Benign Diseases

Definition and Clinical Features

Intracranial AVMs are rare vascular abnormalities consisting of widened arteries with connections to abnormal capillary beds that enable oxygenated blood to directly enter the venous system. Approximately 80% of AVMs are located supratentorially. The incidence of AVMs is unknown; prevalence is below 0.01% (≈ 18 : 100,000) in the Western hemisphere. Most AVMs are discovered between the ages of 20 and 40 years. AVMs can extend to aneurysms and rupture (2%-5% per year). Neurological symptoms associated with AVMs are due to hemorrhage and include headaches, seizures, and focal neurological deficits, which may culminate in sudden death. Increased risk of hemorrhage includes prior hemorrhage, exclusive deep venous drainage, associated aneurysms, and deep location, which can influence surgery and or radiosurgery decision-making. Lethality after the first bleeding episode occurs in up to 30%; 10% to 20% of survivors have long-term neurological defects. Spontaneous regression is rare. Diagnosis of AVMs is made with imaging techniques such as angiography and magnetic resonance imaging (MRI).

The aim of therapy is the prevention of bleeding by complete obliteration of the nidus, the improvement of neurological malfunctions, if feasible, and, preferably, minimal therapy-induced side effects. For this purpose, the options of minimally invasive endoscopic surgery, endovascular embolization, and stereotactic radiosurgery (SRS) are available. For therapy planning, precise knowledge regarding the size, location, arterial feeders, and venous drainage of the nidus is required.

Surgical Treatment

The therapy of choice is the elective complete excision of the AVM vascular abnormality. Particularly with small AVMs in superficial, noneloquent regions of the brain, microsurgery results in high cure rates. Larger AVMs are treated initially with embolization before surgery or SRS. Only in special cases is surgery performed under emergency conditions to remove life-threatening brain hemorrhages.

Irradiation Options

Arteriovenous malformations are irradiated with stereotactic radiotherapy (SRT)/SRS with a linear accelerator or Gamma Knife (see Chapter 7 ).

SRS for AVMs dates back to the 1970s. The mechanism of action of SRT/SRS is linked to injury to the vascular endothelium, which causes proliferation of smooth muscle cells and the elaboration of extracellular collagen, causing progressive stenosis and obliteration of the AVM.

Fractionated radiation with total doses of up to 60 Gy produced inadequate results. Depending on the size and location of the AVM, a single dose of 15 to 30 Gy is required to the periphery of the nidus. If therapy is successful, complete obliteration of the nidus will occur usually no sooner than 2 years from treatment, with many taking 3 years or longer. This delay in obliteration leads to a risk of bleeding until complete obliteration occurs. The obliteration rate after SRT or SRS is 65% to 95% ( Table 76.3 ).

The side effects of SRT/SRS are mostly chronic and follow the time course of AVM obliteration: focal radionecroses or leukoencephalopathies occur 9 months to 3 years after SRT, but they may also appear after several weeks. Toxicity risk correlates strongly with irradiated brain volume, location of the AVM, and the total dose. Brain volume irradiated with more than 10 Gy is an important predictive factor.

Whether unruptured AVMs should be treated or observed has been a matter of debate. The ARUBA trial, a randomized trial of unruptured brain AVMs, compared the risk of death and symptomatic stroke. Patients were randomized to either medical management for symptoms treated with pharmacological agents alone or medical management with interventional therapy, including neurosurgery, SRT, or embolization, alone or in combination. The trial was halted early owing to the superiority of the medical management group because the risk of death or stroke was significantly lower compared to the intervention group.

Definition and Clinical Features

Paragangliomas, often known as glomus tumors or chemodectomas, are rare benign neuroendocrine tumors that can occur in multiple anatomic locations:

• 1.

  Glomus vagale is a paraganglioma occurring along the path of the vagus nerve. It is also known as a carotid body tumor.

• 2.

  Glomus jugulare is a paraganglioma found near the skull base in the region of the jugular bulb.

• 3.

  Glomus tympanicum is a paraganglioma that occurs in the region of the tympanum.

• 4.

  Other paragangliomas occur at the larynx, near the aorta, in pulmonary locations, and in the orbit.

Approximately 50% of tumors are located near the skull base in the jugular fossa. The age of peak diagnosis is 45 years. The tumors are usually unilateral; only 10% to 20% are bilateral or multiple. When multiple or bilateral, paragangliomas are usually associated with heritable syndromes such as multiple endocrine neoplasia (MEN) type II or Carney syndrome. Paragangliomas grow slowly, rarely have endocrinological activity, and degenerate into malignant forms in only 3% to 5% of patients. The main symptoms are dependent on anatomic location and can include headache, CN failure (CN V–XII), dysphagia, pulsatile tinnitus, vertigo, and hypoacusis. Without therapy, there is the risk for CN injury; the swelling can be so extreme as to be life-threatening. The diagnosis is made clinically and with high-resolution computed tomography (CT) and MRI demonstrating a well-circumscribed, vascular mass.

Surgical Treatment

Although glomus tumors grow slowly, they can cause severe problems and, therefore, must be treated. In the carotid region, primary tumor resection after previous embolization is the therapy of choice. At the skull base or at the tympanum, neurosurgical interventions carry more risk; therefore, fractionated radiation is often favored. In the case of incomplete surgery, the patient should initially be observed; further treatment should be started only if the tumor grows.

Irradiation Options

Depending on the size and location of the lesions, the indication for radiotherapy may be either primary irradiation in the case of functional or other inoperability (mostly, jugular paragangliomas) or adjuvant irradiation for R1 to R2 resections or irradiation of recurrence if there is progression after surgery. Conventional fractionated three-dimensional (3D) conformal radiotherapy with 45 to 55 Gy is the most common technique. The clinical target volume (CTV) is restricted to the tumor region with a safety margin to cover microscopic extensions.

Irradiation of paragangliomas produces control rates as good as or even better than surgery. Even in large, diffusely growing or multiple tumors, radiation produces a local control rate of 88% to 100%. Kim et al. noted a recurrence rate of 22% with doses of less than 40 Gy, whereas recurrences occurred in only 1.4% with doses of more than 40 Gy. Frequently, tumor rests are detectable on imaging for several years. Therapeutic success is usually assessed in terms of the regression of CN failures and the lack of tumor progression. A dose of 45 to 50 Gy does not complicate surgery that might become necessary later.

Stereotactic single-dose radiation and Gamma knife therapy have efficacy in the treatment of paragangliomas. The results are favorable compared with fractionated radiation, with excellent local control rates and acceptable side effects. Sheehan et al. reported data regarding 134 patient procedures from eight Gamma knife centers, including prior resection in 51 patients. The median tumor margin dose was 15 Gy. With a median duration of follow-up of 50.5 months (range, 5-220 months), overall tumor control was 93% at last follow-up with an 88% actuarial tumor control 5 years after surgery. Worsening CN function was seen in 11% of patients despite radiological evidence of control. No secondary malignancies were noted.

Irradiation of paragangliomas of the carotid glomus can acutely cause pharyngeal mucositis and chronically may lead to skin fibrosis and dryness of the pharyngeal mucosa on the irradiated side. Irradiation of jugular or tympanic paragangliomas can lead to acute skin reactions in the external acoustic canal, tube ventilation dysfunction, reduced sound conduction, and salivary retention on the ipsilateral side.

Definition and Clinical Features

Juvenile nasopharyngeal fibromas (JNFs), a synonym for angiofibromas, are rare, benign, strongly vascularized tumors in the head and neck region, affecting mainly male juveniles. JNFs develop in the sphenoethmoidal suture and can spread from the epipharynx and the main nasal cavity via the sphenopalatine foramen and into the pterygopalatine fossa. After bony destruction, there is spread into the paranasal sinuses, infratemporal fossa, orbital space, and middle cranial fossa.

Intracranial spread occurs in about 25% of cases. Typical symptoms are nasal obstruction, causing impaired nose breathing, which may be accompanied by epistaxis. Depending on the pattern of spread, facial swelling as well as orbital (e.g., blindness) and intracranial symptoms (e.g., CN failure) may occur. Other symptoms may include anosmia, decreased hearing, voice change, proptosis, and weight loss. A biopsy can cause massive bleeding; thus, histological confirmation of diagnosis is often not performed. The presence of hormone receptors shows the influence of androgynous hormones, likely explaining their usual occurrence in males. Spontaneous remission after puberty is possible, but therapy can hardly be delayed when the symptoms increase and when complications are threatening.

Surgical Treatment

In JNF, the main emphasis is placed on surgery combined with embolization to decrease the size of the tumor. Small tumors that are restricted to the posterior nasal cavity and nasopharynx can be completely removed after embolization. A JNF with lateral spread is also an indication for surgery. Endoscopic surgical approaches have increasingly been used in treating early-stage tumors rather than an open approach as a means of decreasing morbidity. A craniofacial approach may be needed with more advanced disease. Through surgery, the local control rates for most JNFs without intracranial spread range up to 100% with minimal toxicity.

Irradiation Options

Radiotherapy is an effective treatment for JNF. Controversy remains about the optimal management strategy for patients with intracranial extension. In locally advanced disease, complete resection is often not possible, and in tumors with intracranial spread, primary irradiation may be considered. Adjuvant irradiation may be considered after subtotal resection or intracranial extension owing to reports of recurrence of at least 30%. Other indications for radiation are inoperability or local recurrence after initial surgical resection.

Long-term sequelae and the risk of secondary malignancy associated with radiotherapy have remained a concern. With modern imaging-based treatment planning allowing for more conformal delivery of dose, high control rates are achieved in locally advanced JNF as well. Intensity-modulated radiotherapy (IMRT) is often recommended. Total doses of 30 to 55 Gy (1.8-2.0 Gy per fraction) are said to be effective; however, for large tumors, doses of 40 to 46 Gy are currently recommended. With conventional fractionated radiation, control rates of 80% to 100% can be reached. Remission of JNFs after radiation often requires several months. Sometimes, complete remission—as detected by imaging techniques—does not occur even after years, although there is no further growth.

Radiation side effects include mucositis, xerostomia and caries, dysfunction of the pituitary gland, CN failure, temporal lobe necrosis, osteoradionecrosis, growth impairment of the facial skull, cataract, glaucoma, and atrophic rhinitis. However, these can be limited through careful radiation planning and highly conformal radiation. In 31 patients treated by Mallick et al., no grade 3 or grade 4 toxicity due to radiation was reported. Radiation-induced tumors occur in up to 4% of cases, particularly in young patients; this has to be weighed against the risk for sudden death or severe morbidity after surgery.

Definition and Clinical Features

Pterygium is a wing-shaped fibrovascular proliferating tissue originating at the lens epithelium at the border between the conjunctiva and cornea. It normally extends from the medial (nasal) corner of the eye to the cornea and beyond. The highest incidence occurs in hot, dusty, dry, and sun-exposed regions (desert belts). In such areas, even people in their 20s and 30s can be affected. Typical symptoms are the sensation of having a foreign body in the eye and tearing. Motility problems are sometimes present. If the cornea is affected, vision may be impaired.

Surgical Treatment

Surgery is the mainstay of treatment, indicated if vision is threatened by the pterygium growing toward the pupil, relief of discomfort, or if cosmesis is affected. Historically, the initial approach was bare sclera excision, which removes the pterygium from the cornea and conjunctiva, leaving the bare sclera exposed. Absent adjuvant therapy, recurrence rates have been reported to be as high as 88%. Currently accepted therapeutic strategies include conjunctival or limbal autografts with or without 5-fluorouracil or mitomycin C intraoperatively or postoperatively. Amniotic membrane grafting has been used, but appears to be inferior to conjunctival or limbal autografting. There has been recent interest in the use of subconjunctival or topical bevacizumab and ranibizumab (antivascular endothelial growth factor therapy), with mixed results reported. With the use of the aforementioned adjuvants, recurrence rate reduction (compared to bare sclera excision alone) in both primary and recurrent cases is in the range of 40% to 95%. Vision-threatening and non-vision-threatening complications are relatively rare but can include scleral thinning or ulceration, delayed conjunctival epithelialization, iritis, corneal edema, corneal perforation, symblepharon, corneal dellen, astigmatism, pyogenic granuloma formation, ocular pain, photophobia, and foreign body sensation.

Irradiation Options

Radiotherapy is indicated after local resection of a recurrent pterygium, but some centers also report success with primary or preoperative radiation of the pterygium. Besides rare orthovoltage therapy, brachytherapy with beta radiators and eye applicators is usually employed. Normally, radionuclide strontium-90, a fission product of uranium-235 (half-life period, 28 years), which decays to yttrium-90 (half-life of 64 days) is used. Strontium-90 radiation has a maximum energy of 0.546 MeV; for yttrium-90 it reaches 2.27 MeV. The eye applicators have an effective diameter of 8 to 12 mm. The affected lesion is generously covered by the applicator for a certain period of time. If lesions are large, they are treated with a circular motion toward the corneal limbus.

Most clinical studies have used postoperative radiation for recurrence prophylaxis with subsequent relapse rates of 1.5% to 11%. Van den Brenk et al. observed only 1.4% recurrences in 1300 treated pterygia (1064 patients). Irradiation was carried out once a week (days 0, 7, and 14 postoperatively). Paryani et al. achieved a recurrence rate of only 1.7% in 825 eyes with 60 Gy in 6 fractions of 10 Gy (once a week). Wilder et al. report a recurrence rate of more than 11% in 244 eyes after 24 Gy in 3 fractions of 8 Gy (once a week). In comparison to placebo irradiation, a Dutch double-blind randomized study with 1 fraction of 25 Gy showed significantly lower recurrence rates (local relapse in the irradiation arm in only 3 of 44 tumors and in the placebo arm in 28 of 42 tumors). A randomized clinical trial examining 20 Gy in 10 fractions versus 35 Gy in 7 fractions noted no significant differences in 3-year local control (92.3% vs. 93.8%, p = 0.616). However, differences in cosmetic effects, photophobia, irritation, and scleromalacia favored the lower dose regimen.

Radiogenic consequences, such as severe scleromalacia and corneal ulcerations, occur in up to 4% to 5% of cases after application of higher total doses and after single-dose radiation of 20 to 22 Gy.