010 [25]	70	M	Diplopia	Pituitary, right cavernous sinus	Stomach	Yes	NA	Yes (Pituitary lesion)	Subtotal	NR	Imatinib	Regression of cavernous lesion, no recurrence of pituitary lesion	2 months	
Barrière et al., 2009 [26]	57	M	Diplopia, strabismus, headache	Clivus	Rectal	Yes	NA	No	NA	NR	Imatinib, followed by sunitinib, RT	Lesion unchanged at 3 months; Died	18 months	
Brooks et al., 2002 [27]	76	M	Altered mental status	Multiple parenchymal (not specified)	Mesentery	Yes	14 months	No	NA	NR	Imatinib	CNS resolution, no recurrence	4 months	
Carvalho et al., 2020 [28]	76	F	Behavioural change, dysarthria, dysmetria, gait imbalance	Left frontal, right cerebellar	Oesophageal	Yes	156 months	No	NA	NR	WBRT, imatinib	Died	6 months	
Drazin et al., 2012 [29]	60	M	Headache, diplopia	Left cerebellum, left frontal lobe	Stomach	No	18 months	Yes(cerebellar lesion)	Total	NR	SRT	No recurrence	15 months	
Gerin et al., 2007 [30]	45	M	Hiccups, nausea, tongue deviation	Right medulla, multiple parenchymal and leptomeningeal	Small intestine	No	60 months	No	NA	NR	–	Died	NR	
Gil-Arnaiz et al., 2009 [31]	66	M	Palpable skull lump	Right frontoparietal bone (dural invasion)	Rectal	Yes	NA	No	NA	NR	Imatinib	Recurrence at 13 months	13 months	
Gupta et al., 2016 [32]	64	F	Palpable skull lump	Right frontal bone
Right frontal bone (dural invasion)	Rectal	Yes	108 months
129 months	Yes	Total	Exon 11 and 17 mutations	SRT + sunitinib	Recurrence at 21 months
No recurrence	24 months	
Hamada et al., 2010 [33]	54	F	Memory disturbance, language difficulties	Left frontal lobe	Oesophageal	Yes	72 months	Yes	Total	Exon 11 mutation	SRT	No recurrence	6 months	
Hughes et al., 2004 [34]	50	M	Right foot drop	Left frontoparietal parasagittal (dural based)	Small intestine	Yes	30 months	Yes	Total	Exon 9 mutation	Imatinib	Recurrence at 4 months and 11 months; Died	18 months	
Jagannathan et al., 2012 [35]	27	M	Headache, neck stiffness, incoordination	Right frontoparietal (dural based)	Stomach	Yes	144 months	Yes	Total	No mutations detected	Nilotinib	No recurrence	6 months	
Janku et al., 2011 [36]	56	F	Drowsiness, nausea	Multiple parenchymal (not specified)	Large intestine	Yes	3 weeks	No	NA	NR	–	Died	NR	
Kaku et al., 2006 [37]	68	F	Left focal seizures, left hemiparesis, hemidysaesthesia	Right frontoparietal (dural based)	Perisacral	Yes	24 months	Yes	Total	NR	–	Recurrence at 7 months with re-resection	NR	
Leske et al., 2017 [38]	40	F	Headache	Right frontal + parietal (dural based)	Small intestine	Yes	NA	Yes	Total	NR	–	Recurrence at 12 and 24 months	24 months	
Li et al., 2011 [39]	32	M	Left facial numbness, diplopia	Left sphenoid wing + anterior clinoid process, left orbital roof	Small intestine	Yes	72 months	Yes	Subtotal	NR	Nilotinib + SRT	NR	NR	
Naoe et al., 2011 [40]	77	F	Left hemiplegia, right ptosis	Right cerebral peduncle, left occipital lobe	Small intestine	No	NA	Yes (Occipital lesion)	Total	No mutations detected	WBRT + imatinib (discontinued after 1 month)	Died; no recurrence of occipital lesion at death, slight enlargement of peduncle tumour	4 months	
O'Halloran et al., 2016 [41]	61	M	Headache, diplopia, ptosis	Pituitary	Stomach	No	NA	Yes	Total	Exon 11 mutation	SRT + imatinib	No recurrence	2 months	
Park et al., 2017 [42]	50	F	Palpable skull lump	Right parietal bone (dural invasion)	Stomach	Yes	120 months	Yes	Total	NR	Imatinib/sunitinib	Died; no recurrence at death	14 months	
Prablek et al., 2019 [43]	57	F	Left facial palsy & numbness, left hearing loss	Left temporal (dural based)	Stomach	Yes	3 months	Yes	Total	NR	imatinib	NR	NR	
Puri et al., 2006 [44]	42	M	Headache, vomiting, left hemiplegia	Right parietal	Mesentery	No	NA	Yes	Total	NR	RT + imatinib	Died; no follow-up of CNS lesion	21 months	
Sato et al., 2014 [45]	80	M	Nausea, incoordination, gait disturbance	Cerebellar vermis
Right frontal lobe (recurrence)	Small intestine	Yes	NA	Yes
No	Total
NA	NR
NR	RT
Nil	Recurrence at 7 weeks
Died	4 months	
Takeuchi et al., 2014 [46]	74	M	Left hemiparesis	Right precentral gyrus
Right lateral ventricle (recurrence)	Small intestine	Yes	24 months
28 months	No
No	NA
NA	NR
NR	Sunitinib
SRS	No recurrence, development of new lesion at 4 months
No recurrence	9 months	
Wong & Chu, 2011 [47]	26	M	Left facial numbness, left proptosis	Left frontotemporal bone	Small intestine	Yes	72 months	Yes	Total	NR	WBRT	No recurrence	4 months	
Current	49	M	Left hemiplegia, gait imbalance	Right parietal lobe, left cingulate gyrus, left hemipons	Stomach	No	72 months	Yes	Total	Exon 11 mutation	Imatinib	No recurrence	16 months	
Abbreviations: NA, Not Applicable; NR, Not Reported; RT, Radiotherapy; SRT, Stereotactic Radiotherapy; WBRT, Whole Brain Radiotherapy; SRS, Stereotactic Radiosurgery.

Of the 26 patients, 17 (65.4 %) were male. The median age at diagnosis was 58.5 years. The small intestine (38.5 %) and stomach (26.9 %) were the most common sites of origin. Extra-cranial metastasis was seen in the majority of patients (73.1 %). Eight patients (30.8 %) had intracranial metastasis as the first presentation; extra-cranial spread was seen in only half of them. The median time to diagnosis of intracranial metastasis in patients with previously known GIST tumors was 66 months. Solitary metastasis was seen in 16 cases (59.3 %). Although no location predilection was observed, bony or meningeal involvement was seen in half of cases.

Eighteen patients (69.7 %) underwent surgical resection; 2 (11.1 %) had subtotal resection of which 1 received imatinib as additive treatment and the other was given nilotinib with RT. Of the 16 patients with complete resection, 5 received TKIs alone, 4 had RT alone, 4 received TKIs and RT, 1 had RT and unspecified chemotherapy, and 2 had no additive treatment.

Recurrence was seen in 5 cases (27.8 %): 1 had RT alone; 1 had TKIs alone; 1 had TKIs and RT; 2 had no additive treatment. Progression-free survival ranged from 4 to 21 months. Duration of follow-up ranged from 2 to 24 months. Eleven patients had no intracranial recurrence (61.1 %); 1 patient developed a new lesion at a separate site: 4 received RT alone; 5 received TKIs alone; 2 received TKIs and RT; and 1 received RT and chemotherapy. The duration of follow-up ranged from 2 to 16 months. Death was reported in 5 patients who had surgical resection. All 5 received additive therapy: 1 with RT alone; 2 with TKIs alone; and 2 with TKIs and RT. Death was attributable to intracranial metastasis in two patients, while two patients had no intracranial recurrence at point of death. Progression-free survival was reported in 4 cases and ranged from 2 to 14 months. Overall survival ranged from 4 to 21 months. Outcomes were not reported in two cases.

Of the 8 patients managed non-surgically, 1 patient received RT alone, 3 received TKIs alone, 2 had TKIs with RT and 2 were managed conservatively. One patient was initially treated with sunitinib with resolution of the first lesion but subsequently developed a new lesion which was treated with stereotactic radiosurgery (Gamma knife surgery).

Clinical response was seen in 3 patients in the non-surgical group; all 3 were treated with TKIs alone. One patient was disease free at 4 months; 1 had recurrence at 13 months; the last developed a new lesion at 4 months that was treated with RT. The remaining 5 patients died within 18 months of initial diagnosis of intracranial metastasis.

6 Discussion

6.1 The role of TKI in intracranial GIST metastasis

The introduction of TKI as standard of care treatment for GIST has made a significant impact in progression free survival. In the advanced extracranial disease setting, TKI treatment has dramatically improved median survival from 18 months to more than 5 years in the past 20 years. Different GIST subtypes have varying sensitivities to TKIs which makes molecular characterization with mutational analysis of GIST even more crucial as part of the diagnostic workup. Although previous case reports have questioned the effectiveness of TKI in intracranial metastasis of GIST due to its limited ability to penetrate the blood brain barrier (BBB), our review indicates that TKIs are still widely used in such patients with reasonably good outcomes. Next generation TKIs such as Avapritinib have demonstrated better CNS penetration in pre-clinical models [7] and may potentially become the preferred choice of TKI for GIST with intracranial metastasis. If results from further clinical trials are similarly encouraging, these agents may eventually be preferred over surgery as first-line therapy, especially in asymptomatic patients or as initial therapy in symptomatic cases to reduce the surgical burden.

The exuberant use of TKI, however, must be tempered by their inherent limitations. Side-effect related non-adherence rates of 20–30 % have been observed both in trials [8] and in clinical practice [9,10]. Clinical response to TKI is delayed, the median time to an objective response to Imatinib was 3 months. Most patients also develop resistance and experience disease progression after 2–3 years of first line Imatinib therapy [11]. TKI has also been associated with several severe adverse events including interstitial lung disease with Imatinib [12], arterial thrombotic events with Nilotinib, hypertension and glomerulopathy with Sunitinib [13], and cognitive effects and intracranial haemorrhage with Avapritinib [14,15].

6.2 The role of radiotherapy in intracranial GIST metastasis

Reported modalities of radiotherapy (RT) used to treat intracranial disease include stereotactic radiotherapy (SRT), stereotactic radiosurgery (SRS) and whole brain radiotherapy (WBRT). Historically, GISTs have been thought of as radio-resistant tumors [16,17], and the use of RT was sporadic and poorly described. However, with new and mounting evidence of GIST as moderately radiosensitive, RT has found its niche in symptom palliation. It is now recommended by the latest National Comprehensive Cancer Network guidelines for the palliative treatment of bone metastasis [18]. Its utility in the treatment of intracranial disease remains uncertain, treatment with RT did not appear to confer a survival benefit in our review.

6.3 The role of surgery in intracranial GIST metastasis

Despite the increasing use of TKI in the management of GISTs, surgery for intracranial metastasis remains valuable. Firstly, surgery is pertinent for symptomatic lesions where removal of tumor results in immediate relief of mass effect with earlier neurological recovery, better functional outcomes, and improved quality of life. Surgery is also necessary for histological diagnosis and identifying the molecular profile to permit matching of the appropriate TKI. With improved survival rates, the incidence of intracranial metastasis despite TKI use is expected to increase. In patients with refractory disease, surgery remains an option for palliative management even in eloquent areas of the brain using advanced techniques such as awake brain surgery. In cases of multiple brain metastasis, the symptomatic lesion(s) can be surgically excised while the remaining asymptomatic lesions are treated with TKI or additive RT.

Surgery may also provide a secondary benefit via the unintended side effect of disrupting the BBB. This phenomenon could conceivably increase the CNS bioavailability of Imatinib to therapeutic levels thereby potentiating the effect of additive TKI. We suspect that such a mechanism could have contributed to the dramatic response observed in our case where there was complete resolution of the smaller lesions on follow-up imaging.

Based on the available literature, the median survival for patients with intracranial metastatic GISTs who received multimodal treatment is at least 12 months. Due to the limited duration of follow up in some of the reports, we expect that the actual survival in these patients is more than reported. It is therefore reasonable to consider patients with intracranial metastatic GISTs under the same umbrella as those with extra-cranial metastasis. In appropriately selected patients, multimodal treatment that incorporates maximal safe surgical resection with additive systemic therapy appears to be a safe and effective strategy [19].

6.4 Risk stratifying the malignant potential of GISTs

There are multiple classifications aimed at risk stratifying the aggressiveness of GIST tumors such as the modified National Institutes of Health Consensus criteria and Armed Forces Institute of Pathology criteria. Our review did not identify any significant risk factor which predisposes a patient with GIST to the development of intracranial metastasis. However, this analysis is hampered by the limited number of cases in which mutational analysis was reported; only 6 of the 25 cases provided a description. Nevertheless, among the 6 done, 3 (50 %) of these cases had a mutation present on KIT exon 11. A population study found exon 11 mutations to be the most common in metastatic GISTs [20]. GISTs with KIT exon 11 deletions or insertions on codons 557 and 558 were found to represent a subgroup with malignant clinical behavior [21] and are also reported to have a higher risk of relapse [22]. The results of our review, though limited, support such findings. Mutational analysis for GIST is important not only for decision on the choice of TKI but also in the surveillance for systemic metastasis. As more evidence comes to light, better risk stratification systems can be developed to identify the subset of patients for which more frequent surveillance for metastasis is warranted.

7 Conclusion

The management of intracranial metastatic GISTs remains poorly established. Despite reservations over their ability to penetrate the BBB, TKIs viable both as first-line treatment for asymptomatic lesions and as an additive therapy post-surgery. Nevertheless, surgery retains a crucial role in establishing histological diagnosis and for relief of mass effect. A multimodal treatment strategy is the most commonly employed and affords the best outcomes. Mutational analysis is crucial and more research into the genetic characteristics of GIST tumors will improve risk stratification of malignant potential thereby allowing detection of early systemic metastasis.

Data availability

The data associated with this study has not been deposited into a publicly available repository due to confidentiality.

CRediT authorship contribution statement

Zhiquan Damian Lee: Writing – review & editing, Writing – original draft, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Daniel De-Liang Loh: Writing – original draft, Methodology, Investigation, Formal analysis, Data curation. Valerie Shiwen Yang: Supervision. Mohamad Farid Bin Harunal Rashid: Supervision. Min Wei Chen: Writing – review & editing, Supervision, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A Supplementary data

The following are the Supplementary data to this article.Multimedia component 1

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Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.heliyon.2024.e35952.
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References

1 Parab T.M. DeRogatis M.J. Boaz A.M. Gastrointestinal stromal tumors: a comprehensive review J. Gastrointest. Oncol. 10 1 2019 Feb 144 154 10.21037/jgo.2018.08.20 30788170
2 Nilsson B. Bümming P. Meis-Kindblom J.M. Odén A. Dortok A. Gustavsson B. Sablinska K. Kindblom L.-G. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era† Cancer 103 2005 821 829 10.1002/cncr.20862 15648083
3 Bartelt S. Momm F. Weissenberger C. Lutterbach J. Patients with brain metastases from gastrointestinal tract cancer treated with whole brain radiation therapy: prognostic factors and survival World J. Gastroenterol. 10 2004 3345 3348 10.3748/wjg.v10.i22.3345 15484315
4 Blay J.Y. Kang Y.K. Nishida T. Gastrointestinal stromal tumours Nat Rev Dis Primers 7 2021 22 10.1038/s41572-021-00254-5 33737510
5 Senior K. Gleevec does not cross blood-brain barrier Lancet Oncol. 4 4 2003 Apr 198 10.1016/s1470-2045(03)01050-7 12681250
6 Takayama N. Sato N. O'Brien S.G. Ikeda Y. Okamoto S. Imatinib mesylate has limited activity against the central nervous system involvement of Philadelphia chromosome-positive acute lymphoblastic leukaemia due to poor penetration into cerebrospinal fluid Br. J. Haematol. 119 1 2002 Oct 106 108 10.1046/j.1365-2141.2002.03881.x 12358909
7 Chi S. Hsieh A. Foley M. EPCT-05. A phase 1/2 study of avapritinib for KIT- or pdgfra-mutant pediatric relapsed/refractory solid tumors Neuro Oncol. 23 Suppl 1 2021 Jun 1 i47 10.1093/neuonc/noab090.191
8 Amitai I. Leader A. Raanani P. Adherence to tyrosine kinase inhibitors in chronic myeloid leukemia: the challenge that lies ahead Acta Haematol. 136 1 2016 43 44 10.1159/000445674 27160309
9 De Almeida M.H. Pagnano K.B. Vigorito A.C. Lorand-Metze I. de Souza C.A. Adherence to tyrosine kinase inhibitor therapy for chronic myeloid leukemia: a Brazilian single-center cohort Acta Haematol. 130 1 2013 16 22 10.1159/000345722 23363706
10 Tsai Y.F. Huang W.C. Cho S.F. Side effects and medication adherence of tyrosine kinase inhibitors for patients with chronic myeloid leukemia in Taiwan Medicine (Baltim.) 97 26 2018 Jun e11322 10.1097/MD.0000000000011322
11 Kelly C.M. Gutierrez Sainz L. Chi P. The management of metastatic GIST: current standard and investigational therapeutics J. Hematol. Oncol. 14 1 2021 Jan 5 2 10.1186/s13045-020-01026-6 33402214
12 Weatherald J. Bondeelle L. Chaumais M.C. Pulmonary complications of Bcr-Abl tyrosine kinase inhibitors Eur. Respir. J. 56 4 2020 Oct 29 2000279 10.1183/13993003.00279-2020
13 Wu M.D. Moslehi J.J. Lindner J.R. Arterial thrombotic complications of tyrosine kinase inhibitors Arterioscler. Thromb. Vasc. Biol. 41 1 2021 Jan 3 10 10.1161/ATVBAHA.120.314694 33275447
14 Trullas-Jimeno A. Delgado J. Garcia-Ochoa B. The EMA assessment of avapritinib in the treatment of gastrointestinal stromal tumours harbouring the PDGFRA D842V mutation ESMO Open 6 3 2021 Jun 100159 10.1016/j.esmoop.2021.100159
15 Joseph C.P. Abaricia S.N. Angelis M.A. Optimal avapritinib treatment strategies for patients with metastatic or unresectable gastrointestinal stromal tumors Oncol. 26 4 2021 Apr e622 e631 10.1002/onco.13632
16 Zhang H. Jiang T. Mu M. Radiotherapy in the management of gastrointestinal stromal tumors: a systematic review Cancers 14 13 2022 Jun 28 3169 10.3390/cancers14133169 35804945
17 Ahmed K.A. Caudell J.J. El-Haddad G. Radiosensitivity differences between liver metastases based on primary histology suggest implications for clinical outcomes after stereotactic body radiation therapy Int. J. Radiat. Oncol. Biol. Phys. 95 2016 1399 1404 10.1016/j.ijrobp.2016.03.050 27319288
18 Gatto L. Nannini M. Saponara M. Radiotherapy in the management of gist: state of the art and new potential scenarios Clin. Sarcoma Res. 7 2017 Jan 10 1 10.1186/s13569-016-0065-z 28078078
19 Lim L.H.S. Baiwen L. Pei YiSC. Tang P.Y. Chen M.W. Rare intracranial relapse of a resected gastrointestinal stromal tumour: a case report Clin Oncol Case Rep 4 2021 8
20 Braconi C. Bracci R. Bearzi I. KIT and PDGFRalpha mutations in 104 patients with gastrointestinal stromal tumors (GISTs): a population-based study Ann. Oncol. 19 4 2008 Apr 706 710 10.1093/annonc/mdm503 18187489
21 Kontogianni-Katsarou K. Dimitriadis E. Lariou C. Kairi-Vassilatou E. Pandis N. Kondi-Paphiti A. KIT exon 11 codon 557/558 deletion/insertion mutations define a subset of gastrointestinal stromal tumors with malignant potential World J. Gastroenterol. 14 12 2008 Mar 28 1891 1897 10.3748/wjg.14.1891 18350628
22 Martin-Broto J. Gutierrez A. Garcia-Del-Muro X. Prognostic time dependence of deletions affecting codons 557 and/or 558 of KIT gene for relapse-free survival (RFS) in localized GIST: a Spanish Group for Sarcoma Research (GEIS) Study Ann. Oncol. 21 7 2010 Jul 1552 1557 10.1093/annonc/mdq047 Epub 2010 Mar 1 20231303
23 Akiyama K. Numaga J. Kagaya F. Case of optic nerve involvement in metastasis of a gastrointestinal stromal tumor Jpn. J. Ophthalmol. 48 2 2004 Mar-Apr 166 168 10.1007/s10384-003-0028-9 15060797
24 Badri M. Chabaane M. Gader G. Bahri K. Zammel I. Cerebellar metastasis of gastrointestinal stromal tumor: a case report and review of the literature Int J Surg Case Rep 42 2018 165 168 10.1016/j.ijscr.2017.12.009 29248834
25 Baeg M.K. Bae S.H. Lee K.H. Kim J. Park I.S. Jin J.Y. Diplopia as a presenting symptom in a gastric gastrointestinal stromal tumor Jpn. J. Clin. Oncol. 41 2 2011 Feb 265 268 10.1093/jjco/hyq176 20930018
26 Barrière J. Thariat J. Vandenbos F. Bondiau P.Y. Peyrottes I. Peyrade F. Diplopia as the first symptom of an aggressive metastatic rectal stromal tumor Onkologie 32 6 2009 Jun 345 347 10.1159/000215712 19521122
27 Brooks B.J. Bani J.C. Fletcher C.D. Demeteri G.D. Challenges in oncology. Case 4. Response of metastatic gastrointestinal stromal tumor including CNS involvement to imatinib mesylate (STI-571) J. Clin. Oncol. 20 3 2002 Feb 1 870 872 10.1200/JCO.2002.20.3.870 11821475
28 Carvalho J. Teixeira M. Silva F.T. Esteves A. Ribeiro C. Guerra D. Esophageal gastrointestinal stromal tumor with rare intracranial metastasis Case Rep Gastrointest Med 11 2020 Oct 8842006 10.1155/2020/8842006 2020
29 Drazin D. Spitler K. Jeswani S. Shirzadi A. Bannykh S. Patil C. Multiple intracranial metastases from a gastric gastrointestinal stromal tumor J. Clin. Neurosci. 20 3 2013 Mar 471 473 10.1016/j.jocn.2012.02.037 23164823
30 Gerin F. Baloglu O. Morgan J.A. Kesari S. Central nervous system metastases from imatinib mesylate resistant gastrointestinal stromal tumor J. Neuro Oncol. 82 2 2007 Apr 227 228 10.1007/s11060-006-9277-z
31 Gil-Arnaiz I. Martínez-Trufero J. Pazo-Cid R.A. Felipo F. Lecumberri M.J. Calderero V. Skull metastasis from rectal gastrointestinal stromal tumours Clin. Transl. Oncol. 11 9 2009 Sep 625 627 10.1007/s12094-009-0415-x 19776004
32 Gupta S. Bi W.L. Dunn I.F. Metastatic gastrointestinal stromal tumor to the skull World Neurosurg 89 2016 May 725.e11 725.e16 10.1016/j.wneu.2016.01.019
33 Hamada S. Itami A. Watanabe G. Intracranial metastasis from an esophageal gastrointestinal stromal tumor Intern Med 49 8 2010 781 785 10.2169/internalmedicine.49.3124 20424371
34 Hughes B. Yip D. Goldstein D. Waring P. Beshay V. Chong G. Cerebral relapse of metastatic gastrointestinal stromal tumor during treatment with imatinib mesylate: case report BMC Cancer 4 2004 Oct 9 74 10.1186/1471-2407-4-74 15473910
35 Jagannathan J.P. Ramaiya N.H. Shinagare A.B. Hornick J.L. George S. Intracranial metastasis from pediatric GI stromal tumor J. Clin. Oncol. 30 10 2012 Apr 1 e122 e125 10.1200/JCO.2011.38.1798 22370323
36 Janku F. Kidney D. Coyne J. Unusual presentation of gastrointestinal stromal tumor with early cerebral involvement Ir. J. Med. Sci. 180 3 2011 Sep 765 766 10.1007/s11845-010-0591-2 20878498
37 Kaku S. Tanaka T. Ohtuka T. Perisacral gastrointestinal stromal tumor with intracranial metastasis. Case report Neurol. Med.-Chir. 46 5 2006 May 254 257 10.2176/nmc.46.254
38 Leske H. Rushing E. Bernays R. A 40-year-old female with dural-based lesions Brain Pathol. 28 2 2018 Mar 299 300 10.1111/bpa.12588 29516656
39 Li L.F. Tse Y.H. Ho S.L. Yan K.W. Lui W.M. Duodenal GIST metastasized to skull and orbit managed by surgery: a case report Asian J. Surg. 34 4 2011 Oct 181 184 10.1016/j.asjsur.2011.11.001 22464835
40 Naoe H. Kaku E. Ido Y. Brain metastasis from gastrointestinal stromal tumor: a case report and review of the literature Case Rep Gastroenterol 5 3 2011 Sep 583 589 10.1159/000333403 22110419
41 O'Halloran P.J. Hannon A.M. Bartels C. Gastrointestinal stromal tumor metastases to the pituitary: a rare entity Br. J. Neurosurg. 31 5 2017 Oct 603 604 10.3109/02688697.2016.1173194 27080418
42 Park I. Chung D.H. Yoo C.J. Shin D.B. Skull metastasis of gastric gastrointestinal stromal tumor successfully managed by surgery J Korean Neurosurg Soc 60 1 2017 Jan 1 94 97 10.3340/jkns.2014.0506.007 28061498
43 Prablek M. Srinivasan V.M. Srivatsan A. Gastrointestinal stromal tumor with intracranial metastasis: case presentation and systematic review of literature BMC Cancer 19 1 2019 Nov 15 1119 10.1186/s12885-019-6316-7 31730471
44 Puri T. Gunabushanam G. Malik M. Mesenteric gastrointestinal stromal tumour presenting as intracranial space occupying lesion World J. Surg. Oncol. 4 2006 Nov 14 78 10.1186/1477-7819-4-78 17105654
45 Sato K. Tanaka T. Kato N. Ishii T. Terao T. Murayama Y. Metastatic cerebellar gastrointestinal stromal tumor with obstructive hydrocephalus arising from the small intestine: a case report and review of the literature Case Rep Oncol Med 2014 2014 343178 10.1155/2014/343178
46 Takeuchi H. Koike H. Fujita T. Tsujino H. Iwamoto Y. Sunitinib treatment for multiple brain metastases from jejunal gastrointestinal stromal tumor: case report Neurol. Med.-Chir. 54 8 2014 664 669 10.2176/nmc.cr2012-0426
47 Wong C.S. Chu Y.C. Intra-cranial metastasis of gastrointestinal stromal tumor Chin Med J (Engl). 124 21 2011 Nov 3595 3597 22340184
