—  SPECIALTY CONFERENCE  —

Pediatric Pathology

Case 2 - Epithelioid Hemangioma of Bone (with Spindle Cell Component)

Elisabeth Bruder
Institute of Pathology, University Hospital
Basel Switzerland

Antonio Perez-Atayde
Department of Pathology, Children's Hospital Boston
Harvard Medical School

Gernot Jundt
Institute of Pathology, University Hospital
Basel Switzerland

Harry Kozakewich
Department of Pathology, Children's Hospital Boston
Harvard Medical School





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History :
A 16 year-old female patient had been suffering from a swelling of the left mandibular angle for three weeks. Radiographs showed a localized osteolysis involving mandibular regio 38. The third molar was extracted and curettage of the alveolus was performed.

Nine months later, the tumor recurred. A left mandibular resection was then performed. The seminar slide originates from the mandibular resection. Follow-up for nine years was uneventful.


Case 2 - Slide 1
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Case 2 - Figure 1 - H&E Low power: Tumor composed of vascular proliferation with lobular architecture and peripheral new bone formation.
Case 2 - Figure 2 - H&E x100: Vascular proliferation with plump endothelial cells and loose stroma.
Case 2 - Figure 3 - H&E x 400: Epithelioid endothelial lining. Predominantly monomorphic nuclei. Scattered stromal inflammatory cells including eosinophils.

Case 2 - Figure 4 - H&E high power x 400: Focus of moderately pleomorphic endothelial nuclei and prominent nucleoli.
Case 2 - Figure 5 - H&E x100: Area of strands of solid endothelial aggregates.
Case 2 - Figure 6 - H&E high power x 400: Solid endothelial strands and small capillary vascular proliferations with plump epithelioid endothelia. Moderately pleomorphic folded nuclei with pominent nucleoli. Occasional cytoplasmic vacuoles.


Radiologic Imaging:
A pre-surgical conventional radiograph from 1983 showed a well-delineated osteolysis of the left mandibular angle with displacement of teeth. CT or MRI was not performed.

Macroscopy:
The first surgical procedure yielded curetted fragments of tan colour. The recurrent tumor was treated with a resection of the mandibular angle including 4.5cm of the ascending and 4 cm of the horizontal rami mandibulae. Longitudinal sectioning shows a tan-hemorrhagic tumor (maximal diameter approximately 5 cm) centered in the mandibula with medullary and cortical destruction and focal soft tissue extension.

Microscopy:

Initial Curettage:
Curetted fragments were comprised of a solid spindled cell tumor. Spindled cells were arranged in a streaming fashion without discernible architecture or significant matrix. Tumor cells were of medium size and contained a moderate amount of pale to eosinophilic cytoplasm with occasional vacuoles. Epithelioid tumor cells were not seen. Nuclei were uniform and of medium size with fine, granular chromatin and inconspicuous nucleoli. Necrosis was not observed and mitoses were rare. A diagnosis of 'capillary hemangioma' was made.

Mandibular Resection:
The tumor showed a lobular architecture of well-formed vascular spaces lined by large epithelioid endothelial cells. Endothelial cells had ample eosinophilic cytoplasm with occasional vacuoles. Nuclei were monomorphic to moderately pleomorphic, some with nucleoli. There were occasional mitotic figures and small foci of necrosis. In small areas, the tumor cells formed solid strands.The stroma was loose and fibrous without chondroid, myxoid or hyaline matrix. Some eosinophils were dispersed between tumor vessels.

The tumor destroyed preexisting bone, eroded the cortex and extended to soft tissue but not skeletal muscle. Tumor lobules were focally surrounded by newly formed reactive woven bone, particularly at the tumor periphery, but destruction outweighed new bone formation.

Immunohistochemically, the endothelial tumor cells expressed CD31, focally CD34 and WT1. Surrounding the endothelial cells, a collar of SMA positive cells was present. D2-40 and Caldesmon were negative. CD68 highlighted scattered osteoclast-like giant cells between tumor lobules. MIB1 was expressed in a small percentage of endothelial tumor cell nuclei. A diagnosis of 'hemangioendothelioma' was made.

Discussion:
This tumor is an example of epithelioid vascular tumors of bone. Epithelioid vascular tumors of bone form a spectrum of disease and a difficult and controversial area in osseous pathology. They have recently been reviewed in an attempt to clarify the relationship of epithelioid hemangioma to epithelioid hemangioendothelioma and high-grade epithelioid angiosarcoma (O'Connell 2001, Evans 2003).

Epithelioid vascular tumors with a benign clinical course are regarded as a separate entity by some authors and are termed epithelioid hemangiomas (EH) (O'Connell 1993. O'Connell 2001). Usually, EH of bone manifests as a painful mass between the 2nd and 8th decade of life. Twenty five percent of EH are multifocal underscoring that multicentricity does not necessarily imply malignancy. The majority of EH is confined to the affected bone and abuts or erodes the cortex (O'Connell 2001). A soft tissue component may occur.

Macroscopically, EH range from 2-15 cm in diameter, are dark red and well circumscribed. These tumors have a lobular growth pattern and the majority of tumor cells line well-formed vessels or are arranged in cords and solid sheets. Nuclei are hyperlobated, vesicular, grooved and nucleoli can be prominent, but without severe nuclear atypia or hyperchromasia. The cytoplasm is abundant, eosinophilic and frequently contains one or more large clear vacuoles.

Reactive woven bone is often present and when prominent can even mimic a bone-forming neoplasm.

EH may contain a spindle cell component. Epithelioid and spindle cell hemangioma of bone has recently been delineated as a separate entity (Keel 1999). It may be considered as a variant of epithelioid hemangioma. Clinical follow-up of two patients with epithelioid and spindle cell hemangiomas was uneventful for 2 to 26 years, in favor of a benign nature. Our own experience with three epithelioid and spindle cell hemangiomas in young patients is in accordance with the report from Keel and Rosenberg . Epithelioid and spindle cell hemangioma should be regarded as a benign tumor without potential to metastasize and should be distinguished from epithelioid hemangioendothelioma of bone (EHE).

Most EH can be separated from EHE histologically (O'Connell 2001). In contrast to EHE, stromal hyalinization or basophilic ground substance resembling cartilage is usually absent in EH.

Epithelioid hemangioendothelioma (EHE) was originally described by Rosai in 1979 as histiocytoid hemangioma (Rosai 1979), and subsequently termed EHE by Weiss and Enzinger in 1982 (Weiss 1982). In contrast to the benign course of EH and its variant, epithelioid and spindle cell hemangioma, EHE has the potential to metastasize. EHE pursues a prolonged clinical course intermediate between the benign epithelioid hemangioma and conventional high-grade angiosarcoma, and is therefore most often classified as low-grade malignant. It is a rare tumor with a male predominance and a peak incidence in the second and third decades of life. The tumor occurs in soft tissue, and deep organs such as lung, liver and bone. The tibia is most often involved, but the tumor can occur in any part of the skeleton. EHE has a tendency to be multifocal. Most patients have multifocal lesions that involve the same skeletal region. Synchronous involvement of paired bones is common. The issue of metastases versus multicentricity has not been resolved. The radiology is usually that of a predominantly lytic lesion with varying degrees of peripheral sclerosis. Purely sclerotic lesions are unusual. The bone may be expanded and cortical erosion or disruption may be seen. A more aggressive moth-eaten pattern can occur, but invasion into soft tissue is rare, and periosteal new bone formation is usually absent.

Microscopically, EHE consists of solid nests or anastomosing cords of epithelioid cells that may form narrow vascular channels and may mimic various stages of angiogenesis. In contrast to epithelioid hemangioma, EHE lacks lobular architecture. The supporting connective tissue typically exhibits myxoid change and individual epithelioid cells are embedded in a basophilic matrix that may resemble hyaline cartilage. The cells are rather monomorphic with little pleomorphism. The round nuclei with prominent nucleoli demonstrate a greater variability in size and degree of atypia than those found in epithelioid hemangioma. If the atypia is marked, distinction from epithelioid angiosarcoma may be difficult. The cytoplasm is densely eosinophilic and characteristically shows vacuolization, which may even impart a signet ring appearance to the cells. Cytoplasmic vacuoles are usually interpreted as abortive lumen formation. An inflammatory infiltrate of eosinophils, plasma cells and lymphocytes is often present. Mitotic activity is low (1-2 MF/ 10 HPF). There may be foci of necrosis and hemorrhage.

The differential diagnosis of EHE includes osteofibrous dysplasia, metastatic carcinoma, melanoma, epithelioid sarcoma, angiosarcoma and cartilaginous tumors. EHE may express cytokeratins, but metastatic carcinoma can be separated on the basis of its negativity for endothelial markers. Epithelioid angiosarcoma has more nuclear pleomorphism, hyperchromasia and a higher mitotic rate. Extensive myxoid and chondroid matrix may suggest a cartilaginous neoplasm, but in contrast to cartilaginous tumors, EHE is negative for S100. Treatment of EHE relies on local complete resection and is complemented by radiotherapy, especially with multifocal lesions. Chemotherapy is usually administered for progressive and metastasizing tumors.

The molecular pathogenesis of EHE is gradually being unravelled. In one patient with metachronous visceral spread of EHE the appearance of less well-differentiated tumor was paralleled by an accumulation of TP53, murine double minute-2 (MDM2) protein, decreased caveolin-1 (CAV1) expression, and increased vascular endothelial growth factor (VEGF) expression (Theurillat 2003). Mutations of the von-Hippel-Lindau-tumor-suppressor-gene (VHL) were excluded as a mechanism of VEGF upregulation (Theurillat 2003). Interestingly, cytogenetic analysis of two EHE revealed a recurrent non-random translocation t(1;3)(p36.3;q25) and may prove to be of potential future diagnostic utility (Mendlick 2001). In contrast to KIT tyrosine kinase overexpression in a majority of angiosarcomas and a minority of Kaposi sarcomas, EH and EHE were immunohistochemically negative for KIT (Miettinen 2000). Neither of the KIT positive angiosarcomas nor the KIT positive Kaposi sarcoma showed KIT mutations in the juxtamembrane or tyrosine kinase domain (Miettinen 2000).

Epithelioid angiosarcoma forms the malignant end of the spectrum of epithelioid vascular osseous neoplasms. Epithelioid angiosarcoma appears to be the rarest of the epithelioid vascular tumors of bone and fewer than 20 cases have been reported (O'Connell 2001). However, earlier literature referred to these tumors as high-grade hemangioendotheliomas or grouped them together with conventional angiosarcomas. Probably these tumors are considerably more common than the small number of reported cases suggests (O'Connell 2001).

Angiosarcoma accounts for less than 1% of sarcomas of all ages, and most originate in the scalp of adult patients. In young patients, angiosarcoma is more likely to occur in viscera and may be associated with underlying disease, e.g. immunosuppression, radiodermatitis or congenital lymphedema.

Primary angiosarcoma of bone is very rare, and accounts for less than 1% of all angiosarcomas. Angiosarcoma of bone comprised only 1.4% of 2627 primary bone sarcomas (Dorfman 1995). Angiosarcoma is extremely rare in childhood, and primary pediatric angiosarcoma of bone has only rarely been reported (Dehner 2001). Pediatric examples of angiosarcoma tend to have atypical clinical and histological features and pediatric patients may present with widespread metastatic disease. Angiosarcoma in childhood may involve bone and soft tissue (Lezama-del Valle 1998). Interestingly, in this recent series of six malignant vascular tumors in patients younger than 21 years, two angiosarcomas presented in bone (Lezama-del Valle 1998). Epithelioid angiosarcoma occurs most commonly in deep soft tissues and bone.

Angiosarcoma of bone usually arises in long tubular bones. It may be multicentric, involving multiple bones of the lower extremity. However, in contrast to low-grade tumors, more typically, angiosarcoma presents as a solitary lesion.

Macroscopically, angiosarcomas are usually larger than 5 cm in diameter and have a soft red and hemorrhagic cut surface. Angiosarcomas invade the cortex and adjacent soft tissues. They are composed of poorly formed blood vessels that exhibit infoldings and irregular anastomoses. The endothelial cells lining these blood vessels are markedly atypical, with frequently plump intraluminal cells resembling hobnails, frequent and atypical mitoses, and nuclear hyperchromatism, Solid areas, sometimes containing spindled and epithelioid cells, may also be present. Hyalinized or basophilic stroma is absent.

The expression of lymphothelial and endothelial phenotypic markers suggests that many angiosarcomas are of mixed endothelial-lymphothelial lineage (Weninger 1999, Fanburg-Smith 1999, Folpe 2000).

The differential diagnosis of high-grade epithelioid angiosarcoma includes metastatic carcinoma. The epithelioid appearance of the tumor cells associated with their high-grade cytologic appearance often leads to an erroneous diagnosis of metastatic carcinoma particularly in adults.

Clinically, angiosarcoma is characterized by a rapidly fatal course. Unless completely excised in localized disease, like in adults, the prognosis of angiosarcoma is poor also in young patients.

In the differential diagnosis of a skeletal vascular tumor in a young patient, venous malformation and kaposiform-like hemangioendothelioma should also be considered.

Venous malformations constitute the most frequent solitary vascular lesion involving the skeleton in young patients. In contrast to vascular tumors that arise by endothelial proliferation, malformations are structural abnormalities that exhibit normal (slow) endothelial turnover (Enjolras 1997). We apply the concept to designate as venous malformation of what was formerly called 'hemangioma of bone' (Dorfman 1998, Jaffe 1964, Kaban 1986, Lichtenstein 1972, Mirra 1989).

The radiologic aspect varies according to the extent of osteoclastic bone destruction as opposed to reactive osteoblastic bone formation. Venous malformations of skull typically show extensive sunburst-like reactive periosteal bone formation, whereas in vertebrae, osteoclastic bone resorption and perifocal sclerosis predominate. The extensive periosteal reaction in skull and flat bones may be attributed to the narrow width of the skeletal element that is soon outgrown by the vascular lesion. Venous malformations involving long bones are accompanied by new bone formation equaling or exceeding osteoclastic bone resorption, resulting in bone expansion and a typical striated aspect on radiology (Boyd 1984).

Skeletal venous malformations are usually solitary (Mulliken 1988 p207-213). Histologically, venous malformations consist of thin-walled vascular channels of varying caliber lined by flat endothelial cells surrounded by a thin, discontinuous smooth muscle layer. Epithelioid endothelia are not characteristic of venous malformation. Venous malformations do not show a lobular architecture. Immunohistochemistry reveals expression of CD31 and absence of GLUT-1 and D2-40 expression. Weak or absent expression of WT1 has been suggested for vascular malformations (Lawley 2005).

Venous malformations are currently distinguished from malformations of lymphatic channels. Differential development of lymphatic and hemangio-endothelium are being elucidated. The oncofetal glycoprotein D2-40 is expressed in lymphothelium, mesothelium as well as germ cells and is regarded as a sensitive marker of lymphatic endothelial differentiation (Kahn 2002, Kahn 2002).

Kaposiform hemangioendothelioma is a locally aggressive soft tissue tumor that can secondarily involve bone (Tsang 1991, Zukerberg 1993). Kaposiform hemangioendothelioma of skin and soft tissue is rare, and in some patients it is associated with a life threatening platelet-trapping syndrome, the Kasabach Merritt-phenomenon. Interestingly, so far, kaposiform hemangioendothelioma has not been reported to originate in bone. However, we have observed three lesions that are indistinguishable from kaposiform hemangioendothelioma in a series of 84 vascular skeletal lesions in young patients with predominant bone involvement that were therefore judged to have arisen in the skeleton. The tumors have shown only local growth.

Histologically, kaposiform hemangioendothelioma is characterized by sheets and nodular aggregates of spindled and more rounded, slightly epithelioid endothelial cells forming slit-like vascular spaces. Focal hemosiderin deposits and hyaline droplets are also characteristic, as are cytoplasmic vacuoles. Microthrombi may abound, as may entrapped and fragmented erythrocytes. Nuclear atypia is minimal and mitotic activity is low. Immunohistochemically, vascular endothelial markers CD31 and CD34 are expressed, as are the lymphothelial markers D2-40 and LYVE-1 (Debelenko 2005, Folpe 2000). In contrast to Kaposi sarcoma, Human Herpes Virus type 8 is not found in kaposiform hemangioendothelioma (Cheuk 2004).

There is no convincing report of infantile hemangioma or spindle cell hemangioma arising in bone.

The International Society for the Study of Vascular Anomalies (ISSVA) recently approved a classification of vascular lesions. According to this binary scheme, vascular tumors are distinguished from vascular malformations. Whereas vascular tumors arise as proliferative lesions, in contrast, vascular malformations are structural anomalies. This binary ISSVA classification of vascular anomalies is also applicable to bony lesions in young patients in our current study, just like the lesions encountered in skin, soft tissue and viscera (Enjolras 1997)

Diagnosis:
Epithelioid Hemangioma of Bone (with Spindle Cell Component).

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