Abstract

Background: Epithelioid hemangioendothelioma (EHE) is a rare malignant endothelial tumor of blood and lymph vessels composed of epithelioid cells within a distinctive myxohyaline stroma. Its predilection sites are soft tissues, bone, lung, and liver, and intracranial metastases are extremely rare. We describe a case of EHE in an elderly patient with pineal body metastasis.

Case Description: An 84-year-old man presented to our hospital with disturbance of consciousness. Neuroimaging showed hydrocephalus and pineal tumor with hemorrhage on computed tomography and gadolinium enhancement on T1-weighted magnetic resonance imaging. Cerebral angiography showed no obvious tumor staining. ¹⁸F-fluorodeoxyglucose (FDG)-positron emission tomography demonstrated accumulations of FDG consistent with the pineal tumor and in the vessel wall and muscle throughout the body. Various tumor markers in the blood and cerebrospinal fluid were negative. Endoscopic biopsy was performed to confirm the diagnosis and to treat the hydrocephalus by endoscopic third ventriculostomy. Histological examination revealed large epithelioid perivascular cells with abundant pale eosinophilic cytoplasm and cytoplasmic vacuolation. Immunohistochemical studies showed positive results for CD34, CD31, cytokeratin AE1/AE3, and calmodulin binding transcription activator 1, and EHE was therefore diagnosed. Because of poor general condition and progressive tumor growth, radiotherapy was administered 7 days after surgery. At 21 days after surgery, endoscopy performed for progressive anemia revealed metastases in the stomach. The lesions continued to grow and the patient died 2 months after surgery.

Conclusion: We present an extremely rare case of EHE presumed metastasis presenting as an isolated pineal region tumor. If a tumor with hemorrhage is found in the pineal body in an elderly patient, EHE should be considered in the differential diagnosis, even if it is a single tumor lesion.

Keywords: Endothelial tumors of blood and lymph vessels, Epithelioid hemangioendothelioma, Pineal body metastasis, Positron emission tomography, WW domain containing transcription regulator 1-calmodulin-binding transcription activator 1 fusion gene

INTRODUCTION

Epithelioid hemangioendothelioma (EHE) is a rare vascular neoplasm originating from vascular endothelial and preendothelial cells.[ 1 , 3 , 7 , 10 ] This rare disease was first described by Weiss and Enzinger in 1982 as a low-grade malignant vascular tumor usually involving soft tissue.[ 15 ] The tumor is predominantly characterized by the presence of fusion genes such as WW domain containing transcription regulator 1 (WWTR1)-calmodulin-binding transcription activator 1 (CAMTA1) or yes-associated protein 1-Transcription factor E3, with a minority of cases exhibiting other rare fusion genes.[ 1 , 3 , 7 , 13 ] It most commonly affects the soft tissues of the extremities but can also occur in the bones, brain, liver, lungs, and lymph nodes. Among these, EHE of the head and neck, especially of the central nervous system (CNS), is very rare.[ 1 , 12 , 14 ] To the best of our knowledge, no cases of EHE in the pineal region have been reported. We report our experience with an extremely rare case of EHE metastasis in the pineal body, in which diagnosis and treatment were difficult. We also present the pathological and molecular features of this entity.

CASE DESCRIPTION

An 84-year-old man with no relevant medical history presented to our department with a 1-week history of consciousness disturbance. Intracranial computed tomography (CT) revealed marked ventricular enlargement and pineal tumor with hemorrhage. However, an incidental CT performed 2 years ago showed no obvious tumor in the region of the pineal gland [ Figures 1a and b ]. Magnetic resonance imaging demonstrated a tumor mass in the pineal body that appeared hypointense on T1-weighted imaging (WI), T2-WI, fluid-attenuated inversion recovery, and diffusion WI. The center of the tumor was partially hyperintense, indicating hemorrhage, with strong enhancement on T1-WI using gadolinium contrast [ Figures 1b and c ]. Markedly high ¹⁸F-fluorodeoxyglucose uptake was seen on positron emission tomography within the enhancing region (tumor-to-contralateral normal brain tissue ratio: 2.5) and in multiple soft tissues (including the lower extremities) in contact with blood vessels [ Figures 2a - c ]. However, no accumulation was evident in the lungs or any other part of the body. Cerebral angiography showed no obvious tumor staining. Various tumor markers, for example, a-fetoprotein, carcinoembryonic antigen, β2-microglobulin, and so on, in the blood and cerebrospinal fluid (CSF) were negative, and no other laboratory findings were abnormal including CSF findings. On initial consideration, the patient’s history and the results of laboratory examinations and radiological studies seemed most consistent with malignant lymphoma or metastatic tumor of unknown origin than pineal parenchymal tumors.

Figure 1:

(a-1) Incidental computed tomography (CT) performed 2 years ago shows no abnormal masses. (a-2) Axial CT without contrast enhancement shows pineal tumor with hemorrhage and marked ventricular enlargement. (b) Preoperative magnetic resonance imaging demonstrates a tumor mass in the pineal body that appears hypointense on (b-1) axial T1-weighted imaging [WI],(b-2) T2-WI, (b-3) fluid-attenuated inversion recovery, (b-4) and diffusion WI. (c-1, axial view; c-2, sagittal view) The center of the tumor is partially hyperintense, indicating hemorrhage, with strong enhancement on T1-WI using gadolinium contrast.

Figure 2:

¹⁸F-fluorodeoxyglucose-positron emission tomography shows abnormally high uptake in the pineal lesion in the same sites identified on magnetic resonance imaging (white arrows), and throughout the body in multiple soft tissues in contact with blood vessels (white dashed arrows). (a-1, a-2) cranial, (b) whole body: coronal view, (c-1, c-2, c-3, c-4) whole body: axial views.

To confirm a histological diagnosis and plan effective treatment for the primary disease, we therefore performed surgical biopsy and third ventriculostomy by neuro-flexible endoscope. In this case, it was also necessary to perform a biopsy of the pineal tumor and a third ventriculostomy to relieve hydrocephalus simultaneously. Hence, the surgical procedure with piece resection for diagnostic purposes was performed through the foramen of Monro from the anterior horn of the right lateral ventricle. Histological examination revealed that the tumor was composed of densely clustered tumor cells and large epithelioid perivascular cells with abundant pale eosinophilic cytoplasm and cytoplasmic vacuolation. The tumor cells proliferated both inside and outside nontumoral blood vessels, preserving its architecture without forming sinusoidal vascular channels. Mitotic images of tumor cells were inconspicuous with only 2 per 10 high-power fields. Immunohistochemical studies showed positive results for cytokeratin (CK) AE1/AE3, cluster of differentiation 31, and ets-related gene; and the Ki-67 staining index was 25.0%. CAMTA1 immunostaining performed to confirm the presence of the WWTR1-CAMTA1 fusion gene revealed positive staining in the nucleus, and EHE was therefore diagnosed [ Figure 3 ]. In addition, given the multiple lesions throughout the body, we suspected metastatic EHE, although the primary site remained unknown. CT obtained 7 days after surgery showed progressive tumor growth [ Figure 4a ], and radiotherapy was administered promptly for the treatment of metastatic brain tumors (whole brain: 30.0 Gy in 10 fractions). However, at 21 days after surgery, endoscopy performed due to progressive anemia revealed metastases in the stomach [ Figure 4b ]. Although there was no worsening of hydrocephalus or pineal tumor hemorrhage, no therapeutic effects were observed and the lesions continued to grow, and the general condition further deteriorated, the patient died 2 months after surgery. The clinical study of this case was approved by the ethics committee of our institution, and informed consent was obtained from the patient.

Figure 3:

Histopathology of the biopsy specimen. (a) Hematoxylin and eosin (HE) staining shows the tumor is composed of densely clustered tumor cells and large epithelioid perivascular cells with abundant pale eosinophilic cytoplasm and cytoplasmic vacuolation. Immunohistochemistry shows tumor cells positive for (b)cytokeratin (CK) AE1/AE3, (c)cluster of differentiation (CD) 31, and (d) ets-related gene (ERG). (e) The Ki-67 staining index was 25.0%. (f) Nuclei stain positive for calmodulin binding transcription activator 1 (CAMTA1). a-f: magnification, ´400; scale bar, 250 µm.

Figure 4:

(a) Tumor growth is evident on postoperative computed tomography obtained at 7 days after surgery. (b) Photomicrographs show the tumor histopathology of metastases in the stomach. (b-1) Hematoxylin and eosin staining shows abundant tumor cells with clear nucleoli and pale sporangia in the lower part of the gastric orifice epithelium without atypia, consistent with epithelioid hemangioendothelioma. (b-2) Immunohistochemically, the tumor cells are positive for calmodulin binding transcription activator 1. Magnification, ×200; scale bar, 100 µm.

DISCUSSION

Metastatic brain tumors in the pineal region are extremely rare. The most common primary site is the lung, particularly in cases of small cell carcinoma, but reported cases are extremely rare. Furthermore, this is the first reported case of EHE metastasis to the pineal region.[ 8 ] EHE was described by Weiss and Enzinger in l982 as a moderately malignant vascular tumor clinically intermediate between hemangioma and angiosarcoma.[ 15 ] In 2002, the World Health Organization described EHE as lesions that fall into the category of locally aggressive tumors with metastatic potential.[ 3 ] Among adults, EHE occurs with a slight preponderance in women, with a peak age of onset in the fourth to fifth decades. The most common vascular sites of origin are the middle and large veins of multiple organs and tissues, with extremities, bones, liver, and lungs as the predominant sites.[ 1 , 7 , 12 ] Regarding prognosis, Weiss et al. reported the results of patients with primary soft tissue EHE who were followed for an average of 48 months.[ 16 ] Among the 46 patients, 13% had recurrence and 31% had metastases in the lymph nodes, liver, or bone. Average survival was 4–6 years, ranging from 5 months to 15 years. Compared to other organs, the mortality rates were 31% for liver and 65% for lung, indicating that the prognosis of EHE with a soft tissue primary is significantly better than that of EHE with a bone, liver, or lung primary.[ 9 ]

In contrast, Sardaro et al. reported that the biologic behavior of EHE is typically of a more indolent cancer resulting in a mean survival of 4.6 years, ranging from 6 months to 24 years.[ 10 ] In fact, delayed diagnosis is sometimes reported because the presentation is that of local tumor rather than having metastatic potential. Therefore, rapid and appropriate diagnosis requires clinical recognition of the disease and tissue biopsy with appropriate staining. However, the diagnosis of EHE that occurs in CNS can be challenging due to its rarity and because there are very few literature reports.

The optimal treatment strategy following histological diagnosis and staging of brain EHE remains contentious. The histopathological findings are of large epithelioid perivascular cells with abundant pale eosinophilic cytoplasm and cytoplasmic vacuolation (so-called “blister cells”), which may form lumen and have red blood cells within, vesicular nuclei, and prominent nucleoli; tuft-like projections into capillaries; cells may be in well-circumscribed paucicellular nodules; or poorly formed cellular aggregates.[ 3 ] Tumor cells proliferate inside and outside nontumor vessels and maintain their structure without forming the sinusoidal vascular lumens commonly seen in epithelioid angiosarcomas. Furthermore, cellular and nuclear atypia and mitotic activity are generally not prominent[ 4 ] Immunohistochemical staining with endothelial cell markers can help distinguish EHE from other vascular malignancies. In addition, the tumors stain positively for factor VIII-related antigen, CD31 (platelet endothelial cell adhesion molecule 1 transmembrane glycoprotein), CK, CD34, and vimentin.[ 3 , 6 , 10 ] Molecular testing has also been shown to be helpful in identifying common and variant gene fusions associated with distinctive clinical patterns.[ 7 , 13 ] For example, EHE has recently been linked to a reciprocal translocation leading to a WWTR1-CAMTA1 fusion gene that drives proliferation of the malignancy.[ 7 , 13 ] The present patient did not consent to molecular analysis, but immunohistochemistry for CAMTA1 confirmed the presence of WWTR1-CAMTA1 fusion gene, which aided in the diagnosis of EHE.

The intrinsic difficulty of identifying the developing cells in metastatic EHE complicates the selection of appropriate chemotherapy, and the associated benefit is controversial.[ 2 , 7 ] In addition, given the rarity of intracranial EHE and the heterogeneity of treatments, there is little knowledge regarding the optimal therapeutic approach. At present, the most common approach is to perform complete surgical resection, especially for localized single-organ involvement. However, chemotherapy is administered to patients with progressive unresectable tumors. In our present case, a pineal tumor and hydrocephalus were present on admission. It was necessary to perform a biopsy of the pineal tumor to determine the treatment plan and a third ventriculostomy to relieve hydrocephalus simultaneously. Therefore, there was a risk of damage to the fornix during the operation, but we first performed a biopsy through the foramen of Monro from the anterior horn of the right lateral ventricle, followed by the third ventriculostomy. As a result, the pathological diagnosis was EHE. Due to the presence of multiple lesions throughout the body, we could not identify the primary tumor site but considered pineal metastasis to be highly likely. Hence, given that the patient was 84 years old and there was strong suspicion of a metastatic brain tumor, it was decided not to perform any further resection. Some form of treatment for residual tumors is required in such cases. A previous study has reported the utility of chemotherapy such as anthracycline-based regimens, multi-kinase inhibitors (pazopanib and sorafenib), alkylating drugs (trabectedin), an inhibiter of mammalian target of rapamycin (sirolimus), and paclitaxel.[ 13 ] However, no randomized trials have compared these regimens due to the rarity of the condition.[ 1 , 10 , 12 , 13 ] Because EHE is a vascular malignancy that expresses vascular endothelial growth factor (VEGF), anti-angiogenic therapy together with systemic chemotherapy has also been proposed.[ 5 , 7 , 11 ] In the future, it may be possible to use molecularly targeted therapies against VEGF to treat EHE. The present patient could not undergo any chemotherapy due to the extremely aggressive nature of his disease. Although EHE is typically a low-to-intermediate grade vascular malignancy, it can be aggressive, as in this case. The diagnosis can be problematic and treatment options are not standardized. Moreover, prognostic elements blend together, making it difficult to counsel patients. The prognosis is likely to be worse if there is multiorgan involvement that includes the brain and if the patient is symptomatic. Considering that a structural chromosomal translocation has been identified, genetic or immune therapy might enable future improvements in diagnosis, prognosis, and treatment. Further experience with therapy and longer patient follow-up is required to extend our knowledge of this pathological entity.

CONCLUSION

The present case describes one of the few adult patients with presumed EHE metastasis to the pineal body. If a tumor with hemorrhage is found in the pineal body in an elderly patient, EHE should be considered in the differential diagnosis, even if it is a single tumor lesion. Given the rarity of this pathology, a multidisciplinary approach is indispensable. At present, complete surgical resection of the tumor remains the logical approach to tumor management to maximize long-term survival. Treatment options for EHE that cannot be completely excised have not yet been defined, and the discovery of effective therapies targeted at the molecular level is desirable.

Ethical approval:

Institutional Review Board approval is not required.

Declaration of patient consent:

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship:

Nil.

Conflicts of interest:

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation:

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Disclaimer

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.

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