Malignant Sarcomatous Degeneration of Craniofacial Fibrous Dysplasia

Abstract

Background:

Fibrous dysplasia (FD) is an uncommon bone disease characterized by replacement of normal bone architecture with abnormal fibro-osseous connective tissue. Here we discuss two cases of craniofacial FD, with malignant sarcomatous degeneration - a rare and morbid complication of the disease.

Case History:

Two cases of craniofacial FD with malignant degeneration are presented. In the first, a 68-year-old male with a history of FD presented with acutely worsening left-sided facial pain and V2 and V3 hypoesthesia. Imaging findings suggested a large infratemporal fossa mass with biopsy demonstrating sarcomatous degeneration. Radical craniofacial resection achieved a gross total resection with likely microscopic disease. The patient was unable to tolerate adjuvant chemotherapy or radiation and succumbed to his disease 13 months following surgery.

In the second case, a 36-year-old male with McCune-Albright Syndrome and craniofacial FD presented with acutely worsening left-sided headaches and midface hypoesthesia. Imaging revealed a heterogenous and expansile lesion with erosive changes in the left nasal cavity and infratemporal fossa. Pathology was suggestive of low grade sarcomatous degeneration. Given the extensive involvement of the skull base, the tumor was deemed unresectable, and the patient soon died following initiation of chemotherapy

Clinical Relevance:

Malignant sarcomatous transformation is a rare and challenging complication of craniofacial FD. Indolent onset, advanced spread at time of presentation, and close relationship with vital neurovascular structures are all hurdles for the treating clinician. The entity poses a diagnostic dilemma, as pathological analysis can be equivocal and may mimic non-malignant processes, such as locally aggressive FD.

Introduction:

Fibrous dysplasia (FD) is a relatively rare bone disease characterized by replacement of normal bone architecture with abnormal fibro-osseous connective tissue¹. First described by Lichtenstein and Jaffe in 1942, the disease accounts for 5% of benign bone tumors. Clinically, FD can present in a monostotic or polyostotic form, affecting one or multiple bones, respectively¹. Disease can manifest during childhood and may be associated with extraskeletal features, termed McCune-Albright syndrome (MAS)². As many cases of FD can remain asymptomatic, its exact incidence and prevalence remains largely unknown³.

Here we present two cases of craniofacial FD with malignant sarcomatous degeneration, a rare and morbid complication of the disease.

Case #1

A 68-year-old male with a history of FD diagnosed during childhood and previously treated with conservative bone countering procedures without medical therapy presented to our institution with four months of worsening left-sided facial pain, anosmia, and ipsilateral V2-V3 hypoesthesia. Magnetic resonance imaging (MRI) demonstrated extensive FD of the central and left skull base, left maxilla, and mandible. Additionally, a 6.6 × 3.8 × 7.0 cm locally invasive mass involving the left infratemporal fossa, sphenoid and middle cranial fossa was identified (Figure 1). Previous biopsy at an outside institution four months prior had indicated the histological diagnosis of FD, however given the persistence and rapid progression of symptoms, a repeat endoscopy and targeted biopsies were performed. Pathology revealed a highly atypical cellular spindle cell proliferation with focally increased mitotic activity and focal osteoid formation. Immunohistochemistry (IHC) was positive for smooth muscle actin and negative for CD31, CD34, MDM-2, muscle specific actin and S100. Ki-67 was 50%. A final pathological diagnosis was made of high-grade osteosarcoma (Figure 2).

Figure 1:

A. Gadolinium-enhanced T1-weighted coronal MRI demonstrating extensive fibrous dysplasia of the skull base, left mandible, and clivus with complete obliteration of the sphenoid sinuses and left maxillary sinuses. B. Axial view demonstrating mass effect on the left fossa of rosenmüller with abutment of the left petrous internal carotid artery (asterisk).

Figure 2:

A. Low power (50x) hematoxylin and eosin slide demonstrating classic fibrous dysplasia in a portion of tumor. B. High power (200x) slide demonstrating high grade osteoblastic osteosarcoma with focal chondroblastic differentiation, secondary to malignant transformation of fibrous dysplasia in the same specimen.

The patient was recommended for radical surgical resection after positron emission tomography imaging demonstrated no evidence of metastatic disease and consensus agreement following review at multidisciplinary head and neck tumor board. Preoperative balloon occlusion testing was performed given proximity to the petrous and parapharyngeal internal carotid artery (ICA), of which the patient passed. The patient subsequently underwent craniofacial resection including partial maxillectomy, mandibulectomy, subtemporal craniectomy, and resection of the infratemporal fossa contents accomplishing a gross total resection (Figure 3). The large surgical defect and wide exposure of the petrous and parapharyngeal ICA necessitated reconstruction with free tissue transfer via an anterolateral thigh free flap that was staged the following day (Figure 4).

Figure 3:

Intraoperative image following gross total resection of tumor with wide exposure of left infratemporal fossa.

Figure 4:

A. Post operative MRI demonstrating appearance of infratemporal fossa after resection of the tumor (coronal view). B. Axial view of defect in the right temporal dura with herniation of a small portion of the temporal lobe.

The patient did well postoperatively and was recommended for initial chemotherapy followed by chemoradiation. He received a single cycle of adriamycin and cisplatin approximately five weeks after surgical resection though subsequently refused any further adjuvant treatment secondary to intolerable side effects. Repeat MRI at six months postoperatively demonstrated likely recurrence and he ultimately did agree to radiotherapy though halted shortly after initiation secondary again to side effects. In addition, the patient was started on denosumab, however continued to have progression of disease despite treatment. The patient ultimately went on to hospice and succumbed to his disease 13 months following surgery.

Case #2:

A 36-year-old male previously diagnosed with McCune-Albright Syndrome (MAS) presented to an outside institution with six months of severe and progressive left-sided headaches, periorbital pain, nasal obstruction, and midface hypoesthesia. The patient had previously undergone numerous bone contouring procedures, however had not undergone at medical management for his MAS.

He underwent neuroimaging with findings of extensive bony erosive changes in the middle cranial fossa on computed tomography (CT) as well as a large heterogeneously enhancing solid/cystic mass in the left infratemporal fossa on MRI (Figure 5). Initial diagnosis of the left infratemporal fossa lesion was attributed to aneurysmal bone cyst (ABC) formation, however progressive symptoms & serial imaging demonstrated rapid progression and solid tissue growth raising concern of malignant transformation.

Figure 5:

A. CT scan demonstrating diffuse fibrous dysplasia of the calvarium, skull base, and facial bones. B. MRI demonstrating large expansile heterogeneous lesion in left nasal cavity and infratemporal fossa.

Preliminary image-guided core needle biopsy revealed findings consistent with fibrous dysplasia, however given rapid onset and severity of symptoms, malignant degeneration was strongly suspected. The patient subsequently underwent expanded endonasal approach (EEA) for further biopsy and debulking. Intraoperative findings were notable for medial expansion of the maxilla causing complete obstruction with tumor extending from the left nasal cavity to most of the nasopharynx.

Initial pathology was suggestive of low grade sarcomatous transformation demonstrating an atypical fibromyxoid proliferation (Figure 6) with significant cytologic atypia. Immunohistochemical analysis was negative for S100, CD34, desmin, smooth muscle actin and positive for vimentin. Ki-67 was 10–15%. Specimens were reviewed at two other academic institutions for second opinion with similar conclusions. Molecular testing of the tumor demonstrated a p53 mutation further pointing toward malignant degeneration.

Figure 6:

A. Low power slide (50x) demonstrating spindle cell proliferation with possible osteoid production. B. Immunohistochemical analysis with Ki-67 showing an overall mitotic index of 10–15%, supporting the diagnosis of low-grade sarcoma.

The case was reviewed at three separate academic institutions’ multidisciplinary tumor conference with consensus determination of malignant degeneration in light of the pathologic findings, rapidly progressive growth as demonstrated by serial imaging and fulminant clinical course. Based on the extensive involvement of the skull base and critical neurovascular structures the tumor was deemed unresectable. The patient was offered chemotherapy with possible surgical salvage although passed away soon after starting treatment, approximately three months from initial presentation.

Discussion:

Malignant degeneration in fibrous dysplasia is an exceedingly rare event, with only a limited number of single-subject case reports and small case series reported in the literature since its initial description by Coley in 1945⁴. The overall estimated incidence of malignancy is generally accepted as 1% and 4% for the monostotic and polyostotic forms of FD respectively, however this ratio may not be representative of craniofacial FD⁵. A review conducted by Cheng et al. of 35 patients with malignant degeneration of craniofacial FD patients found that 66% had monostotic disease, compared to 26% with the polyostotic variant⁶. Of the anatomical sites of the craniomaxillofacial skeleton, the maxilla is most commonly implicated, followed by the mandible and zygoma⁶. Beyond the head and neck region, the femur, humerus, pelvis, and scapula are also commonly implicated⁵.

To date, the pathophysiological basis for conversion of FD to a malignant entity is poorly understood. Overall, there is no general consensus regarding peak incidence. Although initially believed to be a process which has a predilection for appearing decades after initial diagnosis of FD, several studies have pointed to malignant transformation during early childhood⁷. Furthermore, there are also reports of initial diagnosis of FD and malignant transformation occurring concurrently⁸. Risk factors include concomitant McCune-Albright syndrome and a prior history of radiation therapy⁹.

The diagnosis of malignant transformation of craniofacial fibrous dysplasia is challenging, given that disease presentation is typically indolent, with symptoms typically not appearing until there has been neurovascular compromise or profound craniofacial disfigurement. However, rapid development of symptoms including increasing pain without history of trauma or injury, sudden changes in vision and hearing, worsening nasal obstruction, new paraesthesias and/or hypoesthesias can suggest malignant transformation⁶. The role of laboratory tests in the diagnosis of malignant degeneration of FD remains limited, however profoundly elevated serum alkaline phosphatase (ALP) appears to be correlated and can be a useful tool to monitor for recurrence⁶.

Initial radiographic survey of FD is typically conducted with radionuclear scans to identify areas of involvement¹⁰. Lesions are then imaged anatomically with plain radiographs or computerized tomography, with the latter providing more utility in anatomically complex areas such as the skull base¹¹. The classical appearance includes the replacement of normal, healthy bone with a radiolucent “ground-glass” pattern, with effacement of the normal trabecular pattern¹¹. Radiographic signs suggesting malignant sarcomatous degeneration include rapid transformation of previously mineralized bony lesion to a moth-eaten or lytic focus with cortical destruction or formation of a heterogeneously enhancing soft tissue mass that breaches the bony cortex⁵. MRI appears to have a limited role in the initial diagnosis of FD, as its signal characteristics are relatively non-specific; however, it is an excellent adjunct to CT when malignant degeneration is suspected as it can allow the clinician to study relationships with important neurovascular structures in the skull base¹¹.

Definitive diagnosis of sarcomatous degeneration is made with operative biopsy and relies on an adequate, high-quality specimen with meticulous histopathological analysis¹². Diagnosis of malignant degeneration is made when histology reveals increased cellularity and atypia amongst a characteristically acellular fibrous stroma of FD and may require evaluation of the clinical findings in the face of equivocal histology⁵. Osteosarcoma is the most common entity, which accounts for nearly 70% of malignant degeneration of FD, with histology showing abundance of irregularly organized osteoid-producing spindle cells⁵.

Unfortunately, the concept of irregularity is also seen in the few cases of malignant transformation of craniofacial fibrous dysplasia that have been described previously. A definitive pattern is lacking in both patient demographics and the most effective treatment algorithm. Given that malignant degeneration is a rare phenomenon, limited cases are available for review, leading to difficulty in establishing predisposing factors and describing patterns of spread¹³. The development of a patient registry of FD patients may have utility in distinguishing risk factors and presenting symptoms which are indicative of malignant degeneration. As many cases of FD are asymptomatic, conservative management combined with enhanced knowledge of signs of malignant transformation, based on historical data could prove to be useful.

Given its sparse natural occurrence, there is no standardized protocol for treatment of malignant degeneration of craniofacial FD. Critical components include biopsy for histopathological analysis, surgical resection, and adjuvant therapy¹⁴. Complete surgical excision is often advocated for, however in practice, is often not feasible given disease extension to critical neurovascular structures⁶. Under these circumstances, adjuvant radiotherapy and chemotherapy are often utilized, however observed survival benefits for these modalities is largely derived from evidence studying primary sarcomas of the craniofacial region, rather than those from malignant degeneration of FD^{15, 16}. Overall, despite intervention, disease control and survival in patients with malignant degeneration of FD is generally poor, with most deaths resulting from local recurrence and distant metastases⁶.

Conclusion:

Malignant sarcomatous transformation is a rare and challenging complication of craniofacial fibrous dysplasia. Potentially fulminant clinical presentation, advanced spread, pathological mimicry, and poorly understood risk factors make malignant transformation of craniofacial fibrous dysplasia a significant hurdle for the treating clinician. Overall, much remains to be learned about the disease and further studies are needed to better understand the underlying pathophysiology and to develop an optimum treatment strategy.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request. Please contact the corresponding author, Adnan S. Hussaini, at adnan.hussaini@northwestern.edu to file a request.