Ewing’s
Sarcoma
Ewing’s sarcoma is a small round cell tumor of bone and is the fourth
most common malignant bone neoplasm after myeloma, osteosarcoma, and chondrosarcoma.
The tumor can appear anywhere in the skeleton, but the majority are found in
the pelvis and long tubular bones, particularly the femur. Ewing’s sarcoma
occurs during adolescence, with pain and swelling at the tumor site. The patient
may present with an associated fever, tender mass, an elevated white cell count,
and anemia that may confuse the clinical picture with infection. Radiographs
reveal a poorly marginated, permeative lytic lesion of the medullary cavity.
There is periosteal new bone formation with an "onion-skin" pattern;
this is a consistent radiographic finding, but is not pathognomonic for Ewing’s
sarcoma. It results from the reactive bone production secondary to the tumor
violating the periosteum. The soft tissue mass that usually is present may be
seen on plain films; however, its extent of tumor involvement is better defined
with an MRI or CT scan. An Ewing’s sarcoma has a semi-solid, liquefied
gray-white gross appearance with areas of hemorrhagic necrosis. In keeping with
its mimicking an infection, the lesional tissue can be mistaken for pus. Microscopically,
the lesion is very cellular, with minimal matrix production. It demonstrates
small, rounded, closely packed cells with round uniform nuclei and indistinct
cell membranes. The cells have scant cytoplasm and are two to three times the
size of normal lymphocytes. They are arranged in dense sheets or nests separated
by thin fibrous septa. Areas of necrosis may be extensive, and viable cells
can be identified around the capillary vessels. In some cases, rosette-like
structures are noted in which the center contains necrotic cells. Periodic acid-Schiff
(PAS) stain with diastase digestion identifies glycogen in the cytoplasm of
Ewing’s sarcoma cells in approximately 70 to 75 percent of the cases.
The presence of glycogen is an important finding, but is not specific for Ewing’s
sarcoma cells. Immunohistochemical stains help to differentiate Ewing’s
sarcoma from other round cell tumors of bone. The Ewing’s sarcoma cells
are positive for Vimentin, which is a mesenchymal marker, and are negative for
leukocyte common antigen (LCA), a marker for lymphoid cells. The cells react
positively to the HBA-71 and 013 antibodies, which localize a glycoprotein produced
by the gene MIC2. This latter finding and the presence of reciprocal translocation
of chromosomes 11:22 (q24; q12) indicate that Ewing’s sarcoma belongs
to the group of neuroectodermal tumors.
Ewing’s sarcoma is best treated with chemotherapy. Radiation therapy may
be combined with chemotherapy to treat visceral and lymphatic metastases. Surgical
resection is recommended after chemotherapy in locations where complete removal
is possible. Radiotherapy is indicated in inoperable cases such as in the spine,
and in cases with contaminated margins following surgery. The poor prognosis
of Ewing’s sarcoma relates to its fulminant clinical course and propensity
for widespread metastases. The initial dismal 5-year survival rate for Ewing’s
sarcoma has improved with modern treatment protocols to over 40 percent.
Neuroectodermal tumor of bone (PNET) is a malignant neoplasm that has been recently
described. It is basically indistinguishable from Ewing’s sarcoma on clinical,
radiologic, and histologic grounds. Both tumors share the same abnormal chromosomal
translocation and the gene MIC2. However, neuroectodermal tumor demonstrates
more evidence of neural differentiation than Ewing’s sarcoma. Some authors
do not distinguish between these tumors and refer to them as Ewing’s sarcoma/PNET.
It is possible that they represent the same neoplasm in different stages of
differentiation.
Malignant Lymphoma
(Non-Hodgkin's Lymphoma)
Primary malignant lymphoma of bone is defined as a tumor arising within the
bone and remaining localized at the original site without extraosseous involvement
for at least 6 months. It is a rare tumor with an indolent clinical presentation
during adulthood, particularly the third decade. The patients complain of pain
and swelling in a localized bone. These symptoms are often long-standing and
the patients do not have constitutional complaints. The patients can present
with soft tissue masses if the lesion penetrates the cortex and can have neurologic
complaints due to compression of the spinal cord or nerve roots by tumor. The
knee is the most common location of this tumor with the distal femur and proximal
tibia involved in nearly half of the cases. Malignant lymphoma of bone appears
as a poorly marginated, destructive permeative lesion in the diaphysis of long
bones. The "moth eaten" bone may appear lytic or sclerotic or a mixture
of both. There may be periosteal reaction, and the cortex may be thickened.
Grossly, the tumor appears whitish-gray and the residual bone trabeculae of
this permeative lesion give it a gritty consistency. Histologically, a diffuse
infiltration of round lymphoid cells is seen, varying from small lymphocytes
to large cells, which often have grooved nuclei and conspicuous nucleoli. Areas
of spindle cell proliferation with fibrosis are focally seen. The majority of
primary lymphomas are classified as diffuse large B-cell type. The tumor cells
react immunohistochemically with (LCA) and B-cell markers (L-26). The considerable
variation in size and shape of the lymphoma cells help to distinguish morphologically
this tumor from Ewing’s sarcoma, in which the cells are uniformly rounded.
Adequate biopsy material and the application of immunomarkers help to distinguish
malignant lymphoma from chronic osteomyelitis. Radiation therapy and chemotherapy
are the primary modes of treatment. The prognosis depends on whether the lesion
remains localized in the bone or disseminates to other organs. The 5-year survival
rate varies from 20 to more than 50 percent.
Primary bone lymphoma should be distinguished clinically from secondary bone
involvement by lymphoma arising in the lymph nodes or other extraosseous sites.
Hodgkin’s disease involving bone as a primary clinical manifestation is
rare. Most of the patients have detectable extraosseous lesions following staging
studies.
Myeloma
Myeloma is a malignant plasma cell neoplasm originating from the marrow that
usually presents with multiple osseous lesions (multiple myeloma). It is the
most common primary malignant bone tumor. This condition affects males twice
as often as females, most commonly in the sixth decade of life. The patient
usually has bone pain, is anemic, and has elevated serum calcium, proteinuria,
and plasmacytosis in bone marrow (>30%). Serum electrophoresis reveals a
globulin spike, and immunoelectrophoresis usually demonstrates high levels of
monoclonal immunoglobulins (M component) in the serum and a monoclonal light
chain in the urine (Bence Jones proteinuria). Solitary myeloma is less frequent
than multiple myeloma and presents as a single bone lesion. The majority of
these tumors eventually become disseminated.
In very rare cases, myeloma presents in extraskeletal sites (extramedullary
plasmacytoma). Most of these tumors occur in the upper respiratory site.
On radiographs, the tumors appear as multiple small, well-circumscribed "punched-out"
lytic lesions at one or many sites such as the vertebrae, ribs, or pelvis. There
is little or no reaction by the surrounding host bone, but endosteal scalloping
and medullary expansion may be appreciated. When the tumor involves a long bone
and penetrates the periosteum it creates a soft tissue mass and may result in
a pathologic fracture. The above radiographic and laboratory findings and a
marrow biopsy establish the diagnosis of myeloma. On gross examination, the
tissue appears as a reddish gray homogenous soft mass. The lesion consists of
tightly packed plasma cells with an eccentrically located nucleus, abundant
pink cytoplasm, and a pale-stained juxtanuclear halo that represents the Golgi
apparatus. There is no background stroma with this tumor, and in some cases
it can be mistaken for a lymphoma. There may be amyloid deposits in the tumor,
either as nodular foci or broad areas within the lesion. Intracytoplasmic inclusions
(Russell bodies) are frequently seen at the light microscope, and an increased
amount of rough endoplasmic reticulum is noted in the myeloma cells with the
electron microscope. The clinical course and prognosis are apparently related
to the clinical stage of the disease and, less important, to the histologic
degree of differentiation of the tumor. Well-differentiated solitary lesions
have a longer median survival than poorly differentiated disseminated disease.
Chemotherapy is the recommended treatment for myeloma, however radiation is
effective for solitary lesions. Patients with impending pathologic fractures
in the long bones require internal fixation. Vertebral lesions associated with
myelopathy should be treated with decompressive laminectomy and may need instrumentation
if the spine is unstable. The role of wide excision for solitary lesions is
controversial.
