Retiform endothelial hyperplasia with growing hematoma within a vestibular schwannoma 30 years after Gamma Knife radiosurgery: histopathological evaluation of the lesion and the tumor. Illustrative case

Abstract

BACKGROUND

Gamma Knife radiosurgery (GKRS) is an established therapeutic modality for vestibular schwannomas. However, various late-onset complications, including mass lesions resembling cavernous malformations, have been reported. Retiform endothelial hyperplasia (RFEH), a distinct vascular pathology, has recently been identified as a potential late-onset complication of GKRS for arteriovenous malformations. This report describes the first case of RFEH developing within a vestibular schwannoma 30 years after GKRS, necessitating surgical enucleation.

OBSERVATIONS

A 54-year-old man was diagnosed with a right-sided vestibular schwannoma at age 23 years and underwent GKRS with a dose of 13.6 Gy (40% isodose). The tumor exhibited long-term regression; however, at the 28-year follow-up, MRI revealed a progressively enlarging low-intensity T2-weighted ring within the tumor. At 30 years post-GKRS, resection was performed, revealing a well-circumscribed, encapsulated, hematoma-like lesion within the yellowish schwannoma. Histopathological analysis showed an old hematoma with irregular endothelium-lined cavities lacking fibrous or smooth muscle layers, confirming the diagnosis of RFEH. The surrounding tumor cells were S-100 protein–positive with a Ki-67 labeling index of 3%.

LESSONS

RFEH can develop within a vestibular schwannoma decades after GKRS, extending its known association beyond arteriovenous malformations. Recognizing this unique complication is critical for optimal patient management and surgical decision-making.

https://thejns.org/doi/10.3171/CASE2537

Gamma Knife radiosurgery (GKRS) is an established treatment for vestibular schwannomas, providing long-term and satisfactory tumor control.^1–4 However, late-onset complications from GKRS have been reported, including cyst formation, intratumoral hemorrhage, and de novo vascular malformations after treatment of vestibular schwannoma.^5–8 In particular, GKRS has been associated with de novo formation of cavernous malformations (CMs).^9–11

Kawagishi et al.¹² recently proposed a new clinical entity called retiform endothelial hyperplasia (RFEH), which develops as a late-onset complication of GKRS for cerebral arteriovenous malformations (AVMs) and mimics CMs on neuroimaging. However, RFEH and CM have distinct histological characteristics.

Here, we report the first case of RFEH that developed within a vestibular schwannoma 30 years after GKRS. Although the vestibular schwannoma had been controlled after GKRS, a new hemorrhagic lesion appeared and progressively enlarged over time. Following the resection of the new lesion, which was performed 30 years after GKRS, histopathological analyses confirmed the diagnosis of RFEH. The histology of the original schwannoma was also examined and, surprisingly, remained unchanged even 30 years after GKRS.

Illustrative Case

History and Examination

A 54-year-old male was incidentally diagnosed with right vestibular schwannoma at age 23 years during an examination for recurring headaches. The tumor volume was 20.2 cm³ (Koos grade IV). Pure-tone audiometry showed no significant difference in hearing between the bilateral ears. No other neurological deficits were noted. Based on the patient’s preference for GKRS as an initial treatment, in January 1992, 13.6 Gy at 40% isodose was administered to the tumor boundary (Fig. 1A). Progressive right-sided hearing loss occurred, and the right ear became nonfunctional by 1995. However, no other neurological deficits were observed during the follow-up period. The schwannoma gradually decreased in size after GKRS. The follow-up interval was extended from yearly to biannually at 22 years after GKRS (Fig. 1B–D). In 2020 (28 years after GKRS), a new round lesion with a hypointense hemosiderin rim was noted on MRI along with findings suspicious for intratumoral bleeding (Fig. 1E). The new hemorrhagic lesion increased in size over the 2 years (Fig. 1F– H),prompting a decision for tumor resection (30 years after GKRS).

FIG. 1.

A: Axial T1-weighted MR image of the head with gadolinium enhancement at initial treatment. Irradiation at 13.6 Gy with a 40% isodose line was administered, targeting the right acoustic neuroma (dotted line). B–D: Axial T1-weighted MR images with gadolinium enhancement 1 (B), 3 (C), and 5 (D) years postirradiation. Following Gamma Knife therapy, the acoustic neuroma showed a decreasing trend over time, with sustained tumor control for 28 years thereafter. E: Axial T2-weighted MR image obtained in 2020, showing an intratumoral hemorrhagic lesion (arrowhead) within the acoustic neuroma. F–H: Axial T1-weighted MR image with gadolinium enhancement obtained in 2021 (F) and axial T1-weighted image with gadolinium enhancement (G) and susceptibility-weighted image (H) obtained in 2022. The lesion (arrowheads) within the acoustic neuroma demonstrated progressive enlargement over time.

Preoperative neurological examination showed no neurological deficits other than right-sided hearing impairment. Pure-tone audiometry revealed a pure-tone average of 105.0 dB on the right and 13.8 dB on the left. Digital subtraction angiography demonstrated intense staining of the new lesion from the peripheral branches of the middle meningeal artery (Fig. 2). No staining of the vestibular schwannomas was observed.

FIG. 2.

Digital subtraction angiograms of the right external carotid artery in the early (A) and late (B) arterial phases. Intense staining of the lesion (arrow) was seen via the petrosal branch of the middle meningeal artery (arrowheads).

Operation

During the surgery, a yellowish vestibular schwannoma was visualized via the retrosigmoid approach (Fig. 3A). Vertical sectioning of the vestibular schwannoma revealed a reddish intratumoral lesion (Fig. 3B), which revealed an old hematoma. This lesion was circumferentially detached from the inner wall of the vestibular schwannoma and excised as a single mass (Fig. 3C–E). Strong adhesion to the surrounding tissues secondary to GKRS posed a risk of facial nerve injury, thereby requiring partial excision of the original tumor. The patient had provided informed consent for the surgical removal.

FIG. 3.

Intraoperative findings during tumor resection via the retrosigmoid approach (A–D) and excised lesion from the acoustic neuroma (E). A: A yellow acoustic neuroma was observed during the retrosigmoid approach. B: On longitudinal incision of the acoustic neuroma, a red tumor-like lesion (arrowhead) filled with old hematoma was identified. C and D:Complete circumferential dissection and excision of the tumor-like lesion from the inner wall of the acoustic neuroma. E: The excised tumor-like lesion appeared red and exhibited a vascular malformation–like appearance.

Postoperative Course

Postoperatively, no new neurological deficits, including facial nerve paralysis, were observed. Follow-up head MRI confirmed complete excision of the lesion within the vestibular schwannoma (Fig. 4A). The residual tumor remained stable 2 years after the surgery or 32 years after GKRS (Fig. 4B).

FIG. 4.

Axial T1-weighted MR images of the head with gadolinium enhancement after tumor resection. A:MR image confirming that complete excision of the newly formed lesion within the acoustic neuroma achieved adequate decompression. B: The acoustic neuroma remained stable 2 years after the surgery. There was no recurrence of intratumoral hemorrhage.

Pathological Examination

The lesion excised from the vestibular schwannoma was evaluated by hematoxylin and eosin (H&E), CD31, elastica-Masson, and α-smooth muscle actin (SMA) staining. The interior of the lesion was filled with old hematoma and showed irregular, variably sized structures that closely resembled blood vessels (Fig. 5A). The lumen was lined with CD31-positive endothelial cells (Fig. 5B) but lacked normal vascular wall structures, such as fibrous tissue and smooth muscle cells (Fig. 5C and D). Furthermore, the hematoma was lined by a single layer of endothelial cells. These pathological characteristics were consistent with the recently defined entity of RFEH.¹²

FIG. 5.

A–D: Pathology of the lesion compatible with RFEH. A: H&E staining showing irregularly sized vascular-like structures filled with hematoma proliferated within the lesion. B: The single layer of cells on the lumen showed CD31-positive staining for endothelial cell markers. CD31-positive endothelial cells were fused to form RFEH. C and D: Elastica-Masson (C) and SMA (D) staining showing the absence of connective tissue support, such as fibrous tissue and smooth muscle cells, around the single layer of the endothelial cells, which matched the diagnostic characteristics of RFEH. E–H: Pathology of the vestibular schwannoma 30 years after GKRS. E–G: H&E (E and F) and S-100–positive (G) staining showing a vestibular schwannoma with degenerative tumor cells. H: The Ki-67 index was 3%, indicating low proliferation, which is consistent with sustained tumor control for 30 years after GKRS. Scale bars = 200 μm (A–D), 500 μm (E), and 100 μum (F–H).

To examine the original vestibular schwannoma tissue, H&E, S-100, and Ki-67 staining were further performed. The vestibular schwannoma tumor cells were positive for S-100 staining and showed signs of atrophy and degeneration (Fig. 5E–G). The positive rate for Ki-67 labeling index was as high as 3% (Fig. 5H).

Informed Consent

The necessary informed consent was obtained in this study.

Discussion

Observations

This case report highlights the occurrence of RFEH as a late-onset complication of GKRS for vestibular schwannoma. While RFEH has previously been reported in cases of AVMs, its development within a vestibular schwannoma has not been described before. The MRI characteristics of the new lesion were similar to those of de novo CMs.¹¹ However, histological examinations confirmed the diagnosis of RFEH, which were distinct from those of CM, as summarized in Table 1. RFEH is characterized by proliferative endothelial channels lacking smooth muscle and connective tissue architecture. The hallmark is a single endothelial layer without vessel wall integrity. On the other hand, CM presents as well-formed but thin-walled vascular spaces with supporting fibrous structures occasionally surrounded by gliosis or hemosiderin. The presented case report underscores the potential for RFEH to develop inside GKRS-treated vestibular schwannomas as an unexpected late-onset complication. This case extends the spectrum of known radiation-induced vascular pathologies and underscores the necessity of long-term follow-up.

TABLE 1.

Histological difference between RFEH and CM that occurred after a vestibular schwannoma was treated by radiosurgery

Entity	RFEH Related to VS (this case)	CM Related to VS
Lumen structure	Irregular, dilated lumen not defined as true blood vessel	Sinusoidal, dilated thin-walled vessels
Wall structure	Absent; only endothelial lining lacking vascular supporting tissues	Present; endothelial lining surrounded by vascular supporting tissues
Endothelial lining	CD31-positive, single layer	CD34-positive, flattened endothelial cells
Supporting stroma	Absent	Present; pericytes, fibroblasts, & collagenous fibers
Smooth muscle/fibrous wall	Absent	Often absent or poorly formed
Elastic fibers	Absent	Rarely present
Associated hematoma	Present as organized chronic hematoma	Frequently present
VEGF expression	Not assessed in this case	Variable; occasionally positive
Gliosis/parenchymal changes	Not applicable (intratumoral)	Minimal or no peritumoral gliosis
Inflammatory changes	None observed	Minimal
Lesion location	w/in VS	w/in VS
Latency after GKRS	~30 yrs	10–14 yrs

VEGF = vascular endothelial growth factor; VS = vestibular schwannoma.

RFEH as a Late-Onset Complication of GKRS

RFEH was recently reported as a late-onset vascular lesion that can develop following GKRS, particularly in patients treated for AVMs.¹² However, our case report demonstrated that RFEH might not be exclusive to AVMs but could be generalized as a late complication of GKRS. The mechanisms underlying the development of RFEH remain unclear. However, they may involve radiation-induced endothelial damage leading to aberrant vascular proliferation and remodeling, as proposed previously.^9,13,14 We speculate that RFEH was initially induced by GKRS followed by repetitive bleeding that contributed to the hematoma enlargement. The imaging characteristics of the enlarged hematoma in the presented case were compatible with those of RFEH, as previously reported.¹² According to Kawagishi et al.,¹² RFEH can develop as late as 27.4 years after GKRS for AVMs treated with marginal doses of 12–25 Gy.¹² This precedent supports the possibility of RFEH as a late complication of radiation therapy. Although the marginal dose for vestibular schwannoma treatment in this case was relatively low (13.6 Gy to the 40% isodose line), the latency period observed in this case, i.e., 30 years post-GKRS, is consistent with the proposed time frame.

Radiation-Induced CM-Like Lesion

Before RFEH was defined, previous studies have also reported radiation-induced vascular lesions with similar histological characteristics to CM-like lesions. Cha et al.¹⁵ described the macroscopic and histological characteristics of radiation-induced CM-like lesions observed in 8 patients aged 25–43 years. Background pathologies included 2 AVMs and 6 astrocytic tumors. The representative case in this paper presented with a hematoma-like cut surface of the lesion, which closely resembled the macroscopic view in our case (Fig. 3E). Histologically, the lesions had thin-walled vessels without a well-formed vascular structure on α-SMA immunohistochemical staining, which shared common features of RFEH.

Kleinschmidt-DeMasters and Lillehei¹⁶ described a similar radiation-induced lesion as an “organizing coagulum-like” lesion. The histological characteristics of the coagulum-like lesion included vessels with poorly defined walls and the absence of smooth muscle fibers, which again shared the histological characteristics of the current case of RFEH. In their retrospective analysis, the authors identified 13 cases of radiation-induced vascular lesions, 8 of which were coagulum-like lesions.¹⁶ The other 5 cases actually shared histological characteristics with non–radiation-induced, sporadically occurring CMs. This implies that radiation therapy may induce lesions corresponding to both RFEH and CM. Based on these seminal studies,^15,16 we speculate that the same pathology of RFEH had been described but may have previously been misclassified as radiation-induced CMs or CM-like lesions.

Radiation-Induced CM Following GKRS for Vestibular Schwannoma

Our case report is unique because radiation-induced RFEH or other similar lesions with different names have not yet been associated with vestibular schwannomas. Few reports have described radiation-induced CMs in the treatment of vestibular schwannoma.^5,7,17 Murakami et al.⁵ reviewed 291 vestibular schwannoma cases treated by GKRS. They identified 2 cases of radiation-induced CMs formed within the tumor at 24 and 167 months after the treatment. Sasagawa et al.¹⁷ described the case of a 35-year-old male patient who underwent GKRS (maximum dose 24 Gy, marginal dose 12 Gy) for residual vestibular schwannoma after resection. Ten years after the treatment, a new lesion with characteristics of CM emerged in the adjacent brainstem but not inside the tumor. Another case of radiation-induced CM was observed in a 42-year-old female patient.⁷ Her vestibular schwannoma was treated with CyberKnife (25 Gy in five fractions of 5 Gy). Eleven years after the treatment, a large cystic lesion appeared, exhibiting nodular enhancement and associated hemosiderin on the cyst wall. Resection confirmed the diagnosis of radiation-induced CM within the vestibular schwannoma.

Treatment for RFEH Related to Vestibular Schwannomas

No therapeutic strategies for RFEH have been established, particularly in cases related to the vestibular schwannoma. However, RFEH after GKRS for AVM has an aggressive clinical course with massive perifocal edema.¹² RFEH is also frequently associated with hematoma-inducing neurological symptoms. Furthermore, rapid symptomatic progression in RFEH may require surgical interventions.¹²

Nimjee et al.⁹ reviewed the literature and found 76 cases of radiation-induced CMs. Although no vestibular schwannoma cases were identified, 27 patients (35.5%) underwent surgical interventions, while 44 patients (57.9%) were treated conservatively. A retrospective review by the Mayo clinic evaluated 32 patients with radiation-induced CMs. The characteristics of the radiation-induced CMs included multiple lesions, but were less likely to be symptomatic than solitary CMs.¹⁸ Nine cases (28.1%) underwent surgical interventions for radiation-induced CMs, while the other 23 (71.9%) were managed conservatively. Prospectively, the risks of hemorrhage were calculated at 4.2% per person-years.

As described in our case, hemorrhage occurred, and the hematoma increased in size on successive MR images, necessitating the surgical removal of the lesion. As RFEH with an enlarging hematoma may present with an aggressive clinical course, it must be distinguished from other radiation-induced CMs for appropriate management. To establish a more comprehensive understanding of RFEH, especially those related to vestibular schwannomas, further accumulation of cases and systematic studies is needed to refine diagnostic criteria using MRI and optimize treatment strategies.

Histology of the Vestibular Schwannoma 30 Years After GKRS

Histological reports of vestibular schwannomas after GKRS almost always involve uncontrolled or hemorrhagic cases. If a tumor is controlled after GKRS, histological examination of the tumor would not be performed except at autopsy upon death from other causes. As shown in Fig. 5, histological evaluations of the well-shrunken irradiated schwannoma for 30 years can provide important information. Although the tumor cells atrophied and degenerated, the Ki-67 proliferation index was as high as 3%. To date, the present case presents the longest reported follow-up period of GKRS-treated vestibular schwannoma in the literature. A previous study has suggested that if the tumor control of vestibular schwannomas is favorable within 5 years after GKRS, the likelihood of recurrence or the need for additional treatment thereafter is low.² However, having recognized the presence of viable tumor tissue 30 years after GKRS, a revised follow-up management plan may need to be implemented. Notably, radiation-induced complications have also been reported several decades after treatment, emphasizing the critical need for extended surveillance.^3,5,7

Lessons

In summary, we describe a case of RFEH that developed 30 years after GKRS for vestibular schwannoma. Although the lesion radiographically mimicked a de novo CM, the pathological characteristics were distinct and were consistent with those of RFEH. This case report demonstrates that RFEH is not limited to AVMs but could occur as a late-onset complication of GKRS for various pathologies. The progressive enlargement of an intratumoral hemorrhagic lesion should raise suspicion for RFEH, warranting careful differential diagnosis from radiation-induced CMs. The absence of established therapeutic guidelines for RFEH in vestibular schwannomas highlights the need for further case accumulation and systematic studies to refine diagnostic criteria and optimize management strategies.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Endo, Takahashi, Jokura, Sasaki. Acquisition of data: Endo, Takahashi, Suzuki, Jokura. Analysis and interpretation of data: Endo, Takahashi, Kawagishi, Jokura. Drafting the article: Endo, Takahashi. Critically revising the article: Takahashi, Jokura, Sasaki. Reviewed submitted version of manuscript: Takahashi, Jokura, Sasaki. Approved the final version of the manuscript on behalf of all authors: Endo. Administrative/technical/material support: Endo, Murakami, Sasaki. Study supervision: Nishizawa, Jokura, Sasaki.

Correspondence

Toshiki Endo: Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan. toshendo@tohoku-mpu.ac.jp.