—  SPECIALTY CONFERENCE  —

Bone and Soft Tissue Pathology

Case 2 - Osteosarcoma Arising in a Background of Fibrous Dysplasia Of the Sphenoid Bone, Pterygoids and Extending into the Right Nasal Cavity.

Gene P. Siegal
Professor of Pathology
Cell Biology and Surgery
University of Alabama at Birmingham
Birmingham, AL


Click on each slide thumbnail image for an enlarged view
Clinical History
A 55 year old Caucasian woman presented with headache and neck pain of three months duration. She was otherwise in excellent health without known major illnesses or surgeries. A course of antibiotic therapy did not relieve her pain. A subsequent trial of steroids was similarly unsuccessful in alleviating her symptoms.

Three weeks prior to admission she developed blurred vision and "double vision" with drooping of her left eyelid. On physical examination she appeared healthy but with ptosis of her left eyelid with inhibition of both lateral and medial gaze. An MRI examination was performed which revealed a 4 cm mass replacing the sphenoid sinus and extending into the nasal pharynx while compressing and laterally displacing both internal carotid arteries. The upper tumor margin was seen to be at the level of the optic chiasm. On a T1 weighted image the signal intensity was isointense to muscle but heterogenous. The heterogeneity was slightly increased in its intensity on FLAIR and T2 weighted views.

Following intravenous contrast, the lesion demonstrated homogenous enhancement. Replacement of the cavernous sinuses was noted and the lesion was seen to be slightly larger on the left at the upper margin and eccentrically expanded to the right-inferiorly. The left wing of the sphenoid was enhanced as was the tuberculum sella. The brain parenchyma was viewed as normal throughout.

On maxillofacial CT of the sinuses diffuse changes were seen in the skull bones. A large soft tissue mass was again appreciated involving the sphenoid bone, including its body, greater and lesser wings, and pterygoids and the lesion was also seen to extend into the right nasal cavity. Marked hyperostosis of the posterior ethmoid sinus, mainly on the right, with a mass-effect on the posterior aspect of the nasal septum (causing deviation to the left) was further appreciated. Taken together the changes were thought to favor the diagnosis of a meningioma radiologically within the sphenoid sinus and pitutitary fossa.

Nasal endoscopy demonstrated a bulging of the posterior nasal cavity inferior to the sphenoid sinus and superior to the nasopharynx. This mass was smooth and mucosally covered with a thin shell of bone over the neoplasm. The tumor was white, and fleshy with minimal vascularity. Following endoscopic evaluation she underwent a biopsy of the mass.


Case 2 - Figure 1 - MRI following contrast demonstrating homogenous enhancement of a mass.
Case 2 - Figure 2 - Maxillofacial CT demonstrating marked changes in the bones surrounding the mass.


Case 2 - Figure 3 - Low power photomicrograph - note tumor osteoid admixed with highly vascular neoplastic spindle cell population & woven bone.
Case 2 - Figure 4 - Higher power photomicrograph - increased mitotic activity is seen.

Histopathology
Multiple sections demonstrated a spindle cell neoplasm with osteoid formation. In some fields significant cellular pleomorphism and increased mitotic activity (1-3/HPF) were noted within the spindle cell stroma. Other fields contain woven bone without osteoblastic rimming in the fibrous stromal background.

Immunophenotypically, the spindle cell population was reactive only with antibodies directed against vimentin intermediate filaments. Specifically, no reactivity was noted with broad spectrum cytokeratin, EMA, or S-100 protein antibodies.

Fresh tissue was also collected. After gentle disaggregation and Ficoll separation, 2.2 million cells were retrieved with low viability. On a Wright stained cytospin, spindled cells and other non-specific stromal elements identical to that found in the tissue were identified. Thus, flow cytometry was not performed.

Subsequent Course
The patient was offered pre-operative cisplatin, adriamycin and methrotexate based chemotherapy regimen followed by surgery to debulk the tumor. It was anticipated that she would complete her therapy with post-surgical gamma knife irradiation.

She received three courses of chemotherapy which except for modest marrow suppression was well tolerated. The patient regained function of her left eye and felt clinically significantly improved. She refused further pre-operative therapy and went to a private practitioner in the Midwest for radical resection of the tumor mass. She then sought post-operative care at an eastern academic institution. She died, presumably of her disease or its sequella, approximately nine months following her initial diagnosis.

Final Diagnosis
Osteosarcoma arising in a background of fibrous dysplasia of the sphenoid bone and pterygoids and extending into the right nasal cavity.

Introduction to the Discussion
Fibrous dysplasia (FD) is a proliferative process involving primarily the intramedullary portion of from one to many bones. It is composed of randomly distributed spicules of woven bone, absent prominent osteoblastic rimming, set in a background of swirling fibrous connective tissue with occasional focal cartilaginous differentiation. FD occurs in children and adults on every populated continent and does not favor or spare any racial or ethnic group. Although the monostotic from in some studies slightly favors women, it is considered equally prevalent in both sexes.

Select sites of involvement appear to favor one gender over the other, e.g., long bones more often involve women whereas ribs and the skull are favored sites in men [1]. In the monostotic form, about 35% of cases involve the head, a second 1/3 occur in the femur and tibia, and an additional 20% in the ribs. Whereas, in the polyostotic form, the femur, pelvis, and tibia are involved in the majority of cases [2]. The gnathic bones appear to be over represented [3] while the spine is a relatively rare site of involvement [4].

Clinical Features
FD may present in a monostotic or polyostotic form, and in the latter case, can be confined to one extremity or one side of the body or be diffuse. The polyostotic form is six times less frequent than the monostotic form [5] and it is usually first discovered in late childhood. The polyostotic form often manifest earlier in life than the monostotic form [2]. The lesion is often asymptomatic but pain and fractures may be part of the clinical spectrum [6]. FD may also be associated with oncogenic osteomalacia [7]. FD is linked to many genetic disease and morphologic conditions. Examples of this include: mucoceles [8], simple or empty cysts [9] and aneurysmal bone cysts [10]. The polyostotic form of FD is intimately associated with McCune-Albright syndrome. There is a relationship between polyostotic FD and intramuscular myxomas (Mazabraud's syndrome) [11]. Patients are at increased risk for malignant transformation, even greater than those with FD alone (thought to be <0.5%) [12]. The presence of FD plus osteosarcoma is the most common form of malignant transformation [12, 13] . Other malignant tumors associated with FD include chondrosarcoma [14, 15] , fibrousarcoma [16], angiosarcoma and MFH [17].

Radiology Imaging
Radiologic imaging of FD can be divided in three broad types: sclerotic, osteolytic, and mixed patterns [18]. FD is often said to have pathognomonic radiologic characteristics [19], which include a ground glass texture and sclerotic rim. Classically, FD shows cortical thinning and bony expansion with occasional full thickness bony destruction mimicking aggressive tumors [20]. The value and limitations of computerized tomography in FD has been reported [21]. Its greatest strength lies in its ability to demonstrate the amorphous ground glass appearance of the lesion and its ability to define the extent of the disease [22]. MR better defines FD via sharply defined borders with intermediate signal intensity on T-1 and with T-2 weighted images demonstrating a pattern of either high or intermediate to low intensity [23]. On scintigraphy, FD lesions have slightly increased perfusion and markedly increased uptake of tracer [24].

Etiology
The fibrous areas contain an overabundance of pre-osteogenic cells while the lesional bone is responsible for the biosynthetic output of mature but abnormal osteoblasts [25]. Clonal structural chromosomal aberrations have been noted in chromosomes 3, 8, 10, 12, and 15 [26]. In a manuscript by Dal Cin and colleagues clonal chromosome aberrations were reported in 8 out of 11 cases of FD, suggesting that this entity is neoplastic in nature. The only recurrent changes have been structural rearrangements involving 12p13 and trisomy 2 [27]. An activating missense mutation in the gene encoding for the alpha subunit of heterotrimeric signal transducer of G protein that stimulates cAMP formation apears to be responsible for FD associated with McCune-Albright Syndrome and probably all other forms as well [28].

Pathology
Gross: The bone is often markedly distorted with a firm-to-gritty consistency. Its color varies from and it is often filled with multiple cysts, containing yellow-tinged fluid [29]. When cartilage is present, it often stands out as sharply circumscribed of blue-tinged translucent material [1] .

Histomorphology: The histopathology is that a bizarre C-shaped metaplatic bone devoid of rimming osteoblasts. This atypical woven bone often contains central mineralization and while grossly appearing to be relatively well circumscribed,invades the surroiunding bone. Osteoclasts may be present singularly or in clusters [30]. The fibroblastic spindle cell population dominates in most cases of FD. The density of the fibrous component varies greatly even within the same lesion and cartilage differentiation is not usual [31].

Immunophenotype: Immunohistochemistry has not afforded significant advantage for diagnosis or prognosis. The fibrous component is immunoreactive with antibodies directed against vimentin and with XIIIa [32]. The bone spicules are "positive" with antibodies directed at osteonectin [33]. The lesion is also immunoreactive for prostaglandin E-2, estrogen receptor as well as progesterone receptor [34]. FD is immunoreactive with antibodies directed against c-fos, c-jun, and both osteopontin and osteocalcin as well a type-1 collagen [35].

Ultrastructure: Myofibroblasts as well as fibroblasts are seen in the collagenous background. The osseous component contains immature woven bone lined by abnormal osteoblasts with fibroblast-like appearance. Other cells are noted to have large microfibrillary ctyoplasmic brush borders [36]. Intracytoplasmic myofibrils have also been noted.

Conclusion
The prognosis of patients with FD is quite good. Malignant transformation occurs but is rare. Some lesions have been reported to heal spontaneously [37]. Symptomatic circumscribed lesions require curettage, cryosurgery and/or bone grafting [38] and many individuals have received chemotherapeutic rather than surgical approaches. Radiation to bone affected by FD may result in post-irradiation sarcoma [38]. Spontaneous development of sarcoma in FD bone has an ominous prognosis often with rapid progression as in this case.

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