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Pyothorax-associated angiosarcoma metastasized to the brain with multiple and progressively expanding hematomas: Case report and literature review

The brain metastasis of angiosarcoma is very rare, and little is known about its clinical features or therapeutic strategy. A 74-year-old male was hospitalized for disturbance of consciousness. Radiological examination revealed multiple cerebral hematomas. Gadolinium contrast-enhanced magnetic resonance imaging showed no significant enhancement at any of the lesions. To detect a suspected metastatic brain tumor or abscess, a full-body scan was performed but revealed only a poorly enhanced mass in the removal cavity caused by thoracoplasty in the left upper chest. After admission, a cascade of expansion of those hematomas occurred in the right frontal, left parietal, and right temporal lobes, and each lesion thus had to be sequentially removed by craniotomies. The pathological diagnosis of the right frontal lesion was an abscess with hematoma. However, a malignant vascular tumor was highly suspected because of many CD31(+)/Ki-67(+) cells in the left parietal lesion. A mass in the scar caused by thoracoplasty was suspected to be the primary lesion, and brain metastasis of angiosarcoma was finally diagnosed. Whole-brain irradiation and systemic paclitaxel administration were performed, and a complete response for the brain lesions was obtained for 22 months; the patient then died of an intratracheal hemorrhage. This case represents the first report of multiple brain metastases from pyothorax-associated angiosarcoma accompanied by sequentially and gradually expanding hematomas, as well as the first case with the control of metastatic brain lesions for over 1 year after the onset of neurological symptoms. Control of the lesions could be achieved by their total removal with complete hemostasis, as well as additional radio- and chemotherapy.


Introduction
Angiosarcomas are aggressive and rare malignancies, representing <1% of all sarcomas. Angiosarcomas can metastasize to various organs, but only a small number of reports have described brain metastasis  including only one pyothorax-associated angiosarcoma. [20] Therefore, the clinical features and therapeutic strategies for such cases have not been well elucidated. Here, we report a case of pyothorax-associated angiosarcoma metastasized to the brain with multiple and sequentially expanding intracerebral hematomas. This case represents the first report of the control of metastatic brain lesions for over 1 year after the onset of neurological symptoms. The specific clinical course, radiological findings, and therapeutic strategies are discussed, and a comprehensive literature review is included.

Methods
The informed consent of the patient's spouse was acquired for data publication, and Institutional Review Board approval of Shimane University was obtained, and the patient's informed consent was not required.

Case Report
A 74-year-old male with past histories of thoracoplasty for tuberculosis (50 years earlier) and transurethral resection of bladder cancer (7 years earlier) was hospitalized with disturbance of consciousness. Head computed tomography (CT) revealed four hematomas with perifocal edema [ Figure 1a-c], suggesting several different diagnoses, including a metastatic brain tumor, brain abscess, hemorrhage from bacterial aneurysms, or other vascular abnormality such as cavernoma. On the magnetic resonance imaging (MRI) results [ Figure 2a-f], diffusion-weighted imaging showed low signal intensity [ Figure 2e], and T2* imaging exhibited very low signal intensity at all lesions [ Figure 2d]. Gadolinium (Gd) contrast-enhanced MRI showed no significant enhancement at any of the lesions [ Figure 2f]. Blood testing revealed no evidence of infection. A whole-body CT scan found a poorly enhanced mass in the removal cavity caused by thoracoplasty in the left upper chest [ Figure 3a].
A CT-guided biopsy for the thoracic lesion was performed, but only necrotic tissue was obtained. The right frontal lobe hematoma gradually enlarged, and the patient's consciousness became drowsier. Therefore, total removal of the hematoma was performed through emergent craniotomy [ Figure 1a]. The pathological diagnosis of the specimen was an abscess with bleeding, but the intraoperative view of the hematoma was that of a chronic subdural hematoma. Accordingly, carbapenem antibiotics were initiated based on the diagnosis. Various blood cultures and polymerase chain reaction results for acid-fast bacillus were all negative. One week later, the left parietal lobe hematoma began to enlarge, and disturbance of consciousness and right-side paralysis appeared. This hematoma was also removed through craniotomy [ Figure 1b]. One month after the second surgery, disturbance of consciousness appeared once again. Head CT revealed that the right temporal lobe hematoma had enlarged [ Figure 1c], and total removal of the hematoma through craniotomy was chosen again.
The pathological findings of the left parietal lesion also indicated an abscess, but irregular lumen-like structures consisting of epithelioid cells with highly atypical nuclei and distinct nucleoli were seen in part of the lesion [ Figure 4a]. Immunohistologically, epithelial markers (AE1/AE3 and CK7) were strongly positive although CK20 was negative. Therefore, the lesion was diagnosed as a metastatic brain tumor. Because the immunohistological pattern of the patient's bladder cancer 7 years before was CK7−/CK20+ and no local recurrent lesions or peripheral lymph node swellings were detected, metastasis from the bladder cancer was considered unlikely. Positron-emission tomography was performed in a search for the primary lesion, and a faint accumulation was detected in the mass of the scar due to thoracoplasty [ Figure 3b]. Further examination of the second surgical specimen showed strong positivity for the vascular endothelial marker CD31 [ Figure 4b] although it was negative for CD34 [ Figure 4c]. The lumen-like structures were thus thought to be blood vessel lumens. Considering these abnormal immune profiles, the high MIB-1 index of approximately 30% [ Figure 4d] and a clinical diagnosis of pleural angiosarcoma related to continuous posttuberculosis inflammation of the thoracoplasty site, metastatic angiosarcoma was finally diagnosed.
Whole-brain irradiation of 40 Gy and local-thoracic irradiation of 75 Gy were performed based on a definitive diagnosis of metastatic brain tumor, and chemotherapy was chosen using paclitaxel anticancer agents. No recurrence related to the brain lesions was seen for 22 months after surgery [ Figure 5a-c] although the thoracic mass lesion began to expand gradually. At 24 months after the onset of neurological symptoms, the patient died of an airway obstruction caused by an intratracheal hemorrhage.

Discussion
Angiosarcoma can metastasize to various organs, but metastasis to the brain is very rare. [34,35] Primary pleural angiosarcoma is also rare but occurs 3600 times more frequently in patients affected by chronic tuberculous pyothorax than in those without any specific inflammatory condition. [36] Only one report, containing no brain images, has described a case of pleural angiosarcoma metastasizing to the brain. [20] Our case represents the first report with detailed images of multiple brain metastases from pleural angiosarcoma accompanied by unusual and gradually expanding hematomas; it is also the most controlled case of metastatic brain angiosarcoma in the literature.

Metastatic
brain angiosarcoma often shows a well-circumscribed mass with hypointensity on T2-weighted MRI imaging and partial enhancement by Gd. The hypointensity on T1-and T2-weighted imaging is thought to be useful in differentiating angiosarcoma from other diseases. [8,21] In our patient, all lesions were signal hypointense areas on T1-, T2-, diffusion-, and T2*-weighted imaging, showing almost no enhancement with Gd. Although these findings agree with those of previous reports, angiosarcoma could not be diagnosed. The cerebral hematomas in our case also gradually and sequentially expanded, with accompanying neurological deterioration. A history of chronic expanding intracerebral hematoma     [25] 61/female and pulmonary tuberculosis has been used in differentiating angiosarcoma from conditions such as the progression of brain tuberculoma, but neither symptom was typical. [37,38] It was difficult to correctly diagnose the lesions based on the MRI results, and we struggled to establish a treatment plan.
Immunohistochemical examination of autopsy specimens has been performed for 98 cases diagnosed with angiosarcoma. [39] In the region of vascular formation, the proportion of markers in the cytoplasm or cell surfaces that showed diffuse positive reactions were as follows: factor VIII-related antigen (von Willebrand factor), 84%; CD31, 80%; and Ulex europaeus lectin type 1, 70%. Additional immunohistology results, such as those for CD34, cytokeratin, and vimentin, are reportedly useful in diagnosing angiosarcoma. [39] In the present case, angiosarcoma was diagnosed from the finding of strong positivity for CD31, which is thought to have a high level of specificity for vascular endothelium. Total removal of the thoracic mass that was thought to be the primary lesion would have been difficult, and no malignant findings were obtained from the biopsy specimen. However, the continued enlargement of the thoracic mass and subsequent fatal bleeding suggested that angiosarcoma also existed in parts of the lesion.
The prognosis of angiosarcoma is very poor, with a 2-year survival rate of 17% and a 5-year survival rate of 12%. [34] Even if the lesion disappears temporarily due to radiotherapy or surgical removal, recurrence or metastasis often occurs within 2 years. [9] Nearly all patients with pleural angiosarcoma developed from chronic tuberculosis pyothorax reportedly die within 1 year from onset, regardless of the presence of metastases. [36] To the best of our knowledge, 34 cases of metastatic brain angiosarcoma have been reported, half of which were metastases from the heart [ Table 1].  Metastatic lesions of the brain are usually multiple at diagnosis, and differentiation from intracerebral hemorrhages [26] or cavernous angiomas [23,27] based only on radiological findings is difficult. Only two previous cases had a history of expanding hematoma in a short period as was observed in our case. [8,24] Although 11 cases survived over 1 year after diagnosis of the primary lesion, the mean survival time from the onset of neurological symptoms due to a metastatic brain lesion was approximately 2.7 months (3 days-9 months). The regulation methods for angiosarcoma include the selection of high dose (>50 Gy) and wide treatment fields for radiotherapy. [40] Doxorubicin, liposomal doxorubicin, and taxanes are reported as the most common chemotherapeutic agents for metastatic angiosarcoma. [41] Recently, weekly paclitaxel after radiotherapy has been reported as effective chemotherapy. [42,43] We selected 40 Gy whole-brain irradiation for the intracranial lesions and systemic administration of paclitaxel as adjuvant therapy, and the intracranial lesions were completely controlled through 22 months after surgery. Decompression of the intracranial lesions and complete hemostasis by surgical removal before whole-brain radiotherapy is thought to have successfully controlled the lesions.

Conclusion
When multiple, gradually expanding, and atypical intracranial hematomas are seen, differentiation from brain metastases of angiosarcoma is necessary. Careful histopathological examination is required for definitive diagnosis. When the possibility of angiosarcoma is encountered, total removal of the lesions with complete hemostasis through craniotomy, followed by whole-brain irradiation, is important for their control.

Financial support and sponsorship
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Conflicts of interest
There are no conflicts of interest.