Fibrous dysplasia and McCune–Albright syndrome: Imaging for positive and differential diagnoses, prognosis, and follow-up guidelines

European Journal of Radiology 83 (2014) 1828–1842

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Fibrous dysplasia and McCune–Albright syndrome: Imaging for positive and differential diagnoses, prognosis, and follow-up guidelines Valérie Bousson a,b,∗ , Caroline Rey-Jouvin c,b,1 , Jean-Denis Laredo a,b,2 , Martine Le Merrer d,3 , Nadine Martin-Duverneuil e,4 , Antoine Feydy f,5 , Sébastien Aubert g,6 , Roland Chapurlat h,i,7 , Philippe Orcel c,b,8 a

Radiologie Ostéo-Articulaire, AP-HP, Hôpital Lariboisière, 2 rue Ambroise Paré, 75010 Paris, France Université Paris VII Denis Diderot, Sorbonne Paris Cité, France c Rhumatologie Viggo Petersen, AP-HP, Hôpital Lariboisière, 2 rue Ambroise Paré, 75010 Paris, France d Service de génétique médicale, AP-HP, Hôpital Necker – Enfants malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France e Service de Neuroradiologie, AP-HP, Hôpital Pitié Salpêtrière, 47 Boulevard de l’hôpital, 75013 Paris, France f Service de Radiologie B, AP-HP, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France g Service Anatomie Pathologique, CHRU Lille, Avenue Oscar Lambret, 59037 Lille Cedex, France h INSERM UMR 1033, Université de Lyon, France i Service de rhumatologie et de pathologie osseuse, CHU de Lyon Hôpital Édouard Herriot, 5, place d’Arsonval, 69437 Lyon Cedex 03, France b

a r t i c l e

i n f o

Article history: Received 8 February 2014 Received in revised form 11 June 2014 Accepted 16 June 2014 Keywords: Fibrous dysplasia Guidelines CT MRI Radiograph Radionuclide bone scan

a b s t r a c t Purpose: The radiologist plays a critical role at all steps of the management of patients with fibrous dysplasia (FD) and McCune–Albright syndrome (MAS). The development of a standardized approach to the management of FD/MAS is crucial given the low incidence and multiple clinical presentations of these conditions. Our aim was to develop recommendations for bone imaging in FD/MAS management. Materials and methods: The establishment of National Reference Centers in France as part of a Health Ministry program for orphan diseases has triggered the development of recommendations for the clinical management of FD/MAS. We used a well-established robust methodological approach involving an extensive literature review by a multidisciplinary working group (20 healthcare professionals) and scoring by a peer-review group (20 healthcare professionals different from the 20 previous ones). There were four phases: a systematic literature review, drafting of initial recommendations, peer-review of this initial draft, and drafting of the final recommendations. Results: Fifty-seven specific recommendations are provided as key points for the diagnosis, prognosis, and follow-up of patients with FD/MAS. Issues of special interest are highlighted in the discussion, and areas in which future research is needed are identified.

∗ Corresponding author at: Radiologie Ostéo-Articulaire, AP-HP, Hôpital Lariboisière, 2 rue Ambroise Paré, 75010 Paris, France. Tel.: +33 1 49 95 61 80; fax: +33 1 49 95 86 99. E-mail addresses: [email protected] (V. Bousson), [email protected] (C. Rey-Jouvin), [email protected] (J.-D. Laredo), [email protected] (M. Le Merrer), [email protected] (N. Martin-Duverneuil), [email protected] (A. Feydy), [email protected] (S. Aubert), [email protected] (R. Chapurlat), [email protected] (P. Orcel). 1 Tel.: +33 1 49 95 88 25; fax: +33 1 49 95 86 31. 2 Tel.: +33 1 49 95 91 06; fax: +33 1 49 95 86 99. 3 Tel.: +33 1 44 49 51 57; fax: +33 1 44 49 51 50. 4 Tel.: +33 1 42 16 36 04; fax: +33 1 42 16 35 98. 5 Tel.: +33 1 58 41 24 81. 6 Tel.: +33 3 20 44 49 95; fax: +33 3 20 44 64 21. 7 Tel.: +33 4 72 11 74 79; fax: +33 04 72 11 74 43. 8 Tel.: +33 1 49 95 88 25; fax: +33 1 49 95 86 31. http://dx.doi.org/10.1016/j.ejrad.2014.06.012 0720-048X/© 2014 Elsevier Ireland Ltd. All rights reserved.

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Conclusion: We believe the dissemination of these recommendations within the radiology community may facilitate communication between radiologists and other healthcare providers, thereby substantially improving the management of patients with these rare but potentially disabling conditions. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Fibrous dysplasia of bone (FD) or Jaffe–Lichtenstein disease [1] is a rare benign bone disease that is congenital but not inherited. Fibrous tissue proliferates at one or more marrow sites in a variable number of bones [2]. Monostotic forms account for 70–90% of all cases [3–7]. No bone is exempt, but the most common sites of involvement are the femoral neck, craniofacial bones, and ribs, with variations in relative frequencies across studies [3–5,7]. The radiological features vary with the amount and degree of mineralized tissue within the lesion [8]. About 2–3% of patients with FD have McCune–Albright syndrome (MAS), which is characterized by café-au-lait spots and endocrine abnormalities, among which peripheral precocious puberty is the most common [1,2,9,10]. Hyperthyroidism, acromegaly, and hypercorticism are present in some patients. Renal phosphate wasting and soft tissue myxomas (Mazabraud syndrome) may also be encountered [2]. The establishment of National Reference Centers in France as part of a Health Ministry program for orphan diseases has triggered the development of recommendations for the clinical management of FD/MAS. FD/MAS is a rare disease whose broad spectrum of clinical manifestations results in the involvement of a wide variety of healthcare professionals (Table 1). The radiologist plays a crucial role at all steps of the management of FD/MAS, since bone imaging provides essential information for the diagnosis, prognostic evaluation, and patient follow-up. Optimal selection of single or combined imaging modalities and the best frequency of follow-up in each specific situation are questions that require clear answers, most notably for non-specialists of FD/MAS. The aim of this work was to develop recommendations for bone imaging in FD/MAS, with the goal of improving the diagnosis, prognostic evaluation, and follow-up of patients with FD/MAS. We used a well-established methodology involving a systematic literature review and an analysis of the retrieved data by a group of experts. 2. Materials and methods The French National Authority for Health (HAS) asked the FD/MAS project leaders (PO and RC) to produce high-quality recommendations for this disease [11,12]. These recommendations were developed by two groups of participants, a working group and a peer-review group, and involved four phases: a systematic literature review, drafting of initial recommendations, peer-review of this initial draft, and drafting of the final recommendations [11,12]. Although the entire process is described below, only the recommendations involving bone imaging are presented. 2.1. Participants The working group was a multidisciplinary group of 20 healthcare professionals (including a radiologist, VB) and a representative of the French patient organization ASSYMCAL. These professionals were experts in FD/MAS and were strongly motivated to develop the recommendations. The project leaders (PO and RC) coordinated the efforts of the working group, and a project officer (CM) was in

charge of the systematic literature search and selection of relevant publications, in collaboration with the HAS. The peer-review group was a multidisciplinary group of 20 healthcare professionals (different from the 20 in the working group) including three radiologists (JDL, NMD, and AF). Both groups were representative of the wide variety of healthcare settings and geographical sites of practice, as checked by the project leaders and validated by the HAS. 2.2. Method 2.2.1. Systematic literature review The project officer conducted a systematic search of bibliographic databases for data published over the 11-year period from 1999 to 2009 and retrieved all published scientific papers, clinical practice guidelines, consensus conference reports, articles on medical decision-making, systematic reviews, metaanalyses, and other types of studies, in English or French. Table 2 lists the searched databases and Table 3 the indexing terms used for the search. The project leaders and project officer developed a list of issues for which recommendations were needed. Among these issues, six were in the field of radiology: - What are the radiological features for the diagnosis of FD? - When is a bone biopsy indicated and what are the technical requirements? - How to radiologically assess the osseous/articular prognosis? - What are the best modalities and frequency for imaging followup? - What are the potential complications and best imaging modalities for their diagnosis? - Which patients require referral to reference centers? Of the 567 references retrieved, 189 articles were selected as relevant papers in a variety of specialties. The project leaders, project officer, and working group members critically analyzed these 189 articles, and assigned a level of evidence to each article (Table 4). Furthermore, of the 567 references, 83 that contained words relative to imaging in the title, were written by radiologists, or were published in radiology journals; the working group radiologist reviewed these 83 publications for answers to the issues of interest and assigned a level of evidence to each. The project leaders and project officer wrote a report describing the evidence from the selected articles. 2.2.2. Drafting of the initial recommendations During two full-day meetings, the working group discussed the evidence report and suggested recommendations based on the evidence, existing practice, and each member’s personal experience. The working group, led by the project leaders and project officer, drafted initial recommendations, which were approved by all working group members before being submitted to the peer-review group. 2.2.3. Peer review The project officer emailed the evidence report and initial recommendations to the peer-review group members, who rated each

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V. Bousson et al. / European Journal of Radiology 83 (2014) 1828–1842 Table 1 Array of manifestations of fibrous dysplasia and McCune–Albright syndrome (MAS).

MAS -Precocious puberty Café-aulait spots

-Acromegaly Endocrinopathy

-Hyperthyroidism -Phosphate wasng

Myxomas

Osseous Fibrous Dysplasia Long bones, ribs, spine

Skull Maxillo facial

-Asymptomac

-Asymptomac

-Deformity: coxa

-Deformity: exophthalmos, opc

vara, scoliosis

nerve compression, nasal

-Fracture

obstrucon, hearing loss

-Malignancy

-Malignant transformaon

item in the recommendations using a numerical scale from one (strongly disagrees) to nine (strongly agrees). Peer-review group members were encouraged to add free comments on the content and form of the recommendations, most notably regarding Table 2 Sources used for the literature search. -Medline (National Library of Medicine, USA) -Embase (Elsevier, Netherlands) -Cochrane Library (UK) -National Guideline Clearinghouse (USA) -Cumulative Index to Nursing and Allied Health Literature (CINAHL) -International Network of Agencies for Health Technology Assessment (INAHTA) -Database Public Health, Rennes, France (BDSP) -INIST-CNRE, France (INstitut de l’Information Scientifique et Technique-Centre National de la Recherche Scientifique)

Table 3 Literature search strategy. Study/subject Key indexing terms

Period

Step 1: (“Fibrous Dysplasia, Polyostotic” [Mesh] OR “Fibrous Dysplasia, Monostotic” [Mesh] OR “Fibrous Dysplasia of Bone” [Mesh] OR McCune–Albright syndrome [title]) Limits: English, French Imaging Step 1 AND Step 9 Ultrasonography OR Tomography Scanners, X-Ray Computed OR Tomography, X-Ray Computed OR Tomography OR Tomography Scanners, X-Ray Computed OR Tomography, X-Ray OR CT Scan OR CT Scanning OR MRI OR MR Imaging OR radiography OR scintigraphy Number of references

1999, January – 2009, December

1999, January – 2009, December

567

readability and feasibility. Reviewers could refrain from scoring one or more items if they felt insufficiently competent in the relevant area. Recommendations based on low-level evidence (grade C) or expert opinion were kept only if over 90% of peer-review members assigned ratings in the 5–9 range [11], and comments were taken into account. 2.2.4. Drafting of the final recommendations The working group analyzed the scores and comments of the peer-review group during a third full day meeting involving in-depth discussions of all suggested modifications to the recommendations. The project leaders and project officer then wrote a final version of the recommendations, which they submitted to the Table 4 Recommendation grades. Level of evidence provided by the literature

Recommendation grade

Level 1 -Powerful randomized controlled trials -Metaanalysis of randomized controlled trials -Decision analysis based on well-conducted studies Level 2 -Less powerful randomized controlled trials -Well-conducted non-randomized controlled studies -Cohort studies Level 3 -Case-control studies Level 4 -Comparative studies with considerable bias -Retrospective studies -Case series

A Established scientific evidence

B Scientific presumption

C Low level of evidence

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working group for final approval. The final version and methodology were also validated by the HAS executive board, which authorized the dissemination and publication of the final recommendations. 3. Results The final recommendations contain 186 items, of which 57 involve imaging and form the basis for the present report. All 57 recommendations were based on low-level evidence or expert opinion but received ratings in the 5–9 range by over 90% of peer reviewers. The 20 peer reviewers rated a mean of 41.85/57 (73.4%) recommendations and assigned ratings of 6.70–8.65 (mean 7.93 ± 0.46). The key points of these 57 recommendations are written below. 3.1. Diagnostic strategy 3.1.1. If a bone lesion is diagnosed by imaging studies (radiograph, computed tomography [CT], magnetic resonance imaging [MRI]), or bone scintigraphy), the lesion should be assigned to a category and the strategy appropriate for that category should be followed. Category 1: Definite diagnosis of FD - Lesion exhibiting a constellation of radiological features of FD. Table 5 and Figs. 1–8 show the radiological features most strongly associated with FD. Table 5 Radiological features of fibrous dysplasia. Bones

-No bone exempt -Ribs, tubular bones, pelvis, spine. Most frequent benign lesion of the rib. Frequent benign lesion of the proximal femur -Skull base, sphenoid, ethmoid and frontal and mandibular bones

Distribution

-Infrequent solitary involvement of the ilium (affected concomitantly with femur) -Infrequent solitary involvement of the phalanges -Several FD foci separated by normal osseous tissue within the same bone -Unilateral or predominantly unilateral involvement of a limb; Involvement of vertebra and rib in the same metamere (PFD)

Location in long bones

-Diaphysis, metaphysis (femoral neck). Epiphyses usually spared -Central (intramedullary) rather than peripheral

Shape and size

-Elongated lesion along the long axis of the bone -Spindle-shaped enlargement of tubular bones and ribs -Curvature of the long bones: humerus, femur. “Shepherd’s crook” deformity -Calvarial deformity. Exophthalmos

Margin

-Sharp with a well-defined border of sclerotic bone -Expansile: the shell is thick, thin, or very thin with small perforations. No expansion if the lesion is smaller than the internal diameter of the bone

Matrix

-Variable aspect, depending on the degree of ossification of the fibrous stroma. All aspects from radio transparent to opaque -Characteristic ground-glass appearance -Pure osteoblastic patterns are rare -Few internal trabeculations -Islands of cartilage occur in 10% -Doughnut-shaped aspect in the cranial vault -Increased uptake by bone scan and 18 FDG PET

Mandatory signs

-No soft tissue mass -No lamellar, spiculated, or triangular periosteal reaction

Fig. 1. Fibrous dysplasia of the left proximal femur. Conventional anteroposterior radiograph showing a radiolucent lesion with a characteristic sclerotic border (arrows) involving the femoral neck and proximal diaphysis and sparing the epiphysis.

Fig. 2. Polyostotic fibrous dysplasia involving the left acetabular roof and proximal femur. Conventional anteroposterior radiograph showing two hazy lesions (arrows) with sclerotic rims. Extensive lesion in the proximal femur that exhibits the unusual feature of involving the epiphysis (thick arrow).

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- Lesion exhibiting radiological features of FD + café-au-lait spots (Fig. 9)/or precocious puberty/or myxoma. - Several lesions exhibiting some of the radiological features of FD. Strategy: No need for further diagnostic investigations

Strategy: Seek to obtain additional evidence supporting a diagnosis of FD by performing CT (after a radiograph) or MRI (after CT) and a bone scintigraphy to look for additional FD foci. Category 3: Doubtful diagnosis of FD

Category 2: Probable diagnosis of FD - Lesion exhibiting several radiological features of FD but no caféau-lait spot, precocious puberty, endocrinopathy, or myxoma.

- Lesion discovered by MRI or bone scintigraphy. - Lesion exhibiting only few radiological features of FD. - History of cancer.

Fig. 3. Monostotic fibrous dysplasia of the left proximal femur with extensive cartilaginous differentiation (“fibrocartilaginous dysplasia”). (a) Conventional anteroposterior radiograph. (b and c) Reformatted coronal and axial CT images. (d) Axial fat-suppressed T2-weighted MR image. (e) Axial T1-weighted image. (f) Axial post-contrast fatsuppressed T1-weighted MR image. (a–c) show a well-defined centrally located lesion in the femoral metaphysis and diaphysis, sparing the epiphysis and causing coxa vara deformity (shepherd’s crook deformity). The upper portion of the thick sclerotic rim (arrows) is in contact with the growth cartilage. Extensive bone matrix calcification results in increased density of the lesion. Some parts of the lesion are radiolucent (star). Cartilaginous differentiation is easily identified as rings and arcs on CT images. By MR (d–f), the cartilaginous differentiation is clearly visible as cartilaginous lobules.

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Fig. 4. Monostotic fibrous dysplasia of the tibia. (a) Conventional lateral radiograph. (b) Reformatted axial CT image (a and b) show a focal, sclerotic, expansile, intramedullary lesion in the tibial diaphysis (arrows), with endosteal scalloping (small black arrows) and cortical thinning.

Strategy: - Perform further imaging, CT or MRI of the lesion, to look for additional evidence supporting a diagnosis of FD and to detect signs of activity/aggressiveness (cortical osteolysis, soft tissue mass). Perform bone scintigraphy to look for more typical lesions. - In case of persistent doubt regarding the etiology of an active (Fig. 10) or aggressive lesion, or in patients with a history of cancer (Fig. 11), obtain a bone biopsy. - Remember that interpreting MRI findings in the absence of radiographs and/or CT carries a high risk of misdiagnosis due to the polymorphic MRI features of FD [13,14]. Bone scintigraphy lacks specificity. CT is more accurate than radiography and MR for evaluating matrix mineralization and margins. Category 4: Skull and facial bones Strategy: CT scan and MRI with gadolinium injection are required to assist in ruling out differential diagnoses [15,16]. Two main pitfalls are osseous and en-plaque meningioma (Fig. 12) and mandibular osteitis.

- -At least core needle biopsy is needed to obtain adequate material; fine-needle aspiration is not sufficient. - Testing for the GNAS gene mutation requires that the biopsy specimens be placed in a frozen environment immediately after collection. - Testing for the GNAS gene mutation is recommended only in difficult cases. The GNAS mutation is specific of FD in patients with fibro-osseous lesions [17]. Differential diagnoses include osteofibrous dysplasia and fibrous dysplasia-like low-grade central osteosarcoma [17,18]. 3.1.3. Muscle mass combined with a radiographic lesion exhibiting features of FD - Consider Mazabraud syndrome (Fig. 13) and perform ultrasound or MRI to assess the mass for features of myxoma [19,20]. Myxoma typically exhibits T1- and T2-weighted MR signal similar to fluid, a peripheral rim of enhancement after gadolinium injection, and heterogeneous central enhancement. Table 6 lists the differential diagnoses in patients with a muscle mass and bone lesion. 3.2. Osseous/articular prognosis

3.1.2. Recommendations about bone biopsy and molecular diagnosis - -The technical modalities of the biopsy (percutaneous or surgical, choice of the biopsy site) should be discussed with the surgeon, radiologist, and pathologist.

The prognosis varies widely across patients depending on the location and extension of the lesions, with a satisfactory long-term outcome in monostotic FD and a more complicated course in polyostotic FD and MAS [21]. Function may be impaired

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Fig. 5. Hemimelic polyostotic fibrous dysplasia with severe deformity of the humerus. (a) and (b) Conventional anteroposterior radiograph of the left humerus. (a) Shows an extensive hazy expansile lesion in the left humerus with severe deformity. (b) A typical ground-glass density is visible at the distal part of the lesion (small arrows). A second fibrous lesion is seen in the left radius (arrow). The lesion involves the radial epiphysis but not the humeral epiphysis. (c) Reformatted coronal CT image showing various degrees of matrix mineralization and a dense sclerotic border (small arrows). (d) Fat-suppressed T2-weighted MR image. (e) T1-weighted MR image. (f) Post-contrast fat-suppressed T1-weighted MR image. (d–f) reveal heterogeneous signal intensity on T2- and T1-weighted images and heterogeneous contrast enhancement of the lesion.

in patients with long-bone or spinal deformities [22] or fractures [23]. Craniofacial involvement may result in disfigurement and compression of neurological structures. Regarding these prognostic issues, the following recommendations are proposed. - A bone scintigraphy should be performed to map the involved lesions, thereby assessing the burden of skeletal disease [24]. - Radiographs of each site exhibiting increased radionuclide uptake should be obtained. Use of a low radiation-exposure device such as the EOS imaging system should be considered, especially in children. - CT is recommended to evaluate osteolytic lesions at high risk of fracture, such as those located in the proximal femur.

- If the skull and/or facial bones are involved, CT of the skull is recommended to accurately evaluate the risk of neurological compromise due to alterations of the foramina, although the vast majority of entrapment syndromes (e.g., optic nerve entrapment) remain asymptomatic and do not necessitate decompression [25]. - If the skull base is involved, MRI with gadolinium injection and sequences centered on the pituitary gland to look for a pituitary adenoma is recommended. Skull base and maxillofacial involvement carries a high risk of failing to detect acromegaly early, as the bone deformities due to FD and acromegaly are difficult to distinguish [26].

3.3. Follow-up - In patients without bone deformity or pain, radiographic monitoring every 2–3 years is recommended.

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Fig. 6. Polyostotic fibrous dysplasia involving the left rib and a vertebra in the same metamere. (a and b) Axial and (c) sagittal reformatted CT images. (a) Shows an expansile radiolucent lesion in the posterior left rib with endosteal scalloping and cortical thinning. (b and c) Show typical features of vertebral body fibrous dysplasia: central radiolucent lesion with a sclerotic rim, responsible for vertebral collapse. In (b), a second focus of fibrous dysplasia is seen in the right transverse process. The two vertebral foci are separated by normal bone tissue.

- In case of symptomatic or extensive lesions that have a potential for progression, an annual clinical and radiographic evaluation should be performed to determine the best time for a preventive intervention. - Sudden-onset, severe, localized bone pain should suggest a complication such as a fracture (Fig. 14) or sarcomatous transformation. Radiographs centered on the painful site should be obtained first. If these radiographs fail to show clear evidence of a fracture, CT and/or MRI should be performed. 3.4. Role for reference centers The radiologist should refer the patient to a specialist or reference center, for investigations for renal phosphate wasting [27] or endocrinopathy and for discussion of bisphosphonate treatment [28,29] or surgery in the following situations:

-

polyostotic FD, MAS, Mazabraud syndrome, facial bone and/or skull involvement, pain related to the FD lesion, high risk of fracture.

4. Discussion FD/MAS is a rare disease responsible for a vast spectrum of clinical manifestations and radiological features. The diagnosis raises major challenges for physicians who are not specialized in FD/MAS, most notably radiologists. Guidelines are therefore needed. According to our experience and literature review, the imaging diagnosis is easy in polyostotic forms and typical monostotic forms. However, the typical features must be well known. We listed

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Fig. 7. Monostotic fibrous dysplasia of the T12 vertebra. (a) Axial and (b) coronal reformatted CT images show a typical expansile fibrous dysplasia lesion (black arrows) with a sclerotic border (white arrows) and foci of variably marked mineralization. The stars indicate a ground-glass focus. The right part of the vertebral body is collapsed. (c) Coronal and (d) axial T1-weighted MR images. (e) Post-contrast T1-weighted MR image. By MR (c–e), the expansion of the right border (black arrow) and collapse are also seen. The perivertebral fat (small arrows) is normal, supporting a benign process. The ground-glass zone generates low signal intensity and enhances after contrast administration (stars). The sclerotic border is clearly visible (arrows in d and e). The matrix contains variable signal intensities.

the radiological features most often associated with FD but, to the best of our knowledge, the sensitivity and specificity of these signs used alone or in combination have not been determined. When an incidental finding on a radiograph suggests FD, the first step is to look for clinical features such as café-au-lait spots (usually observed near the affected bone) and precocious puberty. If no such characteristics are present, bone scintigraphy is recommended to look for increased uptake and detect other skeletal lesions, which will then be further imaged and confirm the diagnosis. However, monostotic FD contributes 70–90% of all cases [3–7] and seems very rarely associated with peripheral precocious puberty and café-au-lait spots. False-negative and false-positive diagnoses of FD are not uncommon. Particularly challenging situations include FD with extensive calcifications simulating chondroma or chondrosarcoma [30]; expansile osteolytic monostotic FD consistent with malignancy; FD lesions that change in size or appearance, with increasing lysis suggesting cystic transformation, a secondary

aneurismal bone cyst, or malignant transformation; and a groundglass appearance, considered a classic sign of FD but also observed in a few cases of sclerotic metastasis or low-grade central osteosarcoma [31]. In MR imaging, there is considerable variability in signal intensity depending on the amount of bony trabeculae, cellularity, and collagen [14]. Usually, areas of FD involvement have low signal intensity on T1-weighted images; and low, intermediate, or high signal intensity on T2-weighted images. Postgadolinium enhancement is low, intermediate, or high with a uniform, central patchy, or rim configuration [32]. This variability, together with the poor visibility of tissue mineralization, limits the diagnostic usefulness of MRI, which should be viewed as a second-line imaging study. Fractures are also difficult to diagnose by MRI. In contrast MRI is crucial for identifying cystic degeneration [33] or a secondary aneurismal bone cyst and, when a malignancy is suspected, for detecting soft-tissue involvement and guiding the biopsy according to the

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Table 6 Differential diagnoses of a soft tissue mass coexisting with a bone lesion. Neurofibromatosis type 1

Fig. 8. Fibrous dysplasia, scintigraphic map. Anteroposterior 99mTc-MDP scintigraphy demonstrates several foci of intense radionuclide uptake in the diaphysis and metaphyses of the right femur (arrows). These foci are separated by regions of normal radionuclide concentration.

Benign or malignant peripheral nerve sheath tumor

Sphenoid dysplasia, nonunion, kyphoscoliosis, nonossifying fibromas, posterior vertebral body scalloping

Mafucci syndrome

Hemangiomas

Enchondromatosis

Macrodystrophia lipomatosa

Neural fibrolipoma, fat overgrowth

Macrodactyly

Klippel–Trenaunay Weber syndrome

Varicose veins, soft tissue extensive hemangiomas, fat overgrowth

Bone hypertrophy

Mazabraud syndrome

Myxomas

Fibrous dysplasia

Melorheostosis

Chondroosseous soft tissue mass, desmoid tumors

Cortical thickening (“flowing candle wax”)

Lipomatous lesion

Soft tissue lipomas

Liposarcoma

Metastases

Soft tissue metastasis

Bone metastasis

Multiple solitary plasmacytomas

Soft tissue plasmacytomas

Bone plasmacytomas

Infectious diseases

Abscess

Osteomyelitis

Multiples infarcts

Myonecrosis

Osteonecrosis

Trauma

Hematoma

Fracture

findings by dynamic contrast enhanced MRI. MRI is also invaluable for examining the skull, assessing the nervous structures contained within the foramina (e.g., optic nerve), and ruling out differential diagnoses [34]. Several authors have pointed out that the condition most likely to be mistaken for FD of the skull is hyperostosing meningioma en plaque (carpet meningioma) [35,36], especially in the spheno-orbital region, which is a predominant target for both diseases. Invasion of the bone by meningioma cells can induce marked bony hyperostosis contrasting with the thin underlying intracranial tumor [37]. CT criteria of use for the differential diagnosis [36] include involvement of the inner table (usually spared by FD), periosteal new bone formation (outer table expansion in FD), and surface irregularities (smooth surface in FD). However, demonstration of an enhancing intradural plaque is best achieved using MRI. Finally, a pituitary adenoma may be present in patients with skull base involvement. Although poorly documented

Fig. 9. Café-au-lait spots in two different adults with McCune–Albright syndrome. (a and b) Photographs showing typical, brown, irregularly contoured macules over the low back.

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Fig. 10. Monostotic fibrous dysplasia of the first rib diagnosed histopathologically. (a and b) Reformatted axial CT images showing an expansile lytic lesion in the first rib (arrows). The cortex is thin with a few perforations. No ground-glass foci were observed. Several small round opacities, as well as the lobulated posterior contour, suggest cartilage. A bone biopsy was performed to provide the diagnosis.

in the literature, this possibility warrants routine pituitary gland evaluation in patients with skull base involvement [26]. Mazabraud syndrome should be considered when a soft-tissue mass is identified in a patient with FD, particularly polyostotic FD. The myxoma and FD are usually located near each other. The most common topographic pattern is myxoma of the thigh (chiefly the quadriceps muscle) with FD of the femur. A given patient may have multiple myxomas. A myxoma may recur after surgical excision. The myxoma is usually asymptomatic, and no cases of malignant transformation have been reported. Thus, awareness of this syndrome avoids unnecessary biopsy or surgery. On the other hand, when a myxoma is identified, bone scintigraphy should be performed to look for FD. It has been suggested but not proved that Mazabraud syndrome is associated with a higher risk of malignant FD transformation compared to FD alone [38]. Bone scintigraphy is the best imaging technique for mapping the FD lesions, which usually exhibit increased uptake. Among FD lesions, 90% are present by 15 years of age [39]. Low-irradiation devices such as the EOS imaging system are worth considering for follow-up imaging, especially in children, but are not suitable for the initial evaluation, given their lower spatial resolution compared to radiographs. However, the role for these new devices in FD/MAS requires evaluation. One of the objectives of follow-up imaging is to identify and manage complications of FD/MAS such as deformities, pathologic fractures, and malignant transformation [40–42]. The follow-up interval for radiographs depends largely on the clinical presentation: age of the patient, asymptomatic or painful lesion, and sites of involvement. In children, in the absence of pain, a yearly clinical examination is sufficient to evaluate the appendicular skeleton (deformities and limb length discrepancy) and spine (scoliosis) [43]. Radiographs should be obtained only when a clinical deformity appears or worsens, to evaluate the need for surgery; and periodically for the proximal femur, where deformity may be progressive and detected only when angulation is severe [43]. EOS imaging, when available, is a good way to evaluate children while limiting radiation exposure. In adults, as FD lesions exhibit little or no activity, in the absence of symptoms and when the fracture risk is low, our group of experts suggests radiographs every 2–3 years (or even at wider intervals), mainly to detect malignant transformation, which can occur in both polyostotic and monostotic FD.

Due to the lack of strong published evidence, these suggestions rest on a consensus developed among experts within the working group. However, malignant transformation almost invariably produces severe localized bone pain [40] so that obtaining radiographs periodically in asymptomatic adults may be unhelpful. The risk has ranged across case-series from 0.4% to 4%. Osteosarcoma predominates, although fibrosarcoma or chondrosarcoma may occur [40]. No predictors of malignant transformation have been identified to date. However, malignant transformation is more common in polyostotic forms and after radiotherapy. The delivery of radiation therapy to sites containing FD lesions is therefore contraindicated. Malignant transformation

Fig. 11. Solitary bone metastasis of breast cancer. Unusual headache prompted CT. The reformatted axial CT image shows an oval lesion (long arrow) in the right frontal bone with a ground-glass density and a lucent peripheral halo. Sufficient attention to the soft tissue swelling (short arrow) could have avoided the initial erroneous diagnosis of fibrous dysplasia.

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Fig. 12. Osseous meningioma of the left sphenoidal wing initially diagnosed as monostotic fibrous dysplasia. (a) Axial reformatted CT image. (b) Anteroposterior 99mTc-MDP scintigraphy. (c and d) Axial and (f) sagittal post-contrast fat-suppressed T1-weighted MR images. Based on (a, b) showing a ground-glass lesion in the left sphenoidal wing (black star) with homogeneous increased radionuclide uptake (black arrow), an erroneous diagnosis of monostotic fibrous dysplasia was given. The patient was evaluated 3 years later at a reference center, where MR imaging (c–e) showed a large soft tissue mass corresponding to a meningioma (arrows).

must be considered routinely in patients with rapid changes in the clinical and/or radiological features of FD. Sarcoma produces poorly marginated osteolytic destruction of a preexisting FD lesion, cortical disruption, and a soft tissue mass [40,44]. Our work has several limitations. First, due to the rarity of FD/MAS, most of the studies retrieved by our literature search contained low-level evidence. Consequently, our

recommendations for imaging in FD/MAS should be viewed, not as evidence-based guidelines, but rather as a formal consensus based on a rigorous literature review supplemented with expert opinion. Second, refinements and modifications of these recommendations will probably be required as new evidence is obtained from ongoing research and the creation of reference centers.

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Fig. 13. Mazabraud syndrome. (a) Photograph of the right thigh. (b) Photograph of the left calf. (c) Coronal T1-weighted MR image. (d) Axial T1-weighted MR image. (e) Axial fat-suppressed T2-weighted MR image. (f) Axial post-contrast fat-suppressed T1-weighted MR image. (a and b) show soft tissue masses (arrows). MR images (c–e) show multiple soft tissue masses (stars) of very low signal intensity (compared to muscles) on T1-weighted sequences (c) and high intensity on T2-weighted sequences (d) with scalloping of the medial cortex of the right femur (arrowheads) (c–e). These soft tissue masses are myxomas; the medullary cavity of both femurs is occupied by dysplastic fibrous tissue (arrow). (f) The patterns of enhancement vary across myxomas: highly heterogeneous enhancement is seen in the large myxomas, whereas the small myxomas exhibit either complete homogeneous enhancement or a peripheral rim of enhancement (short arrows).

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Fig. 14. Polyostotic fibrous dysplasia with fractures of the right humerus. (a and b) Conventional anteroposterior radiographs showing an extensive radiolucent lesion (arrowheads) of the humerus, with a complete fracture of the distal diaphysis (short arrow). A healed previous fracture is visible in the proximal diaphysis (arrow).

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