Chapter 64 Benign Diseases
Definition and Classification of Benign Diseases
Many diseases that are pathologically benign (nonmalignant) but not clinically benign can be successfully treated with ionizing radiation. The use of irradiation for painful musculoskeletal diseases has a long tradition in Europe.1 Sokoloff reported positive results in radiotherapy of painful “rheumatoid diseases” as early as 1898.2 The traditional classification of benign diseases amenable to radiotherapy as inflammatory, degenerative, hyperproliferative, functional, and other types of disorders is currently outdated. Worldwide, irradiation of benign diseases has become more important, although indications and treatment concepts have changed considerably and there are clear differences between countries owing to clinical traditions and differences in organization and training.*
Long-Term Risk for Tumor Induction
Considering international data about the emergence of tumors and leukemias after whole-body exposure to ionizing radiation (United Nations Scientific Committee on the Effects of Atomic Radiation [UNSCEAR], Biological Effects of Ionizing Radiation [BEIR]), the risk for tumor induction can be calculated on a gender- and age-related basis.9,10 The average lifetime risk for exposure to radiation is lower in men (9.5%) than in women (11.5%). Table 64-1 summarizes the age- and gender-specific risks for tumor induction.
TABLE 64-1 Tumor Induction Depending on Age and Gender: Relative Lifetime Risk
| Age-group | Men (%/Sv) | Women (%/Sv) |
|---|---|---|
| ≤10 yr | 25.0-26.0 | 32.0-33.0 |
| 11-20 yr | 15.0 | 19.0 |
| 21-30 yr | 13.0-14.0 | 17.0 |
| 31-40 yr | 7.0 | 8.0 |
| 41-50 yr | 5.0 | 6.0 |
| 51-60 yr | 4.5 | 5.0 |
| 61-70 yr | 3.5 | 4.5 |
| 71-80 yr | 2.5 | 3.0 |
| >80 yr | 1.0 | 1.5 |
From Jansen JTM, Broerse J, Zotelief J, et al: Assessment of carcinogenic risk in the treatment of benign disease of knee and shoulder joint. In Seegenschmiedt MH, Makoski H-B, editors: Kolloquium Radioonkologie/Strahlentherapie, Radiotherapie bei gutartigen Erkrankungen, Vol 15, Altenberge, 2001, Diplodocus Verlag, pp 13-15.
Principles of Irradiation of Benign Diseases
The principles of irradiation of benign diseases can be summarized in 10 statements (Table 64-2). These should be carefully considered for each patient in whom irradiation is being evaluated.
Data from Seegenschmiedt MH, Katalinic A, Makoski H, et al: Radiation therapy for benign diseases. Patterns of care study in Germany, Int J Radiat Oncol Biol Phys 47:195-202, 2000; Micke O, Seegenschmiedt MH: The German Working Group guidelines for radiation therapy of benign diseases. A multicenter approach in Germany, Int J Radiat Oncol Biol Phys 52:496-513, 2002.
Radiobiologic Aspects
Reactions in Connective Tissue
Several mechanisms are triggered by ionizing radiation in connective tissues. Following any trauma or acute or chronic inflammation, several cell systems regulate the repair process where fibroblasts play a central role, particularly during the reparative phase, which is characterized by high cell production and stimulation of specific growth factors. Furthermore, ionizing radiation also has a pivotal influence on cellular differentiation.11,12
Reactions in the Vascular System
The endothelial cells of the capillaries and the larger arterial and venous blood vessels are the origins of various cytokine-mediated cellular reactions and possess a high proliferative potential. Intercellular adhesion molecule 1 (ICAM-1), a mediator of the leukocyte-endothelial interaction, is induced by low radiation doses.13 Similarly, selectins mediate the penetration of mononuclear blood cells into the interstitial tissue. Endothelial prostaglandin release is also modulated by ionizing radiation.14 Cellular and membrane functions can be modified when they are exposed to radiation.
Mechanism of Action
To know individual target cells and potential pathogenic mechanisms of the various benign diseases also means to coordinate the radiation therapy concepts accordingly and consistently. The dose concepts applied in benign diseases differ greatly from each other due to other potential mechanisms of action (Table 64-3).
| Mechanisms of Action | Single Dose (Gy) | Total Dose (Gy) |
|---|---|---|
| Cellular gene and protein expression (e.g., eczemas) | <2 | <2 |
| Inhibition of inflammation in lymphocytes (e.g., in pseudotumor orbitae) | 0.3-1 | 2-6 |
| Inhibition of fibroblast proliferation (e.g., in keloids) | 1.5-3 | 8-12 |
| Inhibition of proliferation in benign tumors (e.g., in desmoids) | 1.8-3 | 45-60 |
Benign Disorders of the Head and Neck and Central Nervous System
Pituitary adenoma, meningioma, vestibular schwannoma, and chordoma are important benign CNS tumors treated with irradiation. These are covered fully in Chapters 17, 26, 27, and 28 and will not be discussed here.
Craniopharyngioma
Definition and Clinical Features
Craniopharyngiomas are rare dysontogenetic midline tumors originating from Rathke’s pocket or the ductus craniopharyngicus. They make up 6% to 10% of CNS tumors in children and appear mostly between ages 5 and 15 years. They are located near the sella, with a close connection to the pituitary gland, hypothalamus, chiasma opticum, and visual nerves. Intrasellar tumors are rare; some are also located suprasellarly or intrasellarly. Main symptoms are visual impairment or loss of vision, visual field impairment (bitemporal hemianopia), and endocrine dysfunctions such as dwarfism, fat tissue disturbance, or adrenal cortex insufficiency. Signs of intracranial pressure can appear as well. Diagnosis is made from skull radiographs (sella expansion), computed tomography (CT) (typical calcifications), and magnetic resonance imaging (MRI) (cystic or mixed solid and cystic tumor components).15
Surgical Treatment
Primary therapy consists of complete resection, which is equivalent to permanent cure. Ten-year control rates after complete tumor resection are 60% to 93%.16,17 Because radical neurosurgical procedures can result in relatively high postoperative toxicities, such as visual impairment (20%) and panhypopituitarism (≤95%),16 less radical surgery plus adjuvant three-dimensional conformal RT (3DCRT) is the preferred treatment in many patients.
Irradiation Options
In primary inoperable tumors or after subtotal resection, RT is indicated because otherwise the local progression rate after 2 to 3 years is 70% to 90%.18 After subtotal resection alone, the local recurrence rate is 30% or more; when subtotal resection is combined with postoperative RT, the rate is reduced to 5% to 15% after 5 to 20 years.18–20 Long-term local control after primary RT or after subtotal resection or cyst punctuation plus adjuvant RT, respectively, with a total dose of 50 to 54 Gy (1.8 to 2 Gy per fraction) is comparable to those of complete resection.21,22
Stereotactic RT places less stress on normal tissue. Due to the proximity of the tumor to the chiasm and visual nerves, fractionated stereotactic RT (FSRT) is preferred to single-dose irradiation. Using FSRT, a local 10-year control rate of 100% was reached in Heidelberg.23 With the use of MRI follow-up imaging, complete remission was noted in 4 of 26 patients and partial remission in 14; 8 had a stable MRI finding. In five patients, visual improvement was reached. The hypophyseal hormonal situation deteriorated in seven patients. There were no radionecroses or secondary malignant tumors, and visual deterioration did not occur.
After conformal RT, the rate of visual deterioration is up to 10%. Severe side effects such as radionecroses, cognitive changes, and secondary malignant diseases occur with an incidence of less than 2%.14
Arteriovenous Malformation
Definition and Clinical Features
Intracranial AVMs are rare vascular abnormalities consisting of widened arteries with connections to the normal capillary bed; this enables oxygenated blood to enter directly into the venous system. About 80% of AVMs are located supratentorially. The incidence of AVM is unknown. Its prevalence is below 0.01% (≈18 : 100,000) in the Western hemisphere. Most AVMs are discovered at the age of 20 to 40 years. AVM can extend to aneurysms and rupture (2% to 5% per year).24 Neurologic symptoms characterize the clinical course (headaches, hemorrhage, cramp attacks), which may culminate in sudden death through bleeding. Diagnosis is made with special imaging techniques (angiography, MRI).
Untreated AVMs have a bleeding risk of 2% to 4% per year, which increases after a rupture. Large AVMs with deep arterial feeders or those located at the basal ganglia or thalamus (9%) have an increased bleeding risk.25 Lethality after the first bleeding episode occurs in up to 30%; 10% to 20% of survivors have long-term neurologic defects. Spontaneous regression is very rare.
Irradiation Options
AVMs are irradiated with SRT/SRS with a linear accelerator or Gamma Knife* (see Chapter 17). Fractionated RT with total doses of up to 60 Gy produced inadequate results.28–31 Depending on the size and location of the AVM, a single dose of 15 to 30 Gy is required in the periphery of the nidus. If the therapy is successful, complete obliteration of the nidus will occur within a few years. However, the bleeding risk continues to exist during the interval between SRT/SRS and complete obliteration. The obliteration rate after SRT or SRS is 65% to 95%† (Table 64-4).
TABLE 64-4 Arteriovenous Malformations: Obliteration Rate and Rate of Radiation Side Effects after Radiosurgery
The side effects of SRT/SRS are mostly chronic and follow the time course of AVM obliteration: focal radionecroses or leukoencephalopathies occur 9 to 36 months after SRT,48,49 but they may also appear after several weeks.50 The risk correlates strongly with the irradiated brain volume and the total dose51–53: the brain volume irradiated with more than 10 Gy is an important predictive factor.54,55
Glomus Tumor or Chemodectoma
Definition and Clinical Features
About 50% of tumors are located near the skull base in the jugular fossa. The age peak is 45 years. The tumors are usually unilateral; only 10% to 20% are bilateral or multiple.56 They grow slowly, rarely have endocrinologic activity, and degenerate into malignant forms in 5% to 10% of patients. They can also infiltrate bone, vessels, the middle ear, and cranial nerves (CN). The main symptoms are headaches, CN failure (CN V to XII), dysphagia, pulsatile tinnitus, vertigo, and hypacusis. 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 CT and MRI.
Irradiation Options
Irradiation of paragangliomas produces control rates as good as or even better than surgery.* Even in large, diffusely growing or multiple tumors, RT produces a local control rate of 88% to 93%.57–61 Kim and associates57 noticed 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.
During the past decade, stereotactic single-dose RT and Gamma Knife therapy have been used for the treatment of paragangliomas.62–64 Although the observation time after surgery is short, the results are very favorable.
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 may occur in the middle ear. Long-term sequelae are rare.58–60,61
Juvenile Nasopharyngeal Fibroma
Definition and Clinical Features
Intracranial spread occurs in about 25% of cases. Typical symptoms are epistaxis and impaired nose breathing. Depending on the pattern of spread, facial swelling as well as orbital (e.g., blindness) and intracranial symptoms (e.g., CN failure) may occur. A biopsy can cause massive bleeding so that histologic confirmation of diagnosis is often not performed. The presence of hormone receptors shows the influence of androgynous hormones. Spontaneous remission after puberty is possible, but therapy can hardly be delayed when the symptoms increase and when complications are threatening.65
Surgical Treatment
In JNF, the main emphasis is placed on surgery combined with embolization to decrease the size of the tumor.66–68 Small tumors that are restricted to the posterior nasal cavity and the nasopharynx can be completely removed after embolization. A JNF with lateral spread is also an indication for surgery. Through surgery, the local control rates for most JNFs without intracranial spread range up to 100% with minimal toxicity.66,67
Irradiation Options
Radiotherapy is a very effective treatment for JNF.* In locally advanced disease, complete resection is often not possible, and tumors with intracranial spread should receive primary irradiation. Other indications for 3DCRT are tumor rests, inoperability, or local recurrence after initial surgical resection. With modern CT-based treatment planning, high control rates are achieved in locally advanced JNF as well. FSRT is often recommended.68
Total doses of 30 to 55 Gy (1.8 to 2 Gy per fraction) are said to be effective,69 but for large tumors, doses of 40 to 46 Gy are currently recommended.70 With conventional fractionated RT, control rates of 80% to 100% can be reached.* Remission of JNFs after RT often requires several months71; sometimes, complete remission, as detected by imaging techniques, does not occur even after years, although there is no further growth.
Benign Disorders of the Eye and Orbit
Macular degeneration and endocrine orbitopathy (Graves’ disease) are important benign diseases of the eye or orbit that are treated with irradiation. They are discussed in detail in Chapter 29 and will not be covered here.
Pterygium
Definition and Clinical Features
Pterygium is a wing-shaped fibrovascular proliferating tissue originating at the lens epithelium at the border between the conjunctiva and the 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 are affected.76,77 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
Therapy is indicated if vision is threatened by the pterygium growing toward the pupil and if aesthetics are subjectively affected. Complete surgical excision is the therapy of choice; the several alternatives include open-wound defect (bare sclera technique), primary conjunctival occlusion, rotation flap, keratoplasties, and free transplant. The local control rate is 50% to 70%.76
In patients with local recurrence, additional treatments are indicated postoperatively. In those cases, local cytostatics (e.g., mitomycin C) are administered, which may lead to severe local complications such as scleral ulceration, secondary glaucoma, corneal edema, corneal perforation, iritis, or cataracts.78–80
Irradiation Options
Radiotherapy is indicated after local resection of a recurrent pterygium, but some centers also report success with primary and/or preoperative RT of the pterygium.81 Besides rare orthovoltage therapy,82 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 period, 64 days) is used. Strontium-90 radiation has a maximum energy of 0.546 MeV; for yttrium-90 it reaches 2.27 MeV.86 The eye applicators have an effective diameter of 8 to 12 mm. The affected lesion is generously covered by the applicator for a certain time; if lesions are very large, they are treated with a circular motion toward the corneal limbus.87
Most clinical studies have used postoperative RT for recurrence prophylaxis with subsequent relapse rates of 1.5% to 11%.† Van den Brenk83 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 and others87 achieved a recurrence rate of only 1.7% in 825 eyes with 60 Gy in six fractions of 10 Gy (once a week). Wilder and associates76 report a recurrence rate of more than 11% in 244 eyes after 24 Gy in three fractions of 8 Gy (once a week). In comparison to placebo irradiation, a Dutch double-blind randomized study with one 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).88
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 RT of 20 to 22 Gy.84,85
Choroidal Hemangioma
Definition and Clinical Features
Choroid membrane hemangiomas are slowly growing benign tumors originating from the vessels of the choroid. They can also occur in congenital Sturge-Weber syndrome. The diffuse type (ages 5 to 10 years) and the local type (ages 30 to 50 years) can be distinguished.94 Symptoms are determined by the size and location of the tumor. If the hemangioma is located close to the papilla or macula, “fuzzy or blurred vision,” metamorphopsia, and secondary retinal detachment are observed. In case of direct macular involvement, chronic glaucoma frequently develops. Sometimes there is complete loss of vision. On ophthalmoscopic examination, hemangiomas appear as red-orange swelling with concomitant clinical phenomena (e.g., glaucoma, retinal detachment). Further diagnostic procedures are ultrasound, fluorescence angiography, CT, MRI, and scintigraphy (phosphorus-32).95
Nonradiotherapeutic Treatment
Indications for therapy depend on the progression of the lesion and the severity of symptoms (visual impairment, retinal detachment, or secondary glaucoma). Small lesions outside the field of central vision are treated with photodynamic therapy, photocoagulation, or transpapillary thermotherapy (e.g., to prevent retinal detachment).96,97 Lesions near the macula or papilla are not coagulated because there is a risk for central scotoma; the same holds for incomplete retinal detachment and for the diffuse type (Sturge-Weber syndrome). Overall, ophthalmologists currently favor photodynamic therapy.
Irradiation Options
Irradiation can be done with photons, protons, or brachytherapy. It is indicated in cases of no response to photocoagulation and particularly in cases of critical proximity to the macula or papilla because invasive measures threaten vision.98 After successful irradiation, the retina reattaches partially or, perhaps, completely; the lesion becomes flatter, the eye and vision are maintained, and visual acuity is often improved. Reduction of visual acuity affects almost exclusively eyes with existing location-dependent maculopathy. The earlier RT starts, the better the long-term results.99,100
Schilling and associates101 irradiated 36 localized and 15 diffuse hemangiomas with 20 Gy in ten fractions of 2 Gy. After 5 years, 23 eyes (64%) of the localized type achieved complete retinal reattachment; visual acuity was stable in 50% and improved in 50%. Favorable results were also achieved for the diffuse type. In locally advanced cases, irradiation of the hemangioma cannot conserve visual acuity but it can often maintain the eye as a whole.
Brachytherapy is carried out in localized hemangiomas with eye plaques; iodine-125 seeds are preferred. Doses from the apex to the base of the lesion vary between 30 and 240 Gy. Results are excellent in the sense of a permanent resorption of the subretinal edema, complete retinal attachment, and maintenance of vision.100,102–104
Reactive Lymphoid Hyperplasia or Pseudotumor Orbitae
Definition and Clinical Features
Lymphoid diseases of the orbit are rare and have a broad range, including pseudotumor orbitae (PO) and malignant lymphomas.105 There are three possible causes: (1) an infectious process, for example, in transmitted sinusitis; (2) an autoimmune process; or (3) a fibroproliferative process. Experience shows that corticosteroids or immune suppressants can cause remission.
In differential diagnosis, other causes of orbital space requirement such as granulomatous diseases (e.g., sarcoidosis, Wegener’s granulomatosis), local infections, or autoimmune diseases have to be excluded. Frequently, the acute onset of symptoms, unilateral disease, and impaired eye motility point to pseudotumor. On imaging, the infiltrates appear in retrobulbar adipose tissue (≤80%), enlarged eye muscles (≤60%), thickening of the optic nerve (≤40%), and proptosis (≤70%). On the basis of clinical diagnosis and diagnostic imaging, it is hard to differentiate between benign and malignant changes; therefore, biopsy is essential.106
Nonradiotherapeutic Treatment
Surgical excision can be used in accessible lesions, but recurrences are frequent.107 Corticosteroids are the most important component of medical therapy, but up to 50% do not respond adequately.108 Some patients have to discontinue medication because of side effects.109 Without therapy, visual acuity can deteriorate seriously and permanently. There is no correlation between duration of progression and irreversible loss of visual acuity. The potential for malignant transformation of orbital pseudotumors is unclear.
Irradiation Options
As noted by Lambo and coworkers, radiotherapy has response rates of 70% to 100%.105,106,109–112 Recommended doses vary between 0.5 and 3 Gy per fraction and total doses of 20 to 35 Gy. Careful treatment planning helps to keep radiation side effects low.
Initially, a treatment attempt with a low dose of two fractions of 0.5 Gy per week up to a total dose of 5 Gy (first series) can be used. In acute or chronic inflammation, a gradual dose increase can initiate an early response on the one hand112; in case of nonresponse after 4 weeks, irradiation is changed to daily fractionation with 1.5 to 2 Gy as a single dose and up to 30 to 40 Gy as a total dose (second series). In the United States, most patients are treated with initial doses of approximately 30 Gy at standard fractionation.
Irradiation Technique
After CT planning, patients are treated via anterior and lateral fields with 1 : 3 weighting and wedged filters for dose homogenization while the patient’s eyes are open. In bilateral disease, parallel opposing lateral fields with a half-block technique107 or two anterior electron fields are used.
Benign Diseases of Joints and Tendons
Irradiation Options
In Germany, guidelines and dose concepts for radiotherapy of benign diseases were developed during the past 10 years where a dose per fraction of 0.5 Gy to a total dose of 6 Gy can be used.5,6,8 Conditions that have been treated include bursitis, tendonitis, subacromial syndrome (rotator cuff syndrome), tennis elbow (epicondylopathia humeri), calcaneodynia (heel spur), and degenerative joints with cartilaginous destruction (osteoarthritis).
Benign Diseases of Connective Tissue and Skin
Desmoid (Aggressive Fibromatosis)
Definition and Clinical Features
Desmoids are differentiated into extra-abdominal (≈70%) and intra-abdominal (≈10%) desmoids and those located in the abdominal wall (≈20%). Extra-abdominal forms tend to recur locally. Intra-abdominal forms are associated with the autosomal dominantly inherited Gardner syndrome. Histologically, desmoids are similar to low-grade (G1), highly differentiated fibrosarcomas. Mitotic activity is low, and cellular atypias are rare. Locally infiltrating growth has earned the name of “aggressive fibromatosis” for this disease. Local recurrences after resection alone are quite common.113–115 Pretreatment imaging with MRI is used to estimate the size and infiltration into other organs and incision biopsies are performed to distinguish benign from malignant lesions.
Nonradiotherapeutic Treatment
Desmoids can regress spontaneously or they can grow to a huge size, but they rarely cause death.116 Surgery with a safety margin of 2 to 5 cm is considered the “gold standard.” After R0 resection, no adjuvant therapy is usually required. After R1 resection, treatment options include observation if the lesion is in a site where re-resection is feasible; if not, postoperative RT is reasonable. Good long-term control can be achieved by resection alone, but up to 50% of patients develop local recurrence, which requires surgical and other measures subsequently.117 Tamoxifen and progesterone can exert growth inhibitory effects.118 Nonsteroidal antirheumatics, vitamin C,119 and alkylating substances (vincristine, methotrexate) have been tested.
Irradiation Options
Radiotherapy is indicated in cases of local inoperability and after R2 resection and in R1 resection if repeated surgery would not be feasible or has already been performed for local recurrence.* Radiotherapy is often used adjuvantly or as primary treatment. Adjuvant radiotherapy significantly reduces local recurrence rates compared with surgery alone. With total RT doses of more than 50 Gy, the local recurrence rate decreases from 60% to 80% with surgery alone to 10% to 30% after adjuvant RT. With normal fractionation and single doses of 1.8 to 2 Gy, a total dose of 50 to 55 Gy is recommended postoperatively. For inoperable or recurring desmoids, the recommended total dose is 60 to 65 Gy. After primary radiotherapy, the local control rate does not differ a lot from that after adjuvant irradiation.†
Irradiation Results
In most studies, tumor size has no prognostic influence on local control rates.126 According to a meta-analysis (698 cases in 13 studies),120 the local control rate after R0 resection and radiotherapy was improved by 17% compared with that of surgery alone; for macroscopic (R2) and microscopic (R1) tumor residual, patients treated with adjuvant radiotherapy had even better results.
In 2001 to 2002, the patterns of care study on the use of radiotherapy for treatment of desmoids was carried out in Germany; 345 patients were subjected to evaluation.130 The desmoids were distributed in the extremities (81.2%; 280 tumors), the trunk (13.9%; 48 tumors), and the head and neck region (4.9%; 17 tumors). A total of 204 patients (59%) were irradiated for locally recurrent or unresectable desmoids: 141 (40.8%) for high-risk situations postoperatively, 44 for unclear resection status, 49 after R1 resection, and 28 after R2 resection. Most patients were intensively pretreated, on average with two (range, one to five) operations.
