Polyostotic Fibrous Dysplasia

D. Rama Raju : Annals and Essences of Dentistry; volume II. Issue 1 Jan March 2010

Presented by :

Dr. Kush Pathak

Contents
Case report Discussion Pathology & Pathogenesis Polyostotic fibrous dysplasia Clinical course & Progression Roentogenographic features Monostotic Fibrous Dysplasia Histological features
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Biochemical findings Conclusion Critical Evaluation Review of Article References

Case Report
A 20 year old patient came with a complaint of hard growth on the right side of the upper jaw since 6 months. Growth was small and painless, when first observed by the patient. At the same time he also observed growth on his chest which was first observed by his friends. It was also slow growing.
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 Both lesions were asymptomatic.

On General Examination
Skin was completely normal, without any pigmentation. No endocrinal dysfunction.

Face was slightly asymmetrical, due to growth on right side of the maxilla.
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 Patient had good oral hygiene with full set of teeth.

Growth was extending mesially from right upper canine to distally up to second molar.
Size of the lesion was approximately 4 x 2.5 cm. It was extending superio - inferiorly from cervical level of first molar to beyond the buccal sulcus.
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 Growth was irregular in shape and bony hard in consistency. Gingiva over the lesion is normal.

An another lesion was present on the right side of the chest on second rib extending up to the fourth rib, medially from mediastinum to 1 cm mesial to mid clavicular live
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Provisional diagnosis :
Polyostotic Fibrous Dysplasia

Differential Diagnosis :
Osteoma Ossifying Fibroma

Investigations :
IOPA Occlusal view of right maxilla PNS view of skull PA view of chest Serum Calcium level Serum Alkaline Phosphatase slightly raised Biopsy right buccal region

Radiographic features :
IOPA & Occlusal view ground glass pattern Radiopacity at the 2nd rib.

Final Diagnosis
Fibrous Dysplasia
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Discussion
Fibrous dysplasia usually affects young people and tends to become static after puberty. Without treatment or careful management of the diagnosed cases, severe skeletal deformity can result. There are 2 main clinical types of this disease

Monostotic Involves one bone Polyostotic Involves multiple bones

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Polyostotic is sub classified as : a) Jaffes type, in which several bones of the skeleton are involved, pigmented lesions of the skin (caf-au-lait spots). b) Albrights syndrome, a polyostotic form accompanied by pigmented skin lesions and endocrine dysfunction presenting as precocious puberty in females and sometimes other anomalies (Albright et al,1937)

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Pathology & Pathogenesis

Histopathological appearance can vary according to the relative maturity of the lesion. It consists of well vascularised, cellular fibrous connective tissue containing irregular trabeculae of immature bone sometimes having a Chinese character appearance. Bone in some lesions or some parts of lesion can show osteoclastic activity that are lined by osteoblasts.

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 Moth eaten spicules devoid of osteoblastic activity which can be seen in some lesions, may represent a burned out phase. Calcifications as seen in ossifying fibroma, and minute basophilic and laminated calcifications may be seen. Schlumburger (1946) suggested that infection or trauma might play a role in some cases. But it is possible that there is genetic predisposition to this defect involving osteogenic mesenchymal tissue.
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 Greco and Steiner (1996) examined fibrous dysplasia cases and suggested that abnormal osteoblastic maturation of the bone forming mesenchyme has one of the most important alterations in this condition.

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Polyostotic Fibrous Dysplasia

The first recognized case of polyostotic fibrous dysplasia with skin and endocrine lesions was in 1922 by WELL.

Types :
Jaffes type fibrous dysplasia involving a variable number of bones, where most of the skeletal bones are normal and are accompanied by pigmented lesions of the skin or Caf au lait spots.

Albrights type more severe type involving nearly all bones in the skeleton accompanied by pigmented skin lesions and in addition having endocrinal disturbances of varying types. 16

 Warrick, in 1973, evaluated some endocrinal disorders with polyostotic fibrous dysplasia Sexual Precocity Accelerated skeletal growth with premature fusion of epiphyses Goiter & hyperparathyroidism Cushings syndrome Gynaecomastia Diabetes mellitus Acromegaly
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Clinical Features :
Occurs early in life. Recurrent bone pain is most common. Bowing and thickening of long bones with leg length discrepancies. Deformities such as coxavara, shaephars crook, deformity of femur, bowing of tibia, Harvisons groove and intra pelvic protrusions of acetabula were also seen.

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 Spontaneously, pathologic fractures were commonly seen. Caf au-lait spots on skin were seen most commonly on abdomen, back, thighs.(due to irregular melanin pigmentations) Albrights type Precocious puberty was seen in females. Vaginal bleeding with advent of menarche during 4th month of life have been seen.
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 Early development of breasts. Variety of disturbances involving various endocrine glands.

Bones of face and skull are frequently involved causing an obvious facial asymmetry.
Bony, non tender swelling, obstruction or displacement of adjacent structures. Expansion and deformities of maxilla and mandible along with altered oral pigmentation.

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 Roots were often displaced with loss of lamina dura around the teeth. Less frequently multiple jaw lesions with facial asymmetry and titled occlusal plane caused grotesque appearance.

Clinical Course & Progression

Extension of existing lesions Appearance of new lesions Increasing the deformity of the involved bones
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Roentogenographic Features
Clinical basis behind the roentogenographic changes is, that they are due to rarefaction of medullary portion of the bone.

Pseudo De. Orange or Ground Glass appearance

Alternating areas of granular density and lucency, giving a radiographic appearance resembling the rind of an orange, most common type 40% cases

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Whorled plaque like

The matrix of the well circumscribed expansive lesion was composed of plaques of amorphous material of radio density, intermediate between bone and soft tissue which, on close examination, are seen to be arranged in a whorled, onion peel or whirl pool pattern and is seen in 20% cases.

Diffuse Sclerotic Type

This type presented as a homogeneously dense area of involvement, with no clear view of lesion and normal bone. Seen in 16% cases.
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Cyst like
On close examination faint ground glass matrix due to mineralization in fibrous dysplasia.

Pagetoid type
In this radiologic type of lesion the affected area of bone was markedly expanded and showed alternating areas of radiopacity and radiolucency, such as seen in Pagets diseases of bone.
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Chalky White
The matrix consisted of amorphous radio dense material with sharply, marginated lesions containing whorled plaque like densities rare type

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Monostotic fibrous dysplasia

Monostotic variety of craniofacial region typically presents lesions without a clearly defined boundary. Periphery of the lesion often blends into normal bone and hence it is difficult to clearly delineate the lesion. Unlikely polyostotic variety, monostotic variety is diagnosed only after conducting biopsy.

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Histological features
Minimal collagen production Woven bone is arranged randomly with few osteoblasts on the bony trabeculae. Areas of calcification along with resorption cavities containing osteoblasts and few giant cells seen.

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 Although resorption and formation of bone seen, it did not result in mature lamellar bone formation. This is characteristic difference between reparative bone and fibrous dysplasia histologically.

Multiple islands of cartilage with fluid filled cysts may be seen Cortical thinning is evident

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Biochemical findings
Serum alkaline phosphatase may be slightly raised due to increased bone activity.

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Conclusion
Fibro-osseous lesions of jaw bones appear with a variety of clinical and radiographic characteristics. As they have varied radiographic appearance, the nature of the lesion can only be confirmed through biopsy. Many serious bone diseases and lesions are manifestated radiographically with characteristic fibro osseous bone changes. But differentiation between the various fibro-osseous lesions i.e., fibrous dysplasia, ossifying fibroma and cementifying fibroma is difficult on the biopsy results alone. A review of the clinical and radiographic features together with the histopathologic changes and surgical findings will allow for a definitive diagnosis.
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Critical Evaluation
No introduction Discussion part was insufficient No chest radiographs images Repetitive texts Hyperparathyroidism repeated on page 23, 1st column, last paragraph Shaephars crook 23 page, 2nd column

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Review
Benign fibro osseous lesions are a collection of non neoplastic intraosseous lesions that replace normal bone and consist of a cellular fibrous connective tissue within which nonfunctional osseous structures form.

Contemporary Oral & Maxillofacial Pathology Sapp & Eversole

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Classification of Fibro-osseous Lesions

Fibro Osseous Lesions of the Jaws; Charles Waldron; J Oral Max. 33 Surg. (51). 1993

Benign Fibro-osseous Diseases of the Maxillofacial Bones A review & 34 DD; Faizan Alawi; Am J Clin Pathol 2002;118

 Fibrous dysplasia was first described by Lichtenstein in 1938 & is an asymptomatic regional alteration of bone in which the normal architecture is replaced by fibrous tissue and non functional trabecula like osseous structures. Can be monostotic or Polyostotic, with or without endocrine disturbances. Its not a neoplasm because its self limiting. Begins as a fibrous replacement of the medullary bone, which in turn is replaced gradually by a metaplastic woven bone that eventually matures into dense lamellar bone. 35

 More frequent in childhood In mild form affects only few bones, in severe forms affects all of the skeleton Females > Males (3 : 1)

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 Polyostotic fibrous dysplasia occurs as a part of McCune Albright syndrome, a condition including skin pigmentations and endocrinopathies.
Rarely, in absence of endocrinopathies, it has been termed as Jaffe Lichtenstein syndrome.

Clinical forms of Fibrous Dysplasia of Jaw

A) Monostotic Juvenile Juvenile, aggressive

Adult B) Polyostotic Craniofacial McCune Albright Syndrome Jaffes Syndrome

Contemporary Oral & Maxillofacial Pathology Sapp & Eversole

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Etiopathogenesis
Exact cause is not known Usually caused by mutation of GNAS 1 gene (20q13.2) (guanine nucleotide binding protein, alpha stimulating activity polypeptide), after fertilization in somatic cells. Weinstein et al in 1991 analyzed DNA, from 4 patients with McCune Albright syndrome, and found that all 4 had mutations of the gene that rendered it active for the alpha subunit of the

G1, that inhibits GTPase activity and cause increased cAMP production

Fibrous Dysplasia, Pathophysiology, Evaluation, and treatment; 39 Mathew D Capri et al; Journal of bone & joint surgery; vol 87; 2005

G Protein Encodes

Stimulates

GNAS 1

cAMP production

Mutation

Increased Activation of G Protein

Increased

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Results

Hyperfunction of affected Endocrine Organs

Precocious Puberty Hyperthyroidism Growth hormone Cortisole overproduction

Increased prolilferation of Melanocytes

cAMP, is thought to have an effect on differentiation of osteoblasts leading to Fibrous Dysplasia

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Polyostotic Fibrous Dysplasia

Frequently involves the skull and facial bones, pelvis, spine and shoulder girdle. Other sites are femur, tibia, pelvis, ribs, skull, and facial bones, upper extremities, lumbar spine, clavicle, and cervical spine, in decreasing order of frequency. Can be unilateral or bilateral.

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 Symptomatic before patient is 10 years of age. Leg length discrepancy of varying degrees.

Structural integrity of the bone is weakened, and the weight bearing bones become bowed.
Curvature of the femoral neck and proximal shaft of the femur markedly increase causing a Shepherds crook deformity. Shafers Textbook Of Oral Pathology 6th edition
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Radiographic Features Usual appearance in long and short bones include, a lucent lesion in the diaphysis or metaphysis. With or without bony expansion. The lucent lesion has a thick sclerotic border & is called rind sign. Single or multiple, symmetric or asymmetric, radiolucent or sclerotic lesions in the skull or facial bones are present. Radiographical approach to Jaw Lesions; Neyaz et al; Singapore Med J 45 2008; 49(2) : 166

 The often used "ground glass appearance" description for fibrous dysplasia can be misleading Fibrous dysplasia lesions can just as frequently be seen as purely lytic, sclerotic, mixed/pategoid, or cystic. Maxilla > Mandible

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 Radiographic classification Pagetoid - characterized by bone expansion and alternate areas of radio density and radiolucency. Sclerotic - appears as bone expansion with homogeneous radio density, giving the classic ground-glass appearance. Cyst like - appears as solitary, round or oval well-defined radiolucent lesion with sclerotic margin.

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 Polyostotic FD is often unilateral, sometimes showing a monomelic pattern. It is frequently associated with fractures and severe deformities. Shepherds crook deformity is common.

Involvement of skull may cause cranial nerve dysfunction with visual and hearing impairment.
Imaging findings of Fibrous Dysplasia with Histopathologic & intraoperative correlation; kimberly et al. AJR;182 : June 2004
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Classic shepherds crook deformity of right proximal femur and fibrous dysplasia 49 lesions (arrows) involving both iliac wings.

Lateral radiograph - mixed density FD involving right frontal and parietal bones

MRI shows expansile lesion, which is heterogeneous, predominantly intermediate signal intensity.

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 The term leontiasis ossea describes a rare form of polyostotic disease. It involves the frontal and facial bones, and results in marked deformities resembling lions face

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Frontal radiograph of skull of 7-year-old girl shows sclerotic FD involving right facial and frontal bones, with resultant hypoplasia of right orbit. Outward appearance of these deformities may resemble lions face, such that this form of polyostotic fibrous dysplasia has been termed leontiasis ossea.
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Histopathological Features Irregularly shaped trabeculae of immature (woven) bone in a cellular, loosely arranged fibrous stroma. These irregular trabeculae have been described as "Chinese letters" or "alphabet soup". The stroma has a whorled appearance and is highly vascular. Spindle cells are present all over. Fibrous Dysplasia; digital cases; immunohistochemistry.humanpath.com/article 2149
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 Bony trabeculae are considered to arise by metaplasia and are not rounded by plump appositional osteoblasts (osteoblastic rimming) Tiny calcified spherules may be seen rarely but are never numerous. No lamellar bone is found within FD lesion.

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 McCune-Albright syndrome (MAS) is a sporadic disorder that is characterized by the clinical triad of polyostotic FD, skin hyperpigmentation (caf au lait spots), and multiple endocrinopathies, including gonadal hyperfunction leading to sexual precocity (females). Less common manifestations of MAS include hyperthyroidism, adenomas of various endocrine glands including the pituitary gland, Cushing syndrome, acromegaly, benign ovarian cysts, linear epidermal nevi, and neonatal cholestasis Benign Fibro Osseous Diseases Of the Maxillofacial Bones Review 56 & DD; Faizan Alawi; Am J Clin Pathol 2002;118

 Mazabraud syndrome is another rare, sporadic disease that is characterized primarily by polyostotic FD and intramuscular myxomas. Myxomas appear many years after initial manifestations of FD Total 40 cases have been reported till now.

There is a clinical overlap between MAS and Mazabraud syndrome, since Mazabraud patients have caf au lait spots, and patients with MAS, reportedly have developed soft tissue 57 myxomas.

 FD is derived from osteoprogenitor, fibroblast like cells. Mutations of GNAS 1 leads to elevation in production of cAMP. This in turn induces an alteration in the transcription and expression of several downstream target genes, including

C- fos, a proteo oncogene.

In a study, high levels of c-fos, were identified in the bone marrow spaces of FD affected bones, whereas no c-fos were detected in normal healthy bones.
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 Over expression of c-fos in transgenic mice results in the formation of bone lesions resembling FD. Furthermore, Osteosarcomas develop in the same cases. It is proved by the fact that, there is a 0.5% human risk for spontaneous sarcomatous transformation of FD.

Osteosarcomas develop in an estimated 4% cases of MAS.

Clonal chromosomal abberations also have been identified in 59 FD.

 Thus based on these findings, Cohen & Howell, and others advance the argument that FD should no longer be considered as hamartomatous disorder of bone, but rather a benign neoplasm with malignant potential

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 McCune Albright syndrome is often associated with phosphaturia.

Accompanying phosphaturia and endocrinopathies may have a direct effect on fibrous dysplasia skeleton. It is known that hyperthyroidism and phosphaturia have deleterious effects on normal skeleton.

Fracture Incidence in Polyostotic Fibrous Dysplasia and the McCune-Albright 61 Syndrome; Arabella I Leet; Journal of bone & mineral research; vol 19,2004

 Mutation results in accumulation of progenitor cells and deranged differentiation of these cells, as they progress along the osteogenic pathway. This results in formation of abnormal bone and fibrotic tissue, which are composed of mosaic of mutated and non mutated osteogenic cells.

Hormonal changes that normally occur during puberty, pregnancy and menopause affect normal bone, and can also affect patients with FD.
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 Kaplan et al in 1988, reported worsening of FD during pregnancy.

To better understand the incidence of extremity fractures in PFD, a review of medical records of PFD/MAS patients was performed, by Arabella et al in 2004.

Total 35 patients were included for the retrospective study for a period of 3 years.
It was found that there was a peak in the fracture rate between the ages of 6 to 10 years, with a decline thereafter, most pronounced in femur.

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 It was said that the age of first fracture, number of fractures and fracture rate were aggravated by metabolic derangements, as the patients had first fracture at a younger age.

It was found that phosphaturia had the most significant effect.

These patients fractured more often, not only because they had more skeletal disease, but that the quality of their bone was worse because of renal phosphate wasting including a relative hypophosphatemia.
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 A 32 year old male was reported with a chief complaint of swelling to his right cheek. Swelling had begun 3 months ago, and had noticeably increased in a short interval. No history of trauma or infection to this area was reported. Patient had 6x6x2cm bony prominence to his right zygomatic arch. A case of Craniofacial Polyostotic Fibrous Dysplasia ; Clark et al; 65 Radiology Cases.2010 (9) : 1-6

 It was non tender & non mobile with no skin changes. Facial bone radiograph revealed near complete opacification of right maxillary sinus and a bony prominence in the right frontal/ parietal region.

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 Narrowing of optic canal on right side with approx 3.25mm diameter. Matrix of the lesion was ground glass.

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 Disruption of anterior maxillary wall was noted along with extension into the occipital condyles. A single lesion was present in his right anterior mandible.

Narrowing of the optic canal is present on the right side which is approximately 3.25 mm in diameter , superior orbital fissure, and foramen ovale.

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Complete opacification of the right maxillary sinus (*)

Extending into the right aspect of the maxilla inferiorly (M) , the orbital roof and into the right aspect of the frontal bone in the region of the forehead (long arrow). Disruption of the inferior orbit is noted (short arrow)
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 Diagnosis of PFD was given, but concern was advanced age at its onset. Rapid growth, 3 months of visual and physical symptoms were also concerning. So, they were worried about malignant transformation.

Patient had mild general reduction of sensitivity in his right eye, which confirmed the suspicion that he was suffering from ischemic optic neuritis.
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 Biopsy of right maxilla was performed, which showed fibroblast proliferation and hyalinization consistent with FD. Endoscopic technique was used to decompress his right optic nerve. Right maxillary sinus was debulked using Caldwell Luc approach.

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 Elevated serum alkaline phosphatase and urine hydroxyproline are usually noted in the active stage of the disease, to due the extent of bone remodeling. Checking levels of testosterone, estradiol, estrone are useful when ruling out McCune Albright syndrome. Corticosteroids may be used to reduce the swelling of optic nerve prior to surgery and biphosphonates to inhibit osteoblastic and osteoclastic activity.
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References
Contemporary Oral & Maxillofacial Pathology Sapp & Eversole
Shafers Textbook Of Oral Pathology 6th edition

Oral & Maxillofacial Pathology Neville 2nd edition

Fibrous Dysplasia, Pathophysiology, Evaluation, and treatment; Mathew D Capri et al; Journal of bone & joint surgery; vol 87; 2005 Fibro Osseous Lesions of the Jaws; Charles Waldron; J Oral Max. Surg. (51). 1993
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 Benign Fibro-osseous Diseases of the Maxillofacial Bones A review & DD; Faizan Alawi; Am J Clin Pathol 2002;118
Radio graphical approach to Jaw Lesions; Neyaz et al; Singapore Med J 2008; 49(2) : 166 Imaging findings of Fibrous Dysplasia with Histopathologic & intraoperative correlation; kimberly et al. AJR;182 : June 2004 Fracture Incidence in Polyostotic Fibrous Dysplasia and the McCune-Albright Syndrome; Arabella I Leet; Journal of 74 bone & mineral research; vol 19,2004

 Fibrous Dysplasia; digital cases; histochemistry.humanpath.com/article 2149

immuno

http://www.tumorlibrary.com/case/detail.jsp?image_id=40 41

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