jurnal gilut

Odontogenic Cysts, Odontogenic Tumors,Fibroosseous, and Giant Cell Lesions of the JawsJoseph A. Regezi, D.D.S., M.S.

Oral Pathology and Pathology, Department of Stomatology, University of California, San Francisco,San Francisco, California

Odontogenic cysts that can be problematic becauseof recurrence and/or aggressive growth includeodontogenic keratocyst (OKC), calcifying odonto-genic cyst, and the recently described glandularodontogenic cyst. The OKC has significant growthcapacity and recurrence potential and is occasion-ally indicative of the nevoid basal cell carcinomasyndrome. There is also an orthokeratinized vari-ant, the orthokeratinized odontogenic cyst, which isless aggressive and is not syndrome associated.Ghost cell keratinization, which typifies the calcify-ing odontogenic cyst, can be seen in solid lesionsthat have now been designated odontogenic ghostcell tumor. The glandular odontogenic cyst containsmucous cells and ductlike structures that maymimic central mucoepidermoid carcinoma. Severalodontogenic tumors may provide diagnostic chal-lenges, particularly the cystic ameloblastoma. Iden-tification of this frequently underdiagnosed cystictumor often comes after one or more recurrencesand a destructive course. Other difficult lesions in-clude malignant ameloblastomas, calcifying epithe-lial odontogenic tumor, squamous odontogenic tu-mor, and clear-cell odontogenic tumor. Histologicidentification of myxofibrous lesions of the jaws(odontogenic myxoma, odontogenic fibroma, des-moplastic fibroma) is necessary to avoid the diag-nostic pitfall of overdiagnosis of similar-appearingfollicular sacs and dental pulps. Fibroosseous le-sions of the jaws show considerable microscopicoverlap and include fibrous dysplasia, ossifying fi-broma, periapical cementoosseous dysplasia, andlow-grade chronic osteomyelitis. The term fibrousdysplasia is probably overused in general practiceand should be reserved for the rare lesion that pre-sents as a large, expansile, diffuse opacity of chil-dren and young adults. The need to use clinicopath-

ologic correlation in assessing these lesions is ofparticular importance. Central giant cell granulomais a relatively common jaw lesion of young adultsthat has an unpredictable behavior. Microscopic di-agnosis is relatively straightforward; however, thislesion continues to be somewhat controversial be-cause of its disputed classification (reactive versusneoplastic) and because of its management (surgicalversus. medical). Its relationship to giant cell tumor oflong bone remains undetermined.

KEY WORDS: Ameloblastoma, CEOT, Fibrous dys-plasia, Giant cell granuloma, Odontogenic kerato-cyst, Odontogenic myxoma, Odontogenic tumors.

Mod Pathol 2002;15(3):331341

The jaws are host to a wide variety of cysts andneoplasms, due in large part to the tissues involvedin tooth formation. Many benign jaw tumors andseveral cysts (some recently described), of bothodontogenic and nonodontogenic origin, can ex-hibit a biologically aggressive course and can bediagnostically difficult. Traditional histopathologycontinues to be the mainstay for the diagnosis ofthese lesions, as immunohistochemistry and mo-lecular techniques have had, as yet, little impact inthis area.

ODONTOGENIC CYSTS OFDIAGNOSTIC SIGNIFICANCE

Odontogenic Keratocyst

The odontogenic keratocyst (OKC) is a commonlyencountered developmental cyst (Table 1) of con-siderable importance because of its potential foraggressive clinical behavior and recurrence (1; Fig.1). Also, it may be a component of the nevoid basalcell carcinoma (Gorlin) syndrome. OKC occurs any-where in the jaws and in any position. It may besuperimposed over the apices of tooth roots oradjacent to the crowns of impacted teeth. Radio-graphically, it appears as a well-defined lucency

Copyright 2002 by The United States and Canadian Academy ofPathology, Inc.VOL. 15, NO. 3, P. 331, 2002 Printed in the U.S.A.Date of acceptance: September 27, 2001.Address reprint requests to: Joseph A. Regezi, D.D.S., M.S., 513 Parnassus,S-512, University of California, San Francisco, San Francisco, CA 94143-0424; e-mail: [email protected]; fax: 415-476-6482.

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and is often multilocular. OKCs represent 515% ofall odontogenic cysts. The recurrence rate for soli-tary OKC is 10 30%. Approximately 5% of OKCpatients have multiple jaw cysts (and no syn-drome), and their recurrence rate is greater thanthat for solitary lesions.

Microscopically, the epithelial lining exhibits acharacteristic thickness of 6 10 cell layers (Fig. 2).The epithelium shows basal palisading and a thinrefractile parakeratinized lining layer. Separation ofthe epithelium from the thin and uninflamed sup-porting fibrous wall is often seen. Budding of thebasal layer and daughter cyst formation are fre-quently findings. If the cyst wall becomes second-arily inflamed, hyperplasia ensues and the charac-teristic microscopic pattern disappears. Samplingof large cysts may be important for identifying anunderlying OKC that has become secondarily in-flamed. The epithelial proliferation rate in the OKCis relatively high, especially in the case of those thatare syndrome associated. Other advantageousgrowth mechanisms of OKCs include Bcl-2, cyclinD1, and MDM2 overexpression (2 4).

There is an orthokeratinized variant known asorthokeratinized odontogenic cyst. It exhibits similarmicroscopic features, except that it has a granular

layer, is orthokeratotic, and has a poorly organizedbasal layer (5; Fig. 2). It is not syndrome-associated(see below) and seems to exhibit a less aggressivebehavior than OKC. Rarely, OKCs may show foci oforthokeratinization in an otherwise parakeratinizedlining.

The nevoid basal cell carcinoma syndrome is in-herited as an autosomal dominant trait that con-sists principally of multiple odontogenic kerato-cysts, multiple basal cell carcinomas, skeletalanomalies, and cranial calcifications. Syndrome-associated OKCs have the highest recurrence rateand represent approximately 5% of all OKC pa-tients. Many other syndrome manifestations havebeen described, including medulloblastoma andother neoplasms. The basal cell carcinomas de-velop early in life and may number in the tens orhundreds. The most frequently cited skeletal anom-aly is bifid rib. Calcified falx is also relatively fre-quently seen on skull radiograms. This syndromehas been linked to mutations in the PATCHED tu-mor suppressor gene that encodes a receptor pro-tein that is a component of the hedgehog signalingpathway. Mutations of this gene have been found insyndrome-associated basal cell carcinomas andOKCs (6 9).

Calcifying Odontogenic Cyst

Calcifying odontogenic cyst (COC) is a develop-mental cyst that may exhibit occasional aggressive/recurrent behavior. This is particularly true of anoccasionally encountered solid variant that is re-garded as a neoplasm and termed odontogenicghost cell tumor. A very rare malignant variety ofodontogenic ghost cell tumor has been reported asodontogenic ghost cell carcinoma. COC shows a pre-dilection for females and the maxilla. It occasion-ally is seen in the gingiva. It may be unilocular ormultilocular and may show areas of opacificationbecause of the partial calcification of keratinizedlining cells. The distinctive microscopic feature ofthis lesion, be it cystic or solid, is ghost cellkeratinization of the epithelial lining (Fig. 3). Thekeratin may undergo dystrophic calcification andmay incite a foreign-body reaction in the cystwall, giving it features similar to the piloma-trixoma of skin. Ghost cells alone are not diag-nostic, as they may occasionally be seen in otherodontogenic tumors, such as ameloblastomasand odontomas.

Glandular Odontogenic Cyst(Sialo-Odontogenic Cyst)

This is a rare and recently described developmentaljaw cyst that may superficially mimic a central muco-

TABLE 1. Current Classification of Jaw Cysts

OdontogenicInflammatory

Periapical cyst and granulomaDevelopmental

Dentigerous cyst and eruption cystLateral periodontal cystOdontogenic keratocystCalcifying odontogenic cystGlandular odontogenic cyst

NonodontogenicNasopalatine cyst

PseudocystsTraumatic bone cystStatic bone cystHematopoietic bone marrow defect

FIGURE 1. Odontogenic keratocyst of the entire right mandibularbody.

332 Modern Pathology

epidermoid carcinoma. It is seen in adults in any jawsite, although anterior regions are favored. This mul-tilocular cyst is lined by nonkeratinized epitheliumwith focal thickenings composed of mucous cells in apseudoglandular pattern (Fig. 4). This lesion hasshown local aggressiveness and has recurrence po-tential (10). Dentigerous cysts that exhibit occasionalmucous goblet cells in their linings are not believed tobe related to the glandular odontogenic cyst. Theglandular odontogenic cyst should not be confusedwith the more exuberant intraluminal lobular prolif-eration of adenomatoid odontogenic tumor.

DIAGNOSTICALLY CHALLENGING EPITHELIALODONTOGENIC TUMORS

AmeloblastomaAmeloblastoma can exhibit one or more micro-

scopic patterns, none of which is of more clinicalsignificance than the others. Peripheral palisadingand budding are a common denominator of allsubtypes. The most recently described microscopicpattern is one in which there is extensive desmo-plasia, and hence, the designation desmoplasticameloblastoma (Fig. 5). This microscopic subtype isusually seen in the anterior jaws (11). A plexiformmicroscopic pattern is often seen in association

with ameloblastoma of sinonasal origin (12). Theappearance of ghost cells, with or without dentin-like islands, in a tumor that otherwise has the ap-pearance of ameloblastoma has prompted the des-ignation of odontogenic ghost cell tumor (13; seeCOC). The behavior of this rare lesion is believed tobe the same as that of ameloblastoma. The growthmechanisms that have been attributed to amelo-blastomas have been overexpression of Bcl-2, Bcl-x,and MDM2 proteins. The proliferation index, asdetermined by Ki67 staining, is unexpectedly low.Expression of fibroblast growth factors, interleu-kins, and matrix metalloproteinases (MMPs) mayaccount, in part, for the invasive capacity of thesetumors (14 23).

Cystic Ameloblastoma

This biologic subtype of ameloblastoma is alsoknown as unicystic ameloblastoma and, occasion-ally, as plexiform unicystic ameloblastoma. It wasseparated from the solid type because it appearedat a younger age, had a lower recurrence rate, and

FIGURE 2. Left, odontogenic keratocyst showing thin parakeratinizedlining with basal palisading. Separation of epithelium from connectivetissue wall is often seen in surgical specimens. Right, orthokeratinizedodontogenic cyst showing granular layer and in undistinguished basallayer.

FIGURE 3. Calcifying odontogenic cyst featuring ghost cellkeratinization with dystrophic calcification and palisaded basal layer.

FIGURE 4. Glandular odontogenic cyst represented by a focalthickening in which there is mucin production and smallpseudoglandular spaces.

FIGURE 5. Desmoplastic ameloblastoma showing compressedodontogenic epithelial nests in a desmoplastic stroma.

Lesions of the Jaws (J.A. Regezi) 333

seemed to require less aggressive surgery (24 27).Recent evidence, however, indicates that cysticameloblastomas can be destructive and can oftenrecur after simple curettage.

Cystic ameloblastoma usually occurs in the 2ndto 3rd decades and usually in the mandibular molararea. Maxillary lesions are very uncommon. Thelesion is entirely cystic and consists usually of asingle space, although many have cystic locula-tions. Radiographically, the lesion is lucent withwell-defined margins. It may appear at the apex ofa tooth or around the crown of an impacted tooth.It is usually small, although it can reach severalcentimeters in size. Cystic ameloblastomas havethe capacity to expand or perforate jaw cortex (Fig.6).

Microscopically, this is a deceptively innocentappearing lesion that is often underdiagnosed assimple odontogenic cyst. The diagnosis is oftenmade in retrospect when the lesion recurs. Theentire cystic epithelial lining represents neoplasm.The reason for the cystic change is unknown, al-though it may be related to enzymatic destructionof the epithelium by MMPs or serine proteinases.Features that help in microscopic diagnosis includebasal cell palisading, epithelial invagination, andepithelial edema and separation (Fig. 7). Mural in-vasion has been linked to an increased risk of re-currence. Clinicopathologic correlation is helpful.

Malignant Ameloblastomas

The malignant forms of ameloblastoma havebeen classified into two subtypes: (1) malignantameloblastoma, or metastasizing ameloblastoma inwhich the metastatic lesion microscopically resem-bles ameloblastoma and (2) ameloblastic carci-noma, in which the primary and metastatic lesionsshow dedifferentiation and cytologic atypia (Fig. 8;28 29). There is also another rare malignancy of

odontogenic origin, called primary intraosseouscarcinoma, that may occur centrally in the jaws.This lesion, thought to arise from odontogenic restsin bone, looks like squamous cell carcinoma andshows no microscopic features of ameloblastoma.

Malignant ameloblastomas occur at a youngerage than their benign counterpart and are usuallyseen in the mandible. Metastasis is typically to thelung and occasionally to local lymph nodes.

Calcifying Epithelial Odontogenic Tumor

Also known as Pindborg tumor, calcifying epithe-lial odontogenic tumor (CEOT) is a rare odonto-genic neoplasm of disputed histogenesis. Originfrom stratum intermedium-type cells (enamel or-gan) and dental lamina have been hypothesized.This tumor occurs in the same age range (30 50years) and in the same jaw sites (posterior mandiblefavored) as ameloblastoma. It is a slow-growing,benign neoplasm. It may be unilocular or multiloc-ular. Because of focal areas of calcification, the ra-diographic image occasionally exhibits a mixedlucent-opaque pattern. This tumor rarely occurs inthe soft tissues of the gingiva, in which case it isdesignated as peripheral CEOT. Believed to have alower recurrence rate than ameloblastoma, CEOT istreated less aggressively than ameloblastoma.

CEOT consists of sheets of large epithelioid cellswith zones of amyloid deposits that may show dys-

FIGURE 6. Computed tomography scan of a cystic ameloblastoma ofthe mandible showing cortical penetration.

FIGURE 7. Recurrent cystic ameloblastoma. This completely cysticlesion was lined by edematous epithelium with palisaded basal cells.

FIGURE 8. Ameloblastic carcinoma. Left, initial lesion in whichnumerous mitotic figures were found with moderate nuclear atypia.Right, same tumor, now dedifferentiated, after 6 years, severalrecurrences, and extension to the base of the skull.


trophic calcification (30; Fig. 9). The amyloid mate-rial is an epithelial product (keratins) that stainspositive with Congo red and thioflavine T. The tu-mor cells may exhibit considerable range in nuclearsize and shape, but mitotic figures are not seen. Theratio of epithelium to extracellular product can bequite different from one tumor to the next, resultingin a histologic spectrum that ranges from lesionsthat are composed predominantly of epithelium, tolesions that are composed mostly of extracellularmaterial and relatively little epithelium. Occasion-ally, the epithelial cells will exhibit clear cytoplasmproducing the so-called clear-cell variant of CEOT.

Squamous Odontogenic Tumor

Squamous odontogenic tumor is a benign odon-togenic lesion that can be considered a hamartoma.Because of its presentation in the alveolar process,it is believed to originate (stimulus unknown) fromrests of Malassez found in the periodontal ligament.It occurs in the mandible and maxilla with equalfrequency and may be multiple. In the alveolarprocess, it is well circumscribed and is usually as-sociated with the roots of teeth. It is typically smalland characteristically appears radiographically as awedge-shaped lucency at the crest of the alveolarprocess. As it seems to have limited growth poten-tial, conservative surgical treatment is indicated.

Microscopically, squamous odontogenic tumorappears as islands of bland squamous epithelium(no cellular atypia or mitotic figures) without aninflammatory infiltrate (Fig. 10). Peripheral pali-sades are not seen. The epithelial islands are occa-sionally closely associated with bone spicules.There is superficial resemblance to ameloblastoma(acanthomatous type) and well-differentiated squa-mous cell carcinoma

Clear-Cell Odontogenic Tumor (Carcinoma)

This is a rare jaw tumor that some consider to bea carcinoma because of reported metastases. Thehistogenesis is unknown, although it is believed tobe derived from odontogenic epithelium because ofits primary occurrence in the jaws. Clear-cell odon-

togenic tumor (carcinoma) has been describedmostly in women over the age of 60 years. It maycause some pain. Radiographically, the lesion islucent and either unilocular or multilocular. Thisrare lesion has an aggressive biologic behavior. Me-tastases to lung and regional lymph nodes havebeen reported (3132).

Microscopically, nests and cords of clear cells areseen (Fig. 11). Some peripheral palisading may bepresent. Differential diagnosis would include clear-cell variant of calcifying epithelial odontogenic tu-mor, central mucoepidermoid carcinoma, meta-static renal cell carcinoma, and poorly fixedameloblastoma.

MICROSCOPICALLY SIMILAR MYXOID/FIBROUSJAW TUMORS

Odontogenic MyxomaThis benign and sometimes clinically aggressive

tumor mimics the dental pulp microscopically.However, immunohistochemical studies have beeninconsistent and have not been able to confirmpulp tissue origin (3335). Odontogenic myxoma

FIGURE 9. Calcifying epithelial odontogenic tumor. Left, sheet ofatypical epithelial cells; right, amyloid droplets with dystrophiccalcification in epithelial field.

FIGURE 10. Squamous odontogenic tumor exhibiting characteristicbland epithelial islands in a fibrous stroma.

FIGURE 11. Clear-cell odontogenic tumor in nested pattern.


occurs typically in adults (mean age, 30 years;range, 10 50 years) as a radiolucent lesion, oftenwith small loculations (honeycomb pattern). Thisjaw neoplasm may exhibit aggressive growth andrecurrence.

Odontogenic myxoma has a bland myxoid micro-scopic appearance (Fig. 12). If collagen is promi-nent, the designation of myxofibroma or fibromyx-oma may be used. Bony islands, representingresidual trabeculae, are found throughout the le-sion. Odontogenic epithelium is very uncommon inthese lesions. If odontogenic rests are found in amyxomatous jaw lesion, follicular sac (normal tis-sue found around the crowns of unerupted teeth)should be seriously considered (Fig. 12). Reducedenamel epithelium that is a part of the follicular sacresiduum is also frequently found along one edge ofthese specimens. Occasionally, as part of a jaw bi-opsy, normal dental pulp of a developing tooth maybe submitted for microscopic diagnosis. This tissuehas the appearance of an odontogenic myxomaexcept for peripherally positioned columnar-shaped odontoblasts. An accurate clinical historyand radiographs can be invaluable in separatingfollicular sac and normal dental pulp from this tu-mor. Odontogenic myxomas have a low prolifera-tion rate (as determined by Ki67 staining) but over-express Bcl-2 and Bcl-x proteins. Overexpression ofMMP2 protein may contribute to their expansion(unpublished data).

Odontogenic FibromaThis jaw tumor is considered a neoplasm that is

derived from periodontal ligament or pulp-relatedfibroblasts. It is a tumor of adults and appears as awell-defined radiolucency in either jaw. It is not,however, particularly aggressive, and it infrequentlyrecurs after simple curettage (36 38).

Microscopically, these lesions are more collage-nous than myxomas but may range from myxofi-brous to densely fibrous (Fig. 13). Characteristicallyseen in odontogenic fibromas are few to many is-lands and strands of bland odontogenic epithelium.Calcific deposits may also be found. A variant(granular cell odontogenic fibroma), in which gran-ular cells are seen in the connective tissue, has been

described. The behavior of this tumor does notappear to be different from odontogenic fibroma.Abundant rest proliferation in follicular sacs canoccasionally simulate the appearance of odonto-genic fibroma or ameloblastic fibroma. Clinico-pathologic correlation is important for the diagno-sis of these lesions.

Desmoplastic FibromaThis is a rare fibrous lesion of the jaws. It is

benign, but aggressive, exhibiting a biologic behav-ior similar to fibromatosis of soft tissue or low-grade fibrosarcoma. It is seen in young adults, es-pecially in the mandible. Radiographically,desmoplastic fibroma is lucent, with margins thatmay be distinct or poorly defined (39 40).

Histologically, these lesions exhibit an interlacingor fascicular growth pattern of benign fibroblastsand collagen. They neither contain epithelial restsnor make bone. Multinucleated giant cells arerarely present. Desmoplastic fibroma should not beconfused with central low-grade osteosarcomawhich is more cellular and has cytologic atypia.

DIFFERENTIAL DIAGNOSIS OF FIBROOSSEOUSLESIONS OF THE JAWS

Fibroosseous jaw lesions are a clinically diverse,but histologically similar group of conditions thatare characterized microscopically by a benign fi-broblastic stroma in which there is new bone dep-osition. Although ossifying fibromas and fibrousdysplasia are the most conspicuous examples ofthis group of jaw lesions, other commonly encoun-tered fibroosseous jaw lesions, such as periapicalcementoosseous dysplasia and chronic low-gradeosteomyelitis, should be considered in differentialdiagnoses of these lesions. Fibroblastic and centrallow-grade osteosarcomas of the jaws may occasion-ally mimic benign fibroosseous lesions. Clinico-pathologic correlation is essential for definitive di-agnosis of a jaw fibroosseous lesion.

Ossifying FibromaOssifying fibroma is classified as a benign neo-

plasm of bone. It is essentially identical to lesions

FIGURE 12. Left, odontogenic myxoma. Right, myxoid follicular sacwith odontogenic rests. Fragments of reduced enamel epithelium at farright.

FIGURE 13. Left, odontogenic fibroma of the mandible containingodontogenic rests. Right, desmoplastic fibroma of the mandiblecomposed of evenly distributed and benign fibroblasts in a collagenousstroma.


that have been designated as cementifying fibromaand cemento-ossifying fibroma. Although the dif-ferentiation of ossifying fibroma from fibrous dys-plasia may, at times, be difficult, the separationremains important because of differences in treat-ment and prognosis (41 42).

Ossifying fibroma is a slow-growing, well-circumscribed lesion that has a predilection for themandibular body and ramus of the jaw. Usually, itis discovered on routine radiographic exam, thoughoccasionally a patient may complain of facial asym-metry or painless swelling. It is most commonlyseen in the third and fourth decades, and womenseem to be more frequently affected than men. Avariant designated as juvenile ossifying fibroma ap-pears a decade earlier. Lesions in this latter sub-group have also been called active or aggressivejuvenile ossifying fibroma. This variant is generallyfelt to have a greater propensity for recurrence andexhibits aggressive clinical behavior (43, 44).

Microscopically, ossifying fibroma is well demar-cated from surrounding resident bone. The tumorbone is seen as trabeculae and/or oval (spherical)islands distributed in a relatively uniform patternthroughout the lesion (Fig. 14). Jaw lesions thatcontain predominantly oval hard-tissue islands, in-stead of osseous trabeculae, have been referred toas cemento- or psammomatoid-ossifying fibromas.This segregation is essentially academic becausethe behavior of these lesions are the same. Osteo-blasts are usually prominent, typically rimming thenew bone, and osteoclasts are scant. Stromal cellu-larity, which may vary slightly from one area toanother, may be relatively high in contrast tofibrous dysplasia. The stroma in the so-calledjuvenile ossifying fibroma is particularly cellularbut is still cytologically benign. The bone in thesejuvenile lesions appears in the form of strands ortrabeculae, although psammomatoid or spheroidislands may be present. With time, ossifying fi-bromas show continued expansion, with littlechange microscopically.

Fibrous DysplasiaBecause of its self-limited growth and apparent

responsiveness to the hormonal changes of pu-

berty, fibrous dysplasia is classified as a dysplasticprocess. It may be limited to one bone (monostotictype), several bones (polyostotic type), or severalbones with endocrine abnormalities and pig-mented skin macules (McCune-Albright syn-drome). It is a self-limiting, slow-growing processthat starts in childhood and is usually diagnosed byage 20 years. A diagnosis of fibrous dysplasia of thejaws in an adult should be considered when there isexcellent clinicopathologic correlation. Swelling isunilateral and asymptomatic. It exhibits ill-definedmargins, blends into surrounding bone, and ap-pears as a diffusely radiopaque lesion with a char-acteristic ground glass image. Although the af-fected bone may surround teeth, neither loosenessor exfoliation are seen. Serum laboratory values areusually within normal limits, unless the patient hasextensive polyostotic disease, in which case an ele-vation of serum alkaline phosphatase may bedetected.

In the craniofacial complex, fibrous dysplasia ismost commonly seen in the maxilla and calvarium,whereas in the remainder of the skeleton, it is seenin most frequently seen in the rib, femur, and tibia(45). The process usually stabilizes during puberty,persisting in a nearly quiescent state indefinitely.When treatment is necessary to alleviate unaccept-able facial deformity, surgical recontouring ratherthan complete excision is preferred. Regrowth ofsurgically recontoured fibrous dysplasia is seen inapproximately 25% of cases. Complete or partialexcision with bone grafting has been recently usedwith some success.

Microscopically, fibrous dysplasia consists of arelatively vascular and loose benign fibrous con-nective tissue stroma surrounding immature fibril-lar or woven bony trabeculae (Fig. 15). The stromagenerally exhibits only low to moderate cellularity.The incompletely calcified bony trabeculae showsome regularity in size and are uniformly distrib-

FIGURE 14. Two ossifying fibromas of the mandible showing cellularstromas with trabecular (left) and droplet or psammomatoid (right)bone.

FIGURE 15. Fibrous dysplasia of the jaw showing fibrillar bonytrabecular bone that is supposed to be characteristic of this condition.


uted throughout, gradually blending into normalsurrounding bone. Osteoclasts are typically incon-spicuous, and osteoblasts are scant, providing anappearance to the tumor bone that has been re-ferred to as osseous metaplasia. As patients withfibrous dysplasia age, affected bone may showsome maturation in the form of lamellations.

Periapical Cementoosseous DysplasiaThat the name of this condition continues to

change (cementomas, multiple cementomas, peria-pical osteofibrosis, cemental dysplasia) underscoresour ignorance of its etiopathogenesis. This is ancommon reactive/dysplastic process of unknownstimulus. Its significance lies in its clinical and mi-croscopic confusion with more important neoplas-tic and inflammatory jaw lesions. It occurs at theapices of vital mandibular (especially incisors)teeth, predominantly in middle-aged women (4142). It is occasionally seen at the apex of posteriorteeth, where it is more likely to be confused clini-cally with a periapical granuloma or cyst and mi-croscopically, with fibroosseous disease. These le-sions, unlike the typical anterior lesions, are likelyto be biopsied. This asymptomatic process passesthrough several radiographic stages: lucent, mixedlucent opaque, and opaque. This lesion is usuallynot biopsied or treated because the process is self-limited and is diagnostic on clinical-radiographiccorrelation. Microscopically, periapical cemento-osseous dysplasia appears as a benign fibroosseouslesion. A benign fibroblastic matrix contains a het-erogeneous distribution of new and old bone in theform of islands and trabeculae. Inflammatory cellsare scant.

Florid cementosseous dysplasia is believed to bean exuberant form of periapical cementoosseousdysplasia (Fig. 16). It may affect the entire jaw (usu-ally mandible) and may be seen in association withtraumatic bone cysts. Florid cementosseous dyspla-sia appears microscopically as a benign fibroosse-ous lesion (Fig. 17). Bony islands and trabeculae are

seen in a bland connective tissue matrix. Inflam-matory cells are scant. Clinical correlation is neces-sary to make a definitive diagnosis. Unfortunately,florid osseous dysplasia may become secondarilyinflamed, superimposing a chronic osteomyelitison the process and making diagnosis more difficult(46, 47). Florid cementosseous dysplasia, like itsperiapical counterpart, requires no treatment, un-less secondarily infected.

Chronic OsteomyelitisChronic osteomyelitis (including Garres osteo-

myelitis) of the jaws is usually a low-grade inflam-matory process that is often relatively asymptom-atic. It is one of several lesions that may showmicroscopic overlap with fibroosseous lesions, es-pecially ossifying fibroma and fibrous dysplasia. In-flammatory cells in chronic osteomyelitis may bequite scant, and there may be much new boneformation, giving the tissue a fibroosseous appear-ance. Both osteoblasts and osteoclasts are seen typ-ically. The low-power microscopic pattern is heter-ogeneous, with new bony trabeculae admixed withmore mature lamellated bone. The new bone is ofirregular size, shape, and distribution.

OsteosarcomasFibroblastic osteosarcoma and central low-grade

osteosarcoma may be a consideration in the differ-ential diagnosis of fibroosseous jaw lesions becauseof the relatively well-differentiated and fibrous na-ture of these lesions (48 51). Definitive diagnosis isbased upon hematoxylin and eosin microscopytaken in an appropriate clinical context. Diagnosisof fibroblastic osteosarcoma and central low-gradeosteosarcomas requires the finding of atypical cellsin association with immature, haphazardly distrib-uted osteoid. Peripheral margins are usually poorlydefined. Central low-grade osteosarcomas typically

FIGURE 16. Florid osseous dysplasia of the entire body mandible. Amixed lucent and opaque pattern is evident in this case.

FIGURE 17. Heterogeneous pattern of florid osseous dysplasia. Theappearance is fibroosseous, with both immature and mature bonepresent.


have a prolonged course and a correspondinglygood prognosis. Transformation to a higher gradeosteosarcoma may be seen many years after theoriginal diagnosis. Prognosis also worsens with thisevent because of a more aggressive behavior andincreased risk of metastasis.

CENTRAL GIANT CELL GRANULOMA ANDOTHER GIANT CELL LESIONS OF THE JAWS

Central giant cell granuloma (CGCG) appears tobe a lesion that is unique to the jaws, althoughso-called giant cell reaction of the hands and feetshares many features. CGCG was formerly regardedas a reparative process and was, accordingly, calledcentral giant cell reparative granuloma (51). Al-though this is not a granulomatous inflammatoryprocess, the term granuloma has persisted in thiscase because of tradition/habit. Although many in-vestigators believe that CGCG should be classifiedas a reactive lesion, numerous documented aggres-sive and recurrent cases suggest that it may behaveas a neoplasm. There is currently no way to predict,either clinically or microscopically, which lesionswill behave badly.

CGCGs occur typically in the second and thirddecades (mean age of approximately 25 years). Fe-males are more frequently affected than males.CGCG has a predilection for the mandible, espe-cially the body and anterior portions of the jaw. Thelesion is radiolucent and usually multilocular. Re-sorption and/or movement of teeth may be seen,and penetration of jaw cortex may occur. Most pa-tients are asymptomatic, although pain or pares-thesia may be a presenting complaint, particularlyin aggressive lesions. Recurrences are more likely tobe seen in children than adults. Surgery has beenthe treatment of choice, although alternative med-ical therapy with calcitonin injections has shownsome promising results in reducing the size of largelesions. A less rational therapy of corticosteroid in-jections has been advocated by some who believethat CGCGs are reactive lesions.

Microscopically, a number of patterns may beseen (Fig. 18). The stroma may vary from vascular

to fibrotic to myxoid in appearance. New bone,rimmed by osteoid, may be present, particularly atthe periphery of the lesion. Recent and old hemor-rhage is typically found, but necrosis is not seen.The dominant stromal cells are fibroblastic in ori-gin. They are round, oval, or spindle in shape. Theymay be particularly numerous, and mitotic figuresmay be frequently seen (no prognostic signifi-cance). Although a heterogeneous pattern consist-ing of groups of giant cells separated by fibroblasticareas is typical of CGCGs, homogeneous patterns,in which large numbers of giant cells are evenlydistributed throughout the lesion, are seen. Thegiant cells (CD68 positive) themselves vary in size,shape, and number. None of the histologic or im-munohistologic features yet described have allowedseparation of aggressive from nonaggressive le-sions. CGCG appears to be a tumor in which oste-oclasts or their precursors are recruited into a pre-dominantly fibroblastic field (5253). The fibroblastsare in cell cycle and may be responsible for produc-tion of cytokines or growth factors that support tumorgrowth.

The aggressive, recurrent (50 60%) giant cell tu-mor of long bone (GCT), which is generally believedto be an entity that is separate from the CGCG,probably makes a rare appearance in the jaws. Be-cause CGCG and GCT have overlapping histopatho-logic features, separation of these two lesions canbe difficult. Some features that suggest GCT overCGCG include very large giant cells, large numbersof nuclei in giant cells, central aggregation of giantcell nuclei, diffusely distributed giant cells, highstromal cellularity, and necrosis. Microscopic dif-ferential diagnosis of CGCG look-alikes include an-eurysmal bone cyst, hyperparathyroidism, andcherubism, all of which can be considered rare inthe jaws relative to the frequency of occurrence ofCGCG. Microscopically, aneurysmal bone cyst ischaracterized by large sinusoidal spaces lined byconnective tissue with giant cells. Hyperparathy-roidism is essentially identical to that of CGCG;however, lab values are altered (elevated serum cal-cium and parathormone), and the radiographic pic-ture can be distinctive (multiple lesions and loss oflamina dura around roots of teeth). Cherubism ap-pears microscopically indistinguishable fromCGCG, except occasionally, when a fairly character-istic condensation of perivascular collagen is evi-dent. Clinicopathologic correlation (children, auto-somal dominant, bilateral multilocular jaw lucencies)is definitive.

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FIGURE 18. Two central giant cell granulomas. Left, the usualheterogeneous low-power appearance of the lesions. Right, giant cellscan occasionally be relatively large, evenly distributed, and containmany nuclei.


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