Diffusion‐weighted imaging‐documented bilateral small embolic stroke involving multiple vascular territories may indicate occult cancer: A retrospective case series and a brief review of the literature

Abstract Diffusion‐weighted imaging (DWI) MRI is very sensitive for detecting small embolic brain infarctions. Stroke as the first manifestation of cancer is extremely rare. We performed a retrospective study to identify the clinical and DWI features of patients with acute ischemic stroke as the first manifestation of occult cancer. A total of five patients in our hospital from January 2017 to May 2019 were analyzed. We also reviewed the literature and seven case series (16 patients) were included. Most of these patients were aged in their sixties and lung cancer was the most common type of occult cancer. Patients showed various presentations of ischemic stroke. All of the patients showed small multiple lesions on DWI that involved mostly the anterior or both anterior and posterior territories. The lesions were mostly in both the supratentorium and infratentorium, with the mechanisms of embolic and watershed infarcts. These features were useful for identifying the causes of embolic stroke. Therefore, patients with small bilateral embolic stroke, especially those involved in multiple vascular territories, should be examined for concealed malignancy.

the DWI presentations of cancer-related stroke. Here, we report five cancer patients with ischemic stroke as the first presentation. We also briefly review the literature on this topic.

| PATIENTS AND ME THODS
This study included all patients who had presented with acute brain infarction and had been first diagnosed with cancer at the time of stroke presentation at the Department of Neurology of the Affiliated Hospital of the Medical School of Qingdao University from January 2017 to May 2019. Symptom duration was not considered for patient inclusion as long as an acute infarct was identified in DWI. 6 Patients with known cancer who were admitted because of a new stroke were excluded. Patients whose cancers had been diagnosed 1 month after the presentation of acute ischemic stroke were also excluded. A total of five patients were analyzed. None of them had cancer history. All patients underwent brain DWI. Magnetic resonance (MR) angiography, computed tomography (CT) angiography, or transcranial Doppler ultrasonography was performed to evaluate the vessels. DWI findings were evaluated by a neuroradiologist blinded to the clinical symptoms and TEE findings. Lesions were considered small when the largest axial diameter was <15 mm, and large if ≥15 mm. Lesions were considered multiple if they were noncontiguous on contiguous slices.
We also systematically searched the studies reporting on embolic stroke as the first manifestation of cancer in PubMed (until May 5, 2019). The following search terms were used: ("stroke," "cancer," "first manifestation") or ("stroke," "malignancy," "first manifestation") or ("stroke," "cancer", "initial manifestation") or ("stroke," "malignancy," "initial manifestation"). Studies reporting stroke as the first presentation of cancer and pictures of DWI were included for further evaluation. Each patient's DWI picture was reviewed by a neuroradiologist.

| Case 1
A 75-year-old man was admitted to our hospital because of dysarthria, which had begun 4 days prior to admission. He had no history of hypertension, diabetes, or heart disease, no familial history of cardiovascular disease, and no use of preventive medication for stroke.

| Case 2
A 79-year-old woman was admitted with confusion and mental dullness, which had begun 3 days before admission. Two months previously, she had had a bad temper and had become irritable; sometimes she had had hallucinations and delusions of persecution. She had undergone excision of a left eye cataract 5 months before admission.
On admission, she was confused and could not cooperate with the doctors. Laboratory tests, including blood routine test, serum electrolytes, renal and hepatic function, blood sugar, coagulation profile, syphilis and HIV tests, and blood fat, were all normal. There were no abnormalities on her ECG, TEE, 24-hour Holter monitoring, or transcranial Doppler.
The DWI showed multiple high signal intensities in the territories of both internal carotid arteries and vertebrobasilar artery. Her chest CT scan showed lung cancer and multiple lung and bone metastases.

| Case 3
A 68-year-old woman was admitted to the hospital with dizziness, disequilibrium, and dysarthria, which she had had for about 2 weeks.
She had a history of hypertension, but no history of diabetes or heart disease, no familial history of cardiovascular disease, and no use of preventive medication for stroke.

| Case 4
A 60-year-old man was admitted with numbness and weakness of the left arm, which had begun 7 days before admission. His symptoms had remitted after about half an hour, but relapsed twice again. Except for the habit of smoking, he had no history of hypertension, diabetes or heart disease, and no familial history of cardiovascular diseases.
On admission, he was oriented and had no lymphadenopathy, no abnormal auscultation respiratory sound, and no palpable masses in his abdomen. His vital signs were normal. There was no abnormality on the ECG. His neurological examination was normal except for right mild central facial palsy and decreased pain in the right arm.
Laboratory tests, including blood routine test, serum electrolytes, renal and hepatic function, blood sugar, coagulation profile, syphilis and HIV tests, and blood fat, were all normal. There were no abnormalities on his TEE or 24-hour Holter monitoring.
A diffusion-weighted brain MRI showed multiple high signal intensities in the territories of both anterior and posterior circulations. CT angiography showed no culprit vessels. His chest CT scan showed lung cancer. The patient was diagnosed with squamous cell lung cancer by transbronchial lung biopsy.

| Case 5
A 68-year-old man was admitted with dizziness and mental dullness,

| RE SULTS
The mean age of our patients was 70 ± 7.31 years. The baseline clinical characteristics of these patients are shown in Table 1. All of the patients had lung cancers and had received no anti-tumor treatment before stroke. Only one patient had no conventional common vascular risk factors of cerebral infarction. The common risk factors were hyperlipidemia, hypertension, and habits of alcohol and smoking. Three patients had increased D-dimer levels, and one patient showed decreased antithrombin III levels. None of the patients had abnormal findings through TEE.

Seven previous case series (16 patients) with DWI sequence
were also analyzed in our study. 3,[7][8][9][10][11][12][13] The mean age of the total patients (21 patients) was 66 years (mean ± SD, 66 ± 11.74 years). Lung cancer was the most common cancer with embolic stroke as the first manifestation. Pancreatic cancer was also common. Fifteen patients underwent D-dimer level detection, and 11 of them showed highly

Cerebral infarction is not uncommon in patients with cancer.
However, it is very rare that infarction presents as the first manifestation of a concealed cancer. Here, we present five patients with multiple cerebral infarctions as an initial presentation of occult cancer. Coincidentally, all of these five patients were diagnosed with lung cancer. This was inconsistent with other case series in which many different cancer origins showed infarction as their first manifestation. However, lung cancer was the most common origin with embolic brain stroke as the first manifestation. This is consistent with the study of Cestari et al. 14 Pancreatic cancer was also a common type with embolic stroke as the initial presentation. The mean age of these patients was in their sixties and they had no common cause of embolic stroke.
The characteristics of stroke with cancer are usually multiple and embolic. 6 16 Tumor embolism, most commonly with primary or metastatic neoplasms of the lung, is a rare cause of cerebral infarction. Infarcts from tumor emboli are typically larger than those seen with nonbacterial thrombotic endocarditis. Non-bacterial thrombotic endocarditis is the most common etiology for stroke in cancer patients. 14 However, it is difficult to diagnose through TEE. Highly increased D-dimer level may indicate hypercoagulation and may be associated with cancer-related stroke. 17 However, abnormal findings could be seen in the coagulation profiles of our patients and previous case series. This may also indicate the dysfunction of the coagulation system. Therefore, the mechanisms of embolic infarctions associated with cancers in our patients could not be confirmed.
Although this study was conducted in a small number of cases, it may indicate that brain multiple embolisms, especially small and bilateral infarctions involved in both anterior and posterior circulations in DWI with unknown causes, could be the first manifestation of occult cancer. Early diagnosis of occult cancer is beneficial for initiating the early management of cancer patients.

ACK N OWLED G M ENTS
This work was supported by the National Science Foundation of China (30901324). F I G U R E 1 Diffusion-weighted imaging patterns of our five patients.