Introduction: Patients with cancer are known to have an increased risk of ischemic stroke (IS) around the time of their diagnosis. However, there is a paucity of data in Asian populations, and as such, we aimed to determine cancer incidence rates and patterns in Asian IS patients as well as investigate the differences in vascular risk profile of IS patients with and without concomitant cancer. Methods: We conducted a retrospective cross-sectional study using data from the Singapore Stroke and Cancer registries. We defined cases as patients with IS and a cancer diagnosis 2 years before or after the index IS. Cancer incidence was determined using the same direct age-standardization method performed for the Singapore general population in the 2015 Singapore cancer report. Multivariable logistic regression was used to analyze differences in vascular risk factors. Results: Among 21,068 IS patients (mean age, 67.9 ± 13.3 years), 6.3% (1,330) were found to have concomitant cancer; 4.4% (935) had prior cancer while 1.8% (395) had cancer diagnoses within 2 years following IS. The cancer incidence among IS patients was 3,393 (95% confidence interval [CI], 1,937–4,849) per 100,000 person-years compared to 219–231 per 100,000 person-years in the general population. Older age (odds ratio [OR], 1.02 [95% CI, 1.01–1.02] per year), males (OR, 1.25 [95% CI, 1.11–1.41), Chinese ethnicity (OR, 1.61 [95% CI, 1.37–1.89]) and a lower prevalence of hypertension (OR, 0.84 [95% CI, 0.73–0.97)]), and hyperlipidemia (OR, 0.53 [95% CI, 0.45–0.62]) were independently associated with cancer-related IS. Conclusions: The age-standardized cancer incidence was 15 times higher in IS patients than the general population. IS patients with concomitant cancer were older and had a lower prevalence of vascular risk factors.

Ischemic stroke (IS) and cancer are both top 10 causes of death globally. Associations between the two have been found, with cancer patients exhibiting a higher stroke risk [1] and IS patients having a higher prevalence of cancer compared to the general population [2‒4]. IS may also be the first manifestation of an occult malignancy [5‒8]. Efforts have been made to identify differences in profile of IS patients with and without cancer in order to develop clinical scores to predict active cancer in IS patients [9, 10].

The profile of cancer risk and survival is different amongst patients with African, Asian, and Caucasian ancestry, especially so within breast, prostate, and colorectal cancer [11]. Even within Asian cancer patients, specific ancestry has been known to affect subtypes of cancer [12]. Studies from Asia thus far have shown that there is an association between stroke and cancer [6, 13, 14] in specific cancer subtypes; however, these studies have been mainly in East Asian populations. In this study, we aimed to look at the association between IS and cancer in a multiethnic population.

Aims

Using data from the Singapore Stroke Registry (SSR) and Singapore Cancer Registry (SCR), we aimed to determine the cancer incidence and patterns in IS patients in our multiethnic cohort. We also investigated differences in vascular risk factors in IS patients with and without concomitant cancer.

Registry Data

We conducted a retrospective cross-sectional study using the data from the SSR and SCR, both which are maintained by the National Registry of Disease Office (NDRO) [15]. The SSR [16] was established in 2002 with data from two major public hospitals in Singapore but expanded to receive data from all public healthcare institutions in Singapore from 2005. Hospital admission data are reviewed by trained research nurses to record data on stroke characteristics, as well as stroke-related outcomes. The SSR reviews all public hospital admissions from MediClaims listings, discharge summaries, and from the death registry. The data fields of the SSR are available in the online supplement materials (online suppl. eMethods 1; for all online suppl. material, see https://doi.org/10.1159/000534267). The latest report from the SSR is from 2020 [17].

The SCR was established in 1968 and contains data on all reportable cancer cases (online suppl. eMethods 2) including those from public and private healthcare institutions. Data sources include notifications by medical profession, pathology records, hospital records, public insurance claims, and the death registry. Clinical data in the NRDO database were captured from medical records from relevant institutions and verified by registry coordinators and a visiting consultant pathologist. The latest available report from the SCR is from 2020 [18]. For the purposes of these analyses, borderline and benign tumors were excluded from a cancer diagnosis.

Study Population

In this study, we included IS patients from the SSR from years 2008 to 2012 who were aged ≥18 years and of Asian ethnicity. Patients who were identified as having IS secondary to primary brain tumors or metastases and venous strokes were excluded. We screened the SSR for IS patients and then overlapped records with the SCR from year 2006 to 2014 to determine presence of concomitant cancer. We defined cancer-IS patients as cancer diagnoses up to 2 years before or after IS onset in accordance with findings from previous studies [3]. In situations of multiple IS admissions, data from the first IS admission were extracted for non-cancer-IS patients while data from the IS admission within ±2 years of cancer diagnosis was extracted for cancer-IS patients. IS patients with cancer occurring before or after more than 2 years were excluded from this study.

Relevant Exposures

Age, sex, ethnicity (Chinese, Malay, Indian), and vascular risk factors (online suppl. eMethods 1) were obtained from the SSR. These included hypertension, diabetes mellitus, hyperlipidemia, transient ischemic attack, ischemic heart disease, atrial fibrillation/flutter, valvular heart disease, peripheral vascular disease, and smoking. These diagnoses were extracted from medical notes (general practitioner, emergency department, referral letters, hospital inpatient discharge records, and clinical notes of the index event). Smoking status, previous transient ischemic attack, known ischemic heart disease, valvular heart disease, or peripheral heart disease were fields with missing data (number of subjects with data available is indicated in Table 1). Cancer diagnosis date, primary site of malignancy, staging, histology, grade differentiation, and treatment data were obtained from the SCR. Staging in the SCR was in accordance to the American Joint Committee on Cancer Staging. Primary sites of malignancy were grouped into 15 main systems (online suppl. eMethods 3).

Table 1.

Demographics and vascular risk factors between cancer IS and non-cancer IS patients

CharacteristicsaWhole cohort (n = 21,068)Cancer IS patients (n = 1,330)Non-cancer IS patients (n = 19,738)p valueb
Demographics 
 Age, mean (SD), years 67.9 (13.3) 71.2 (11.6) 67.7 (13.3) <0.001 
 Age categories, years 
  ≤65 9,068 (43.0) 402 (30.2) 8,666 (43.9) <0.001 
  >65 12,000 (57.0) 928 (69.8) 11,072 (56.1)  
 Sex, male 11,914 (56.6) 776 (58.4) 11,138 (56.4) 0.172 
 Ethnicity <0.001 
  Chinese 16,304 (77.4) 1,141 (85.8) 15,163 (76.8)  
  Indian 1,429 (6.8) 55 (4.1) 1,374 (7.0)  
  Malay 3,335 (15.8) 134 (10.1) 3,201 (16.2)  
Vascular risk factors 
 Hypertension 17,305 (82.1) 1,053 (79.2) 16,252 (82.3) 0.004 
 Diabetes mellitus 9,584 (45.5) 546 (41.1) 9,038 (45.8) <0.001 
 Hyperlipidemia 18,907 (89.7) 1,079 (81.1) 17,828 (90.3) <0.001 
 Atrial arrhythmia 4,012 (19.0) 260 (19.6) 3,752 (19.0) 0.627 
 Current or ex-smoker (n = 20,030) 8,129 (40.6) 563 (44.5) 7,566 (40.3) 0.003 
 Transient ischemic attack (n = 6,888) 906 (13.2) 61 (16.4) 845 (13.0) 0.057 
 Ischemic heart disease (n = 11,248) 5,086 (45.2) 324 (50.8) 4,762 (44.9) 0.004 
 Valvular heart disease (n = 5,423) 456 (8.4) 28 (10.2) 428 (8.3) 0.268 
 Peripheral vascular disease (n = 6,680) 767 (11.5) 46 (13.0) 721 (11.4) 0.370 
Number of risk factorsc <0.001 
 No risk factor 335 (1.6) 43 (3.2) 292 (1.5)  
 1 risk factor 1,767 (8.4) 153 (11.5) 1,614 (8.2)  
 2 risk factors 5,680 (27.0) 368 (27.7) 5,312 (26.9)  
 ≥3 risk factors 13,286 (63.1) 766 (57.6) 12,520 (63.4)  
CharacteristicsaWhole cohort (n = 21,068)Cancer IS patients (n = 1,330)Non-cancer IS patients (n = 19,738)p valueb
Demographics 
 Age, mean (SD), years 67.9 (13.3) 71.2 (11.6) 67.7 (13.3) <0.001 
 Age categories, years 
  ≤65 9,068 (43.0) 402 (30.2) 8,666 (43.9) <0.001 
  >65 12,000 (57.0) 928 (69.8) 11,072 (56.1)  
 Sex, male 11,914 (56.6) 776 (58.4) 11,138 (56.4) 0.172 
 Ethnicity <0.001 
  Chinese 16,304 (77.4) 1,141 (85.8) 15,163 (76.8)  
  Indian 1,429 (6.8) 55 (4.1) 1,374 (7.0)  
  Malay 3,335 (15.8) 134 (10.1) 3,201 (16.2)  
Vascular risk factors 
 Hypertension 17,305 (82.1) 1,053 (79.2) 16,252 (82.3) 0.004 
 Diabetes mellitus 9,584 (45.5) 546 (41.1) 9,038 (45.8) <0.001 
 Hyperlipidemia 18,907 (89.7) 1,079 (81.1) 17,828 (90.3) <0.001 
 Atrial arrhythmia 4,012 (19.0) 260 (19.6) 3,752 (19.0) 0.627 
 Current or ex-smoker (n = 20,030) 8,129 (40.6) 563 (44.5) 7,566 (40.3) 0.003 
 Transient ischemic attack (n = 6,888) 906 (13.2) 61 (16.4) 845 (13.0) 0.057 
 Ischemic heart disease (n = 11,248) 5,086 (45.2) 324 (50.8) 4,762 (44.9) 0.004 
 Valvular heart disease (n = 5,423) 456 (8.4) 28 (10.2) 428 (8.3) 0.268 
 Peripheral vascular disease (n = 6,680) 767 (11.5) 46 (13.0) 721 (11.4) 0.370 
Number of risk factorsc <0.001 
 No risk factor 335 (1.6) 43 (3.2) 292 (1.5)  
 1 risk factor 1,767 (8.4) 153 (11.5) 1,614 (8.2)  
 2 risk factors 5,680 (27.0) 368 (27.7) 5,312 (26.9)  
 ≥3 risk factors 13,286 (63.1) 766 (57.6) 12,520 (63.4)  

IS, ischemic stroke; SD, standard deviation.

aAll data represented in n (%) unless otherwise specified.

bχ2 or Fisher’s exact test for categorical variables; two-sample t test for continuous variables.

cIncludes age, hypertension, diabetes mellitus, hyperlipidemia, atrial arrhythmia and ex/current smoking.

Statistical Analysis

Demographic and clinical variables were compared using χ2 or Fisher’s exact test for categorical variables and two-sided two-sample t test for continuous variables as appropriate. Cancer incidence rate was determined using the same direct age-standardization method with Segi’s world population as the 2015 SCR report [19]. Complete case multivariable logistic regression was performed to identify differences in the vascular risk profile of cancer-IS and non-cancer-IS patients. The inclusion criteria for multivariable analysis were p < 0.1 on univariate analysis and no missing data. Statistical significance was set at p ≤ 0.05. Analyses were performed using SAS software v9.4 for Windows (SAS, Inc, Cary, NC, USA).

The study diagram detailing the derivation of the study cohort is summarized in Figure 1. Among 21,068 IS patients analyzed in this study, 11,914 (56.6%) were males and the mean age was 67.9 ± 13.3 years. The risk factor profile for the overall cohort is shown in Table 1. Cancer-IS patients were significantly older and had a higher proportion of Chinese compared to non-Chinese.

Fig. 1.

Consolidated Standards of Reporting Trials (CONSORT) diagram of stages of patient screening. IS indicates ischemic stroke.

Fig. 1.

Consolidated Standards of Reporting Trials (CONSORT) diagram of stages of patient screening. IS indicates ischemic stroke.

Close modal

The prevalence of concomitant cancer was 6.3% with 935 (4.4%) had cancer diagnoses up to 2 years prior to IS onset while 395 (1.9%) were diagnosed with cancer in the 2 years following IS onset. Direct age-standardization using Segi’s world population [20] revealed the age-standardized cancer incidence rate in our cohort of IS patients to be 3,392.9 (95% confidence interval [CI], 1,937.1–4,848.7) per 100,000 person-years. The age-standardized cancer incidence rate of IS prior to a cancer diagnosis was 4,102.5 (95% CI, 4,101.6–4,103.4), while the age-standardized cancer incidence rate of IS after a cancer diagnosis was 1,810.0 (95% CI, 1,809.4–1,810.6).

In multivariable analyses, older age (odds ratio [OR], 1.02 [95% CI, 1.01–1.02] per year), males (OR, 1.25 [95% CI, 1.11–1.41), Chinese ethnicity (OR, 1.61 [95% CI, 1.37–1.89]), and a lack of hypertension (OR, 0.84 [95% CI, 0.73–0.97]), or hyperlipidemia (OR, 0.53 [95% CI, 0.45–0.62]) remained independent associations of cancer-IS (Table 2).

Table 2.

Summaries of association analysis of cancer IS and non-cancer IS patients using logistic regression model

VariablesUnivariateMultivariable
crude OR (95% CI)p valueadjusted ORa (95% CI)p value
Age, years 1.02 (1.02–1.03) <0.001 1.02 (1.01–1.02) <0.001 
Male (vs. female) 1.09 (0.96–1.20) 0.174 1.25 (1.11–1.41) 0.000 
Chinese (vs. non-Chinese) 1.82 (1.55–2.13) <0.001 1.61 (1.37–1.89) <0.001 
Vascular risk factors 
 Hypertension 0.81 (0.71–0.93) 0.003 0.84 (0.73–0.97) 0.018 
 Diabetes mellitus 0.82 (0.74–0.92) 0.001 0.98 (0.87–1.11) 0.776 
 Hyperlipidemia 0.46 (0.40–0.53) <0.001 0.53 (0.45–0.62) <0.001 
 Atrial arrhythmia 1.04 (0.90–1.19) 0.610 … … 
 Current or ex-smoker 1.19 (1.06–1.33) 0.003 … … 
 Transient ischemic attack 1.32 (1.00–1.76) 0.051 … … 
 Ischemic heart disease 1.27 (1.08–1.49) 0.004 … … 
 Valvular heart disease 1.27 (0.85–1.90) 0.236 … … 
 Peripheral vascular disease 1.17 (0.85–1.60) 0.341 … … 
 <3 risk factorsb 1.28 (1.14, 1.43) <0.001 … … 
VariablesUnivariateMultivariable
crude OR (95% CI)p valueadjusted ORa (95% CI)p value
Age, years 1.02 (1.02–1.03) <0.001 1.02 (1.01–1.02) <0.001 
Male (vs. female) 1.09 (0.96–1.20) 0.174 1.25 (1.11–1.41) 0.000 
Chinese (vs. non-Chinese) 1.82 (1.55–2.13) <0.001 1.61 (1.37–1.89) <0.001 
Vascular risk factors 
 Hypertension 0.81 (0.71–0.93) 0.003 0.84 (0.73–0.97) 0.018 
 Diabetes mellitus 0.82 (0.74–0.92) 0.001 0.98 (0.87–1.11) 0.776 
 Hyperlipidemia 0.46 (0.40–0.53) <0.001 0.53 (0.45–0.62) <0.001 
 Atrial arrhythmia 1.04 (0.90–1.19) 0.610 … … 
 Current or ex-smoker 1.19 (1.06–1.33) 0.003 … … 
 Transient ischemic attack 1.32 (1.00–1.76) 0.051 … … 
 Ischemic heart disease 1.27 (1.08–1.49) 0.004 … … 
 Valvular heart disease 1.27 (0.85–1.90) 0.236 … … 
 Peripheral vascular disease 1.17 (0.85–1.60) 0.341 … … 
 <3 risk factorsb 1.28 (1.14, 1.43) <0.001 … … 

Blank cells represent variables that are not included in multivariable analysis due to missing numbers or p > 0.1 in univariate analysis.

CI, confidence interval; IS, ischemic stroke; OR, odds ratio.

aAdjusted for age, sex, ethnicity, hypertension, diabetes mellitus, hyperlipidemia in the multivariable logistic regression analysis.

bIncludes age, hypertension, diabetes mellitus, hyperlipidemia, atrial arrhythmia and ex/current smoking.

The most prevalent cancers occurring in cancer-IS patients were lower gastrointestinal (19.7%), lung (13.8%), genitourinary (11.5%), hepatopancreatobiliary (10.8%), and upper gastrointestinal (7.8%), of which majority were stage III or IV (Table 3). In male cancer-IS patients, the top cancers were lower gastrointestinal (19.1%), genitourinary (18.0%), lung (16.2%), hepatopancreatobiliary (16.2%), and upper gastrointestinal (8.1%). In female cancer-IS patients, the top cancers were lower gastrointestinal (20.6%), breast (16.6%), lung (10.4%), gynecological (10.1%), and hepatopancreatobiliary (9.6%) (online suppl. eTable 1).

Table 3.

Baseline characteristics of overall, pre-stroke, and post-stroke cancer IS patients and the top 5 most common cancers

CharacteristicsaOverall (n = 1,330)Cancer diagnosis prior IS onset (n = 935)Cancer diagnosis after IS onset (n = 395)
Demographics 
 Age, mean (SD), years 71.2 (11.6) 71.4 (11.6) 70.69 (11.7) 
 Age categories, years 
  ≤65 402 (30.2) 277 (29.6) 125 (31.6) 
  >65 928 (69.8) 658 (70.4) 270 (68.3) 
 Sex, male 776 (58.3) 523 (55.9) 253 (64.1) 
 Ethnicity 
  Chinese 1,141 (85.8) 807 (86.3) 334 (84.6) 
  Indian 55 (4.1) 38 (4.1) 17 (4.3) 
  Malay 134 (10.1) 90 (9.6) 44 (11.1) 
Cancer treatment prior to stroke 
 No treatment  266 (28.4) NA 
 Surgery  252 (27.0) NA 
 Chemotherapy  69 (7.4) NA 
 Radiotherapy  114 (12.2) NA 
 Othersb  109 (11.7) NA 
 Combinationc  125 (13.4) NA 
Top cancers 
 1st Lower GI 262 (19.7) Lower GI 196 (21.0) Lower GI 66 (16.7) 
 2nd Lung 184 (13.8) Lung 119 (12.7) Lung 65 (16.5) 
 3rd Genitourinary 153 (11.5) HPB 96 (10.3) Genitourinary 58 (14.7) 
 4th HPB 144 (10.8) Genitourinary 95 (10.2) HPB 48 (12.2) 
 5th Upper GI 104 (7.8) Upper GI 76 (8.1) Upper GI 28 (7.1) 
 Others 483 (36.3) Others 353 (37.8) Others 130 (32.9) 
CharacteristicsaOverall (n = 1,330)Cancer diagnosis prior IS onset (n = 935)Cancer diagnosis after IS onset (n = 395)
Demographics 
 Age, mean (SD), years 71.2 (11.6) 71.4 (11.6) 70.69 (11.7) 
 Age categories, years 
  ≤65 402 (30.2) 277 (29.6) 125 (31.6) 
  >65 928 (69.8) 658 (70.4) 270 (68.3) 
 Sex, male 776 (58.3) 523 (55.9) 253 (64.1) 
 Ethnicity 
  Chinese 1,141 (85.8) 807 (86.3) 334 (84.6) 
  Indian 55 (4.1) 38 (4.1) 17 (4.3) 
  Malay 134 (10.1) 90 (9.6) 44 (11.1) 
Cancer treatment prior to stroke 
 No treatment  266 (28.4) NA 
 Surgery  252 (27.0) NA 
 Chemotherapy  69 (7.4) NA 
 Radiotherapy  114 (12.2) NA 
 Othersb  109 (11.7) NA 
 Combinationc  125 (13.4) NA 
Top cancers 
 1st Lower GI 262 (19.7) Lower GI 196 (21.0) Lower GI 66 (16.7) 
 2nd Lung 184 (13.8) Lung 119 (12.7) Lung 65 (16.5) 
 3rd Genitourinary 153 (11.5) HPB 96 (10.3) Genitourinary 58 (14.7) 
 4th HPB 144 (10.8) Genitourinary 95 (10.2) HPB 48 (12.2) 
 5th Upper GI 104 (7.8) Upper GI 76 (8.1) Upper GI 28 (7.1) 
 Others 483 (36.3) Others 353 (37.8) Others 130 (32.9) 

GI, gastrointestinal; HPB, hepatopancreatobiliary; IS, ischemic stroke; NA, not applicable.

aAll data represented in n (%) unless otherwise specified.

bIncludes hormonal, biological, and unspecified therapy.

cIncludes any combination of surgery, chemotherapy, and radiotherapy.

In this nationwide registry study of cancer-related IS in ethnic Asians, the age-standardized cancer incidence rate in IS patients was 3,392.9 per 100,000 person-years, about 15 times that reported in the general population (219.4–230.9 per 100,000 person-years) [19], supporting the association of IS with cancer. This higher stroke risk in cancer patients was also reflected in a recent meta-analysis of 20 cohort studies which reported that cancer survivors are 1.66 times more likely to sustain a stroke compared to non-cancer controls [21].

Concomitant cancer was found in 6.3% of the IS patients in our study. This was similar to the cancer prevalence of 7.5% found in the NAVIGATE ESUS trial despite only including a specific subset of IS patients with embolic stroke of undetermined source [22]. Data from the Bergen NORSTROKE study also showed a comparable prevalence of active cancer in 5% of IS patients, albeit within a shorter period of 1 year within stroke onset [10]. Of the cancer-IS patients, majority suffered a stroke subsequent to cancer diagnosis while an estimated one-third of them presented with a stroke prior to cancer diagnosis. Overall, 1.9% of IS patients were diagnosed with cancer in the 2 years following the index stroke. This was less than half of the 4.5% cancer prevalence reported in Lindvig et al. [3], the largest prospective study to date, despite sharing comparable follow-up durations. This disparity may be in part due to their inclusion of additional patients with transient ischemic attack, non-IS, and patients with brain tumors. Conversely, recent meta-analyses have also suggested that the incidence of IS after a new cancer diagnosis is approximately 1.4% [8].

Cancer-IS patients were found to be older, more likely to be male, and had a significantly lower prevalence of vascular risk factors compared to non-cancer-IS patients. Specifically, a lower prevalence of hypertension and hyperlipidemia were independently associated with cancer-IS patients. Our findings replicated that found in smaller Western [23] and Asian studies [24], however, were contrary to those from other larger scale studies.

Zhang et al. [21] found that cancer tends to promote development of stroke in females and a younger age group (age of cancer diagnosis <20 or 45) in their meta-analysis while other large studies failed to demonstrate differences in vascular risk profile [2, 9]. These differences are likely to due to patient selection such as inclusion of a younger population and hemorrhagic stroke patients in the meta-analysis of Zhang et al. [21].

In our study, the relative lack of conventional risk factors for stroke in cancer-IS patients suggests that additional cancer-specific mechanisms such as hypercoagulability, non-bacterial thrombotic endocarditis, and treatment complications [25] may contribute to stroke pathogenesis in cancer-IS patients. While this suggests the possibility of cancer screening in IS patients without hypertension or hyperlipidemia, none of the variables alone are suitable to identify IS patients at high risk of cancer as the differences in vascular risk factors between the two groups were not sufficiently marked. Smoking was the only vascular risk factor that was significantly higher in cancer-IS patients. This was expected given that smoking is a risk factor shared by cancer, especially those pertaining to the lung, pancreas, and bladder [26] which were amongst the top cancers found in this study.

The top 5 cancers identified in this study were lower gastrointestinal followed by lung, genitourinary, hepatopancreatobiliary, and upper gastrointestinal, all of which were top cancers in cancer-associated stroke literature [6], including the meta-analysis of Zhang et al. [21], with the exception of hematologic and head and neck cancers. Our cohort most closely replicates the Japanese cohort of Uemura et al. [6]. Gastrointestinal, lung, and pancreatic cancers have consistently been ranked as top cancers across cancer-IS studies [4], and this is in line with findings on them being cancers with the highest incidence of thromboembolic events [27]. In addition, majority of these top cancers were found to be stage III and beyond in this study and studies have shown that cancers at advanced stages tend to be associated with a higher stroke risk [27]. Theorized links between malignancies and pro-thrombotic states include activation of endothelium, production of cancer pro-coagulants, inflammatory cytokines, and cancer therapy which perturb the balance in the Virchow’s triad, leading to thrombosis.

There have been studies which investigated laboratory and imaging parameters in addition to vascular risk factors to assess cancer risk in IS patients. Selvik et al. [10] proposed a clinical score of elevated D-dimer, lower hemoglobin, and previous or current smoking for predicting active cancer in IS patients <75 years old while Kassubek et al. [9] developed a model comprising of number of stroke territories, granulocyte percentage, C-reactive protein and serum lactate dehydrogenase activity to identify IS patients with occult solid malignancies. This study was limited by registry data which did not include laboratory and imaging variables. There is currently no basis for cancer screening guidelines in a specific profile of IS patients, and further research involving laboratory and imaging parameters is needed.

The strength of this study lies in it being a large multiethnic study on cancer-related IS and the utilization of reported registry data which are nationally representative. However, this study has limitations. The study is a cross-sectional study hence causality cannot be determined. There were missing data for certain vascular risk factors parameters which precluded them from being controlled for in the multivariate analysis. Reporting of vascular risk factors to the registry by clinicians was also not standardized. In addition, D-dimer levels, imaging parameters, IS etiology subtype, alcohol intake, and cellular typing of cancers that were unobtainable from the registries may have provided further insights. The effect of cancer treatment on IS risk was also not analyzed. Given that the stroke registry data used was from 2008 to 2012, the results of this study may not be generalizable to current data given the increase in both IS and cancer rates in Singapore from 2008 to present.

In this large multiethnic population, the burden of cancer-IS amounted to 6.3% and there is evidence of a 15-times increase in age-standardized cancer incidence in IS patients, supporting the association between stroke and cancer. Lower gastrointestinal cancer was the top cancer involved in cancer-related IS. Older age and a lower prevalence of vascular risk factors were independently associated with IS patients with concomitant cancer.

The authors would also like to thank the Singapore Cancer and Stroke Registries Advisory Committee Members, as well as staff from the National Registry of Diseases Office, Singapore for providing anonymized data from the Singapore Cancer and Stroke Registries.

This study was approved by the SingHealth Centralized Institutional Review Board (approval no. 2017/2450) and was granted waiver of informed consent as this study utilized deidentified data.

The authors have no conflicts of interest to declare.

This study was funded by AM-ETHOS Medical Student Fellowship 2018 (AM-ETHOS01/FY2017/17-A17).

Kendra Jing Ying Tang: conceptualization (supporting), methodology (supporting), writing – original draft (lead), and writing – review and editing (equal). Seyed Ehsan Saffari: formal analysis (lead). Kaavya Narasimhalu: writing – review and editing (supporting). Kian Kheng Queck: conceptualization (equal) and methodology (supporting). Deidre Anne De Silva: conceptualization (lead), methodology (lead), writing – review and editing (equal), and supervision (lead).

Data used in this analysis is kept by the National Registry of Diseases Office (NRDO) and restricted due to potentially identifiable participant information. These data cannot be made publicly available but qualified investigators who have been granted access by the NRDO can obtain deidentified data on request to [email protected]. Further inquiries can be directed to the corresponding author.

1.
Graus
F
,
Rogers
LR
,
Posner
JB
.
Cerebrovascular complications in patients with cancer
.
Medicine
.
1985 Jan
64
1
16
35
.
2.
Stefan
O
,
Vera
N
,
Otto
B
,
Heinz
L
,
Wolfgang
G
.
Stroke in cancer patients: a risk factor analysis
.
J Neurooncol
.
2009 Sep 1
94
2
221
6
.
3.
Lindvig
K
,
Moller
H
,
Mosbech
J
,
Jensen
OM
.
The pattern of cancer in a large cohort of stroke patients
.
Int J Epidemiol
.
1990 Sep
19
3
498
504
.
4.
Turner
M
,
Murchie
P
,
Derby
S
,
Ong
AY
,
Walji
L
,
McLernon
D
.
Is stroke incidence increased in survivors of adult cancers? A systematic review and meta-analysis
.
J Cancer Surviv
.
2022 Dec
16
6
1414
48
.
5.
Taccone
FS
,
Jeangette
SM
,
Blecic
SA
.
First-ever stroke as initial presentation of systemic cancer
.
J Stroke Cerebrovasc Dis
.
2008 Jul–Aug
17
4
169
74
.
6.
Uemura
J
,
Kimura
K
,
Sibazaki
K
,
Inoue
T
,
Iguchi
Y
,
Yamashita
S
.
Acute stroke patients have occult malignancy more often than expected
.
Eur Neurol
.
2010
;
64
(
3
):
140
4
.
7.
Stefanou
MI
,
Richter
H
,
Hartig
F
,
Wang
Y
,
Orgel
A
,
Bender
B
.
Recurrent ischaemic cerebrovascular events as presenting manifestations of myeloproliferative neoplasms
.
Eur J Neurol
.
2019 Jun
26
6
903
e64
.
8.
Lun
R
,
Roy
DC
,
Hao
Y
,
Deka
R
,
Huang
WK
,
Navi
BB
.
Incidence of stroke in the first year after diagnosis of cancer-a systematic review and meta-analysis
.
Front Neurol
.
2022 Sep 20
13
966190
.
9.
Kassubek
R
,
Bullinger
L
,
Kassubek
J
,
Dreyhaupt
J
,
Ludolph
AC
,
Althaus
K
.
Identifying ischemic stroke associated with cancer: a multiple model derived from a case-control analysis
.
J Neurol
.
2017 Apr
264
4
781
91
.
10.
Selvik
HA
,
Bjerkreim
AT
,
Thomassen
L
,
Waje-Andreassen
U
,
Naess
H
,
Kvistad
CE
.
When to screen ischaemic stroke patients for cancer
.
Cerebrovasc Dis
.
2018
45
1–2
42
7
.
11.
Parise
CA
,
Bauer
KR
,
Caggiano
V
.
Variation in breast cancer subtypes with age and race/ethnicity
.
Crit Rev Oncol Hematol
.
2010 Oct
76
1
44
52
.
12.
Telli
ML
,
Chang
ET
,
Kurian
AW
,
Keegan
TH
,
McClure
LA
,
Lichtensztajn
D
.
Asian ethnicity and breast cancer subtypes: a study from the California Cancer Registry
.
Breast Cancer Res Treat
.
2011 Jun
127
2
471
8
.
13.
Chen
PC
,
Muo
CH
,
Lee
YT
,
Yu
YH
,
Sung
FC
.
Lung cancer and incidence of stroke: a population-based cohort study
.
Stroke
.
2011 Nov
42
11
3034
9
.
14.
Jang
HS
,
Choi
J
,
Shin
J
,
Chung
JW
,
Bang
OY
,
Kim
GM
.
The long-term effect of cancer on incident stroke: a nationwide population-based cohort study in korea
.
Front Neurol
.
2019 Feb 5
10
52
.
15.
Home: National Registry of Diseases Office [Internet]
.
Singapore: National Registry of Diseases Office
.
c2014
. [updated 2022 Apr 1; cited 2023 Jan 18]. Available from: https://nrdo.gov.sg/.
16.
Venketasubramanian
N
,
Chang
HM
,
Chan
BPL
,
Young
SH
,
Kong
KH
,
Tang
KF
.
Countrywide stroke incidence, subtypes, management and outcome in a multiethnic Asian population: the Singapore Stroke Registry–methodology
.
Int J Stroke
.
2015 Jul
10
5
767
9
.
17.
National Registry of Diseases Office
Singapore Stroke Registry Annual Report 2020
Singapore
National Registry of Diseases Office, Health Promotion Board
2022 Oct
. p.
52
. https://nrdo.gov.sg/docs/librariesprovider3/default-document-library/ssr-web-report-2020c544bb698cf04ad1aaaa7a1472296132.pdf.
18.
National Registry of Diseases Office
Singapore Cancer Registry Annual Report 2020
National Registry of Diseases Office, Health Promotion Board
2022 Dec 23
. p.
52
. https://nrdo.gov.sg/docs/librariesprovider3/default-document-library/scr-2020-annual-report_web-release.pdf.
19.
National Registry of Diseases Office
Singapore Cancer Registry Annual Registry Report 2015
Singapore
National Registry of Diseases Office, Health Promotion Board
2017 Jun 19
. p.
43
. https://www.nrdo.gov.sg/docs/librariesprovider3/Publications-Cancer/cancer-registry-annual-report-2015_web.pdf.
20.
Bray
F
Chapter 8: Age-standardization. In:
Parkin
DM
,
Whelan
SL
,
Ferlay
J
,
Teppo
L
,
Thomas
DB
, eds.
Cancer Incidence in Five Continents. IARC Scientific Publications No. 155, VII
Lyon, France
International Agency for Research on Cancer
2002
. p.
87
9
. https://publications.iarc.who.int/Book-And-Report-Series/Iarc-Scientific-Publications/Cancer-Incidence-In-Five-Continents-Volume-VIII-2002.
21.
Zhang
F
,
Wang
K
,
Du
P
,
Yang
W
,
He
Y
,
Li
T
.
Risk of stroke in cancer survivors: a meta-analysis of population-based cohort studies
.
Neurology
.
2021 Jan 26
96
4
e513
26
.
22.
Martinez-Majander
N
,
Ntaios
G
,
Liu
YY
,
Ylikotila
P
,
Joensuu
H
,
Saarinen
J
.
versus aspirin for secondary prevention of ischaemic stroke in patients with cancer: a subgroup analysis of the NAVIGATE ESUS randomized trial
.
Eur J Neurol
.
2020 May
27
5
841
8
.
23.
Schwarzbach
CJ
,
Schaefer
A
,
Ebert
A
,
Held
V
,
Bolognese
M
,
Kablau
M
.
Stroke and cancer: the importance of cancer-associated hypercoagulation as a possible stroke etiology
.
Stroke
.
2012
;
43
(
11
):
3029
34
.
24.
Kono
T
,
Ohtsuki
T
,
Hosomi
N
,
Takeda
I
,
Aoki
S
,
Sueda
Y
.
Cancer-associated ischemic stroke is associated with elevated D-dimer and fibrin degradation product levels in acute ischemic stroke with advanced cancer
.
Geriatr Gerontol Int
.
2012 Jul
12
3
468
74
.
25.
Bang
OY
,
Seok
JM
,
Kim
SG
,
Hong
JM
,
Kim
HY
,
Lee
J
.
Ischemic stroke and cancer: stroke severely impacts cancer patients, while cancer increases the number of strokes
.
J Clin Neurol
.
2011 Jun
7
2
53
9
.
26.
Vineis
P
,
Alavanja
M
,
Buffler
P
,
Fontham
E
,
Franceschi
S
,
Gao
YT
.
Tobacco and cancer: recent epidemiological evidence
.
J Natl Cancer Inst
.
2004 Jan 21
96
2
99
106
.
27.
Caine
GJ
,
Stonelake
PS
,
Lip
GYH
,
Kehoe
ST
.
The hypercoagulable state of malignancy: pathogenesis and current debate
.
Neoplasia
.
2002 Nov–Dec
4
6
465
73
.