Fibrous dysplasia is a degenerative bone disorder characterized by the replacement of normal bone with abnormal fibrous tissue. This challenging condition often necessitates a multidisciplinary approach for optimal screening and management of the affected individuals. In the absence of comorbidities, such as growth hormone (GH) excess or secondary bone disorders, these lesions are typically slow-growing, without any significant functional consequences. For patients who have enlarging bony mass and associated cosmetic problems, it is recommended that surgical management be postponed until after skeletal maturity is achieved, when lesions typically are quiescent and progress more slowly. Surgical resection or contouring of the abnormal bone with immediate skull reconstruction might be warranted when new symptoms appear or rapid lesion growth is observed; in such cases the patient should be informed of the risk of regrowth. Medical management is primarily used for the management of refractory pain at the lesion site, which these patients commonly experience. Biphosphonates are one of the most frequently prescribed and effective medications. In the absence of symptomatic cranial nerve involvement, such as optic nerve compression, or external auditory canal narrowing, conservative management is preferred. Evidence of rapid lesion growth, new onset of pain or paresthesias, or visual or hearing changes may require immediate surgical referral and evaluation. Considering the unpredictable course and recurrent nature of the disease, meticulous long-term follow-up of this patient population is of paramount importance.
42 Fibro-Osseous Lesions of the Skull Base
Fibrous dysplasia (FD) is a benign genetic bone disorder that is characterized by the replacement of normal bone with abnormal fibrous tissue proliferation.1 , 2 The first report in the literature is credited to Dr. von Recklinghausen (1891), who more than a century ago described, patients who had a pathologic condition of the bone that was characterized by deformity and fibrotic changes, which he called osteitis fibrosa generalisata.3 The term fibrous dysplasia was introduced by Lichtenstein in 1938.4 Finally, in 1937, McCune, Albright, and colleagues recognized the entity of osteodystrophia fibrosa disseminata, defined by endocrinopathies, cutaneous hyperpigmentation, and precocious puberty in females associated with polyostotic FD.5 , 6 The differential diagnosis often includes Paget’s disease, intraosseous meningioma, or metastasis (Table 42.1).
42.2 Illustrative Case
A 20-year-old right-handed man with a past medical history of severe FD involving the left skull base presented with enlarging occipital mass and progressive left-sided hearing loss. He had prior surgical history of left external auditory canaloplasty for his hearing loss. For a short period his hearing had improved, but serial imaging suggested progression of the FD with restenosis of the left external auditory canal (EAC). He also complained of constant tinnitus and suffered with repeated cerumen impaction. Additionally, he reported a long history of headaches, occipital in nature, that started at age 15, usually lasting 15 minutes to 48 hours. Review of symptoms and clinical examination did not reveal any signs or symptoms of cranial nerve compression. Audiogram was consistent with conductive hearing loss. Brain CT imaging revealed progressive enlargement of his temporo-occipital mass, with scattered areas of cystic degeneration as well as significant narrowing of the EAC (Fig. 42.1; Fig. 42.2).
MRI showed only mild evidence of brain parenchyma compression and no radiographic findings of secondary Chiari’s malformation (Fig. 42.3). Digital subtraction angiography was notable for narrowing of the left sigmoid sinus (Fig. 42.4).
Out of concern for possible malignant transformation of the lesion—considering the prominent cystic degeneration, the nondurable canaloplasty, and the worsening hearing loss—an operation was offered to resect a large portion of the occipital bone FD and to more thoroughly decompress the stenotic EAC. Accordingly, the patient underwent bioccipital craniectomy, resection of the dysplastic bone, left mastoidectomy and partial petrosectomy, decompression of the sigmoid sinus, and revision canaloplasty of the left EAC. At 7-year follow-up, the residual FD remained radiographically stable in size and the EAC was still patent.
42.3 Incidence and Epidemiology
FD is a relatively rare disease, accounting for approximately 7% of benign bone lesions.7 The true incidence is unknown, as many cases are asymptomatic. It can be divided into three forms. Monostotic, involving only one bone, is the mildest and most common form, representing about 70% of all cases.1 It is typically diagnosed during the second or third decade of life, primarily involving the femur, the ribs, and the craniofacial bones.8 , 9 , 10 The polyostotic form (approximately 30%) has an earlier onset, most often in childhood, with extensive and severe skeletal and craniofacial involvement. The last and most serious form of the disorder, McCune-Albright syndrome (MAS; less than 3% of cases), is associated with short stature secondary to premature closure of the epiphyses as well as endocrine abnormalities and pigmented cutaneous lesions.5 , 6 Other syndromes within the spectrum of polyostotic FD are Jaffe-Lichtenstein syndrome, which is characterized by cafe-au-lait skin lesions, and Mazabraud syndrome, which is defined by the presence of intramuscular myxomas.7 , 11
The incidence of craniofacial involvement in FD has been reported to be 10 to 25% in the monostotic form and 50 to 90% in the polyostotic form.12 , 13 , 14 Lesions in FD are typically slow-growing and are often identified incidentally, particularly in the monostotic forms, or when facial asymmetry and gradual swelling become apparent. Also, FD may be discovered when cranial imaging with CT or MRI is performed for nonspecific symptoms such as headache.
42.4.1 Gene Mutation
FD is a genetic disease caused by somatic mutations (i.e., after fertilization in somatic cells) in the GNAS1 gene, which is located on chromosome 20q and encodes the alpha subunit of a stimulatory G protein.15 , 16 The mutation results in formation of excess cyclic adenosine monophosphate (cAMP) in mutated cells, which in turn is thought to prevent the differentiation of cells within the osteoblastic lineage.17 This excess of cAMP also contributes to the overexpression of interleukin (IL)-6 by mutated osteoblastic cells, activating the surrounding osteoclasts and causing the bony lesions to expand.14 , 16 , 17
Variability in disease severity and progression is related to the stage at which the postzygotic mutation occurred.14 , 15 , 18 Severe disease is typically associated with an early mutational event such that all three germ cell layers (endoderm, mesoderm, and ectoderm) are affected with a more widespread distribution of mutant cells, such as that seen in MAS. It is also postulated that somatic mutations that occur later in life result in a limited distribution of the mutant cells and that the resulting phenotype is less severe, as seen in monostotic FD.14 , 15 , 18 This hypothesis might also provide a biological rationale for monostotic FD’s not converting to polyostotic disease over time.
42.4.2 Histologic Findings
FD lesions are characterized by the gradual replacement of normal bone with firm and rubbery fibrous tissue. They are microscopically identifiable by the irregular trabeculae of woven bone intermixed with a connective tissue stroma (Fig. 42.5).2 Skull lesions tend generally to have a firmer consistency than those in the long bones, which have greater proportion of bony spicules.19 Furthermore, as lesions expand, they become cystic and can occasionally be vascular. Overall, lesions may vary in bone density as well as in the cellularity and vascularity of the fibrous stroma.2
42.4.3 Associated Endocrinopathies
In children, the most commonly encountered endocrinopathy in MAS is precocious puberty, predominantly in girls. In adults, hyperthyroidism, acromegaly, and renal phosphate wasting are the most common endocrine complications of MAS.18 , 20 GH excess occurs in approximately 20% of patients who have MAS and has been associated with an increase in the relative risk (RR) for complete encasement of the optic nerve (RR = 4.1) and optic neuropathy (RR = 3.8).21
42.4.4 Pain Pathophysiology
Pain is a common manifestation in FD and is often the presenting symptom of the disease.22 , 23 , 24 Although not yet fully elucidated, proposed mechanisms suggest ectopic sprouting and formation of neuroma-like structures by sensory and sympathetic nerve fibers within the dysplastic skeleton.23 Endogenous stromal cells as well as inflammatory and immune cells accumulate in the area of the lesion and secrete nerve growth factor (NGF), which binds to the TrkA receptor on the nerve fibers, promoting their pathological reorganization and providing an anatomical substrate that promotes skeletal pain.23 , 25 , 26
42.5 Nonsurgical Management
Currently, no medical treatment option is available to cure or arrest the progression of FD. Conservative management is typically employed in cases of asymptomatic, nondisfiguring lesions, and it primarily aims to control pain symptoms, which are present in up to 67% of patients.23 Interestingly, pain intensity does not seem to correlate with disease burden. In a study of 78 patients (34 children and 44 adults), adults were more likely to report worse pain scores than children, suggesting an age-related increase in the prevalence of pain in FD.23
Pain is commonly undertreated; patients often need multiple analgesic medications, including nonsteroidal anti-inflammatory drugs (NSAIDs) with or without opioids. Biphosphonates, such as alendronate, pamidronate, or zoledronic acid constitute a class of drugs prescribed to patients who have FD for management of pain and reduction of the lesion growth rate.27 , 28 , 29 Clinical studies have demonstrated mixed results with regard to the efficacy of bisphosphonates and FD-related pain, featuring limited sample sizes and with most studies examining all skeletal regions, not just the craniofacial sites.
In a study by Chapurlat and colleagues, approximately 20% of patients were treated with bisphosphonates, and 75% reported pain relief or improvement from this class of drugs compared with 50% for NSAIDs.23 Plotkin and colleagues examined 18 children and adolescents who had polyostotic FD or MAS treated using IV pamidronate therapy and noticed a decrease in reported pain, serum alkaline phosphatase, and urinary N-telopeptides.30 However, they did not notice radiographic or histomorphometric improvement of the FD lesions.30
In another report of 13 patients who had MAS and who were treated with pamidronate for 2 to 6 years, a decrease in long bone pain, fracture rate, and bone turnover markers was found, with the most encouraging results in adults.29 Chan and colleagues followed three children younger than 5 years old who had MAS treated with pamidronate and noted a decrease in long bone pain and fracture rate. The facial lesions remained stable, whereas the lesions located in the long bones continued to expand.31 Considering this variation in response between children and adults who have FD, and the dubious safety of prolonged bisphosphonate use in children, further studies are needed to provide insight into the effectiveness of biphosphonates for slowing the progression of the lesion and addressing intractable FD pain. Apart from biphosphonates, NSAIDs, and opioids, potential future therapeutic strategies include monoclonal antibodies that block the osteoclast-induced bone remodeling (e.g., denosumab,32 tocilizumab33), as well as blockers of peripheral sensitization (e.g., NGF/TrkA inhibitors). Pregabalin is also considered, having been shown to attenuate neuropathic pain and ectopic reorganization of nerve fibers.23
Underlying endocrinopathies, and particularly growth hormone (GH) excess, might accelerate the growth of the lesion. Accordingly, there must be concomitant control and management of the underlying endocrinopathy. Finally, it is worth mentioning that radiotherapy represents a historical treatment option for the management of FD. However, its effectiveness is limited, and it has been shown to be associated with malignant transformation of the lesions.34
42.6 Surgical Management
Surgery remains the primary treatment modality for the management of patients who have FD. In general, surgical treatment is generally avoided in young patients; because revision surgery is often necessary, it makes most sense to defer treatment as long as possible in an attempt to reduce the total number of procedures that any single patient might have to endure. It is worth emphasizing, however, that there is always some risk of regrowth, even when surgery is performed after puberty.14 Kusano and colleagues found in their long-term follow-up of 11 patients that the growth of monostotic FD was arrested in adolescence, but polyostotic FD was less predictable.35 In cases that warrant surgical intervention, a variety of techniques can be employed, ranging from endoscopic decompression of the orbital walls to contouring or complete orbitofrontal craniotomy with resection of the lesion and immediate reconstruction of the bony defect, such as in patients who have a monostotic or aggressive lesion.36 , 37 , 38
42.6.1 Restoration of Facial Aesthetics
Surgical intervention for the restoration of facial aesthetics can be performed at any age. The risk of regrowth is greater in younger patients.39 Accordingly, the literature suggests waiting until patients are beyond puberty and are skeletally mature, with their lesions stable in growth.40 The selection of excisional surgery over contouring depends on a constellation of factors, including patient age, type of FD, lesion location and growth rate, associated symptoms, aesthetic disturbance, and patient preference. Evidence from the 2000s suggests that a radical approach followed by surgical reconstruction is associated with higher rates of successful elimination of the underlying diseased bone and prevention of relapse.41 This can be achieved using synthetic materials or using free fibula or autologous rib bone grafts, with good functional and aesthetic results.
42.6.2 Optic Canal Involvement
FD involving the skull base usually affects frontal, ethmoid, sphenoid, and temporal bone.2 , 42 Common findings include eye proptosis, hypertelorism, and dystopia, as well as visual loss. Other reported findings include nasolacrimal duct obstruction, lid closure difficulty, trigeminal neuralgia, and extraocular muscle palsy. The optimal management of FD in the region of the optic nerve is a matter of contention among surgeons. Owing to the paucity of large scale studies and long-term follow-up, guidelines on the optimal management of patients who have FD are limited. Overall, patients can be categorized into those who have no evidence of optic neuropathy, who have gradual optic neuropathy, and who have acute visual disturbance.14
No Evidence of Optic Neuropathy
Several studies have shown that close observation is an acceptable practice for asymptomatic cases, because optic neuropathy and vision loss are not necessarily the natural progression in encased optic nerves.8 , 13 , 21 , 38 , 43 , 44 Cutler and colleagues reported that 88% of their series (87 patients) had no evidence of optic neuropathy despite complete encasement of the optic nerve by the dysplastic bone.21 Interestingly, no relationship between patient age and degree of involvement of the optic canal has been established, suggesting that optic canal encasement is not simply an inevitable consequence of increasing age. Lee and colleagues conducted a case–control study of patients who had extensive cranial base FD and concluded that observation with regular ophthalmologic examinations in patients who have asymptomatic encasement is a reasonable treatment option that obviates the need for optic nerve decompression despite significant narrowing of the optic canal.13
Surgical intervention should also be avoided in the absence of vision loss or optic neuropathy for fear of potential surgical complications, most notably severe damage to the optic nerve secondary to nerve traction, thermal damage, postoperative edema, or hemorrhage as the main suspected causes. Although steroids have been proposed as well, benefits are based on limited evidence and are transient.1 , 45
Gradual Optic Neuropathy
Optic neuropathy is difficult to evaluate and follow, because the changes may be gradual and subtle, without evidence of papilledema or visual compromise. Clinical observation has shown that a patient’s vision decreases in very advanced cases in which the optic canal is severely encased and the optic nerve greatly compressed.8 , 13 , 21 , 38 , 43 , 44 As previously mentioned, GH excess increases the risk of optic neuropathy. Accordingly, referral to an endocrinologist for prompt evaluation of GH excess and hormone suppression is also imperative to disease control. During optic nerve decompression, the surgeon needs to carefully remove the bone surrounding the optic canal using a high-speed drill, with constant irrigation for cooling.46 Attention should also be paid during endoscopic removal of the optic canal floor, as it might likewise lead to unintentional damage to the optic nerve.46 Postoperative recovery of visual loss is unfortunately unpredictable and largely depends on the severity and the duration of the preoperative visual loss. In the largest surgical series to date, Chen and colleagues have proposed that visual loss of more than 1 month’s duration is not reversible by decompression.47 The same author team also preserved effective vision in 67% of the patients who were experiencing visual compromise.47 Similarly, Henderson estimated that 50% of the patients will salvage their vision.1 , 48 However, there are reported cases of postoperative blindness following orbital decompression,1 , 49 which might be attributed to postoperative edema or occlusion of the ophthalmic artery secondary to thrombosis, hemorrhage, or spasm.1 , 49 , 50 , 51 , 52
Acute Visual Disturbance
Acute visual changes usually develop due to secondary disorders, such as mucocele and aneurysmal bone cyst (ABC).13 , 53 Most commonly, acute visual deterioration is thought to occur due to intralesional hemorrhage associated with ABC and subsequent compression of the optic nerve.37 , 54 Accordingly, patients who have a documented cystic lesion near the optic canal or who have increased GH require vigilant observation. In cases of acute vision loss, management of increased pressure using acetazolamide with or without steroids and urgent surgical decompression might be indicated.
Temporal Bone Involvement
The temporal bone is commonly affected (> 70%) in patients who have craniofacial polyostotic FD or MAS55; nevertheless patients remain asymptomatic in the majority of the cases.56 , 57 DeKlotz and colleagues found that nearly 85% of patients had normal or near normal hearing in spite of the high incidence of temporal bone involvement in the polyostotic cases.55 Ten percent of the patients had conductive hearing loss, and approximately 4% had sensorineural or mixed hearing loss. Furthermore, the degree of hearing loss was mild in most instances (77%) and did not correlate to the amount of disease involvement of the temporal bone.
Hearing loss is attributed to EAC narrowing as a result of the expansile surrounding FD or fixation of the ossicles from adjacent involved bone. The narrowing of the EAC can result in cerumen impaction, external otitis, or cholesteatoma.55 , 58 Involvement of the middle ear or Eustachian tube may lead to chronic otitis media and cholesteatoma. Although rare, some case reports have suggested that the contouring and excision of the surrounding dysplastic lesion can lead to exacerbation or regrowth of the lesion in polyostotic forms or in MAS. In more advanced cases, sensorineural hearing loss may occur secondary to impingement of the vestibulocochlear nerve within the internal auditory canal (IAC). Consistent with this, there have been cases of reversal of hearing loss after decompression of the IAC.59 However, in most cases of sudden or gradual loss, decompression does not result in hearing improvement. Because hearing is fragile and can deteriorate suddenly, some surgeons advocate prophylactic decompression when there is significant and progressive stenosis, hoping thereby to preserve hearing. Evidence of hearing changes on audiometric testing, including auditory brainstem response testing, may help in distinguishing patients who are at higher risk. Interestingly, extensive and progressive disease involving the IAC does not predictably result in sensorineural hearing or vestibular or facial nerve deficits.
In light of these concerns, after the temporal bone is discovered to be involved, a comprehensive audiology examination and periodic exams by an otolaryngologist are recommended. Unless symptoms are severe or progress rapidly, watchful waiting is generally advisable until the growth has slowed or the patient passes puberty. Surgery for the EAC is typically reserved for cases of recurrent otitis externa, canal cholesteatoma, or near total ear canal stenosis. In such cases, canaloplasty with some skin grafting to reline the expanded bony canal is the treatment option. Chance of recurrence is high, however, with almost half of all patients requiring two or more operations.2 The wider the ear canal is made, the longer another surgery can be avoided, but there may be a less favorable cosmetic outcome.
Finally, another rare finding secondary to temporal bone involvement is facial weakness or paralysis resulting from compression of the facial nerve in the petrous temporal bone.60 , 61 Unfortunately, the precise location of the symptomatic compression may be impossible to determine, necessitating extensive surgery through both a middle fossa and a transmastoid approach. In contrast to a sudden sensorineural hearing loss resulting from nerve compression in the IAC, it is more likely that the facial nerve will recover after decompression. Accordingly, a prophylactic decompression of a “threatened” facial nerve is not indicated.