Keywords
Bone - epithelioid hemangioendothelioma - lower extremities - metastasis - spine
Introduction
Epithelioid hemangioendothelioma (EH) is a rare vasoformative tumor with a malignant
potential intermediate between hemangioma and angiosarcoma. Bone as a primary site
is exceedingly rare accounting for less than 1% of malignant bone tumors.[1] Less than 10% of the lesions occur in the spinal location.[2] Approximately one-third to one-half of osseous EH are multicentric within a bone
or multifocal within multiple bones throughout the skeleton or clustered in an anatomical
region, most commonly the lower extremity.[1],[3] We report a unique case of a 20-year-old male with multifocal EH presenting as multiple
lytic lesions in the skull vault, vertebral bones, bilateral proximal femur, and both
radii and humerii with metastasis to the lungs and liver.
Case Report
A 20-year-old male patient developed pain in the neck with mild restriction of neck
movement initially felt during exercise in August 2014.
He underwent imaging of the skull, spine, chest, and pelvis which revealed multiple
large mildly expansile sharply marginated osteolytic lesions with variable peripheral
sclerosis involving the calvarial bones, C1, C7, L5 vertebrae, posterior part of 12th
rib, atlanto-occipital, atlanto-axial, ilio-sarcral joints, right iliac bone, iliopubic
rami, ischiopubic rami, bilateral proximal femur, and both radii and humerii [Figure 1]. Rest of the spine showed altered signal intensity in D4, D5, D10, D11, D1, and
L4 vertebrae. In addition, numerous interstitial nodules were visualized in both lung
fields. Radiologists offered Langerhans cell histiocytosis (LCH) as the most probable
underlying disease. However, multiple myeloma, though less likely, was also considered
in the clinical differentials. Subsequently, 2-deoxy-2-(18 F) fluoro-D-glucose positron
emission tomography (FDG-PET) scan also highlighted multiple FDG avid pulmonary and
hepatic metastatic lesions.
Figure 1: X-ray shows (a) multiple lytic lesions in skull, (b) lumbar vertebrae and
(c) bilateral lung nodules
His complete blood counts, urine routine examination, kidney function tests, serum
uric acid, serum calcium, and tumor markers were all within normal limits. Urine for
Bence Jones protein was negative. The serum free light chain level and ratio were
also within normal limits.
A bone biopsy from right iliac bone was submitted to the Department of pathology which
showed a tumor comprising of plump polygonal to spindle-shaped cells arranged predominantly
in solid nests [Figure 2]. These cells had a moderate amount of eosinophilic cytoplasm, vesicular nuclei exhibiting
mild to moderate pleomorphism and small nucleoli. Mitotic figures were sparse. Few
of the cells showed the presence of intracytoplasmic lumina mimicking a signet ring
appearance. However, close inspection revealed erythrocytes present within some of
the lumina. In addition, a few slit-like ill-defined vasoformative structures were
also appreciated. A panel of immunohistochemical stains was performed. CD31 and CD
34 immunopositivity in the tumor cells confirmed the endothelial nature of the cells.
They were immunonegative for CD68 (histiocytic marker), S100, CD1a, Langerin (marker
for Langerhans cells), and CD138 (plasma cell marker) thereby ruling out LCH and myeloma.
A final pathological diagnosis of EH was rendered.
Figure 2: (a) Polygonal to spindle shaped tumor cells are arranged in solid sheet;
(H and E ×200), (b) the tumor cells show moderate nuclear pleomorphism, eosinophilic
cytoplasm, small nucleoli and intracytoplasmic lumina with presence of red blood cells
in the lumina; (H and E; ×400), the tumor cells are immunopositive for (c) CD34; ×200
and (d) CD31; ×400
He was initially administered a chemotherapeutic cocktail of vinblastine and methotrexate
along with parenteral zoledronic acid and oral celecoxib. Subsequently, he has been
treated with a maintenance antiangiogenic therapy with thalidomide in addition to
zoledronic acid, celecoxib, and calcium supplementation. A follow-up PET-computerized
tomography done 6 months later showed a reduction in FDG avidity of the hepatic and
most skeletal lesions. The pulmonary lesions remain largely unchanged.
Discussion
Weiss and Enzinger first described EH in soft tissue location and also recognized
its endothelial nature as well as intermediate malignant potential in a case series
of 46 patients published in 1982.[4],[5] Subsequently, EH has been reported in multiple osseous and virtually all visceral
sites, particularly liver and lung.[4]
EH of bone is extremely rare lesion that can affect any age group, but most commonly
occurs during the second and third decade of life with a slight male predilection.[1],[6] Patients mostly present with nonspecific symptoms of pain, swelling, and less commonly
pathological fracture. Concomitant visceral involvement is rarely observed in few
patients.[6]
The distinction between multifocal and metastatic disease, especially with synchronous
foci in anatomically distant sites such as femur and spine, has been debated by many
authors considering this tumor has definite hematogenous metastatic potential.[1] Our patient presented with an extensive disease afflicting not only both the upper
and lower extremities but also the spine and calvarium with simultaneous visceral
(liver and lung) involvement.
The imaging features are largely nonspecific. The tumors are mostly purely lytic,
poorly marginated with varying degrees of peripheral sclerosis prompting a host of
radiological differential diagnosis, namely LCH, myeloma, metastasis, lymphoma, angiosarcoma,
and even osteomyelitis.[6]
The diagnosis can be equally challenging on a core biopsy. The vasoformative nature
of the malignancy may not be readily apparent on initial inspection. A myxohyaline
character of the stroma often prompts the first suspicion. A close scrutiny usually
reveals tumor cells with intracytoplasmic lumina often housing red blood cells indicating
its endothelial nature which is confirmed by positive immunostaining with antibodies
to CD31, CD34, and factor VIII.[1],[2],[3]
Much like its variable presentation, EH also has a widely variable clinical course.
The disease may recur locally in approximately 13% of cases, whereas up to 31% of
patients may develop metastasis.[1],[2] Surgical resection is most commonly employed for surgically amenable lesion(s) with
adjuvant radiation often given to decrease the risk of local recurrence. However in
patients with the multifocal/metastatic disease or surgically inaccessible site, the
treatment protocol is even more poorly defined. A multimodal approach with radiation
therapy is frequently adopted. Although the role of chemotherapy is not yet clear,
it may be concurrently offered, especially to patients with extensive multifocal or
metastatic disease.[1],[3],[6]
Our patient was administered chemotherapy and has a stable disease on 6-month follow
up with in fact reduction in FDG avidity in the hepatic and most skeletal lesions.
Conclusion
EH of the bone is a rare tumor with a widely variable presentation, prognosis and
poses considerable diagnostic and therapeutic challenge. It lacks any specific imaging
findings and histology can often be quite deceptive, especially to the unwary. A high
index of suspicion on light microscopy coupled with judicious use of immunohistochemical
antibodies remains the gold standard to clinch the diagnosis.
