Successful management of recurrent multiple intracerebral TFE3-rearranged epithelioid hemangioendothelioma with repeated intervention and active surveillance: illustrative case

Abstract

BACKGROUND

Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor with intermediate malignant potential. TFE3-rearranged intracerebral EHEs (iEHEs) have not been reported to date. Herein, the authors describe a rare case of recurrent multiple TFE3-rearranged iEHEs involving the lung and liver, which exhibited a favorable clinical course after repeated surgeries, radiation therapy, and active surveillance.

OBSERVATIONS

A 20-year-old man presented with multiple pulmonary, hepatic, and intracerebral lesions. The patient was diagnosed with EHE via biopsy of pulmonary lesions. During follow-up without treatment, progressive perilesional edema was observed in the left temporal lobe, leading to resection. Histological findings were consistent with EHE, and immunohistochemical analysis revealed overexpression of TFE3 in the tumor cells. Hence, a diagnosis of TFE3-rearranged iEHE was established. Immediately after detecting progressive lesions, the patient received multiple interventions including surgery and radiation therapy. Radiological findings revealed multiple cystic lesions with hemorrhagic components. The tumor has been successfully controlled for 13 years with repeated surgeries, radiation therapy, and active surveillance.

LESSONS

TFE3-rearranged iEHE is an extremely rare type of tumor and can present with multiple cystic lesions containing hemorrhagic components on imaging. TFE3-rearranged iEHE can be successfully managed with repeated intervention and active surveillance.

https://thejns.org/doi/10.3171/CASE25416

Epithelioid hemangioendothelioma (EHE) is a rare type of tumor originating from the vascular endothelium. Weiss and Enzinger introduced the term “epithelioid hemangioendothelioma” in 1982.¹ EHE exhibits intermediate features between angiosarcoma and hemangioma.^1–4 It is commonly found in the liver, lung, soft tissue, and bone. Intracerebral EHEs (iEHEs) are remarkably rare.^5–7 In most cases, EHEs have a relatively favorable course. However, in some cases, metastasis is detected and associated with a poor clinical course.^8–13 Approximately 90% of EHEs are characterized by the presence of WWTR1::CAMTA1 fusion (CAMTA1-rearranged EHE). Nevertheless, a smaller proportion (about 10%) of patients exhibit YAP1::TFE3 fusion (TFE3-rearranged EHE), and other fusion genes are occasionally reported.^14,15 Previous studies have reported iEHE. Nonetheless, no cases of TFE3-rearranged iEHE have been documented to date.^{4,8,9,11–14,16–25} The effective treatment for iEHEs has not yet been established.^5–7,14,16 Herein, we described an extremely rare case of recurrent multiple TFE3-rearranged iEHEs involving the lung and liver, which exhibited a favorable clinical course after repeated surgeries, radiation therapy, and active surveillance.

Illustrative Case

Clinical History

The patient was a 20-year-old man who presented with a pulmonary lesion that was incidentally detected during a routine health checkup. There was no relevant past medical or family history. The lesion was monitored conservatively without further examination. After 3 years, multiple pulmonary nodules were identified on imaging performed as part of a routine health screening. Further evaluation revealed multiple pulmonary (Fig. 1A), hepatic (Fig. 1B), and brain (Fig. 1C–F) lesions. A diagnosis of EHE was established via biopsy of the pulmonary lesions (Fig. 1A). The patient was referred to our institution for treatment. Brain MRI showed a small lesion in the left inferior temporal gyrus. The tumor was hypointense on T1-weighted (T1W) imaging (Fig. 1C). The tumor exhibited a concentric band-like or target-like appearance on T2-weighted (T2W) imaging (Fig. 1D). Contrast-enhanced T1W imaging revealed a hypointense cystic component and an enhanced solid component (Fig. 1E). Susceptibility-weighted imaging showed hemorrhagic changes within the tumor (Fig. 1F). Based on the clinical course, the lesion was suspected to be a brain metastasis of EHE, although no pathological diagnosis had been obtained. There is no established evidence supporting the efficacy of radiotherapy for iEHE. Considering the presence of extensive peritumoral edema and the risk of future symptomatic progression, resection was planned. Awake surgery was performed with cortico-cortical evoked potentials because the patient’s dominant side was the left hemisphere (Fig. 1G). The tumor exhibited cyst formation with yellow fluid and accompanying reddish-brown solid components. The postoperative course was uneventful, and the patient did not exhibit neurological deficits.

FIG. 1.

Radiological findings of a multiorgan EHE. A: Diffuse micronodular lesions in the lung. B: Contrast-enhanced CT scan showing multiple lesions in the liver. C–E: T1W (C), T2W (D), and T1W contrast-enhanced images showing that the lesion in the left temporal lobe (arrows) was cystic and had solid enhanced components in the cyst. F: Susceptibility-weighted image revealing hemorrhagic changes within the tumor (arrow). G: The lesion was removed.

Histopathological examination of the resected specimen revealed solid nests of tumor cells intermingled with granulation tissues and hemosiderin deposits. The tumor cells were epithelioid, with abundant eosinophilic cytoplasm forming the vascular spaces. The intracytoplasmic vacuoles were not prominent (Fig. 2A and B). Immunohistochemical analysis revealed positivity for factor VIII–related antigen (not shown), CD31 (Fig. 2C), CD34 (not shown), and ERG (Fig. 2D); overexpression of TFE3 (Fig. 2E); and negativity for CAMTA1 (Fig. 2F). Based on these findings and the World Health Organization Classification of Soft Tissue and Bone Tumours, the tumor was diagnosed as TFE3-rearranged EHE.^17,26

FIG. 2.

Histopathological and immunohistochemical findings of the iEHE. A: H&E staining. Low-power histopathological image of the iEHE resected in the initial surgery. B: H&E staining, high-power image. The neoplastic cells exhibited three distinct morphologies: dendritic cells with spindle-shaped or irregular appearances and interdigitating processes, epithelioid cells with round-shaped and abundant cytoplasm, and intermediate cells with features of both. Nuclear atypia and mitotic activity were mainly observed in the epithelioid cells. Cytoplasmic vacuoles representing intracellular vascular lumens were frequently identified, with some containing red blood cells. C: CD31 was detected in the tumor cells. D: ERG was found in the tumor cells. E: TFE3 was overexpressed in the tumor cells. F:CAMTA1 was not detected in the tumor cells.

At 13 months after the initial surgery, a new contrast-enhanced lesion was detected in the left cerebellum (Fig. 3A and B). The size of the lesion gradually increased, and the second surgery was performed under endoscopic guidance 19 months after the initial craniotomy (Fig. 3C). When the lesion is extremely small, conventional craniotomy often results in disorientation due to brain shift. Navigation-guided endoscopic resection offers a valuable alternative by minimizing dural opening and effectively reducing the impact of brain shift. Similar to the previous surgery, the tumor exhibited cyst formation with yellow fluid and accompanying reddish-brown solid components. The patient was discharged without any neurological deficits. Subsequently, multiple lesions were detected on the follow-up imaging. Brain imaging revealed multiple cystic intracerebral lesions with associated hemorrhagic changes and solid components within the cysts (Fig. 3D–F). The patient underwent volumetric modulated arc therapy–stereotactic irradiation at a dose of 28 Gy in 5 fractions for the untreated lesions, 22 months after the second surgery. At 21 months after the radiotherapy, a cystic lesion developed in the left parietal lobe (Fig. 3G), and it was resected under endoscopic guidance. The cyst contained fluid mixed with the hematoma. After irrigation of the cyst cavity, the reddish-brown tumor was resected under a wet field (Fig. 3H). The patient was diagnosed with EHE, which has been successfully controlled for 13 years with repeated surgeries, radiation therapy, and active surveillance at 6-month intervals. The pulmonary and hepatic lesions have also remained stable. No chemotherapy has been administered throughout the entire clinical course.

FIG. 3.

Radiological findings of multiple iEHE. A–C: Postoperative FLAIR (A) and T1W contrast-enhanced (B and C) images showing a new lesion (arrows) in the left cerebellum. D–F: FLAIR (D), T1W contrast-enhanced (E), and susceptibility-weighted (F) images showing nultiple lesions (arrowheads) with hemorrhagic change in the bilateral cerebral hemispheres. G: A cystic lesion (arrowhead) developed in the left parietal lobe. H: The contrast-enhanced nodule in the cyst was removed.

Informed Consent

The necessary informed consent was obtained in this study.

Discussion

We herein described an extremely rare case of recurrent multiple TFE3-rearranged iEHEs involving the lung and liver, which exhibited a relatively favorable clinical course after repeated surgeries, radiation therapy, and active surveillance. Cases of TFE3-rearranged iEHEs have not been reported to date.

Observations

In general, the behavior of TFE3-rearranged EHE is distinct from that of conventional EHE (CAMTA1-rearranged EHE). In particular, patients have considerably lower rates of disease progression. CAMTA1-rearranged EHE has a more aggressive clinical behavior, with a higher propensity for local recurrence and distant metastasis. Multifocality and metastatic presentation were significantly more common in CAMTA1-rearranged EHE than in TFE3-rearranged EHE.^5,14,17,18 Interestingly, in the current case, EHE presented with multiorgan involvement, including the liver, lung, and brain. Based on the immunohistochemical analysis and World Health Organization Classification of Soft Tissue and Bone Tumours, the iEHE in the current case was diagnosed as TFE3-rearranged EHE.^17,26 To date, cases of multiple TFE3-rearranged iEHEs have not been reported. However, multiple iEHEs have been described in cases without immunohistochemical and genetic confirmation.¹⁹ To the best of our knowledge, this report first showed recurrent multiple TFE3-rearranged iEHEs involving the lung and liver. Intracerebral EHE and TFE3-rearranged iEHE do not have typical CT or MRI findings.^{13,19–22,27} In this case, multiple cystic intracerebral lesions with associated hemorrhagic changes were observed on brain imaging. Tsuchiya et al. reported multiple hemorrhagic iEHEs with similar radiological features. However, they did not refer to the cystic appearance.¹⁹ Multiple cystic hemorrhagic lesions are likely to be characteristics of TFE3-rearranged iEHE.

Histopathologically, TFE3-rearranged EHE exhibits remarkable inter- and intratumoral heterogeneity, with only a minority of cases presenting with morphological features similar to those of classic CAMTA1-rearranged EHE. Dermawan et al. performed a multi-institutional clinicopathological study of genetically confirmed cases.¹⁷ They showed three dominant architectural patterns of TFE3-rearranged EHE: solid sheets of coalescing nests, pseudoalveolar and pseudovasoformative patterns, and discohesive strands and clusters of cells set in a myxoid to myxohyaline stroma. The dominant cytomorphology was the presence of large epithelioid cells with abundant, glassy eosinophilic to vacuolated cytoplasm, prominent nucleoli, and well-demarcated cell borders.¹⁷ In the current case, histopathological examination of the resected specimen revealed solid nests of tumor cells intermingled with granulation tissues and hemosiderin deposits. Furthermore, the tumor cells were epithelioid, with abundant eosinophilic cytoplasm forming the vascular spaces. The intracytoplasmic vacuoles were not prominent. Previous reports have shown that immunohistochemically, ERG, CD31, and TFE3 were expressed in the tumor cells of TFE3-rearranged EHE. However, CAMTA1 was not detected in most cases of TFE3-rearranged EHE.^17,18 In the current case, immunohistochemical analysis revealed CD31 and ERG positivity, overexpression of TFE3, and CAMTA1 negativity in the tumor cells. TFE3 is a sensitive marker for screening TFE3-rearranged EHE. Immunohistochemistry for CAMTA1 has become a reliable diagnostic marker for CAMTA1-rearranged EHE.^17,23 According to the World Health Organization Classification of Soft Tissue and Bone Tumours, the suitable diagnostic criteria for diagnosing EHE as TFE3-rearranged EHE are TFE3 overexpression on immunohistochemistry and/or TFE3 gene rearrangement (YAP1::TFE3 gene fusion).²⁶ Based on these findings, these intracerebral lesions were diagnosed as TFE3-rearranged iEHE. However, an accurate diagnosis can be achieved using combined morphological, immunohistochemical, and genetic findings.^24,25 Although genetic analysis was performed in the current case, TFE3 gene rearrangement (YAP1::TFE3 gene fusion) was not detected. Therefore, this is considered a limitation of the current study.

Patients with EHE should be referred to specialized centers experienced in EHE management, where treatment should be performed by an expert multidisciplinary team. Resection is the primary choice for patients presenting with localized disease confined to a single organ. Prognostic improvement has been observed with prompt surgical management in cases of localized EHE.^5,6,28 There are numerous reports on the use of chemotherapies for EHE, and some clinical trials on novel therapeutic drugs for EHE are ongoing. However, the treatment strategy for EHE has not been established yet. Active surveillance is an option for patients with asymptomatic locoregional or systemic metastases. However, specific criteria for identifying appropriate candidates remain undefined.^5,28 Therefore, further data accumulation is essential for identifying patients who are candidates for active surveillance. In the current case, as the patient remained asymptomatic and stable, active surveillance was selected for the pulmonary and hepatic lesions. For the intracerebral lesions, resection was initially performed, with consideration of the presence of perilesional edema. Subsequently, due to enlargement of the cystic component and progressive perilesional edema, the patient was managed with both repeated resection and radiotherapy. Active surveillance allowed for timely intervention without delay in treatment initiation. Thus, the patient has maintained a favorable clinical course for 13 years since the initial treatment. Based on these findings, in cases of TFE3-rearranged iEHE, the combined use of active surveillance and appropriately timed surgical and radiotherapeutic interventions may contribute to long-term disease control. Whether the treatment strategy should differ between TFE3-rearranged and CAMTA1-rearranged iEHE remains unclear, as there is currently no established standard therapy for iEHE. Further accumulation of cases is necessary to clarify potential differences in treatment approaches based on molecular subtypes.

Lessons

We described an extremely rare case of recurrent multiple TFE3-rearranged iEHEs involving the lung and liver, which exhibited a relatively favorable clinical course after repeated surgeries, radiation therapy, and active surveillance. TFE3-rearranged iEHE is an extremely rare type of tumor and can present with multiple cystic lesions containing hemorrhagic components on imaging. TFE3-rearranged iEHEs can be successfully controlled with repeated intervention and active surveillance. This report emphasizes the importance of close imaging follow-up and timely multidisciplinary intervention to optimize patient outcomes.

Acknowledgments

We thank Enago, the editing brand of Crimson Interactive Pvt. Ltd., for the English-language review.

Disclosures

Dr. Arakawa reported grants from Philips, Otsuka, Chugai, Nihon Medi-Physic, Daiichi Sankyo, Stryker, Eisai, Japan Blood Products Organization, Ono Pharmaceutical, Taiho Pharma, Sumitomo Dainippon Pharma, Astellas Pharma, Incyte Biosciences, and Servier; and personal fees from Nippon Kayaku, Novocure, UCB Japan, Ono Pharmaceutical, Brainlab, Merck, Chugai, Eisai, Daiichi Sankyo, Carl Zeiss, Nihon Medi-Physics, and Stryker outside the submitted work.

Author Contributions

Conception and design: Takada, Matsui, Arakawa. Acquisition of data: Takada, Matsui, Takeuchi, Tokunaga, Sano. Analysis and interpretation of data: Takada, Matsui, Takeuchi, Tokunaga, Mineharu. Drafting the article: Takada, Matsui, Tokunaga, Mineharu, Arakawa. Critically revising the article: Takada, Matsui, Tokunaga, Hattori, Ikeda, Sano, Tanji, Mineharu, Arakawa. Reviewed submitted version of manuscript: Takada, Matsui, Tokunaga, Ikeda, Sano, Tanji, Mineharu, Arakawa. Approved the final version of the manuscript on behalf of all authors: Takada. Study supervision: Takada.

Correspondence

Shigeki Takada: Kyoto University Graduate School of Medicine, Kyoto, Japan. takashige826@kuhp.kyoto-u.ac.jp.