Radiation therapy (RT), traditionally reserved for malignant conditions, has emerged as a valuable tool in the management of select benign tumors and proliferative disorders. In clinical scenarios where surgery is not feasible, incomplete, or associated with significant morbidity, RT offers a noninvasive and effective alternative, often yielding excellent local control and long-term symptom relief. For instance, although surgery is relatively safe and effective, radiation is the preferred treatment for many patients with acoustic neuroma. Many benign entities have demonstrated favorable responses to radiation.1 Among these, paragangliomas (PGL)—notably glomus jugulare tumors—have emerged as prime examples where RT plays a critical role. These tumors, while histologically benign, often present with local invasiveness, cranial nerve involvement, and high recurrence rates, making complete surgical resection difficult and frequently associated with significant morbidity.

Beyond PGLs, RT has shown promise in a range of other benign conditions, including many benign vascular and lymphoid disorders.2, 3, 4 These entities, although benign, may behave in an infiltrative or recurrent manner, necessitating a multidisciplinary approach to treatment. In particular, localized lymphoid lesions may benefit from RT. This section focuses specifically on the role of RT in the management of PGL, pheochromocytoma (PCC), hemangioma, ameloblastoma, angiofibroma, Castleman disease, cutaneous pseudolymphoma, and adamantinoma. Other benign entities are discussed in a separate section of the current issue.

Paraganglia are non-neuronal, nonepithelial cells derived from the neural crest. Neuroendocrine in nature, they may be sympathetic or parasympathetic. Sympathetic cells historically turned brown when fixed with chromate salts and are thus referred to as “chromaffin”. Sympathetic tumors may be associated with pathological hormone secretion whereas the chemosensory function of parasympathetic cells does not have a systemic manifestation.

Those PGLs arising in the adrenal glands or abdomen are referred to as PCCs. Head and neck tumors most commonly arise in anatomically defined paraganglial centers but can also arise in dispersed microscopic elements of the autonomic nervous system.5 Carotid body tumors are the most common, followed by jugular, tympanic, and less commonly, vagal PGLs. Head and neck tumors are most commonly (although not exclusively) parasympathetic and have a low metastatic potential. Predictors of worse clinical behavior may include large size (>5 cm), elevated methoxytyramine levels, succinate dehydrogenase subunit B (SDHB) mutations and a high Ki67.6

Paraganglial tumors are amongst those with the highest association with cancer predisposition syndromes. Forty percent are associated with a germline mutation. Such mutations include: VHL, SDH (Succinate Dehydrogenase), RET (associated with MEN2), NF1, TMEM127 (TransMEMbrane protein 127), MAX (MYC Associated factor X), HIF2A, HRAS, KIF1B (Kinesin family Member 1B), PHD2 (Prolyl Hydroxylase Domain-containing protein 2), and FH (Fumarate Hydratase). In addition to germline mutations, 25%-30% are associated with somatic mutations, including those of RET, VHL, NF1, MAX and HIF2A.7 Although germline findings are less common in older patients without a family history of endocrine tumors — genetic evaluation should be considered for all patients. Knowledge of a predisposition may be useful in assessing whether multiple tumors represent metastases or independent primary tumors.

The 2022 WHO classification of neuroendocrine tumors no longer divides them into benign and malignant categories; instead, all sympathetic paragangliomas are recognized as having variable metastatic potential.5,8 In the 8th edition of the AJCC TNM staging manual, the staging of PGLs specifically excludes parasympathetic head and neck tumors.9 These tumors are rare, occurring in less than 1 per 100,000. Although they occur in young patients (especially in the context of a genetic predisposition), the mean age at diagnosis is in the fifth decade of life.10 Named classification systems have been proposed (Fisch or Glasscock-Jackson) describing the tumor local extension — these have not been widely adopted in the RT community.11, 12, 13

PCCs and PGLs are rare neuroendocrine tumors that arise from paraganglionic tissue of the autonomic nervous system.14 These tumors are broadly categorized based on their anatomical location and functional characteristics. PCCs originate within the adrenal medulla and are confined to this site. In contrast, extra-adrenal PGLs can develop along the sympathetic chain (typically in the abdomen, pelvis, or thorax) or in association with the parasympathetic system (primarily in the head and neck region).14,15 Functionally, tumors arising from sympathetic paraganglia—including adrenal PCCs and sympathetic extra-adrenal PGLs—are chromaffin-positive and capable of secreting catecholamines. They frequently present with symptoms such as hypertension, palpitations, headaches, tachycardia, and excessive sweating. Parasympathetic PGLs, also referred to as nonchromaffin tumors, generally do not secrete catecholamines and are most often located in the head and neck. These include tumors historically termed chemodectomas, glomus jugulare tumors, or carotid body tumors.15 The current World Health Organization classification distinguishes these entities based strictly on location: tumors of adrenal origin are termed PCCs, whereas all extra-adrenal tumors—regardless of sympathetic or parasympathetic origin—are classified as PGLs.16

Surgical resection, typically performed laparoscopically, is the preferred treatment approach for both adrenal PCCs and sympathetic PGLs.15

However, the role of RT in these tumors varies depending on location. For intra-abdominal and thoracic lesions, data supporting the use of RT remain limited. Conversely, RT has long played a significant role in the management of head and neck PGLs, where surgical morbidity is considerable due to complex anatomy and proximity to cranial nerves and vascular structures.17,18 Advances in imaging and operative techniques have made embolization followed by surgical excision the standard of care for many head and neck PGLs (see Fig. 1). Nonetheless, RT remains an important treatment modality, particularly in cases where surgery is contraindicated or incomplete. RT, delivered at doses of 40–54 Gy in 1.8–2 Gy fractions, has demonstrated local control rates approaching 90%.19, 20, 21 Table 1 shows a summary of selected RT series for PGL. In selected small, intracranial tumors, stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy offers similarly high local control outcomes.22, 23, 24, 25 RT typically halts tumor progression and stabilizes symptoms, with partial symptomatic improvement observed in approximately 20% of cases.26 For patients with inoperable or metastatic disease, peptide receptor radionuclide therapy has emerged as an effective systemic treatment option, capitalizing on the overexpression of somatostatin receptors in these tumors.27,28

A glomus jugulare is a PGL arising in the jugular foramen at the base of the skull. In 1941 Guild initially used the term “glomus jugularis” before accepting the now widespread “glomus jugulare”.40 Glomus is from the Latin for “ball” or “lump” and jugulare from the Latin jugulum (for “neck” or “throat”). Because of the location, these tumors may present with:•

Symptoms related to the location: hearing loss, pulsatile tinnitus, pain, otorrhea or vertigo.

•

Cranial nerve symptoms (VII to XII): facial palsy, dysphagia, hoarseness, shoulder or tongue weakness

•

In a minority of patients, symptoms of catecholamine secretion (high blood pressure, anxiety, flushing, palpitations, or headaches)

With the increased use of imaging, there is a trend towards discovering smaller asymptomatic tumors.41 As the expected clinical course is indolent, observation is reasonable for a subset of patients —tumors may remain stable for many years and, even with progression, cranial nerve function may remain intact.42

Most patients will be offered a local treatment — surgery or radiation. Although there will be situations where only 1 option is reasonable — many patients will be amenable to both approaches. In this choice, there has been a strong shift towards RT.43 Surgery is more costly and has a higher morbidity. The potential for late radiation-induced malignancy will be outweighed by the higher short-term mortality of skull base surgery.44

Radiation of any type should lead to a high rate of local control (approximately 95% at 5 years), improved symptoms in slightly less than half of patients and slow tumor regression in a similar proportion of patients. Catecholamine secretion can respond to radiation, but the response will be slower and less reliable than after surgery.45,46 Serious complications, typically radiation necrosis, hearing loss, or worsening cranial nerve function will occur in approximately 10% and may resolve with conservative management.

As with most indolent and well-defined tumors, it is not necessary to treat nodal areas or a margin around the tumor. However, in areas (often inferiorly) where there is some doubt on the exact extent, adding a few millimeters of clinical target volume is reasonable. As many volumetric imaging series as possible should be used to define tumor extent (high resolution CT and T1 contrast MRI at a minimum). A volumetric T2 series is helpful, and, despite the lower spatial resolution, somatostatin receptor PET (68Ga-DOTATOC-PET, 68Ga-DOTATATE-PET) can increase targeting confidence.47

Standard fractionated radiotherapy (45-54 Gy in 1.8-2 Gy fractions) is associated with favorable outcomes (see Table 2). There is no obvious dose response above 45 Gy. Single fraction treatments of 14-16 Gy are the most common. With the advent of frameless SRS, treatments of 21-27 Gy in 3 or 25-35 Gy in 5 fractions are also reported. Rare cases have been treated with protons with the purported benefit of reducing integral dose. When lesions are amenable to SRS, conventional fractionation is, however, difficult to justify due to its inconvenience and higher integral dose. Figure 2 shows an example of radiosurgical dosimetry for glomus jugulare tumor.

PCC is a rare neuroendocrine tumor arising from chromaffin cells in the adrenal medulla, whose primary function is catecholamine production, storage, and secretion.64 Figure 3 illustrates the characteristic coagulative necrosis that may be observed in PCC. PGLs are a closely associated tumor which is from extra-adrenal chromaffin cells; about 85%-90% of these tumors are PCCs.65 Most PCCs occur in the fourth and fifth decades of life, but some arise in younger patients (especially with a genetic predisposition).64,66 Incidence is estimated at around 0.6 per 100,000 individuals globally.64 PCCs characteristically secrete catecholamines, though the specific type can vary based on association with genetic syndromes. For example, PCCs associated with MEN II or NF1 are typically epinephrine-producing, whereas those associated with VHL often produce norepinephrine or normetanephrine.66

The most frequent presenting symptom is hypertension, in about 90% of cases, but characteristic findings (paroxysms) include headaches, palpitations, and sweating, all associated with adrenergic response.65 Patients who present with paroxysms, young patients with hypertension, or refractory hypertension, and those with predisposition (familial history or diagnosed associated genetic syndrome) should be screened for these tumors.65 About 25% of PCCs are genetic in origin and many of those have pathogenic germline variants; syndromes include NF1, MEN II, VHL, and SDH (types A-D).65,67 Diagnosis is mainly dependent on catecholamine excess as measured by 24-hour urinary catecholamine and metanephrine excretion or plasma metanephrine levels.68 The tumor should also be localized with imaging; traditionally CT with contrast or MRI without contrast has been used but functional imaging has become much more popular including PET, SPECT, and theranostic nuclear medicine scan with various radiolabeled tracers (e.g., 68Ga-DOTA somatostatin analogues, 18F-FDOPA, 131I-MIBG, 18F-FDG, etc.).68, 69, 70 These can be especially helpful when distinguishing between PCC and other adrenal tumors.

Treatment of PCC begins with preoperative therapy, with 7-30 days of medications aiming to prevent intraoperative hypertensive crises and arrhythmias; the preferred therapy is an α-blockers (doxazosin, phenoxybenzamine, prazosin).65,71,72 Calcium channel blockers, ACE inhibitors, or β-blockers can also be used after initial therapy with α-blocker.72,73 Minimally invasive laparoscopic resection is the standard of care, with partial adrenalectomy if technically possible for patients with hereditary PCC.71, 72, 73 Patients should be monitored closely as recurrence or metastasis can occur, estimated at 5% at 5 years even with apparent gross total resection.71

RT is sometimes used for treatment of PCC, especially in the medically inoperable setting, but most often useful for PGLs due to their location. A review of 16 cases of PGLs treated with SBRT (25 Gy in 5 fractions) was promising, with a 5-year control rate of 88%.74 Another experience with frameless linac-based SRS showed local control comparable to multifraction regimens with 97% progression-free survival at 7 years.55 Conventional fractionation has been used for many years; a recent review of 156 cases treated with 45 Gy in 25 fractions had local control rates of 99% at 5 years and 96% at 10 years.75

The historical classification of “malignant” vs “benign” PCC has been revised as all PCCs have malignant potential, though only about 5%-10% of PCCs metastasize.76 External beam radiation can be used; a review of 14 patients with metastatic/advanced PCC with BED of 74.4 Gy/130 Gy (α/β =10 Gy/3 Gy, respectively) showed 78% overall survival at 2 years, with stable disease of the target lesion in 94% of cases.77

Radiopharmaceuticals are also being used as targeted treatments for PCC especially in the metastatic setting.

A long-term review of 125 patients treated with 131I-MIBG showed that about half of the patients had stable disease and about a third had a treatment response at first follow up, which was predictive of improved median overall survival (6.3 vs. 2.4 years) in responders compared to nonresponders.78 Other radiopharmaceutical therapies including Y-90 or Lu-177 have also been reported.79 Table 3 summarizes selected radiation therapy outcomes for PCC, including both external beam and radionuclide-based treatments.

Angiofibromas encompass a broad range of lesions that share microscopic features of spindle- and stellate- shaped cells centered around vessels with fibrous or collagenous stroma,83 as seen in Figure 4. Specifically, RT can be utilized in juvenile nasopharyngeal angiofibromas (JNA), which are unencapsulated neoplasms that can be locally advanced and destructive. JNAs originate in the nasopharynx and posterior nasal cavity of almost exclusively males, with a mean age of onset between 13 and 22 years old.84 The strong disposition to younger males is hypothesized to be secondary to significant androgen stimulation, though other possible contributors include genetic factors, molecular alterations, and HPV infection.83 These tumors commonly grow to occupy the sphenoid sinus, but may also involve the ethmoids by anterior extension or the infratemporal fossa by lateral extension. In addition, there can be intracranial extension and involvement of critical anatomic structures such as the cavernous sinus, internal carotid artery (ICA), and orbital apex.85

Presenting symptoms of JNA frequently include unilateral nasal obstruction and recurrent epistaxis, but may also include headache, anosmia, facial swelling, and cranial neuropathy.86,87 Given the vascularized nature of JNAs with their high propensity for bleeding, diagnosis is primarily established through otolaryngological examination and imaging instead of biopsy.88 CT imaging can evaluate the extent of bony invasion, MRI imaging can assess involvement of adjacent soft tissues, and angiography can confirm vascular supply for possible preoperative embolization.87 Figure 5 shows an angiofibroma in the sphenopalatine foramen. There is no standard staging system for JNAs. Various staging systems describing extension of tumor and amount of intracranial extension have been designed to predict local disease control.89 Residual vascularity from the ICA has been proposed as a critical prognostic factor for surgical morbidity.90

For extracranial tumors, definitive management involves endoscopic, external, or combined surgical resection, often combined with preoperative embolization to reduce intraoperative bleeding.87,91,92 Open surgical approaches are typically reserved for more locally advanced disease. Optimal management is more controversial in JNAs with intracranial involvement, where gross tumor resection is challenging and there is a greater risk of surgical complications.93

RT is recognized as an effective treatment approach for residual, recurrent, and inoperable JNAs. In tumors where resection would compromise vision or in JNAs that involve the ICA, cavernous sinus, or dura, RT should be offered as primary treatment.92 Fields should cover the entire tumor with a 1 to 2 cm margin without elective coverage of cervical lymph nodes, sparing optic structures as much as possible. Opposing lateral fields are appropriate for smaller tumors, while more extensive disease requires 3-field or wedge-pair arrangements of 3D-CRT or IMRT.94 Due to the close proximity to critical organs at the skull base in locally advanced cases and the younger ages at presentation, use of conformal radiation modalities reduces radiation-induced long-term complications such as hypopituitarism, secondary neoplasms, temporal lobe necrosis, cataracts, and decreased bone maturation. Proton therapy has also been shown to offer comparable local control outcomes with better sparing of structures such as the contralateral cochlea and infratentorial brain.95 Gamma-Knife Stereotactic Radiosurgery (GKSRS) has also been used as an adjuvant treatment for residual advanced JNAs near the cavernous sinus, achieving long-term control even with larger tumors treated at a 14 Gy marginal dose.96

There is no standardized radiation dosing regimen for JNAs, with doses historically ranging from 30 Gy in 15 fractions to 50 Gy in 24 to 28 fractions.97 Local control rates using RT are at least 70%, with several studies suggesting better local control in patients receiving doses over 32 Gy (Table 4). JNAs regress slowly after RT, with around 50% still present after 12 months and taking at least 3 years to completely regress in some cases.98 Tumor-related symptoms, however, resolve within 6 months of treatment.99

Recurrence rates between 13% and 46% have been reported and are mostly dependent on tumor characteristics such as location, size, and extension.87,100 Tumor extension to the posterior infratemporal fossa or intracranially is associated with a higher risk of recurrence.101 Recurrences, likely representing growth of residual disease, have been reported an average of 6 to 36 months after surgical resection.102,103