Fibrosarcoma of the Jaws: Two Cases of Primary Tumors with

Abstract. Fibrosarcoma (FS) is a malignant mesenchymalneoplasm of the fibroblasts that rarely affects the oral cavity.Two cases of primary FS of the jaws with intraosseous growth(2 men, aged 53 and 71 years) are described. Microscopically,in one case the tumor showed an intense proliferation ofspindle-shaped cells, varying little in size and shape andarranged in parallel bands, partly crossing each other, withsignificant mitotic activity and nuclear pleomorphism; thesecond case was characterized by low cellularity comprisingspindle-shaped cells, deposited in a variably fibrous andmyxoid stroma. On immunohistochemistry, cells in bothcases were strongly immunoreactive for MIB-1 and vimentin,focally positive for CD68, and negative for S-100 protein,pancytokeratin, HMB45, CD34, desmin, smooth muscle actin(SMA) and epithelial membrane antigen (EMA). Based onclinical, histological and immunohistochemical findings, thefinal diagnosis was FS in the first case, myxofibrosarcoma inthe second. Treatment was radical surgery with mandibularreconstruction. After two years, the first patient displayedmultiple metastases and died during the third year after theinitial diagnosis; the second patient was still alive and doingwell five years after treatment. We discuss the differentialdiagnosis versus other forms of sarcoma, examining themorphological appearance that is frequently very similar, theimmunohistochemical expression of MIB-1, vimentin, S-100, CD-34, CD68, EMA, as well as conventionalclinicopathological features that may help to distinguish FSfrom other sarcomas.

Fibrosarcoma (FS) is a malignant neoplasm of fibroblasticorigin and may either arise in the soft tissue or be of primary

intraosseous origin (20% of all cases) (1, 2). The latter originhas been debated since 1940, when Ewing (3) established theinitial entity, and is now generally accepted.

It is a rare tumor, accounting for approximately 5% of allmalignant intraosseous tumors (4-6), and especially affects thelong bones. Its occurrence in the head and neck is about 10%of cases, of these the mandible being the commonest site (7).More than 75 cases in the mandible have been reported in theEnglish language literature (8).

FS may arise as a primary tumor in any part of the jaws andmay be classified as of either peripheral (periosteal) or central(endosteal) type (9, 10). Secondary fibrosarcoma of the bonemay be associated with fibrous dysplasia, Paget’s disease, boneinfarct or cyst, and/or osteomyelitis; it may also occur as amalignant transformation of giant-cell tumor of the bone orbe induced by prior irradiation (11).

Clinically, in the oral cavity the major symptoms are pain,swelling, and sometimes loosening of the teeth (12, 13),paresthesia and occasionally ulceration of the overlyingmucosa (14).

Radiographically, an osteolytic lesion is usually present,with ill-defined borders; however, fibrosarcoma of the jawscannot be distinguished from other destructive lesions of thebone (15).

Microscopically there is proliferation of fibroblasts withvariable amounts of collagen and reticulin fiber formation(16). FS sometimes contains hyalinized collagen that cannotbe differentiated from osteoid substance. Characteristically,the cells are uniform spindle-shaped (spindle cell sarcoma),multipolar, with elongated oval or round hyperchromaticnuclei and vary little in size and shape. These cells arearranged in interlocking bands or fascicles that run in differentdirections, and may be arranged in a herringbone pattern withareas of myxomatous, pseudomyxomatous and cartilaginouschanges (17). Its histological grading is based on the degreeof cellularity, degree of cellular differentiation, mitotic activity,the amount of collagen produced by the tumor cells and theextent of necrosis. Different histological types of this tumorexist, one of which is myxofibrosarcoma, which was initially

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Correspondence to: Professor Michele Stefani, Istituto di AnatomiaPatologica sez. Patologia Orale, Via della Commenda 19, 20122Milan, Italy. Tel: +39 0250320807, Fax: +39 02799007, e-mail:[email protected]

Key Words: Fibrosarcoma, jaws, bone tumor, myxofibrosarcoma.

ANTICANCER RESEARCH 27: 2573-2582 (2007)

Fibrosarcoma of the Jaws: Two Cases of Primary Tumors with Intraosseous Growth

FRANCESCA ANGIERO1, TOMMASO RIZZUTI2, ROLANDO CRIPPA3 and MICHELE STEFANI1

1Università degli studi di Milano Istituto di Anatomia Patologica sez. Patologia Orale, 20122 Milan;2Anatomia Patologica, Istituti Clinici di Perfezionamento, Milan;3Oral Surgery Service, Stomatological Italian Institute Milan, Italy

0250-7005/2007 $2.00+.40

described by Angerval in 1977 (18). It is characterized by lowcellularity composed of spindle-shaped cells with minimalcytological atypia, and with cells deposited in a variably fibrousand myxoid stroma, usually appearing more myxoid thanfibrous. Myxofibrosarcoma has been defined as a malignantfibroblastic lesion in which at least 50% of the entire tumordisplays a highly vascularized and myxoid stroma withdistinctive curvilinear vessels (16).

Histologically it is often difficult to distinguish fibrosarcomasfrom other soft tissue sarcomas and diagnosis is often achievedby exclusion. Differential diagnosis must consider othermalignant tumors, i.e. monophasic fibrous synovial sarcoma,malignant fibrous histiocytoma, malignant nerve sheath tumorand liposarcoma, as well as benign tumors, i.e. benign fibroushistiocytoma, nodular fasciitis, fibroma and fibromatosis. Thelow-grade myxofibrosarcoma type, however, is often confusedwith the fibromyxoid sarcoma type, and morphologicaldistinction is sometimes difficult and problematic (9).

Given the diagnostic difficulty in differentiating betweenthese different forms, immunohistochemical analysis is ofconsiderable help in diagnosing fibrosarcomas.

We report two cases of primary mandibular fibrosarcomatogether with clinical, histological and immunohistochemicalfindings, and discuss differential diagnosis of this rare tumorof the oral cavity.

Case Reports

Case 1. A 53-year-old man presented with a 10-month historyof a mass in the left submandibular region, the posteriormandible thereafter showing an enlargement of the

mandibular gingiva and pain. On intraoral examination, aswollen area was observed in the posterior region of theinferior alveolar ridge covered by erythematous mucosa. Thelesion was firm and measured about 5.0x2.0 cm. Panoramicradiography showed a radiolucent lesion with irregularborders infiltrating the superior cortical bone of the mandible(Figure 1). An incisional biopsy was performed and onmicroscopic examination a diagnosis of FS was rendered. Thepatient underwent surgical tumor resection, bilateral neckdissection and mandibular reconstruction. At microscopic


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Figure 1. A panoramic X-ray showed a radiolucent lesion with irregular borders infiltrating the superior cortical bone of the left mandible.

Table I. Immunohistochemical findings of the presented cases.

Antibody Supplier Dilution Reactivity Case 1 Case 2(fibro- (myxofibro-

sarcoma) sarcoma)

MIB-1 Dako 1:200 ++ ++Desmin Dako 1:200 – –Vimentin Ventana prediluted ++ + +S-100 Dako 1:200 – –Pancytokeratin Ventana prediluted – –CD68 Dako 1:500 + +HMB45 Ventana prediluted – –SMA Sigma 1:400 – –EMA Ventana prediluted – –CD34 Novocastra 1:100 – –

: – (negative), no staining; + (positive), focally positive for a limitednumber of cells; and ++ (intensely positive), focally or diffuselypositive for numerous cells. EMA: epithelial membrane antigen; SMA:alpha smooth-muscle actin.

Angiero et al: Fibrosarcoma of the Jaws

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Figure 2. (A-B) Fibrosarcoma (case 1). A: low-power view, B: high-power view with typical histological features of fibrosarcoma with fascicles of spindle-shaped cells distributed in interlacing fascicles with a ‘herringbone’ growth pattern. The tumor cells showed evident mitotic activity and pleomorphis.(hematoxylin and eosin staining; original magnification, A x150 and Bx200).

examination, all lymph nodes were without malignant cells.Almost two years later after surgery, during checkup, an X-ray was requested and showed pulmonary masses, indicatingprogressive systemic disease. Further metastatic spreadquickly occurred and affected bones such as the ribs andpelvis. Thereafter, the health of the patient rapidly declinedand he died, seven months after identification of systemicspread and three years after the initial surgery.

Case 2. A 71-year-old man presented for evaluation of a leftmaxillary swelling, present for several months. At initialclinical examination, the mass appeared as a palpable bonyprotuberance in the left posterior region of the maxilla,measuring 3.0x2.0 cm at its greatest dimension. Clinically,no regional lymphadenopathy was noted. Radiologicalinvestigation revealed a large radiolucent lesion withindistinct margins. The tumor extended from the first molarto the maxillary tuber, deeply eroding the cortical bone.Incisional biopsy revealed a malignant neoplasm containingmesenchymal elements, and a diagnosis of low grademyxofibrosarcoma was rendered. The patient underwentsegmental resection of the mandible including wide surgicalexcision of the surrounding soft tissues; he recovered welland has been followed up for five years without signs ofrecurrence or metastases.

Materials and Methods

The excised biopsy specimens were fixed in 10% buffered-formalinand paraffin embedded. They were cut in 4-Ìm-thick sections,mounted on glass slides and stained with hematoxylin and eosin. Forimmunohistochemistry, the avidin-biotin complex (ABC) method wasapplied (18). The immunohistochemical antibodies, their sources anddilutions are listed in Table I. Immunohistochemical studies using theABC technique were performed in both cases and are summarizedin Table I. The tumor cells of both cases were intensely positive forMIB-1 (Figure 4) and vimentin (Figure 5), focally positive for CD68(Figure 6), and negative for S-100, EMA, SMA, pancytokeratin,CD34, HMB45 and desmin.

Appropriate controls were tested simultaneously. The immuno-histochemical reactivity was determined and graded as follows:negative, no staining; positive, focally positive for a limited numberof cells; and intensely positive, focally or diffusely positive fornumerous cells.

Results

The microscopic examination of case 1 (Figure 2) revealedinterlacing fascicles of spindle-shaped with a ‘herringbone’growth pattern. The tumor was cellularized with evidentmitotic activity. The nuclei were hyperchromatic andpleomorphic, and most of the cells had elongated cytoplasmwith peripheral nuclei. The histological examination of Case2 (Figure 3) revealed low cellularity of spindle-shaped cellswith hyperchromatic nuclei and minimal mitotic activity. The

cells were deposited in a variable amount of fibrous andmyxoid stoma, with the myxoid part prevailing. The spindle-shaped cells were arranged around a curvilinear vasculature.The microscopic evidence indicated a diagnosis of well-differentiated fibrosarcoma in case one and myxofibrosarcomatype fibrosarcoma in case two. Immunohistochemical studiesusing the ABC technique were performed in both cases andare summarized in Table I.

Discussion

From the morphological standpoint, the two entities canfrequently present very similar aspects, in some cases virtuallyidentical, and only careful histological and immuno-histochemical examination enables the various forms to bedifferentiated.

In our cases, immunohistochemistry included MIB-1, amonoclonal antibody that identifies the Ki-67 antigen and isuseful in determining the proliferation index; S-100, a proteinwidely distributed in peripheral and central nervous system,enabling a distinction to be made from malignant peripheralnerve sheath tumor; CD68, a fibrohistiocytic marker; theendothelial and vascular marker CD34; HMB45, amelanocytic marker; vimentin a mesenchymal marker; musclemarkers, i.e. desmin and SMA, and lastly epithelial markersincluding cytokeratins and EMA.

The diagnosis of ‘fibrosarcoma' in these two cases resultedfrom the following observations. Firstly, the tumor cells in case1 showed fibroblastic characteristics, they were spindle-shapedwith fusiform nuclei and eosinophilic cytoplasm. Throughimmunohistochemistry, the cells did not show any lineagespecificity (negative for ·1-smooth muscle actin, desmin, S100and epithelial membrane antigen) (20-22). CD68 was focallypositive, however, such expression is well recognized infibroblastic tumors (23, 24). Secondly, the cells werefrequently oriented in curving or interlacing fascicles forminga classic herring-bone pattern. Thirdly, these tumors displayedinfiltration of the surrounding tissue, some pleomorphism ofnuclei and cells revealing a significant mitotic count. Fourthly,the low-grade myxofibrosarcoma sarcoma was characterizedby an alternation of fibrous and myxoid stroma,predominantly myxoid, having distinctive curvilinear vessels.Lastly, both cases were positive for vimentin and MIB-1, andfocally positive for CD68.

The clinical follow-up of these cases showed that thesetumors displayed similar behavior to the establishedfibrosarcoma entities. Although primary intraosseousfibrosarcoma is usually asymptomatic, in about 30% of cases itmay present some symptoms (16, 25). Both of our patientswere symptomatic, presenting swelling and pain located at themandible, and at orthopantomography the lesions appearedradiolucent with an irregular border infiltrating the superiorcortical bone.


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The treatment of choice is surgical resection with a widemargin (26, 27). The need for adjuvant radiotherapy and/orchemotherapy is still unclear, and is normally indicated inhigh-grade tumors because these may present subclinical ormicroscopic metastases at the time of diagnosis. Prophylacticneck dissection is also controversial (16, 28, 29). Our caseswere treated with surgical resection followed by mandibularreconstruction.

The prognosis is influenced by the site (bone or soft tissue)of origin and the histological appearance of the fibrosarcoma;however, no site distinction may be made based on thehistological morphology (5, 30). Tumors of the oral cavitydiffer in clinical course from those arising in the long bonesin that they exhibit a lower rate of metastasis (15, 31-34). Ithas been calculated that, in the oral region, the 5-year survivalrate is 60% for oral soft tissue fibrosarcomas and 27% forthose of medullary origin (35), whereas in the long bones itranges from 4.3% to 31.7%.

A high grade of differentiation of the tumor improves thesurvival rate (36). The overall survival rate at 10 years mayvary from 21.8% to 83%; clinical stage, histological grade ofmalignancy and local recurrences are the most importantprognostic factors (25).

The potential to recur and to spread of the myxo-fibrosarcoma type seems also to be related to the

anatomical depth of the primary tumor and the histologicalgrade. Although histologically this tumour is relativelybland (low-grade), it does carry a significant risk ofrecurrence and quite often progresses to a higher gradelesion. The local recurrence rate of the low-grade type is ashigh (50-60%) as that of the high-grade type, with anoverall risk of approximately 20% to 25% of metastasis (37,38); thus, it is obvious that wide surgical treatment isnecessary to suppress the risk of local recurrence and therisk of histological progression.

Conclusion

This rare tumor, which generally affects the long bones anddeep soft tissue, must be differentiated from other similarlyrare forms of sarcoma that may involve the oral cavity.Immunohistochemical tests, such as MIB-1, vimentin,CD68, CD34, HMB45, S-100, desmin and cytokeratins, aswell as conventional clinicopathological features may behelpful to distinguish the various types. Clinical follow-upon only two patients cannot provide any significantconclusions concerning prognosis, but the data undoubtedlyshow the malignant biological nature of these neoplasms,and imply a similar prognosis to that of other fibrosarcomasdescribed in the oral cavity.


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Figure 3. Low-grade fibromyxoid sarcoma (Case 2). Low-power view showing typical morphological features with spindle-shaped cells in an alternatingmyxoid and fibrous stroma. Cytological atypia of tumour cells are minimal (hematoxylin and eosin staining; original magnification, x150).


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Figure 4. The fibrosarcoma component shows a high MIB-1 immunopositivity (Case 1; A), the fibromyxoid (Case 2; B) also shows a high MIB-1(original magnification, x150).


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Figure 5. A strong vimentin immunoreactivity can be seen in both Case 1 (A) and Case 2 (B). Original magnification, x150.


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Figure 6. Focal positive immunoreactivity for CD68 expression in Case 1 (A) and also Case 2 (B). Original magnification, x150.

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Received March 8, 2007Revised April 13, 2007

Accepted April 24, 2007


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Fibrosarcoma of the Jaws: Two Cases of Primary Tumors with