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Epithelioid and epithelial neoplasms of bone.

* Context.--Epithelioid and epithelial neoplasms seen in bone are rare and include epithelioid variants of vascular lesions, osteoblastoma, osteosarcoma, chordoma, and chondroblastoma as well as adamantinoma and metastatic carcinoma.

Objective.--To provide an overview of tumors with epithelioid histology and address the clinical context and diagnostic issues.

Data Sources.--Pertinent literature is reviewed with emphasis on recent and controversial issues.

Conclusions.--The differential diagnosis in epithelioid/ epithelial lesions of bone is limited. The primary consideration in many cases is distinguishing primary from metastatic lesions.

(Arch Pathol Lab Med. 2007;131:205-216)

Epithelioid neoplasms of bone are rare. Those most commonly encountered include epithelioid vascular lesions (ie, hemangioma, hemangioendothelioma, and angiosarcoma), adamantinoma, epithelioid osteoblastoma, epithelioid osteosarcoma, chordoma, and epithelioid chondroblastoma. In addition, rare cases have been reported of epithelioid variants of leiomyosarcoma, (1) fibrosarcoma, (2,3) nerve sheath tumors, (4,5) and angiomyolipoma. (6)

The differential diagnosis in these cases is substantially increased by the inclusion of metastatic carcinomas and melanoma. In this review, however, we focus on the more common primary epithelioid neoplasms of bone with specific emphasis on diagnostic criteria and treatment considerations.


In both reactive and neoplastic conditions, endothelial cells can assume an epithelioid appearance characterized by abundant, deeply eosinophilic cytoplasm and a cuboidal to polygonal shape (Figure 1, A). The increased cytoplasmic volume is attributable to the accumulation of intermediate filaments of which vimentin predominates. These enlarged cells bulge from the vessel wall and can obscure the lumen, suggesting a solid sheet of cells. In 1979, Rosai (7) grouped all vascular tumors with these features under the rubric of "histiocytoid hemangiomas," a reflection of the histologic appearance, cytoplasmic enzyme profile, and ultrastructural features. Since that time, however, it has been recognized that entities of differing biologic potential may display this phenotype and that "epithelioid" is a more biologically apt descriptor for such vascular lesions.


Although considerable effort has been expended in the classification of epithelioid vascular tumors in soft tissue with some resulting consensus, there is no uniform classification for such lesions arising in bone. In the most recent World Health Organization classification of soft tissue tumors, epithelioid vascular tumors are categorized as benign, epithelioid hemangioma (EH), malignant, epithelioid hemangioendothelioma (EHE), and epithelioid angiosarcoma (EA). (8) Despite the fact that both of the latter entities are considered malignant, it has been recognized that soft tissue EHE behaves as an intermediate-grade (grade 2 of 3) neoplasm with a metastatic rate of 31% and mortality of 13% (9) compared with 49% and 53%, respectively, for EA. (10)

In this same edition of the World Health Organization classification, vascular tumors of bone are categorized as hemangioma (benign) or angiosarcoma (malignant), with "hemangioendothelioma" being subsumed by the latter. (8) There have been frequent calls to restructure and to more clearly define diagnostic categories of vascular lesions arising in bone (11); however, these tumors are even more uncommon than those of soft tissue and, accordingly, clinicopathologic analysis has been difficult. Depending on the diagnostic criteria, well-characterized cases of EH, EHE, and EA of bone number fewer than 50, (12,13) 100, (14,15) and 30, (16-19) respectively. Although some experts suggest that, as in soft tissue, distinct classifications of benign, intermediate-grade malignant, and malignant tumors can be made based on histologic (architecture, nuclear grade, cytologic features, necrosis) and clinical (focality, patient age) features, (11,13) others believe that vascular tumors of bone represent a spectrum of entities that cannot be morphologically distinguished. (15,20-22) In this review, we use the standard soft tissue classifications, namely, EH, EHE, and EA, to represent benign, intermediate-grade malignant, and malignant neoplasms, respectively.

Epithelioid Hemangioma

Epithelioid hemangioma arises in adult patients and is usually solitary, although up to 25% may be multifocal. (12) Skeletal distribution is widespread with prevalence in the femur followed by the tibia, bones of the hand and foot, and bones of the axial skeleton. (12)

The radiographic appearance of these tumors is predominantly lytic with sharply defined or sclerotic margins, which may be lobulated. Intralesional bone can be seen.

The cells of EH are bland and have lobated nuclei with occasional grooves, fine chromatin, and small nucleoli, which may be somewhat prominent (Figure 1, A and B). Large, clear intracytoplasmic vacuoles are usually present; however, the vasoformative potential of these cells is most often realized as well-formed vessels arranged in lobules. Sheets and cords of cells can be seen and, in the absence of malignant cytologic features, do not portend a worse prognosis. Mitotic figures are rare. An inflammatory infiltrate with a prominent component of eosinophils and plasma cells is often present.

Even this most bland of epithelioid vascular lesions has proponents arguing its (low-grade) malignancy. (22) A recent review of 29 cases has confirmed, however, that although these tumors may recur, in the context of strict diagnostic criteria, none has metastasized. (12) Features that distinguish EH from EA include the absence of significant cytologic atypia, brisk mitotic activity, and necrosis and the presence of well-formed vessels. Lobulation is an inconstant finding that also suggests benignity. The more difficult distinction of EH from EHE is discussed later.

Recently, another tumor that may be a variant of EH of bone, hemorrhagic epithelioid and spindle cell hemangioma, has expanded the morphologic spectrum of this lesion. Often multifocal, hemorrhagic epithelioid and spindle cell hemangioma affects the distal extremities and is characterized by a mixed population of epithelioid and spindle cells arranged in a lobular pattern and associated with abundant extravasated red blood cells (Figure 2, A and B). In a small series, none of the cases displayed overtly malignant histologic features nor was there documented metastasis or locally aggressive behavior. (23)


Epithelioid Hemangioendothelioma

Epithelioid hemangioendotheliomas of bone occur primarily in adults, although children may be affected. Male patients slightly outnumber female, (9,14) and there is a predilection for the appendicular skeleton with a greater prevalence in the lower extremity. Radiologically, these tumors arise in the medullary cavity and display osteolysis with bony expansion or peripheral sclerosis; however, the appearance is not specific. Epithelioid hemangioendothelioma is multifocal in up to 50% of cases and may be mono-ostotic or polyostotic. (14) Both widespread disease and restriction to a single anatomic region have been described. (24,25)

The histologic appearance is characterized by cords and nests of epithelioid cells in a myxohyaline matrix (Figure 3, A and B). The lesional cells may have a vacuolated appearance and intracytoplasmic lumina with entrapped erythrocytes can be seen; however, spindled cells may predominate with only rare vacuolated cells. Cellular pleomorphism is minimal and tumor cells are generally characterized by round to oval nuclei with enlarged eosinophilic nucleoli. Mitotic activity averages about 1 to 2 mitotic figures per 10 high-power fields. (26) Although the vasoformative nature is generally evident, an immunohistochemical panel of vascular markers may aid in diagnosis (Figure 3, C). The incidence of cytokeratin expression is similar to that of EHE of soft tissue (Figure 3, D). (9)


Significant controversy remains regarding the clinical behavior of these tumors. Because it has been the practice of some pathologists to classify all malignant epithelioid vascular tumors of bone as EHE, (27) it has been difficult to compare data across institutions. Although EHE of soft tissue is now widely accepted as an intermediate-grade malignancy, (9) opinions diverge regarding its nosology in bone. (11) Two early studies, Camapanacci et al (24) in 1980 and Tsuneyoshi et al (14) in 1986, recognized that, in the absence of malignant features, EHE of bone pursued an indolent clinical course with only 1 metastasis (4%) in 28 patients and all others with either stable or absent disease. In sharp contrast, in a more recent study by Kleer et al, (15) 5 (31%) of 16 patients with low-grade EHE died of disease, all of whom had parenchymal organ (primarily lung, liver, and spleen) involvement (Table 1). Histologic criteria appear similar in all 3 studies and treatment did not differ significantly (it could even be argued that the patients in the study by Kleer et al were treated more aggressively than those in the earlier 2 studies). A key point, however, is that, in the study by Kleer et al, the radiologic interpretation in most cases was "malignant" (including cortical destruction in 12 cases), whereas in the 2 prior studies, lesions were purely lytic with or without peripheral sclerosis. (14,15,24) Clearly, diagnosis of EHE requires close correlation of radiologic and histologic data that, when carefully applied, support the view that EHE is an intermediate-grade malignancy.

Epithelioid Angiosarcoma

Epithelioid angiosarcoma is an extremely rare tumor of bone that has been examined primarily in case reports and in 1 series of 10 cases. (19) These tumors can be multifocal, affect predominantly older male patients, and are often considered radiologically to be metastatic carcinoma.

Microscopically, unlike the tumor cells of EH and EHE, the epithelioid endothelial cells in EA display significant pleomorphism and cytologic atypia with irregular nuclear membranes and prominent nucleoli (Figure 4, A and B). The vasoformative potential is less obvious and sheets or nests of epithelioid cells may be seen. Irregularly shaped, anastomosing blood-filled spaces with peripheral infiltration is another architectural arrangement; however, the only clue to an endothelial line of differentiation may be the abundant hemorrhage (appreciated grossly as well as microscopically) and scattered cytoplasmic vacuoles with entrapped erythrocytes. Necrosis is common as are abundant, often abnormal, mitotic figures and a neutrophilic infiltrate. (19)


Immunohistochemical analysis for endothelial markers is a useful adjunct. However, epithelial markers are often positive. This immunophenotype combined with the older patient age and common multifocality may contribute to a misdiagnosis as metastatic carcinoma (Figure 4, C). A panel of vascular markers such as CD31 (most specific and sensitive), CD34 (positive in 40% of cases), and Fli-1 should be used as not all tumors are positive for all markers (Figure 4, D). Although Fli-1 has not been specifically assessed in EA of bone, approximately 95% of EA of soft tissue express Fli-1. (28,29)

Epithelioid angiosarcoma is an extremely aggressive tumor with a poor prognosis. Despite wide resection and adjuvant therapy, almost all patients so diagnosed die within 1 to 2 years of diagnosis.

Diagnostic and Treatment Considerations

Because of the widespread use of neoadjuvant therapy in high-grade bone tumors, initial diagnosis must often be performed on biopsy or limited curettage material. The importance of tumor architecture (lobulated vs infiltrative, well-formed vessels vs sheets of cells) and the risk of sampling artifact may compromise accurate histologic diagnosis. (30) In the presence of classic histologic features of EH such as well-formed blood vessels and a mixed inflammatory infiltrate and the appropriate clinicoradiologic presentation, we are comfortable making a diagnosis of EH on biopsy specimens and the patient is considered adequately treated following curettage.

Furthermore, we feel that a clearly malignant epithelioid vascular tumor can also be identified in a biopsy specimen, provided that strict diagnostic criteria are employed: brisk mitotic activity, significant cytologic atypia, cellular pleomorphism, and necrosis. Architectural features alone are insufficient and nuclear atypia must be marked. In addition, as discussed previously, an aggressive radiologic presentation is supportive. In these cases, wide surgical resection followed by adjuvant therapy is appropriate.

However, distinguishing EHE from EA on a biopsy specimen can be treacherous. Even in the presence of areas of classic EHE--nests and cords of epithelioid cells with limited cellular pleomorphism and low mitotic activity (1-2 mitoses per 10 high-power fields) distributed in a basophilic myxohyaline matrix--we feel that the following diagnosis should be made: "malignant epithelioid vascular tumor, at least intermediate grade" followed by a comment that, although EHE is an indolent tumor, there may be an associated higher grade, more aggressive component. (30)

The onus on the pathologist in accurately making this difficult distinction is limited by 2 additional considerations: (1) neoadjuvant therapy is not the standard of care in high-grade vascular lesions and grading can await careful examination of the final resection specimen and (2) unlike sarcomas of soft tissue, whose behavior must be intuited primarily from their histologic grade, sarcomas of bone provide radiologic evidence of their clinical progress and it could even be argued that, in vascular neoplasms of bone, radiology may even "trump" histology.


Adamantinomas are rare biphasic tumors, predominantly of the tibia, of unknown histogenesis. To early pathologists, the admixture of epithelioid islands with basal palisading and spindled stroma recalled the histologic appearance of odontogenic adamantinoma of the jaw (ameloblastoma). (31) A vascular (angioblastic), (32) epithelial, (33) and synovial cell (malignant synovioma) (34,35) origin were later suggested. During the years, the weight of histologic, immunohistochemical, and ultrastructural evidence supports an epithelial line of differentiation; however, the pathogenesis of the lesion, specifically, how these epithelial tumors arise in bone, remains unclear. (33,36-38) Early theories included origination in misplaced embryonic epithelial rests (31,39) and traumatic implantation of basal cells. (40) Alternatively, transformation of a mesenchymal stem cell has been imputed based on coexpression of vimentin and cytokeratin. (41) However, this scenario seems less likely in view of the virtual absence of cytokeratin (CK) 8 and CK18 (present in other mesenchymal tumors such as synovial sarcoma, epithelioid sarcoma, and chordoma) (36,39) and the evidence supporting the epithelial cells as neoplastic and the stromal cells as reactive. (42)

Adamantinomas predominantly affect young adults with the overwhelming majority (about 85%) arising in the tibia with synchronous involvement in the fibula in 10% of cases. In addition, rare cases have been reported in bones of the upper extremities, pelvis, and ribs. The radiologic appearance is typically an eccentric, lytic lesion arising in the cortex and expanding the anterior mid-diaphyseal tibia (Figure 5). Secondary extension into the medullary cavity and soft tissue can be seen. Tumors are oriented longitudinally and may appear "multilocular" because of the sclerotic margins of overlapping radiolucencies.


In classic adamantinoma, 2 cell populations can be seen: neoplastic, cytokeratin-positive epithelial cells and bland, probably reactive, spindled cells (Figure 6, A and B). These 2 populations are also seen in differentiated adamantinoma (41) and osteofibrous dysplasia (OFD) although with a significantly reduced epithelial component: Differentiated adamantinoma displays scattered strands of epithelial cells distributed in a fibro-osseous matrix, whereas OFD has this same background with only rare epithelial cells detected by immunohistochemistry (Figure 6, C).


Several histologic variants of classic adamantinoma have been described including tubular, basaloid, squamous, and spindled variants. Tubular adamantinomas are composed of narrow cords of epithelial cells that may have central discohesion, resulting in a vascular or glandular appearance (Figure 6, A and B). In the basaloid variant, the epithelial cells display a characteristic peripheral palisading (Figure 6, D), which can be useful in distinguishing this lesion from metastatic carcinoma. The squamous variant may recall well-differentiated squamous cell carcinoma with keratinization or may display central discohesion reminiscent of the stellate reticulum of ameloblastoma (formerly adamantinoma). The spindled variant may be difficult to differentiate from primary sarcomas of bone resulting from its uniform appearance; the presence of clefts lined by a single layer of epithelial cells may be the primary aid in diagnosis.

Our understanding of the relationship among classic adamantinoma, differentiated adamantinoma (osteofibrous dysplasia-like adamantinoma), and OFD continues to evolve. All 3 lesions have a strong predilection for the tibial diaphysis, express cytokeratin, at least focally, and have similar cytogenetic findings. (43) In addition, OFD and classic adamantinoma have a similar immunoprofile with cytokeratin AE1/AE3 and CK19 expression and reduced expression of CK8 and CK18. (36)

Some controversy remains regarding the nosology of these entities. It has been suggested that the increased spindled component and diminished epithelial presence in differentiated adamantinoma reflects regression of classic adamantinoma. (41) However, based on reports of progression from OFD and differentiated adamantinoma to classic adamantinoma, others have suggested that these 2 entities are actually precursor lesions. (44,45) This interpretation is also more consistent with the clinical presentation inasmuch as both OFD and differentiated adamantinoma are smaller, intracortical lesions occurring in a younger patient population that that of classic adamantinoma.

Adamantinoma is a low-grade malignancy that grows slowly but may eventually metastasize in more than one fourth of cases. (44) Wide operative margins appear to be the key to disease-free survival, with intralesional or marginal excision having a significantly greater risk of recurrence or metastasis. (44,46) Long-term clinical follow-up is recommended as both recurrence and metastasis can occur at a significant interval after diagnosis. (47) Lungs are the most common site, although metastases to lymph nodes and bone can be seen. Metastatic lesions may be composed of sarcomatous spindled cells or malignant epithelial cells. Dedifferentiation is a rare complication and can be recognized by areas of frank sarcomatous change in the setting or clinical history of classic adamantinoma. (39)


Epithelioid morphology is uncommon in osteosarcomas and rarely poses a diagnostic dilemma. Osteosarcoma with gland formation was illustrated by Ackerman and Spjut (48) in the first edition of the Armed Forces Institute of Pathology bone fascicle in 1962. Subsequently, a tumor with epithelioid features was described by Scranton et al (49) in 1975, and several case reports have followed. (50-52) As in conventional osteosarcoma, the age range is broad and bimodal, including patients from the second to the seventh decades. Tumors have been reported predominantly in long bones and also in the ilium and the vertebral column. Radiographically the lesions tend to be metaphyseal and lytic, with mineralization and periosteal reaction, as in conventional osteosarcoma. Histologically, epithelioid differentiation in cells of osteoblast origin is defined as cells twice the size of ordinary osteoblasts with abundant eosinophilic cytoplasm and usually with vesicular nuclei with nucleoli (Figure 7, A and B). Epithelioid features vary from trabeculae and cords to nests and even glandular structures. (53) Most cases are variants of osteoblastic osteosarcoma, and extensive sampling of the tumor will usually reveal osteoblastic foci and osteoid formation.


As in other mesenchymal tumors, the epithelioid phenotype in osteosarcoma may be accompanied by the expression of epithelial antigens, albeit in a small number of cases (Table 2). There has been some inconsistency in the data regarding coexpression of epithelial membrane antigen (EMA) and cytokeratin: 0 of 6 cytokeratin-positive cases in a series by Okada et al (54) coexpressed EMA, whereas 2 other studies (52,53) identified 5 tumors with coexpression. Expression of epithelial antigens does not appear to correlate with histologic subtype as this finding has been reported in osteoblastic, fibroblastic, chondroblastic, and epithelioid osteosarcomas. (52,54)

The differential diagnosis of epithelioid osteosarcoma includes osteoblastoma, other epithelioid tumors, and metastatic carcinoma. Although the latter can generally be excluded in pediatric cases, nearly half of the cases of epithelioid osteosarcoma have occurred in adults older than 40 years, in whom metastatic lesions are common. Moreover, metastatic tumors of breast, prostate, and other sites can elicit osteoblastic activity, further blurring the histologic distinction between carcinoma and epithelioid osteosarcoma. As detailed previously, expression of cytokeratin and/or EMA may be seen in osteosarcoma and should be interpreted with caution when focal. An immunohistochemical panel incorporating the bone-related antigens osteocalcin and osteonectin may be helpful. Osteocalcin is highly specific for osteoblastic differentiation (specificity 100%, sensitivity 70%), whereas osteonectin is somewhat more sensitive but much less specific (90% and 54%, respectively) being expressed in a number of carcinomas. (55) Both proteins are detected in osteoid matrix in the majority of cases of osteosarcoma, whereas collagenous nonosteoid matrix is negative.

A variant of epithelioid osteoblastic osteosarcoma has been described that is characterized by rosettelike structures surrounding a central nidus of stellate-shaped or fine netlike osteoid. (27,56) A recent study of 16 cases of rosette-forming osteosarcoma found that most cases occurred in men in the second decade with a predilection for the lower extremity (femur or tibia). (57) Radiographically the lesions were similar to conventional osteosarcoma.

Tumors were negative for cytokeratins; however, two thirds of the cases were positive for EMA. Chromogranin, synaptophysin, and neurofilament were negative, greatly aiding in distinguishing these tumors from neuroblastoma, the primary entity to be excluded in this age group. The limited expression of CD99 combined with Fli-1 negativity similarly differentiate this variant of osteosarcoma from Ewing sarcoma.

The diagnosis of rosette-forming osteosarcoma carries a grave prognosis, even for osteosarcoma. (58) In a review of 131 patients with conventional nonmetastatic osteosarcoma at presentation, 18 patients had rosette formation and experienced a 5-year survival of 13.5% versus 45.8% for all other osteosarcomas (P = .008).


Osteoblastomas are rare benign bone tumors with a predilection for the posterior elements of the spine. The age and gender distribution parallels that of conventional osteosarcoma: males outnumber females 2:1, and age at presentation ranges from infancy to the eighth decade. The most common sites of involvement are the vertebral column and sacrum (32%), relatively uncommon sites for osteosarcoma (3%). As osteosarcoma is much more common than osteoblastoma, with a relative incidence of 20: 1, the likelihood of primary osteoid forming lesion of the vertebral column being osteosarcoma versus osteoblastoma is approximately 2:3.

The radiologic appearance of both osteoblastoma and osteosarcoma is typically that of a lytic lesion with mineralization. Osteoblastoma often has peripheral sclerosis and may expand small bones in a fusiform manner. Unfortunately, cortical expansion and destruction are seen in 39% of osteoblastoma, and 12% appear radiologically suggestive of malignancy. (59) Epithelioid morphology correlates strongly with multifocal lesions, typically as multiple nidi in the same bone, with more than half of multifocal lesions having epithelioid histology; conversely, two thirds of epithelioid osteoblastomas are multifocal. Typically, multifocal lesions appear radiographically more aggressive.

Conventional osteoblastoma and osteosarcoma are 2 extremes of the spectrum of atypical osteoblastic lesions. During the years, several overlapping and indistinct diagnostic terms (including aggressive osteoblastoma, malignant osteoblastoma, and epithelioid osteoblastoma) have developed for these lesions, any of which may exhibit some degree of epithelioid histology (Figure 8). Several studies have associated aggressive behavior with atypical histologic features such as abundant nontrabecular osteoid, plump, atypical nuclei with nucleoli, and epithelioid morphology. (60,61) However, in a study of 306 osteoblastomas, Lucas et al (59) found no difference in clinical aggressiveness between epithelioid and conventional osteoblastoma. Analysis of an additional 55 cases for features typical of aggressive osteoblastoma, including epithelioid osteoblasts, lacelike osteoid, and a permeative growth pattern, also found no predictive value for any of the histologic features. (59,62) It can be assumed, therefore, that although there is no consensus on the appropriate terminology for such lesions, there is a subset of osteoblastomas with an atypical appearance that, in addition to the characteristic histologic features of osteoblastoma, also display an epithelioid phenotype, lacelike osteoid production, and occasionally a permeative growth pattern.


Accordingly, the primary diagnostic challenge is distinguishing epithelioid osteoblastoma from osteosarcoma, a problem compounded by the existence of an entity displaying the histologic features of osteoblastoma combined with the clinical aggressiveness of osteosarcoma: osteoblastoma-like osteosarcoma. In 2 studies, Bertoni et al (63,64) reported a total of 28 cases of these tumors and concluded that a permeative growth pattern at the periphery was the diagnostic discriminant in separating these tumors from true osteoblastomas. Features favoring osteoblastoma are sharp circumscription with lack of permeative growth pattern, loose connective tissue between spicules of osteoid without fine netlike osteoid, and well-defined osteoblastic rimming, usually limited to a single layer. Of these criteria, the permeative growth pattern is probably the most helpful feature in identifying osteosarcoma, although not necessarily diagnostic. The presence of other elements of osteosarcoma, such as cartilaginous matrix, is suggestive of osteosarcoma but can rarely be seen in conventional osteoblastoma and may be mimicked by fracture in an osteoblastoma. (65) Pronounced cytologic atypia favors osteosarcoma; however, the increased cell size and prominent nucleoli seen in epithelioid osteoblastoma may be misinterpreted as malignant and caution should be exercised. Rarely, conventional osteoblastomas may have regions of marked cytologic atypia similar to that seen in symplastic leiomyomas or ancient neurilemmoma, so-called pseudomalignant or pseudosarcomatous changes. (66) Differentiation of this feature from true anaplasia requires careful consideration of clinical history, radiographs, and histologic features. Pseudomalignant osteoblastomas are clinically indolent lesions and are radiographically indistinguishable from benign osteoblastomas. Mitotic figures are absent or extremely uncommon and are typical. Areas of conventional histology are frequently intermixed, and an adequate sampling of the lesion is essential.


Chordoma typically has the distinctive presentation of a midline axial lesion in an adult, most frequently older than 50 years, although the lesion can be seen rarely in the pediatric age group. Ninety percent occur in the sacrococcygeal area or base of skull, and, as such, presenting symptoms include pain, nerve compression, incontinence, headache, and visual changes. On imaging studies, chordoma appears as a lytic lesion, which may suggest the possibility of a metastatic tumor.

Histologically, chordoma is composed of 2 cell populations, multivacuolated physaliphorous cells (Figure 9, A) and pink epithelioid cells (Figure 9, B), arranged in anastomosing cords in a myxoid or occasionally cartilaginous matrix, the latter typically seen in chondroid chordomas occurring predominantly in the skull base. Cytologic atypia is minimal to moderate, and occasionally rare severely atypical cells can be seen. Mitoses are infrequent and do not include atypical forms. In most tumors, 1 cell type predominates, usually physaliphorous cells. (67) In this context, the differential diagnosis of metastatic mucinous carcinoma must be considered. Carcinomas frequently display increased cytologic atypia and atypical mitoses and in some cases intracytoplasmic mucicarmine or periodic acid-Schiff positive mucin, which is absent in chordoma. Chordoma typically expresses S100; however, various S100 proteins are expressed in a variety of adenocarcinomas, including breast and gastrointestinal tumors, and as such this finding alone is not diagnostic. Chordoma typically expresses cytokeratins AE1/AE3, CK8, CK19, and CK5, although they are, at best, only focally positive for CK7 and CK20. (67,68) In those cases in which the eosinophilic epithelioid cells predominate with minimal matrix and few or no physaliphorous cells, the possibility of squamous cell carcinoma or transitional cell carcinoma should be considered. (69) Although CK8 and CK19 are expressed in both squamous cell carcinomas and chordomas, (70) neural-type cadherin is typically only focally expressed in the former and consistently positive in the latter. (71)


Dedifferentiation of a conventional chordoma typically presents as a high-grade pleomorphic sarcoma (malignant fibrohistiocytoma-like) arising in a conventional chordoma, although other histologies such as osteosarcoma have been reported. Occasionally, a highly pleomorphic epithelioid tumor may arise from a pre-existing chordoma, suggesting a highly aggressive variant of the epithelioid cell predominant histology. In both case, immunohistochemistry tends to be positive for AE1/3, CK8, CK19, and EMA. (72)


Chondroblastoma tends to occur in the epiphyses of long bones in the second decade of life, frequently prior to closure of the epiphyseal plate. It also may occur in small bones of the extremity, the pelvis, and in approximately 5% of cases in the bones of the skull and face. (68) Radiographically the tumor is typically centered in the epiphysis, is radiolucent, and displays a well-defined margin and variable calcification. In its classic form the tumor is composed of closely packed polygonal mononuclear cells with oval, dark, and clefted nuclei. Tumor cells tend to be separated by scant matrix, which may calcify in areas to give a characteristic chicken-wire pattern. Well-formed cartilaginous matrix is variable, as are giant cells. Occasionally, areas of spindle cell proliferation are present, and cystic degeneration mimicking aneurysmal bone cyst may be seen, particularly in lesions of the hands and feet. (73) Variable cellular features include spindle cell differentiation, foam cells, and epithelioid cells, the latter present in 31% of cases in one series. (74)

Recognition of potential epithelioid differentiation of chondroblastoma is particularly important in the rare cases that occur in the temporal bone and other bones of the skull (Figure 10). Patients are on average older (mean 43 years, range up to the 70s), radiographs are frequently not suggestive of chondroblastoma, (75) and the radiologic differential may include metastasis. Areas of epithelioid differentiation, typically with more closely packed chondroblasts with eosinophilic cytoplasm, may be mistaken for metastatic breast or lung carcinoma, the 2 lesions that most frequently metastasize to the temporal bone. (76) Differentiation is complicated by the expression of cytokeratin and EMA in as many as 80% (77) and 85% (78) of cases, respectively. S100 protein, which is typically expressed in chondroblastoma, may also be expressed by many carcinomas of the breast and other organs. In general, cytokeratin and EMA expression by chondroblastoma will be in the minority of cells and not of the intensity typical of carcinoma. Adequate biopsy and excision specimens will yield more typical chondroblastoma histology in most cases.



Metastatic disease, both carcinomatous and noncarcinomatous, is an important differential diagnosis in epithelioid lesions of bone. In patients with metastatic carcinoma, the frequency of bone metastases at autopsy is greater than 50%. As is well known, the most common tumors to metastasize to bone are breast, prostate, lung, kidney, and thyroid. (79) In patients without a previously known primary, lung and kidney are the most common sites of origin, followed by liver, thyroid, breast, prostate, and pancreas. (80-82) When the site of origin remains occult after initial clinical and radiographic workup, the primary is found later to be lung in more than 50% of cases. (83)

Melanoma seldom metastasizes to bone, representing approximately 7% of cases, according to a study of 1677 melanoma patients. (84) Amelanotic melanoma presents a particular problem: It can mimic a spindle cell sarcoma, an osteoblastic lesion, or an epithelioid tumor (Figure 11, A). Careful searching may reveal melanin (Figure 11, B) and immunohistochemical analysis for melanocytic markers is particularly useful in identifying metastatic melanoma (Figure 11, C); however, cytokeratin can be variably expressed (Figure 11, D).



The differential diagnosis of epithelioid tumors in bone is limited and includes epithelioid vascular lesions, adamantinoma, epithelioid osteoblastoma, epithelioid osteosarcoma, and chordoma. Clinically, the most important distinction is between these primary tumors of bone and metastatic malignancies (carcinoma and rarely melanoma).

In view of the disparity between the incidence of primary bone tumors and carcinomas metastatic to bone, it is much more likely that a poorly marginated lytic bone lesion in a patient older than 40 years is a metastasis. (85) The distinction is critical: Therapy for a potentially early-stage bone primary is vastly different from a stage IV carcinoma. Inadvertent internal fixation of a primary bone malignancy contaminates the field and often the adjacent joint, leading to loss of the option of doing limb salvage surgery. (80,81)

All of the tumors discussed in this review may express cytokeratins and/or EMA, thereby reducing the utility of immunohistochemical analysis for epithelial antigens. However, careful radiologic and clinical examination combined with histologic analysis, including a panel of antibodies, can greatly facilitate diagnosis.

We thank Edward McCarthy, MD, and Andrew E. Rosenberg, MD, for histologic sections.


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Accepted for publication August 3, 2006.

Andrea T. Deyrup, MD, PhD; Anthony G. Montag, MD

From the Department of Pathology, Emory University, Atlanta, Ga (Dr Deyrup); and the Department of Pathology, University of Chicago, Chicago, Ill (Dr Montag).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Andrea T. Deyrup, MD, PhD, Department of Pathology, Davis Fischer Building, Room 1323, Emory Crawford Long Hospital, Atlanta, GA 30308 (e-mail:
Table 1. Outcome in Low-Grade Epithelioid
Hemangioendothelioma *

Source, y ANED AWD Met DOD LTF Total

Campanacci et
 al, (24) 1980 5 1 0 0 0 6
Tsuneyoshi et al, (14)
 1986 10 0 1 0 0 11
Kleer et al, (15) 1996 5 4 5 5 2 16
Total 20 5 6 5 2 33

* ANED indicates alive, no evidence of disease; AWD, alive with
disease; Met, metastasis; DOD, died of disease; and LTF, lost to

Table 2. Epithelial Antigen Expression in Osteosarcomas *

Source, y EMA AE1/3 CAM 5.2 BerEP4

Okada et al, (54)
 2003 0/6 6/131 ND ND
Hasegawa et al, (86)
 1997 3/30 3/30 ND ND
Kramer et al, (53)
 1993 1/1 1/1 1/1 ND
Hasegawa et al, (52)
 1993 1/1 1/1 ND 0/1

* Values are number positive/total number. EMA indicates epithelial
membrane antigen; ND, not done.
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Author:Deyrup, Andrea T.; Montag, Anthony G.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Disease/Disorder overview
Geographic Code:1USA
Date:Feb 1, 2007
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