What is New in Bone Tumors
Moderators: K. Krishnan Unni and Franco Bertoni
Section 3 -
What's New in Vascular Tumors of Bone
Andrew E. Rosenberg
Massachusetts General Hospital
Harvard Medical School
Boston , MA USA
Vascular tumor of bone is defined as a neoplastic proliferation of endothelial cells that may be
benign or malignant. Although vascular tumors of the skeleton are very common, most involve the
vertebral column and the vast majority is asymptomatic. Clinically significant neoplasms are infrequent
and their biology ranges from those that are relatively indolent to those that are extremely aggressive
and frequently fatal. An important group of vascular tumors of bone are composed of epithelioid
endothelial cells, and their unusual morphology complicates pathologic interpretation. New information
regarding the realm of skeletal vascular neoplasia largely resides in the recognition and classification
of epithelioid vascular tumors, which is still somewhat controversial  . This discussion
will provide an update on these entities within the framework of vascular tumors in general
Hemangioma is the most common vascular tumor of bone and may be found in vertebral bodies
in approximately 10% of the population at the time of autopsy. Clinically detectable tumors, however,
are uncommon and account for less than 1% of primary bone tumors  . Hemangiomas may be
solitary or multifocal. Solitary lesions like some capillary hemangiomas are usually indolent tumors and
are stable or slowly enlarge. Multifocal disease has been subclassified into two distinct entities:
multiple primary hemangiomas and diffuse cystic angiomatosis. Multiple primary
hemangiomas of bone consist of collections of lesions that individually have the radiographic
findings and clinical behavior of solitary hemangiomas. Aside from their multifocality they are not
clinically important. In contrast, the vascular lesions in diffuse cystic
angiomatosis are large and destructive and may appear cystic on x-rays. Visceral involvement is
common and can result in fatal hemorrhage. Gorham's syndrome ("disappearing
bone disease") is a rare disorder characterized by an osseous hemangioma or lymphangioma that produces
extensive osteolysis without forming a tumorous mass. The tumor can spread across joints from one bone
to another and extend into adjacent soft tissues. Gorham's syndrome most frequently affects the bones of
the skull and extremities  .
Hemangiomas of bone most commonly arise in the vertebral column, followed by the
craniofacial skeleton and the metaphyses of long bones
. The tumors are
usually diagnosed in adulthood, with the peak incidence in the 5th decade of life. They are
more common in women than men
Radiographically, hemangiomas including epithelioid hemangioma are radiolucent and have
coarse trabeculations  . In the vertebral bodies they produce the characteristic "polka
dot" pattern. The craniofacial tumors are usually centered within the diploŽ, and have a lytic
appearance, often with prominent intra-lesional radiating spicules of bone which creates the so-called
"sun burst" appearance
. Elsewhere, the tumors are usually well circumscribed, may be
expansile, and are lucent, with an internal web-like trabecular pattern.
The tumors are usually centered in the medullary cavity and are gritty and dark red with a
sponge-like appearance. They resemble conventional capillary or cavernous hemangiomas of skin and soft
tissue and are composed of thin walled vascular spaces that may or may not be filled with red blood
cells. The lumina are lined by a single layer of flat, uniform, cytologically bland, endothelial cells.
The vessels are surrounded by loose connective tissue and typically infiltrate the pre-existing
cancellous bone. Entrapped, thickened, bony trabeculae produce the radiographically detectable
intralesional spicules. The endothelial cells exhibit positive immunostaining for the endothelial
markers Factor VIII related antigen, ulex europeus lectin, CD34 and CD31  .
Smears obtained from hemangiomas are dominated by red blood cells in which are dispersed
rare individual bland spindle cells and small tissue fragments composed of similar short bland spindle
cells with plump ovoid cells along the edge of the tissue fragments  .
Curettage is usually the mode of therapy for symptomatic lesions and is associated with a
low rate of local recurrence.
The differential diagnosis of conventional skeletal hemangioma is limited. The vascular
spaces may be difficult to appreciate and, as a result, one may fail to recognize the lesion. A
hemangioma should always be considered when confronting a bone biopsy that appears to be normal, as the
vessels can be subtle and on biopsy may consist of a few fragments of thin walled structures.
Epithelioid hemangioma is most commonly encountered in the
skin and subcutis. The skeleton, however, is probably the second most common location for this type of
neoplasm where it is multifocal in less than 50% of cases. The tumors range in size from 2.5-15 cms
(mean 5 cm), and are usually are not very destructive in that they uncommonly expand the bone or extend
into the soft tissues. They frequently pose diagnostic difficulty because of the plump "histiocyte-like"
or epithelioid appearance of the neoplastic endothelial cells
hallmark of epithelioid endothelial cells is their polyhedral shape and their abundant densely
eosinophilic cytoplasm that frequently contains one or more large vacuoles. The vacuoles represent the
earliest stage of vessel lumen formation and may be empty or contain intact or fragmented red blood
cells. As vacuoles from neighboring cells fuse they create vascular spaces of varying degrees of
differentiation. Well-formed vessels are numerous in epithelioid hemangioma, and the epithelioid
endothelial cells bulge into their lumens in a "tombstone " or "hobnailed-like" fashion. In some cases,
the cells are arranged in solid cords and even sheets, which can cause confusion with more aggressive
lesions. Numerous inflammatory cells, including plasma cells and eosinophils present in the stroma of
occasional cases can mimic osteomyelitis. In a minority tumors there is abundant intralesional
hemorrhage admixed with cytologically bland spindle cells, and little or no accompanying inflammation
Immunohistochemically, the epithelioid endothelial cells express the usual markers of
endothelial cells (CD31, CD34, factor VIII related antigen), however, approximately 50% also stain for
keratin and epithelial membrane antigen and the staining can be extensive and strong  .
Treatment generally consists of intralesional curettage or local resection. Local
recurrences are uncommon
. In patients with multiple lesions in which only the
largest tumors are ablated, the untreated tumors usually remain stable. No definite metastases have been
reported, however, tumors involving bone and other distant sites and types of tissue have rarely been
The differential diagnosis of epithelioid hemangioma includes epithelioid
hemangioendothelioma and epithelioid angiosarcoma, which are both discussed in detail below.
Epithelioid hemangioendothelioma (EHE) is an uncommon endothelial tumor that most
frequently arises in the soft tissues, liver, lung, and skeleton
. It usually behaves
as a low-grade sarcoma, however, a minority are aggressive and life threatening. Similar to other
skeletal vascular tumors, epithelioid hemangioendothelioma demonstrates multifocal osseous involvement in
approximately one-third to one-half of cases  . Unfortunately, some of the literature
analyzing skeletal epithelioid hemangioendothelioma is confusing, because, in our opinion, many of the
reported cases represent epithelioid hemangioma or other types of vascular neoplasms
Epithelioid hemangioendothelioma can be seen in most age groups and has its peak frequency
in the 2nd decade
 . The tumor affects males and females equally and develops in
whites disproportionately more often than members of other races. Like other vascular tumors of bone,
epithelioid hemangioendothelioma frequently involves multiple sites in a single bone or multiple bones
simultaneously. The tumor tends to arise in the extremities, pelvis and spine. In the extremities, the
long bones, as well as the small bones of the hands and feet are commonly involved and typically cause
localized pain that may be associated with swelling. Some patients also have disease in the soft
tissues, liver or lung at the time of diagnosis of the skeletal disease.
The radiographic features of epithelioid hemangioendothelioma are
variable. Most lesions range in size from 1-3cm and are round or elongate and predominately lytic. The
margins may be well delineated or poorly defined, and the adjacent bone is usually sclerotic
Epithelioid hemangioendothelioma is pale tan in color, and lacks the red, hemorrhagic
appearance of conventional hemangiomas. Microscopically, it is composed of large epithelioid and spindle
endothelial cells with round or elongate nuclei, prominent nucleoli, and abundant eosinophilic
cytoplasm. Intracytoplasmic lumens appear as vacuoles that may contain intact or fragmented red blood
cells. The vacuoles may coalesce to form primitive vascular channels, recapitulating embryonic
angiogenesis, however well-formed blood vessels are not prominent in most cases. Instead, the tumor
cells are arranged in cords and nests which are embedded within a myxoid to hyalinized ground substance
that may resemble cartilaginous matrix
Only in a minority of cases is a
prominent inflammatory infiltrate present. The neoplastic cells generally show limited cytologic atypia
and mitotic activity, but in some cases, nuclear hyperchromasia and pleomorphism are significant and
mitoses numerous, making it difficult to distinguish the neoplasm from high-grade angiosarcoma.
Scattered single, polygonal or even plasmacytoid appearing cells admixed within a
background rich in red blood cells, typifies the smears from epithelioid hemangioendotheliomas. The
tumor cells have eccentric nuclei and abundant cytoplasm. The cytoplasm frequently contains one or two
vacuoles, representing an early stage in lumen formation. Cytologic atypia is usually minimal.
The tumor cells express the full spectrum of immunohistochemical endothelial markers
including Factor VIII, CD34, and CD31 and, like epithelioid endothelial cells in general, may also
exhibit intense and extensive positive staining for keratin and epithelial membrane antigen. The tumor
cells usually do not stain with antibodies to S-100 protein, and desmin. Ultrastructurally, the
neoplastic cells contain abundant intermediate filaments, pinocytotic vesicles, intracytoplasmic lumens
and basal lamina material.
Epithelioid hemangioendothelioma is treated by complete surgical excision if feasible.
However, multifocal lesions may be difficult to excise and may require radiation or thermal ablation.
Predicting the outcome for patients with osseous epithelioid hemangioendothelioma is problematic as the
clinical behavior is not always predicted by the morphologic features of the tumor. In one large series,
20% of patients succumbed to disease; of those who died most had concurrent visceral tumors 
. In the absence of parenchymal organ involvement, epithelioid hemangioendothelioma of bone usually
behaves in an indolent fashion and infrequently metastasize. They may locally recur following curettage
or slowly enlarge if left untreated.
The differential diagnosis of epithelioid hemangioendothelioma includes other epithelioid
vascular neoplasms particularly epithelioid hemangioma and angiosarcoma. Epithelioid
hemangioendothelioma is distinguished from epithelioid hemangioma by its characteristic hyalinized stroma
and the paucity of well-formed vessels. Angiosarcoma also lacks the hyalinized stroma and usually shows
a greater degree of cytologic atypia and mitotic activity. The epithelioid features of the tumor cells,
their cohesive nature, and intracytoplasmic vacuoles can also mimic metastatic adenocarcinoma. The
staining of tumor cells of epithelioid hemangioendothelioma for epithelial markers can further complicate
this distinction. Fortunately, metastatic carcinomas do not stain for endothelial markers, and the
myxoid or hyalinized stroma is distinct from the desmoplastic seen in metastatic carcinoma. The cells in
cartilaginous tumors do not form cohesive nests, stain immunohistochemically for S-100 protein, and are
negative for endothelial markers.
Skeletal angiosarcoma, also known as hemangioendothelial sarcoma, is a very uncommon tumor
and accounts for little more than 1% of primary bone sarcomas  . It is a neoplasm of
adulthood and usually arises in the appendicular skeleton
angiosarcomas are solitary, however as many as one-third present with involvement of multiple bones
 . Angiosarcoma of bone is usually a high-grade, poorly differentiated neoplasm and we feel
thatmany tumors that were previously classified as low-grade
hemangioendothelial sarcoma, likely represent examples of epithelioid hemangioma  .
Angiosarcoma of bone usually presents as a painful enlarging mass that may cause pathologic fracture. It
rarely arises in association with previous radiation, Paget's disease, bone infarction, and skeletal
The tumor manifests on x-ray as an ill-defined, lytic mass with prominent destruction of
the underlying bone. The tumor may erode the cortex, elicit a periosteal reaction, and extend into the
Skeletal angiosarcoma is usually 5-10 cm in size, appears dark red and hemorrhagic, has
poorly defined, irregular borders and may infiltrate the neighboring soft tissues. Frequently, the
underlying bone appears ravaged, and tumor necrosis may be prominent. Angiosarcoma is composed of
cytologically malignant spindle and epithelioid endothelial cells that have the capacity to form
rudimentary blood vessels. In the epithelioid variant, the tumor is composed almost entirely of
epithelioid cells, and, as with the other epithelioid vascular tumors, some of the cells contain
intracytoplasmic vacuoles  . Mitoses are numerous, and atypical mitotic figures are
frequently present. The stroma is inconspicuous and consists of small amounts of fibrous tissue.
Smears from angiosarcomas are characterized by abundant background blood and contain a
population of anaplastic spindle or ovoid cells  . The malignant endothelial cells may form
three-dimensional clusters of tightly packed cuboidal or polygonal cells forming slit-like structures
 . The nuclear atypia is usually obvious and severe.
Immunohistochemistry shows that the neoplastic cells express one or more of the
endothelial markers including Factor VIII, CD31, and CD34. The neoplastic cells in epithelioid
angiosarcoma may also stain prominently with antibodies to keratin and epithelial membrane antigen.
Ultrastructurally, the neoplastic cells have the features of primitive endothelial cells.
Angiosarcoma of bone is best treated with complete en bloc excision. Adjuvant radiation
and chemotherapy have little proven effect. The prognosis is poor, as most of the tumors are high-grade,
and usually metastasize.
The differential diagnosis of osseous angiosarcoma includes vascular tumors such as
epithelioid hemangioma and epithelioid hemangioendothelioma, as well as metastatic carcinoma, malignant
melanoma, and other high-grade sarcomas. Epithelioid angiosarcoma differs from epithelioid hemangioma
because it demonstrates significantly more cytologic atypia and a paucity of well-formed blood vessels.
It is distinguished from epithelioid hemangioendothelioma mainly by the lack of hyalinized or chondroid
stroma. Immunohistochemistry and electron microscopy are very useful in excluding metastatic carcinoma
and melanoma. In this differential diagnosis, it is important to note that most carcinomas and melanomas
are negative for Factor VIII related antigen, CD31 and CD34 and angiosarcoma does not express S-100
protein. Accordingly, immunohistochemistry employing antibodies directed against endothelial markers
should be performed on unusual epithelioid tumors of bone.
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