White Embolus-induced Basilar Artery Occlusion Due to Pulmonary Vein Invasion of a Metastasis of a Malignant Melanoma

Abstract

An 80-year-old woman presented with impaired consciousness after malignant melanoma resection. Magnetic resonance angiography showed basilar artery occlusion, which was subjected to mechanical thrombectomy for recanalization. A pathological analysis of the retrieved embolus revealed that it was derived from a metastasis of malignant melanoma. Contrast-enhanced chest computed tomography showed multiple pulmonary metastases, one of which was in the right upper lobe and invaded the pulmonary vein. To our knowledge, this is the first case of white embolus-induced cerebral embolism due to pulmonary vein invasion of a metastasis of a pathologically diagnosed malignant melanoma.

Introduction

Tumor embolism is a mechanism of cancer-related stroke in which tumor cells themselves form emboli. In recent years, it has been diagnosed by a pathological analysis of emboli retrieved by mechanical thrombectomy (1-3).

We herein report the first case of white embolus-induced cerebral embolism due to pulmonary vein invasion of a metastasis of a pathologically diagnosed malignant melanoma.

Case Report

An 80-year-old woman collapsed at home, underwent intubation to secure her airway, and was transported to our hospital by a helicopter. Four years earlier, a nodule in her right big toe had been resected and pathologically diagnosed as malignant melanoma. The patient received postoperative chemotherapy with nivolumab for one year. Three years after resection, fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (CT) revealed metastasis in the right obturator lymph node, and chemotherapy with nivolumab was resumed.

The duration from last known point of being well to her arrival was 20 h, but the onset was deemed to have been within approximately 6 h, based on where she collapsed. The Glasgow Coma Scale score was 6 (E1VTM4). Neurological examination results revealed a bilateral miosis and quadriplegia, and the National Institutes of Health Stroke Scale score was 33. The electrocardiogram showed a sinus rhythm. Blood test results were as follows: C-reactive protein, 1.39 mg/dL (reference range: 0-0.14 mg/dL); platelets, 274,000 /μL (reference range: 160,000-360,000 /μL); brain natriuretic peptide, 12.9 pg/mL (reference range: <18.4 pg/mL); activated partial thromboplastin time, 28 s (reference range: 24.7-38.7 s); international normalized ratio, 1.02 (reference range: 0.9-1.1); and D-dimer, 2.5 μg/mL (reference range: 0-1.0 μg/mL). Head CT showed low-density areas in the medial midbrain but no hyperdense signs in the basilar artery (Fig. 1A). Imaging findings were as follows: occlusion at the tip of the basilar artery on magnetic resonance angiography; high-signal-intensity areas in the bilateral midbrain and thalamus on diffusion-weighted magnetic resonance imaging; and 6 points in the posterior circulation Alberta Stroke Program Early CT Score (pc-ASPECTS) (Fig. 1B). Mechanical thrombectomy was performed for the possible presence of penumbra areas in the bilateral cerebellum and bilateral occipital lobes.

Figure 1.

Images before and during thrombectomy. (A) Head CT on the day of admission showing no hyperdense signs in the basilar artery. (B) Diffusion-weighted magnetic resonance imaging on the day of admission showing high-signal-intensity areas in the bilateral midbrain and thalamus. (C) Right vertebral angiography before thrombectomy (anteroposterior view) showing occlusion at the tip of the basilar artery. The bilateral posterior cerebral arteries and bilateral superior cerebellar arteries were not visualized. (D) A white embolus retrieved with a stent retriever. (E) The embolus retrieved from the basilar artery was macroscopically white and friable. (F) Right vertebral angiography after thrombectomy (anteroposterior view) showing the recanalization of the basilar artery and right calcarine artery occlusion.

An 8-Fr guiding catheter was placed in the right vertebral artery via a right transfemoral approach because of severe tortuosity at the origin of the left vertebral artery. Right vertebral angiography showed occlusion at the tip of the basilar artery. Bilateral posterior cerebral arteries and bilateral superior cerebellar arteries were not visualized (Fig. 1C). A stent retriever (Embotrap III 5.0×37 mm; Cerenovus, Irvine, USA) was placed via the P2 segment of the right posterior cerebral artery toward the basilar artery. Stenosis was observed in the V4 segment of the right vertebral artery, to which an aspiration catheter (React 71; Medtronic, Minneapolis, USA) was guided. When the stent retriever was retrieved into the aspiration catheter, a white and friable embolus attached to the stent retriever was also retrieved (Fig. 1D, E). Right vertebral angiography showed recanalization of the basilar artery and distal embolization of the calcarine artery in the P4 segment of the right posterior cerebral artery (Fig. 1F).

Results of a pathological analysis of the retrieved embolus showed densely proliferating, loosely connected atypical cells with darkly stained enlarged nuclei and pale eosinophilic cytoplasm. Some areas had a flowing array of spindle-shaped atypical cells with a myxomatous background. No melanin production was noted. Immunostaining was negative for HMB-45, melan-A, desmin, and smooth muscle actin but mostly positive for S-100, indicating that the preexisting malignant melanoma was the embolic source. The embolus contained a small amount of fibrin, platelets, and red blood cells (Fig. 2A-C).

Figure 2.

Pathological findings of the embolus and contrast-enhanced chest CT images. (A, B) Hematoxylin and Eosin staining showing densely proliferating, loosely connected atypical cells with darkly stained enlarged nuclei and pale acidophilic sporangia. A flowing array of spindle-shaped atypical cells was observed in some areas. Panel B is an enlarged view of the area enclosed by the rectangle in panel A. (C) Immunostaining of the embolus showing mostly S-100 positivity. Panel C is an enlarged view of the area enclosed by the rectangle in panel A. (D) Contrast-enhanced chest CT (coronal view) showing a pulmonary metastasis in the right upper lobe (arrowhead) that invaded the pulmonary vein (arrow). (E) Contrast-enhanced chest CT (axial view) showing a mediastinal lymph node metastasis in the right pulmonary hilum (arrowhead) that was in contact with the pulmonary vein (arrow).

The day after thrombectomy, the patient remained unconscious and quadriplegic, and the National Institutes of Health Stroke Scale score was 31. Extubation was possible and thus performed. Imaging findings were as follows: cerebral infarction in the bilateral midbrain, left pons, and bilateral thalami on magnetic resonance imaging; the patency of the basilar artery on magnetic resonance angiography; and multiple pulmonary metastases, one of which was in the right upper lobe and invaded the pulmonary vein, on contrast-enhanced CT. In addition, a mediastinal lymph node metastasis in the right pulmonary hilum was in contact with the pulmonary vein (Fig. 2D, E). Contrast-enhanced CT showed mild calcification in the arterial walls of the aortic arch and its branches but no irregular plaque protrusion or tumor invasion into the aortic wall. No stenosis of the large vessels was noted. A pathological fracture of the left acetabulum was detected due to pelvic metastasis, and the left external iliac vein and left uterine vein were obstructed by tumor invasion. No emboli to organs other than the brain were observed. Contrast-enhanced CT and transthoracic echocardiography showed no evidence of cardiac metastasis or right-to-left shunts. Transesophageal echocardiography was not performed because of her impaired consciousness. Atrial fibrillation was not detected on the monitored electrocardiogram. Based on the pathological and CT findings, cerebral embolism was diagnosed due to pulmonary vein invasion of a metastasis of malignant melanoma. On the 50th day after admission, the patient was transferred to another hospital for recuperation; her modified Rankin Scale score was 5. Unfortunately, on the 93rd day after the onset, she died of tumor progression.

Discussion

In the present case, the laboratory findings were negative for conventional emboli, such as cardiogenic emboli and artery-to-artery emboli. Given the detected metastases of malignant melanoma, cerebral infarction due to cancer-related coagulopathy or nonbacterial thrombotic endocarditis was initially suspected. Blood tests, however, did not indicate thrombocytopenia or coagulation abnormalities; D-dimer, a marker for hypercoagulopathy in cancer patients, was only mildly elevated (4). The laboratory findings did not support cancer-related coagulopathy or nonbacterial thrombotic endocarditis. Although the literature suggests that malignant melanoma increases the risk of both ischemic and hemorrhagic stroke, few studies have discussed the association between cancer-related coagulopathy and malignant melanoma (5,6).

Because melanin-producing melanoma was thought to exhibit a tan to black hue, when a white embolus was retrieved, cerebral embolism due to metastasis of malignant melanoma was initially ruled out; however, a pathological analysis revealed that it was derived from a metastasis of malignant melanoma. The causes of tumor embolism are classified as cardiac tumors, such as left atrial myxoma, and noncardiac tumors. The causes of noncardiac tumor embolism include aortic invasion, pulmonary vein invasion, and embolism via a right-to-left shunt (7-9). In the present case, aortic invasion was not observed on contrast-enhanced CT, and a right-to-left shunt was not detected on transthoracic echocardiography. Transesophageal echocardiography was not performed. Primary or metastatic tumors of the lung are types of tumors that cause tumor embolism due to noncardiac tumors and thus are the most frequently reported. Lung tumors are thought to cause cerebral infarction and systemic embolism due to tumor fragmentation in the pulmonary veins (8,10,11). These cases are not always accompanied by left atrial invasion (12). Bhatia et al. (8) reported cerebral tumor emboli in a case of lung metastasis from breast cancer and suggested that tumor embolism should be considered in the differential diagnosis in cancer patients, especially those with lung metastases. Malignant melanoma is a severe skin cancer prone to invasion and metastasis commonly in the lungs, liver, brain, and bones, as well as in the heart (13). In the present case, there was no evidence of cardiac metastasis, and a metastasis in the right upper lobe of the lung had invaded the pulmonary vein; therefore, the most likely source of cerebral embolism was considered to be pulmonary vein invasion of a pulmonary metastasis.

To our knowledge, four cases of tumor embolism due to malignant melanoma, including this case, have been reported (Table). Kim et al. (14) reported a case of cerebral tumor embolism due to malignant melanoma diagnosed by a pathological analysis of an embolus retrieved by an aspiration catheter. Grazziotin et al. (15) reported a case of tumor embolism in the left lower extremity artery in which urgent femoral embolectomy was performed, and the blood flow to the lower extremity was restored. Harris et al. (16) reported a case of abdominal aortic occlusion due to tumor embolism associated with malignant melanoma, in which the blood flow was restored by embolectomy via a bilateral transfemoral approach.

Table.

Reports of Tumor Emboli Associated with Malignant Melanoma.

Case	Patient age/sex	Occlusion site	Embolus color	Probable embolic source	Reference
1	22/F	Left middle cerebral artery	Not described	Cardiac metastasis	(14)
2	64/F	Left lower extremity artery, right middle cerebral artery	Brown-tan to white-tan	Cardiac metastasis	(15)
3	56/F	Abdominal aorta, iliac, femoral, popliteal artery	Tan	Tumor invasion of the pulmonary vein	(16)
4	80/F	Basilar artery	White	Tumor invasion of the pulmonary vein	Present case
F: female

S-100 positivity in immunostaining is a highly sensitive marker for malignant melanoma, as well as for other tumors (17). Pathological findings of the embolus in this case showed that the tumor cell binding was generally loose, so an epithelial tumor was deemed unlikely. Characteristically, the spindle-shaped cells were arranged in a flowing array with a myxomatous background. This finding led to the differential diagnosis of malignant melanoma or intimal sarcoma. Immunostaining was negative for desmin and smooth muscle actin, which can be positive in intimal sarcoma. HMB-45 and melan-A, which can be positive in malignant melanoma, were negative, while S-100 was almost positive. Since intimal sarcoma is often negative for S-100, we diagnosed it as malignant melanoma (18).

In previous reports of tumor embolism associated with malignant melanoma, the color of the retrieved embolus was tan (15,16). In the present case, the tumor cells were derived from amelanotic melanoma without melanin production, so the retrieved embolus was white with only a small amount of fibrin, platelets, and red blood cells. In some previous reports, tumor emboli were whitish (3,8,11). The gross appearance of tumor emboli is determined by the degree of pigmentation, necrosis, and admixture of erythrocytes, platelets, and fibrin fibers. If a metastatic tumor, not limited to malignant melanoma, is poorly pigmented and contains few erythrocytes, platelets, and fibrin fibers, its emboli are expected to be macroscopically white to grayish white. In the present case, the tumor cells that invaded the pulmonary vein existed with blood, but because there was no coagulopathy or venous congestion, only a small amount of thrombus adhesion may have occurred. Because cancer-related ischemic stroke, such as nonbacterial thrombotic endocarditis, may also present as grossly white thrombi with high platelet fractions (19,20), a pathological analysis as well as the gross observation of emboli are important.

In conclusion, cancer patients with multiple metastases may have cerebral infarction due to tumor embolism, and their tumor emboli may be whitish. A combination of gross observation and the pathological analysis of emboli is useful for determining the source of cerebral embolism.

notes

Written informed consent was obtained from the patient's eldest son for the publication of this case report and all accompanying images.