Baseline characteristics of patients with ischemic stroke in both groups
Of the initial 1889 patients with IS, 799 were included in the final analysis (Fig. 1). Of these, 53 (6.63%) were diagnosed with active cancer at the time of stroke onset and were assigned to the cancer group, while 746 (93.37%) did not have a history of cancer and were assigned to the control group. Patients with inactive cancer were not included in this study.
Table 1 shows the patient characteristics for both groups. Patients in the cancer group had a significantly higher mean age than those without cancer (mean ± SD: 67.21 ± 10.11 years versus 62.11 ± 12.09 years, respectively; t = 3.00, P < 0.01). The frequency of hyperlipidemia was lower in patients with active cancer than that of the control group (22.6% versus 49.3%, respectively; χ2 = 14.13, P < 0.01). The prevalence of other vascular risk factors did not differ significantly between the two groups. We observed that 35 (66.04%) patients with active cancer had SUE compared to 31 (4.16%) patients in the control group (χ2 = 250.06, P < 0.01), while the LAA subtype was less common in the active-cancer group than that in the control group (9.43% versus 60.99%, respectively; χ2 = 53.85, P < 0.01), as per the TOAST criteria. There were no significant differences in the CE, SVO, and SOE subtypes. We found that the average NIHSS score at admission was higher in the cancer group than that of the control group (mean ± SD 6.13 ± 4.10 versus 4.30 ± 4.48; t = 2.89, P < 0.01). AMCIs were observed more frequently in patients with active cancer than in those without cancer (56.60% versus 19.84%; χ2 = 38.63, P < 0.01). The incidence of deep vein thrombosis or pulmonary embolism during hospitalization was higher in the cancer group than in the control group (13.21% versus 3.75%, respectively; χ2 = 10.56, P < 0.01). Patients with active cancer had significantly higher serum levels of fibrinogen (mean ± SD, 4.44 ± 1.82 versus 3.56 ± 1.02, respectively; t = 3.49, P < 0.01), D-dimer [median (IQR): 2.23 (0.98–10.76) versus 0.35 (0.27–0.48), respectively; Z=-9.55, P < 0.01] and CRP [median (IQR): 18.40 (5.45–46.00) versus 3.90 (2.80–6.33), respectively; Z=-7.35, P < 0.01], but lower levels of hemoglobin (mean ± SD: 119.79 ± 25.68 versus 143.61 ± 18.57, respectively; t=-6.63, P < 0.01) than those in the control group.
Table 1
Baseline characteristics of patients with ischemic stroke and active cancer versus those without cancer
Variables | Cancer Group n = 53 | Control Group n = 746 | t/χ2 | P-value |
Demographics | |
Age, Years | 67.21 ± 10.11 | 62.11 ± 12.09 | 3.00 | < 0.01 |
Sex (% Male) | 34 (64.2) | 522 (70.0) | 0.79 | 0.37 |
Vascular Risk Factors | | | | |
Hypertension | 30 (56.6) | 508 (68.1) | 2.97 | 0.09 |
Diabetes Mellitus | 14 (26.4) | 286 (38.3) | 3.00 | 0.08 |
Hyperlipidemia | 12 (22.6) | 368 (49.3) | 14.13 | < 0.01 |
Atrial Fibrillation | 4 (7.6) | 46 (6.2) | | 0.57 |
Coronary Heart Disease | 8 (15.1) | 106 (14.2) | 0.03 | 0.86 |
Previous Stroke/TIA | 7 (13.2) | 129 (17.3) | 0.59 | 0.45 |
Smoking | 25 (47.2) | 351 (47.1) | 0.00 | 0.99 |
Obesity | 6 (11.3) | 121 (16.2) | 0.89 | 0.35 |
TOAST Classification | | | | |
Large Artery Atherosclerosis | 5 (9.4) | 455 (61.0) | 53.85 | < 0.01 |
Cardioembolism | 2 (3.8) | 33 (4.4) | | 1.00 |
Small Vessel Occlusion | 9 (17.0) | 216 (29.0) | 3.51 | 0.06 |
Other Determined Etiology | 2 (3.8) | 11 (1.5) | | 0.21 |
Undetermined Etiology | 35 (66.0) | 31 (4.2) | 250.6 | < 0.01 |
Ischemic Stroke Characteristics | | | | |
Initial NIHSS Score | 6.13 ± 4.10 | 4.30 ± 4.48 | 2.89 | < 0.01 |
AMCI | 30 (56.6) | 148 (19.8) | 38.63 | < 0.01 |
With VTE or PE | 7 (13.2) | 28 (3.8) | 10.56 | < 0.01 |
Laboratory Markers | | | | |
Hemoglobin (g/L) | 119.79 ± 25.68 | 143.61 ± 18.58 | -6.63 | < 0.01 |
Platelet | 213.28 ± 99.86 | 222.17 ± 66.55 | -0.64 | 0.53 |
Fibrinogen (g/L) | 4.44 ± 1.82 | 3.56 ± 1.02 | 3.49 | < 0.01 |
D-Dimer (mg/mL) | 2.23 (0.98–10.76) | 0.35 (0.27–0.48) | -9.55 | < 0.01 |
CRP (mg/L) | 18.40 (5.45–46.00) | 3.90 (2.80–6.33) | -7.35 | < 0.01 |
Data are represented as mean ± SD, median (IQR), or n (%). |
Abbreviations: AMCI, acute multiple cerebral infarction; VTE, venous thromboembolism; PE, pulmonary embolism; CRP, C-reactive protein; NIHSS, National Institute of Health Stroke Scale; TOAST: Trial of Org 10172 in Acute Stroke Treatment, TIA: transient ischemic attack |
Type, histology, and stage of active cancer
The most commonly observed cancer diagnoses among the patients with IS and active cancer were as follows: lung cancer (n=16, 30.19%), followed by gastric cancer (n=8, 15.09%), liver cancer (n=6, 11.32%), colorectal cancer (n=5, 9.43%), breast cancer (n=5, 9.43%), genitourinary cancers (bladder, prostate, and ovarian cancers; n=5, 9.43%), biliary tract cancer (n=4, 7.55%), and pancreatic cancer, nasopharyngeal cancer, renal cancer, and adrenal cancer (n=1, 1.89% each). Thirty-one (58.49%) patients were diagnosed with adenocarcinoma, and 21 (39.62%) were diagnosed with metastatic disease (Table 2).
Univariate and multivariate logisticregression analyses
We assessed all the risk factors with P-values ≤0.05 (Table 1) using a univariate logistic regression model (including age, hyperlipidemia, LAA, SUE, NIHSS score, AMCI, hemoglobin, fibrinogen, D-dimer, and CRP). The results are shown in Table 3. Notably, we observed that the odds ratios (OR) for age, NIHSS score, hemoglobin, and CRP were approximately 1 based on the findings of univariate logistic regression. Therefore, we considered only the remaining risk factors, including hyperlipidemia, SUE, AMCI, presence of venous thromboembolism or pulmonary embolism, and fibrinogen and D-dimer levels, in the multivariate logistic regression model. This analysis showed that the absence of a history of hyperlipidemia [OR=0.17, 95% confidence interval (CI): 0.06–0.48, P<0.01], elevated serum fibrinogen levels (OR=1.72, 95% CI: 1.33–2.22, P<0.01) and D-dimer (OR=1.43, 95% CI 1.24–1.64, P<0.01), and SUE (OR=22.87, 95% CI: 9.91–52.78, P<0.01) were independently associated with active cancer (Table 3).
Predictive score using the area under the receiver operating characteristic curve
We developed a scoring system to predict active cancer in patients with IS, based on the findings of the multivariate analysis, particularly in the subset of patients with SUE. The final score, ranging from 0–3, comprised the sum of individual scores of the history of hyperlipidemia, serum D-dimer levels, and serum fibrinogen levels. We reviewed and compared several studies to determine the appropriate cut-off values for D-dimer and fibrinogen levels for the scoring system. The OASIS-CANCER study conducted by Lee et al. determined the first quartile of the pre-treatment D-dimer concentration as 2.08 μg/mL and the median fibrinogen concentration as 399 mg/dL [10]. Moreover, Quintas et al. found that the median fibrinogen value of patients with IS without cancer was 408.5 mg/dL [21]. They demonstrated that fibrinogen values were associated with the diagnosis of cancer after IS. Therefore, we analyzed multiple data conditions and assigned the following final scores, according to the findings of previous studies, our clinical experience, and the findings of this study: history of hyperlipidemia=0 points, no history of hyperlipidemia=1 point; D-dimer level ≤2.00 μg/mL=0 points, D-dimer level >2.00 μg/mL=1 point; and fibrinogen level ≤4.00 g/L=0 points, fibrinogen level >4.00 g/L=1 point. Table 4 presents the sensitivity, specificity, and posterior probability for each cut-off point based on the supposed cancer prevalence value of 6.63% in our study. Figure 2 shows that the probability of active cancer was 59%, if a patient with IS had a clinical score of 3 points, with a reliable AUC-ROC curve value of 0.83 (95% CI: 0.77–0.89, P<0.01).
Table 2
Characteristics of patients with ischemic stroke and active cancer
Cancer Location | Histological Type | Number |
Lung Cancer | Adenocarcinoma | 15 |
| Small Cell Carcinoma | 1 |
Gastric Cancer | Adenocarcinoma | 8 |
Liver Cancer | Hepatocellular Carcinoma | 6 |
Colon Cancer | Adenocarcinoma | 3 |
Rectal Cancer | Adenocarcinoma | 2 |
Breast Cancer | Infiltrating Ductal Carcinoma | 4 |
| Medullary Carcinoma | 1 |
Biliary Tract Cancer | Epithelial Cell Carcinoma | 3 |
| Adenocarcinoma | 1 |
Bladder Cancer | Transitional Epithelial Carcinoma | 3 |
Prostate Cancer | Adenocarcinoma | 1 |
Ovarian Cancer | Serous Carcinoma | 1 |
Pancreatic Cancer | Adenocarcinoma | 1 |
Nasopharyngeal Cancer | Squamous Cell Carcinoma | 1 |
Renal Cancer | Clear Cell Carcinoma | 1 |
Adrenal Cancer | Cortical Carcinoma | 1 |
Metastatic Disease | | 21 |
Table 3
Univariate and multivariate logistic regression analyses of risk factors in patients with ischemic stroke with active cancer and those without cancer
| Univariate Logistic Regression Analysis | Multivariate Logistic Regression Analysis |
Variables | OR (95% CI) | P-value | OR (95% CI) | P-value |
Age | 1.04 (1.01, 1.07) | < 0.01 | | |
Hyperlipidemia | 0.30 (0.16, 0.58) | < 0.01 | 0.16 (0.06, 0.45) | < 0.01 |
LAA | 0.07 (0.02, 0.17) | < 0.01 | | |
SUE | 44.85 (22.89, 87.88) | < 0.01 | 19.30 (7.93, 48.96) | < 0.01 |
NIHSS score | 1.06 (1.02, 1.11) | < 0.01 | | |
AMCI | 5.27 (2.97, 9.34) | < 0.01 | 1.58 (0.66, 3.81) | 0.31 |
with VTE or PE | 4.56 (1.97, 10.58) | < 0.01 | 0.92 (0.21, 3.94) | 0.91 |
Hemoglobin (g/L) | 0.95 (0.94, 0.96) | < 0.01 | | |
Fibrinogen (g/L) | 1.63 (1.35, 2.00) | < 0.01 | 1.70 (1.31, 2.21) | < 0.01 |
D-dimer (µg/mL) | 1.72 (1.45, 2.03) | < 0.01 | 1.42 (1.23, 1.65) | < 0.01 |
CRP | 1.03(1.02, 1.04) | < 0.01 | | |
Abbreviations: LAA, large-artery atherosclerosis; SUE, stroke of undetermined etiology; NIHSS, National Institute of Health Stroke Scale; AMCI, acute multiple cerebral infarction; VTE, venous thromboembolism; PE, pulmonary embolism; CRP, C-reactive protein |
Table 4
Predictive score values and posterior probabilities for cancer in patients with ischemic stroke
Score | Sensitivity | Specificity | Posterior probability |
1 | 0.96 | 0.37 | 0.09 |
2 | 0.68 | 0.88 | 0.27 |
3 | 0.19 | 0.99 | 0.59 |