Long-term outcomes of radiotherapy for inoperable benign soft tissue tumors in the skull base or head

Joo-Hyun Chung; Hak Jae Kim; Hyun-Cheol Kang; Il Han Kim; Joo Ho Lee

doi:10.3857/roj.2024.00493

Abstract

This study aimed to evaluate the long-term efficacy and complication of radiotherapy for benign soft tissue tumors. Five cases of benign soft tissue tumors (two plexiform neurofibromas, two juvenile nasopharyngeal angiofibromas, and one cavernous sinus hemangioma) who underwent radiotherapy were enrolled. All patients had at least 10 years of follow-up. The median follow-up duration was 12 years (range, 10 to 27). Three patients underwent incomplete excision prior to radiotherapy. Radiation doses were either 54 Gy in 30 fractions or 50.4 Gy in 28 fractions (1.8 Gy per fraction). Every patient achieved complete remission (CR) or near-CR. The tumor volume decreased significantly within the first 2 years of follow-up and continued to decrease slowly up to 10 years; no distinct further decrease in tumor volume was observed after 10 years. One patient developed left mandibular hypoplasia 8 years after radiotherapy. Significant volume decrease was achievable within a few years after radiotherapy in benign soft tissue tumors. Therefore, radiotherapy is a viable option for unresectable or incompletely resected benign soft tissue tumors with a minimum risk of complication.

Keywords: Soft tissue neoplasms, Plexiform neurofibroma, Angiofibroma, Cavernous hemangioma, Radiotherapy

Introduction

Plexiform neurofibromas typically develop along major nerves, and their expansion often results in the destruction and compression of surrounding tissues, leading to considerable morbidity [1]. Plexiform neurofibromas uniquely possess the potential to evolve into a malignant peripheral nerve sheath tumor, a risk of malignancy that is not observed in other classes of neurofibromas [2]. Juvenile nasopharyngeal angiofibroma is a benign yet locally aggressive tumor that predominantly occurs in young males. The most frequent vascular source for juvenile nasopharyngeal angiofibroma is the internal maxillary artery, followed by the ascending pharyngeal artery [3]. Intracranial involvement is seen in approximately 10% to 37% of all juvenile nasopharyngeal angiofibroma cases [4]. Cavernous sinus hemangioma is a rare vascular tumor comprising 1%–3% of all cavernous sinus lesions [5]. These extra-axial, inter-dural, and intra-sinus lesions cause symptoms due to tumor growth and mass effect [6].

Plexiform neurofibromas are typically removed surgically due to discomfort or cosmetic reasons, while juvenile nasopharyngeal angiofibromas are often excised for debulking, with postoperative radiotherapy or watchful waiting employed for extensive lesions. However, benign tumors located at the skull base or head are often at risk of being incompletely resected or deemed inoperable. For cavernous sinus hemangiomas, the risk of massive bleeding often impedes complete excision, making radiotherapy a preferred alternative as either a definitive or adjuvant treatment.

Benign soft tissue tumors require long-term follow-up for evaluating efficacies and complications. Here, we investigated five patients with benign soft tissue tumors at the skull base and head to evaluate the long-term efficacy and complications of radiotherapy.

Case Report

From 1990 to 2011, five cases of benign soft tissue tumors (two plexiform neurofibromas, two juvenile nasopharyngeal angiofibromas, and one cavernous sinus hemangioma) who underwent definitive radiotherapy were enrolled. All patients had at least 10 years of follow-up. The median follow-up duration was 12 years (range, 10 to 27). The characteristics of five patients are summarized in Table 1.

1. Plexiform neurofibroma

Patient 1 presented with extensive swelling mass at the left neck site, accompanying pain, and limitation of arm elevation. Cervical (C) spine magnetic resonance image (MRI) showed an extensive mass stretching from the suboccipital area to the C6 level, anteriorly to retropharyngeal space, and posteriorly to the left neural foramen at the vertebral body (Fig. 1A). Diagnostic neck excision showed pathology consistent with plexiform neurofibroma. Complete surgical resection was not feasible due to the extensiveness of the disease; thus, definitive radiotherapy was planned. Using the intensity-modulated radiotherapy (IMRT) technique, 54 Gy in 30 fractions was administered. No acute or late toxicities were observed. The limitation of arm elevation persisted for 6 years after radiotherapy; arm elevation was relieved afterward, and the range of motion normalized 8 years after radiotherapy. The extent of the disease slowly regressed after radiotherapy. The tumor continued to regress up to 6 years after radiotherapy and reached a plateau (Fig. 2).

Patient 2 presented with a slowly growing mass at the left retroauricular area and sleep apnea caused by the growing mass. Paranasal sinuses MRI showed an extensive mass at the left submandibular gland, parapharyngeal space, retropharyngeal space, prevertebral space, and encasing left large extracranial vessels (Fig. 1B). Biopsy was performed at the left retroauricular mass, and pathology was reported as plexiform neurofibroma. The patient underwent tracheostomy prior to radiotherapy to relieve dyspnea caused by the compressing mass. The patient received 50.4 Gy in 28 fractions using 3-dimensional conformal radiotherapy (3D-CRT). Sleep apnea gradually improved over 1 year after radiotherapy. The volume of the mass decreased slowly up to 8 years after radiotherapy, reaching near complete remission (CR) 10 years after radiotherapy (Fig. 2). The patient developed left mandibular hypoplasia 8 years after radiotherapy (Fig. 3).

2. Juvenile nasopharyngeal angiofibroma

Patient 3 presented with slowly progressing nasal obstruction. Paranasal sinuses MRI revealed extensive mass in both pterygopalatine fossa with skull base infiltration (Fig. 1C). Prior to diagnostic excision, angioembolization was done to prevent hemorrhage. An excisional biopsy was performed to alleviate nasal obstruction, and the pathology result reported angiofibroma. Due to extensive infiltration into the skull base, definitive radiotherapy was planned. A total dose of 50.4 Gy in 28 fractions was delivered via 3D-CRT technique. The volume of the mass significantly decreased within 5 years after radiotherapy and reached CR within 10 years after radiotherapy (Fig. 2).

Patient 4 presented with nasal obstruction and frequent epistaxis. MRI showed mass infiltration at both nasal cavity, posterior pharyngeal wall, cavernous sinus, and infratemporal fossa extension (Fig. 1D). Intranasal biopsy revealed angiofibroma. Definitive radiotherapy with a total dose of 54 Gy in 30 fractions in 3D-CRT technique was delivered. A significant volume decrease was observed within 2 years after radiotherapy, along with marked improvement in nasal obstruction and no occurence of epistaxis thereafter. Near-CR was reached 3 years after radiotherapy (Fig. 2). No acute or late complications were observed.

3. Cavernous sinus hemangioma

Patient 5 presented with decreased visual acuity. MRI diagnosed a 3.5 cm-sized sellar mass extending to the right cavernous, maxillary, and sphenoid sinus, compressing the optic nerve and chiasm (Fig. 1E). The patient underwent partial resection via transsphenoidal approach and was pathologically diagnosed with capillary hemangioma. However, visual acuity in the right eye deteriorated after the operation, eventually leading to blindness. Postoperative radiotherapy with a total dose of 54 Gy in 30 fractions was delivered via 3D-CRT technique. The patient underwent full recovery in the right visual acuity 7 months after radiotherapy. The volume of the mass decreased constantly throughout 10 years after radiotherapy (Fig. 2). No treatment-related complications occurred.

Discussion

Surgery has always been the treatment of choice when complete removal is possible. However, although benign, advanced soft tissue tumors in the skull base or head often make complete surgical removal challenging. Debulking surgery is the primary goal in such cases, especially for tumors near critical structures such as the spinal cord or airway. Needle et al. [7] reported on 121 children with plexiform neurofibroma undergoing 302 surgeries for 168 tumors over 20 years. Twenty percent of patients with complete resection developed tumor progression. Higher recurrence rates of 39.5% for near-total and 44% for subtotal resections were observed. Tyagi et al. [8] found 80% residual disease and 30% recurrence after surgery in 10 angiofibroma patients, while Fagan et al. [9] reported a 37.5% recurrence after surgery for angiofibroma with intracranial extension. Previous studies reported a notably low rate of total surgical excision and a significant incidence of postoperative morbidity in cavernous sinus hemangiomas [5,10].

Radiotherapy is an effective treatment option for extensive soft tissue tumors not eligible for complete surgical excision. Although benign, disease infiltration into the skull base or intracranial extension makes most patients not amenable to complete excision, as demonstrated in the series of cases presented in this study. Chopra et al. [1] reported four neurofibroma patients treated with radiotherapy (3 patients, 50 to 55 Gy) or stereotactic radiosurgery (SRS) (1 patient, 12.5 Gy) followed from 1.7 to 14.8 years. Local control of 100% was achieved without any significant complications. Mallick et al. [3] reported on 31 patients with unresectable angiofibroma who received 3D-CRT at a median dose of 30 Gy, with a median follow-up period of 36 months. Five-year progression-free survival was 91.7%, with CR in 13 patients, progressive disease in 2, and one case of secondary malignancy. Xin et al. [11] explored 54 patients with giant cavernous sinus hemangiomas who received 50 Gy in 25 fractions of radiation. Every patient experienced symptomatic improvement, with an average tumor reduction of 79.7%, and no significant complications were reported.

Several studies have reported treatment results using stereotactic body radiotherapy (SBRT). A series of studies, including neurofibroma, schwannoma, and meningioma, showed an overall local control rate of over 90% when treated with SBRT of 20–25 Gy within 1 to 5 fractions [12,13]. In the Stanford University series, 24 spinal neurofibromas underwent CyberKnife-based SBRT treatment, with a median dose of 20 Gy over approximately two fractions [12]. Following a median follow-up of 29 months, all lesions were locally controlled, although only 18% showed significant radiographic regression; 17% of patients experienced pain relief, 33% reported worsening pain, and two patients needed surgical resection due to refractory symptoms. On the other hand, other series have found neurofibromas challenging to manage. Sahgal et al. [14] observed one radiographic and one symptomatic failure among 11 spinal neurofibroma patients treated with doses of 21 Gy in 3 fractions and 30 Gy in 3 fractions, respectively, at a median follow-up of 25 months. Wang et al.'s meta-analysis [15] of total 59 cavernous sinus hemangioma patients revealed that 93.2% of patients experienced significant tumor shrinkage following SRS (mean dose, 13.87 Gy; range 10.0 to 19.0 Gy), with those receiving higher doses showing more tumor shrinkage. Among those 46 patients with cranial nerve impairments before SRS, symptom improvement was achieved in 35 patients. No statistical significance in tumor control between patients treated with or without surgery was observed.

Proton beam therapy (PBT) offers a promising treatment option for angiofibroma, particularly suitable for young patients, as it addresses the concerns of long-term radiation-induced morbidity associated with traditional photon radiotherapy. Hoeltgen et al. [16] compared PBT with conformal photon radiotherapy by analyzing 10 advanced juvenile nasopharyngeal angiofibroma patients treated with PBT at Heidelberg Ion Beam Therapy Center between 2012 and 2022. The local control rate was 100% after a median follow-up of 27.0 months, with reduced estimated risks for neurocognitive impairment and radiation-induced cranial nerve system malignancies compared to photon radiotherapy.

The recent success of MEK inhibitor (MEKi), specifically targeting a downstream effector of RAS, has significantly altered the approach to managing plexiform neurofibromas. Phase I/II clinical trials in children with inoperable, symptomatic plexiform neurofibroma using the MEKi selumetinib showed partial response rates of 71% and 74%, respectively, leading to not only tumor size reduction but also improvement in pain relief [17,18]. Consequently, selumetinib has been approved by the Food and Drug Administration as the first medical therapy for plexiform neurofibroma in children, with similar positive outcomes observed in ongoing phase II trials for adults with symptomatic, inoperable plexiform neurofibroma [19]. Neurofibromas treated with radiotherapy tend to be highly symptomatic and show poor clinical response, partly due to their infiltrative nature leading to unclear margins and higher recurrence risks. Additionally, their association with neurofibromatosis type 1 and its unique potential to evolve into a malignant peripheral nerve sheath tumor not seen in other classes of neurofibromas can complicate treatment effectiveness. The introduction of MEKi in combination with radiotherapy could potentially enhance treatment effectiveness compared to using radiotherapy alone.

In this study, we showed that radiotherapy effectively controlled inoperable benign tumors without severe complications. Tumor volume experienced a significant decrease in the first 2 years of follow-up and continued to decrease gradually over a period of up to 10 years, with no notable further reduction observed after 10 years. Patients experienced a full recovery from dysfunctions such as nasal obstruction and blindness while consistently maintaining either CR or near-CR. Among five patients, only one developed left mandibular hypoplasia 8 years after radiotherapy (Fig. 3). Radiotherapy during childhood frequently poses risks of various late complications, such as growth retardation or secondary malignancies [20]. Patients 2 and 5 received 3D-CRT in 2008 and 2009, respectively, during the period when IMRT was just being gradually introduced. IMRT and proton therapy in the modern radiotherapy era reduced complications, particularly in pediatric patients.

Our study is limited due to the small number of patients and, as previously noted, includes only a single case of IMRT treatment. Despite the small sample size, this study demonstrates promising outcomes and effective control rates. To achieve more substantial results, further research with a larger patient cohort and advanced radiotherapy technologies such as proton therapy is warranted.

In summary, the radiation dose of 50.4 to 54 Gy inoperable benign soft tissue tumors can successfully be controlled without significant complications: a substantial volume decrease was achievable within a few years, and the tumor volume slowly regresses up to 10 years after radiotherapy, eventually reaching a plateau. Therefore, radiotherapy is recommended as an effective option for unresectable or incompletely resected benign soft tissue tumors with a minimum risk of complication.

Statement of Ethics

This study was reviewed and approved by the Institutional Review Board (IRB) of Seoul National University Hospital (IRB number: H-2003-086-1109), with a waiver of informed consent.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Author Contributions

Conceptualization, IHK; Data curation, JHC, HJK, HCK, and IHK; Formal analysis, JHC, IHK; Investigation, JHC, HJK, HCK, and IHK; Methodology, JHC, IHK; Project administration, all authors; Resources, all authors; Software, all authors; Supervision, JHC, IHK, and JHL; Validation, JHC, IHK, and JHL; Visualization, JHC, IHK, and JHL; Writing-original draft, JHC, IHK; Writing-review & editing, JHC, IHK, and JHL. Approval of final manuscript: all authors.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

Fig. 1.

Dose profiles and images before and after radiotherapy (RT) for cases 1–5 (A–E) are shown. A complete remission (CR) was achieved in case 3 (C), while near-CRs were observed in the others (A, B, D, and E). In case 5, although the right eye was blind prior to RT, visual field defects improved 7 months after RT and maintained throughout the follow-up period (E). yr, year.

Fig. 2.

Volume change after radiotherapy.

Fig. 3.

Left mandibular hypoplasia in patient 2. The patient developed left mandibular hypoplasia 8 years after radiotherapy (arrow).

Table 1.

Patient characteristics

	Case number
	1	2	3	4	5
Histologic diagnosis	Plexiform neurofibroma	Plexiform neurofibroma	Angiofibroma	Angiofibroma	Hemangioma
Age at diagnosis (year)	11	7	7	14	44
Duration of follow-up (year)	12	11	16	27	10
Location	Cervical paravertebral, C2–T1	Lt parapharyngeal space, nasopharynx, oropharynx	Nasal cavity, nasopharynx	Nasal cavity, nasopharynx	Rt cavernous sinus, Rt sphenoid sinus
Initial symptom	Limited range of motion	Sleep apnea	Nasal obstruction	Nasal obstruction, mucosal bleeding	Rt eye blind
Radiotherapy dose	54 Gy/30 fx	50.4 Gy/28 fx	50.4 Gy/28 fx	54 Gy/30 fx	54 Gy/30 fx
Radiotherapy modality	IMRT	3D-CRT	3D-CRT	3D-CRT	3D-CRT
Date (year) of radiotherapy	2009	2008	2003	1990	2009
Outcome	Near-CR	Near-CR	CR	Near-CR	Near-CR
Complication	None with normal growth	Lt mandibular hypoplasia	None with normal growth	None	None

C, cervical; T, thoracic; Lt, left; Rt, right; fx, fractions; IMRT, intensity-modulated radiotherapy; 3D-CRT, 3-dimensional conformal radiotherapy; CR, complete remission.

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