Patients suffering from cancer are reported to have an increased risk of ischemic stroke (IS). We aimed to identify cancer-associated biomarkers found to differentiate between IS associated with cancer from those not associated with cancer.
Summary of review:
We performed a systematic search of PubMed and EMBASE databases according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The study is reported in PROSPERO (#CRD42022355129). In total, 5563 papers were screened, of which 49 papers were included. Seven biomarkers were identified which had the potential to differentiate between patients who had cancer or stroke or both conditions. D-dimer was the most frequently monitored biomarker, and high levels were significantly associated with cancer-related strokes in (42/44) studies. Fibrinogen was significantly associated with cancer-related strokes in 11/27 studies. A higher level of C-reactive protein, investigated in 19 studies, was associated with cancer-related strokes, but conclusive multivariate analysis was not performed. Finally, the four cancer-associated antigens CA125, CA153, CA199, and carcinoembryonic antigen were only reported on in three to six studies, respectively. These studies all originated from the Guangxi province in China. CA125 was associated with an increased risk of IS in four of six studies.
Conclusion:
Increased D-dimer seems associated with cancer-related IS. CRP may also be a candidate as a cancer-associated stroke biomarker, but this requires further verification. Fibrinogen and the more specific cancer biomarkers have not yet been proven helpful for detecting cancer-related strokes.
ZaorskyNGZhangYTchelebiLT, et al. Stroke among cancer patients. Nat Commun2019; 10: 5172.
2.
Salazar-CameloRAMoreno-VargasEACardonaAFBayona-OrtizHF. Ischemic stroke: a paradoxical manifestation of cancer. Crit Rev Oncol Hematol2021; 157: 103181.
3.
GrausFRogersLRPosnerJB. Cerebrovascular complications in patients with cancer. Medicine (Baltimore)1985; 64: 16–35.
4.
WelchHGKramerBSBlackWC. Epidemiologic signatures in cancer. N Engl J Med2019; 381: 1378–1386.
5.
SaverJL.Clinical practice. Cryptogenic stroke. N Engl J Med2016; 374: 2065–2074.
6.
HartRGCataneseLPereraKSNtaiosGConnollySJ. Embolic stroke of undetermined source: a systematic review and clinical update. Stroke2017; 48: 867–872.
7.
NaviBBKasnerSEElkindMSV, et al. Cancer and embolic stroke of undetermined source. Stroke2021; 52: 1121–1130.
8.
Ratajczak-TretelBTancin LambertAAl-AniR, et al. Atrial fibrillation in cryptogenic stroke and TIA patients in The Nordic Atrial Fibrillation and Stroke (NOR-FIB) Study: main results. Eur Stroke J2023; 8: 148–156.
9.
LunRSiegalDRamsayTDowlatshahiD.Cancer and stroke: what do we know and where do we go. Thromb Res2022; 219: 133–140.
10.
SturgeonCMLaiLCDuffyMJ.Serum tumour markers: how to order and interpret them. BMJ2009; 339: b3527.
11.
KassubekRBullingerLKassubekJ, et al. Identifying ischemic stroke associated with cancer: a multiple model derived from a case-control analysis. J Neurol2017; 264: 781–791.
12.
FujinamiJOharaTKitani-MoriiF, et al. Cancer-associated hypercoagulation increases the risk of early recurrent stroke in patients with active cancer. Cerebrovasc Dis2018; 46: 46–51.
13.
WilhelmsenLSvärdsuddKKorsan-BengtsenK, et al. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med1984; 311: 501–505.
14.
den HertogHMvan RossumJAvan der WorpHB, et al. C-reactive protein in the very early phase of acute ischemic stroke: association with poor outcome and death. J Neurol2009; 256: 2003–2008.
15.
PageMJMoherDBossuytPM, et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ2021; 372: n160.
AbdelsalamMAbu-HegazyMEl-HadaadHAWahbaHEgilaHEsmaelA.Pathophysiology, mechanism, and outcome of ischemic stroke in cancer patients. J Stroke Cerebrovasc Dis2020; 29: 105299.
18.
Álvarez-PérezFJVerdeIUsón-MartínMFiguerola-RoigABallabriga-PlanasJEspino-IbañezA.Frequency and mechanism of ischemic stroke associated with malignancy: a retrospective series. Eur Neurol2012; 68: 209–213.
19.
BangOYChungJWChoYH, et al. Circulating DNAs, a marker of neutrophil extracellular traposis and cancer-related stroke: the OASIS-cancer study. Stroke2019; 50: 2944–2947.
20.
BangOYChungJWLeeMJ, et al. Cancer cell-derived extracellular vesicles are associated with coagulopathy causing ischemic stroke via tissue factor-independent way: the OASIS-CANCER study. PLoS ONE2016; 11: e0159170.
21.
ChenYZengJXieXWangZWangXLiangZ.Clinical features of systemic cancer patients with acute cerebral infarction and its underlying pathogenesis. Int J Clin Exp Med2015; 8: 4455–4463.
22.
CochoDGendreJBoltesA, et al. Predictors of occult cancer in acute ischemic stroke patients. J Stroke Cerebrovasc Dis2015; 24: 1324–1328.
23.
EllisDRangarajuSDuncanA, et al. Coagulation markers and echocardiography predict atrial fibrillation, malignancy or recurrent stroke after cryptogenic stroke. Medicine (Baltimore)2018; 97: e13830.
24.
GonYKabataDKawanoT, et al. Hematological abnormalities and malnutrition mediate pathway between cancer and outcomes in ischemic stroke patients. J Stroke Cerebrovasc Dis2020; 29: 104943.
25.
GonYOkazakiSTerasakiY, et al. Characteristics of cryptogenic stroke in cancer patients. Ann Clin Transl Neurol2016; 3: 280–287.
26.
GonYSakaguchiMTakasugiJ, et al. Plasma d-dimer levels and ischaemic lesions in multiple vascular regions can predict occult cancer in patients with cryptogenic stroke. Eur J Neurol2017; 24: 503–508.
27.
GuoYJChangMHChenPLLeeYSChangYCLiaoYC.Predictive value of plasma (d)-dimer levels for cancer-related stroke: a 3-year retrospective study. J Stroke Cerebrovasc Dis2014; 23: e249–e254.
28.
HasegawaYSetoguchiTSakaidaTIuchiT.Utility of a scoring system for differentiating cancer-associated stroke from cryptogenic stroke in patients with cancer. Neurol Sci2020; 41: 1245–1250.
29.
ItoSUedaAMurateK, et al. Differentiation of cancer from atrial fibrillation in patients with acute multifocal stroke. J Neurol Sci2016; 368: 344–348.
30.
IzumiTNanauraHIguchiNOzakiMSugieK.Serum alkaline phosphatase in cryptogenic stroke cases with active cancer. Intern Med2022; 61: 639–646.
31.
JiangHQinCChengD, et al. Potential pathogenesis and biomarkers of kidney cancer-related stroke. Med Sci Monit2017; 23: 2292–2298.
32.
JiangJShangXZhaoJ, et al. Score for predicting active cancer in patients with ischemic stroke: a retrospective study. Biomed Res Int2021; 2021: 5585206.
33.
KarlińskaAGGromadzkaGKarlińskiMACzłonkowskaA.The activity of malignancy may determine stroke pattern in cancer patients. J Stroke Cerebrovasc Dis2015; 24: 778–783.
34.
KataokaYSonodaKTakahashiJC, et al. Histopathological analysis of retrieved thrombi from patients with acute ischemic stroke with malignant tumors. J Neurointerv Surg2022; 14: 017195.
35.
KikunoMUenoYTakekawaH, et al. Distinction in prevalence of atherosclerotic embolic sources in cryptogenic stroke with cancer status. J Am Heart Assoc2021; 10: e021375.
36.
KimJMJungKHParkKHLeeSTChuKRohJK.Clinical manifestation of cancer related stroke: retrospective case-control study. J Neurooncol2013; 111: 295–301.
37.
KimKLeeJ-H.Risk factors and biomarkers of ischemic stroke in cancer patients. J Stroke2014; 16: 91–96.
38.
KimSGHongJMKimHY, et al. Ischemic stroke in cancer patients with and without conventional mechanisms: a multicenter study in Korea. Stroke2010; 41: 798–801.
39.
KimSJParkJHLeeMJParkYGAhnMJBangOY.Clues to occult cancer in patients with ischemic stroke. PLoS ONE2012; 7: e44959.
40.
KneihslMEnzingerCWünschG, et al. Poor short-term outcome in patients with ischaemic stroke and active cancer. J Neurol2016; 263: 150–156.
41.
KonoTOhtsukiTHosomiN, et al. Cancer-associated ischemic stroke is associated with elevated D-dimer and fibrin degradation product levels in acute ischemic stroke with advanced cancer. Geriatr Gerontol Int2012; 12: 468–474.
42.
LeeEJNahHWKwonJYKangDWKwonSUKimJS.Ischemic stroke in patients with cancer: is it different from usual strokes. Int J Stroke2014; 9: 406–412.
43.
LiuMEllisDDuncanA, et al. The utility of the markers of coagulation and hemostatic activation profile in the management of embolic strokes of undetermined source. J Stroke Cerebrovasc Dis2021; 30: 105592.
44.
LiuYLuLChengX, et al. The index of esophageal cancer related ischemic stroke: a retrospective patient control study. Neuropsychiatr Dis Treat2022; 18: 477–485.
45.
LongHQinKChenJ, et al. Biomarkers of gastric cancer-related ischemic stroke and its underlying pathogenesis. Medicine (Baltimore)2018; 97: e0493.
46.
NahabFSharashidzeVLiuM, et al. Markers of coagulation and hemostatic activation aid in identifying causes of cryptogenic stroke. Neurology2020; 94: e1892–e1899.
47.
ParkHKimJHaJ, et al. Histological features of intracranial thrombi in stroke patients with cancer. Ann Neurol2019; 86: 143–149.
48.
QuanXQinQChenY, et al. Independent risk factors and the potential predictors of bladder cancer-related ischemic stroke. J Int Med Res2020; 48: 300060520919227.
49.
QuintasSRogadoJGullónP, et al. Predictors of unknown cancer in patients with ischemic stroke. J Neurooncol2018; 137: 551–557.
50.
RyuJABangOYSuhGY, et al. Ischemic stroke in critically ill patients with malignancy. PLoS ONE2016; 11: e0146836.
51.
SchwarzbachCJSchaeferAEbertA, et al. Stroke and cancer: the importance of cancer-associated hypercoagulation as a possible stroke etiology. Stroke2012; 43: 3029–3034.
SeokJMKimSJSongP, et al. Clinical presentation and ischemic zone on MRI in cancer patients with acute ischemic stroke. Eur Neurol2012; 68: 368–376.
54.
ShenYLiYChenCWangWLiT.D-dimer and diffusion-weighted imaging pattern as two diagnostic indicators for cancer-related stroke: a case-control study based on the STROBE guidelines. Medicine (Baltimore)2020; 99: e18779.
55.
SorgunMHKuzuMOzerIS, et al. Risk factors, biomarkers, etiology, outcome and prognosis of ischemic stroke in cancer patients. Asian Pac J Cancer Prev2018; 19: 649–653.
56.
SunBFanSLiZ, et al. Clinical and neuroimaging features of acute ischemic stroke in cancer patients. Eur Neurol2016; 75: 292–299.
57.
TsushimaMMetokiNHagiiJ, et al. D-dimer and C-reactive protein as potential biomarkers for diagnosis of trousseau’s syndrome in patients with cerebral embolism. J Stroke Cerebrovasc Dis2020; 29: 104534.
58.
UemuraJKimuraKSibazakiKInoueTIguchiYYamashitaS.Acute stroke patients have occult malignancy more often than expected. Eur Neurol2010; 64: 140–144.
59.
WangJYZhangGJZhuoSX, et al. D-dimer >2.785 μg/ml and multiple infarcts ⩾3 vascular territories are two characteristics of identifying cancer-associated ischemic stroke patients. Neurol Res2018; 40: 948–954.
60.
XieXChenLZengJ, et al. Clinical features and biological markers of lung cancer-associated stroke. J Int Med Res2016; 44: 1483–1491.
61.
XuYWuZXuH.Cancer-related cryptogenic stroke involving the bilateral anterior and the posterior circulations: diagnostic value of clinical and imaging characteristics. Front Neurol2022; 13: 1032984.
62.
ZhangJZhaoJ.Clinical characteristics and analysis of lung cancer- associated acute ischemic stroke. J Stroke Cerebrovasc Dis2020; 29: 105164.
63.
AdamsHPBendixenBHKappelleLJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of org 10172 in acute stroke treatment. Stroke1993; 24: 35–41.
64.
Du ClosTWMoldC. C-reactive protein: an activator of innate immunity and a modulator of adaptive immunity. Immunol Res2004; 30: 261–277.
65.
WeitzJIFredenburghJCEikelboomJW.A test in context: D-dimer. J Am Coll Cardiol2017; 70: 2411–2420.
66.
DoumaRAle GalGSöhneM, et al. Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts. BMJ2010; 340: c1475.
67.
EichingerS.Diagnostic issues of VTE in pregnancy. Thromb Res2009; 123(Suppl. 1): S38–S40.
68.
HalabyRPopmaCJCohenA, et al. D-Dimer elevation and adverse outcomes. J Thromb Thrombolysis2015; 39: 55–59.
69.
HaapaniemiETatlisumakT.Is D-dimer helpful in evaluating stroke patients? A systematic review. Acta Neurol Scand2009; 119: 141–150.
70.
RosenbergJDoDCucchiaraBMesséSR.D-dimer and body CT to identify occult malignancy in acute ischemic stroke. J Stroke Cerebrovasc Dis2020; 29: 105366.
71.
NezuTHosomiNAokiS, et al. Short-term or long-term outcomes for stroke patients with cancer according to biological markers. J Neurol Sci2022; 436: 120246.
72.
BeyelerMBirnerBBrancaM, et al. Development of a score for prediction of occult malignancy in stroke patients (occult-5 score). J Stroke Cerebrovasc Dis2022; 31: 106609.
73.
NaviBBIadecolaC.Ischemic stroke in cancer patients: a review of an underappreciated pathology. Ann Neurol2018; 83: 873–883.
74.
LiWShaoCLiC, et al. Metabolomics: a useful tool for ischemic stroke research. J Pharm Anal2023; 13: 968–983.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
