Published Works: General
Principles General Principles Primary tumors of the musculoskeletal system account for
less than 1 percent of all tumors diagnosed in the United States each year (approximately
4,000 cases annually). Since many patients with benign bone tumors are asymptomatic,
the exact incidence of bone tumors is uncertain. Despite their relative paucity,
these tumors represent a diverse group of pathologic entities, exhibiting a
broad spectrum of clinical behavior and aggressiveness. Consequently, the diagnosis
and treatment of these lesions are equally complex and varied.
Strategies exist to simply the evaluation of these tumors and ultimately ensure
appropriate treatment. These strategies include such methods as establishing
consistency in nomenclature, understanding the site-and age- specific predilections
of particular tumors, and characterizing the radiographic and histologic characteristics
of each tumor. The following discussion specifically considers the diagnosis
and treatment of common primary and secondary benign and malignant tumors affecting
the musculoskeletal system.
Clinical Evaluation The definitive diagnosis of bone tumors requires a combined
effort and collaboration among the clinician, radiologist, and pathologist.
The most important criteria to be taken into consideration are the patient’s
medical history, age, location, radiographic features, and pathologic findings.
Medical History It is important to establish the clinical presentation. The
first question is what made the patient seek medical attention? Was it an incidental
finding during a routine check-up? Is there a history of trauma; post-traumatic
ossifying hematoma may resemble a malignant tumor. Information about the patient’s
occupation is as important as the type and level of sport activity the patient
may participate in; long-distance runners may present with a stress fracture
that could mimic an osteogenic sarcoma. The pain pattern (intensity and duration)
are also important factors. Pain at rest during day and night and nocturnal
pain suggest osteoid osteoma; pain at rest that is also associated with activity
suggests multiple stress fractures. Rapid onset of pain over a short period
of time suggests an aggressive process such as osteomyelitis, eosinophilic granuloma,
or Ewing’s sarcoma. Any history of metabolic conditions such as Paget’s
disease, Gaucher’s disease, or dhyperparathyroidism should also be taken
into consideration in forming the differential diagnosis.
Age Distribution Benign bone tumors are far more commonly seen in younger
patients; metastatic tumors are seen almost exclusively in adult patients. Bone
tumors in a 1-year-old infant suggests a metastatic neuroblastoma. The age of
detection for a simple bone cyst, aneurysmal bone cyst, and eosinophilic granuloma
is during the first decade of life. Through the second decade, with the adolescent
years, chondroblastoma, Ewing’s sarcoma, and osteosarcoma are more commonly
seen. In the third decade of life, giant cell tumor is a more visible disorder.
The age of detection for chondrosarcoma and malignant fibrous histiocytoma is
seen in the adult patient, above the fourth decade of life. In old patients,
myeloma is the most common primary bone tumor.
Location Certain tumors favor a specific anatomic site. Most primary
bone tumors tend to develop in areas of rapid bone growth; particularly in the
distal end of the femur, proximal tibia, and proximal femurs. Metastatic tumors
are more commonly seen in persistent, active hematopoietic red marrow bones
such as the axial skeleton and the proximal end of the extremities. Round cell
tumors such as Ewing’s sarcoma are more often seen in the diaphysis metaphyseal
region of the long tubular bone. A frequent site of adamantinoma is the mid
shaft of the tibia. Non-ossifying fibroma are more often found eccentrically
along the metaphyseal diaphysial region of the long tubular bone. Chondroblastomas
are exclusively epiphysial. Giant cell tumors are almost invariably extended
up to the end of the long tubular bone, just adjacent to the subchondral bone.
A parosteal osteosarcoma is more commonly seen over the posterior aspect of
the distal femur.
Most primary bone tumors are solitary. Multiple bone lesions in young patients
may be seen in conditions such as fibrous dysplasia, osteochondromatosis, or
enchondromatosis. Multiple bone lesions in adult patients suggest a metastatic
tumor.
Radiographic Features A plain radiograph is the most important initial study for
evaluation. In select conditions, a plain radiograph is sufficient to establish
the correct diagnosis. Plain radiographs also provide information about the
biological activity and aggressiveness of the lesion. The pattern of bone destruction
and marginal characteristics as seen in radiographs are an index of the biological
activity and growth rate. The most important radiographic features to be identified
and evaluated are the pattern of bone destruction, marginal characteristics,
type of permeation, tumor matrix, and type of periosteal reaction. The pattern
of bone destruction is reflected by the tumor cells and factors that may stimulate
osteoclastic proliferation and bone resorption. Cancellous bone is destroyed
more rapidly than cortical bone. However, a cancellous bone destruction is less
noticeable on plain roentgenogram. Destruction of cortical bone occurs at a
lower rate, but it is more easily noticeable on plain radiographs.
Geographic patterns of bone destruction demonstrate a large
cavity with a narrow zone of a transition. Geographic latent (Stage 1) lesion
demonstrates a well delineated and well demarcated lesion which is surrounded
by a sclerotic margin. Such lesions are seen in nonossifying fibroma, simple
bone cyst, fibrous dysplasia, chondromyxoid fibroma, and rarely, giant cell
tumor. These lesions may be observed or be treated by a simple curetting procedure.
Following such procedures, local recurrence is negligible.
Geographic active (Stage 2) lesion has a well-defined but nonpermeated margin.
There is no sclerotic interface. The host bone tumoral interface is sharply
delineated as could be seen in giant cell tumor. Simple curettage may leave
behind traces of tumor which will be associated with a local recurrence rate
up to 38 percent. Those lesions should be treated by aggressive curettage.
Geographic aggressive (Stage 3) lesions have ill-defined permeated margins as
is demonstrated in some aggressive giant cell tumors where breakthrough of the
outer cortex, and joint invasion has been noted. Such a pattern of aggressive
processes has been described in malignant tumors. Because of the high risk of
local recurrence, those lesions should be treated by wide surgical margins.Moth-eaten
destruction represents an intermittent growth rate with no clear margination.
The lesion typically demonstrates multiple, ill-defined processes such as those
seen in malignant lymphoma.Permeative bone destruction represents a high-grade
malignant tumor with rapid growth, the bone permeates before apparent bone destruction
as can be seen in Ewing’s sarcoma and osteosarcoma.
The above radiographic classification has proven to demonstrate good correlation
between the radiographic grade and the local recurrence rate, and also provides
a useful guideline for treatment.
Periosteal Reaction The periosteal reaction seen on radiographs reflects the
intensity and aggressiveness of the lesion and the stage of maturation. The
extent of periosteal reaction is also related to the patient’s age. Since
young children have a thick, active periosteum, any inciting process would cause
extensive periosteal reaction. Adult patients have thin, nonactive periosteum;
a large metastatic tumor may not be accompanied by a noticeable periosteal reaction.
For the periosteum to be identified radiographically it must be mineralized,
a process which could take up to 2 weeks. Periosteal reaction may be classified
as continuous, interrupted, or complete. Single uninterrupted lamellar reaction
is seen in a biologically non-active process such as a subperiosteal hematoma
or subperiosteal abscess. Uninterrupted multilamellar reaction is seen in biologically
active process such as eosinophilic granuloma or osteomyelitis.
Interrupted multilamellar reaction is seen in biologically
aggressive process such as Ewing’s sarcoma or osteosarcoma.
Speculated reaction (sun-burst) indicates a rapid growth of the tumor with breakthrough
of the cortex into the subperiosteal space. This elevates the periosteum and
stretches the perpendicular-oriented Sharpy’s fibers, as can be seen in
osteosarcoma and Ewing’s sarcoma.
Solid periosteal reaction represents a chronic, slow-growing biologically active
process such as seen in osteoidosteoma and periosteal chondroma. The linear
radiolucent spaces between the layers are filled with dense new bone formation
giving the impression of solid, thick cortical hyperostosis.
A periosteal shell and a rigess are seen in slowly growing processes where bone
resorption is slower as compared to new bone formation. Widening of the cortical
outline with expansion of the bone and preservation of the cortical thickness
signifies a process where the endosteal bone resorption is balanced by periosteal
new bone formation. Such conditions are seen in simple bone cysts and chondromyxoid
fibroma. However, the thinning of the cortical outline with expansion of the
bone signifies a more aggressive process where the endosteal bone resorption
exceeds periosteal new bone formation, as is seen in both aneurysmal bone cyst
and giant cell tumor.
Tumor Matrix Many tumors are named according to the tumor matrix that
they produce. The matrix is the extracellular substance that is produced by
mesenchymal cells. It may be fibrous as in fibrous dysplasia, cartilaginous
as with enchondroma, or osteoid as in osteoid osteoma and osteosarcoma. It should
be emphasized that nonmineralized matrix is not visible on radiographs. Mineralized
cartilaginous matrix can be identified by calcification.
Biopsy The final and definitive diagnosis is confirmed by biopsy.
The biopsy is done only after a complete radiographic work-up and consideration
of the definitive treatment. The biopsy site should be planned very carefully.
The incision should be small, longitudinal, and resectable without contamination
of the surrounding tissue. Tissue samples should reflect the nature of the tumor
and should be representative. A large irreversible surgical procedure based
solely on the frozen section is often not recommended.
Preoperatively, the surgeon should discuss with the pathologist the medical
history, and review the radiographic features. This allows the pathologist to
be prepared for the frozen section and to handle the tissue in the best manner.
The choice of open biopsy versus needle biopsy depends upon the individual situation
as well as the particular preference of the surgeon and pathologist.
Imaging of Musculoskeletal Tumors A variety of imaging methods are available to assist in determining
or predicting the biological activity of a tumor. If the lesion is well circumscribed,
it is generally considered low grade or less aggressive. Alternatively, a tumor
that exhibits tremendous heterogeneity, edema, and invades tissue planes is
generally biologically aggressive.
Radiographs Several radiographic features may be seen that help predict
the biologic activity and behavior of a particular lesion. Enneking has devised
a system of four questions, which should be systematically addressed when characterizing
a tumor based on radiographs. These questions include: What is the anatomic
location involved? What effect does the lesion have on the surrounding bone?
What, if any, is the response of the bone to the lesion? And, what are the unique
characteristics of the tumor? A lesion is referred to as geographic when bone
destruction is slow. This geographic appearance may be well-defined, with an
encasing rim of reactive bone, a so-called stage 1 lesion. An example is a nonossifying
fibroma. When there is a well-defined geographic appearance, but no rim of reactive
bone, the lesion is referred to as a stage 2 lesion. This radiographic appearance
is indicative of ongoing bone destruction, as in a slow-growing chondroblastoma.
In a stage 3 lesion, the appearance is still geographic, but the margins are
even more ill-defined, as in a giant cell tumor.
A moth-eaten appearance represents intermediate growth rate, with no clear margination
of the bony lesion. Finally, a permeative pattern of bone destruction, representative
of an aggressive high-grade lesion, occurs when lesional growth is so rapid
that it invades host bone before the bone is resorbed. In these cases, the boundaries
of the tumor are usually far beyond those that can be seen on radiographs. A
classic example of this pattern is seen in Ewing’s sarcoma and osteosarcoma.
Perosteal response also gives a clue as to the aggressiveness of the tumor.
In general, absent periosteal reaction depicts a non-aggressive tumor, whereas
more aggressive tumors will frequently cause periosteal elevation with a resultant
onionskin appearance or a Codman’s triangle that represent deposition
of subperiosteal bone. Interrupted Codman’s triangles or lamellation,
or a speculated sunburst appearance (as is classically seen with osteosarcoma)
is associated with a greater rate of bone destruction and aggressiveness.
Particular tumors have specific radiographic characteristics
that will be addressed later.
Computed Tomography Computed tomography (CT) scans are useful for demonstrating
the extent of the tumor within bone and the cortical integrity. CT scans are
not very effective for visualizing the soft-tissue components of the tumor,
although differences in tissue densities may be evident.
Technetium 99 Pyrophosphate Bone Scans Technetium-labeled nuclear scans are valuable for localizing
tumors in bone, with the early phase of three-phase scans sometimes helping
to establish the vascularity of the tumor. The bone scan is the most effective
scan for identifying skeletal metastases. Certain tumors stimulate little reaction,
resulting in so-called "cold" scans. These include myeloma, lymphoma,
eosinophilic granuloma, and thyroid, renal, and neuroblastoma metastases.
Magnetic Resonance Imaging MRI is the most effective technique for determining the true
anatomic extent of tumors, particularly in the soft tissues. Unless high in
fat content, musculoskeletal neoplasms tend to be darker on T1-weighted images,
because relaxation times tend to be prolonged. In T2-weighted images, tumors
tend to have a higher signal intensity and appear lighter. Malignant neoplasms
will often appear heterogeneous, indicative of hemorrhage and cell necrosis.
Contrast enhancement (with gadolinium or other agents) will help to distinguish
tumor from scar and reactive or edematous zones.
Laboratory Studies Laboratory tests may be of some value in the evaluation of
musculoskeletal tumors. Erythrocyte sedimentation rate is frequently elevated
in a number of neoplastic conditions but lacks the sensitivity to be considered
a valuable tool. Alkaline phosphatase may be elevated in such disease states
as Paget’s disease and osteosarcoma. Urinary hydroxyproline levels are
helpful in diagnosing Paget’s disease and following the therapeutic response.
Serum electrophoresis, and serum and urine immunoelectrophoresis are routine
tests in diagnosing and following the course of multiple myeloma. Urinary Bence-Jones
proteins are pathognomonic for myeloma. Quantitative paraprotein levels in the
serum protein electrophoresis (SPEP) can be used to follow the disease.
Diagnosis and Evalation
Enneking Staging System The staging system currently used by the Musculoskeletal
Tumor Society for musculoskeletal lesions was developed by William Enneking.
The system is based on the biological characteristics of the neoplasm, taking
into account three factors: the histologic grade of the tumor (G), its anatomic
location as defined by compartmentalization (T), and the presence or absence
of metastases (M). Its purpose is to promote guidelines for surgical planning
and chemotherapy, to predict prognosis, and to facilitate interdisciplinary
communication.
The most important prognostic criteria is the histologic grade. All benign tumors,
no matter how aggressive they may be, are classified as G0. Malignant tumors
are classified as G1 for low-grade malignancies (such as parosteal osteosarcoma)
or G2 for high-grade lesions (such as conventional osteosarcoma). G1 malignant
tumors are classified as stage 1 lesions; G2 tumors are stage 2 lesions. G1
malignant tumor has a low rate of metastasis, less than 10 percent. G2 has a
high rate of metastasis, over 50 percent.
Compartments are bounded by fascial structures or bone which act as barriers
towards the spread of actively growing lesions. A combination of imaging studies,
such as plain radiographs, nuclear studies, CT scan, and magnetic resonance
imaging studies, are key tools in establishing the extent of anatomic involvement.
Examples of compartmental barriers include the bony cortex, articular cartilage,
periosteum, joint capsule, skin and subcutaneous tissue, and fascia. A T0 lesion
remains intracompartmental and within its capsule. T1 lesions display extracapsular
extension, but both the tumor and its surrounding reactive zone remain within
the compartment of origin. T2 lesions have extracompartmental extension, either
by direct tumor growth, trauma, or surgical seeding. Tumors that involve major
neurovascular bundles are generally classified as T2. Malignant lesions that
remain intracompartmental are classified as stage I-A for low-grade sarcomas
and stage II-A for high-grade lesions. If they are extracompartmental, the stages
are I-B or II-B for G1 and G-2 tumors, respectively.
The absence of metastases is classified as M0; regional or distant metastases
qualify the lesion as M1. When patients present with metastases, they are automatically
classified with Stage III disease, regardless of the histologic grading or the
compartmental involvement.
The system for benign lesions characterizes tumors as latent, active, or aggressive.
Stage 1 (latent) lesions are intracapsular, with a course that is considered
unchanging or self-limiting. They are usually diagnosed incidentally or because
of a structural problem like a pathologic fracture. An example is a simple cyst
in the proximal humerus. Stage 2 (active) lesions undergo slow growth and activity
within the confines of the capsule. An example is a giant cell tumor that has
not invaded the cortex of the distal femoral condyle. These lesions have a 5
to 10 percent local recurrence rate after curettage. Stage 3 (aggressive) lesions
undergo extracapsular penetration and may remain intracompartmental or extend
extracompartmentally. These lesions mimic low-grade malignancies in their locally
aggressive behavior. An example is an aggressive giant cell tumor that has broken
through the cortex, extending into the soft tissues or the joint. They are destructive
processes and recurrence rates from 10 to 20 percent after intralesional or
marginal excision. Chondroblastomas and giant cell tumors have the capacity
to metastasize to the lungs. In such cases, however, they are still classified
as benign Stage 3 lesions.
Principles of Intralesional Biopsies Biopsy should be considered only after a complete radiographic
work-up and thorough evaluation of the patient. The biopsy must be carefully
planned so as not to compromise the definitive surgical procedure, if necessary.
An ill-planned biopsy can jeopardize the potential for limb salvage and the
overall course of the disease. Generally, the most active portion of the tumor
is located peripherally; necrotic regions are centrally located. In order to
best establish the type and biologic behavior of the tumor, biopsies should
be representative and preferentially be taken from the periphery of the lesions,
including the capsule or pseudocapsule.
Needle biopsies may be adequate for lesions that are easily diagnosed with small
samples. Needle biopsy tracts must be excised at the time of definitive surgery.
Open biopsies, however, are more reliable and less likely to yield inaccurate
diagnoses. With the latter technique, larger amounts of tissue can be analyzed,
special stains performed, and a more accurate assessment of biological activity
made. Frozen section analysis should be performed routinely. It serves to confirm
sampling of lesional tissue and may establish an early working diagnosis. The
overall accuracy of noninvasive staging studies in differentiating between benign
and malignant lesions is approximately 90 percent; this increases to 97 and
99 percent for frozen and permanent section analysis, respectively. Irreversible
procedures based soley on frozen section are not recommended.
Several key surgical principles must be followed when considering the biopsy
of tumors. Lesions that are obviously benign and small can be excisionally biopsied;
aggressive lesions, or those with uncertain diagnoses, are better suited to
incisional biopsies. Open biopsies should be oriented longitudinally; the entire
biopsy tract must later be excised if the lesion is malignant and definitive
surgery performed. Biopsies are performed through muscle-splitting approaches
without using traditional internervous planes. All biopsy samples should be
sent for bacteriologic analysis. Finally, biopsy of aggressive or malignant
lesions should be done at the institution where the definitive surgery is to
be performed. Otherwise, surgical margins are more likely to be compromised,
there will be a higher incidence of amputations of extremities that are amenable
to limb salvage procedures, and misdiagnosis by nonmusculoskeletal pathologists
will be higher.
Treatment
Principles of Surgical Treatment The appropriate treatment of any musculoskeletal tumor is
determined by location and Enneking stage. Regarding benign tumors, latent lesions
can generally be observed, unless actual or impending pathologic fracture has
occurred or neurovascular compromise by the mass developed. Active and aggressive
benign bone tumors can usually be adequately treated by intralesional curettage
and reconstruction with autograft, allograft, or polymethylmethacrylate. Prophylactic
stabilization may be used as necessary.
The goal of treatment of musculoskeletal sarcomas is to resect the lesion and
minimize the risk of local recurrence. Limb salvage, while an attractive option,
should only be considered if local tumor control is at least equal to that after
amputation and if the salvaged limb is functional. A variety of surgical resections
exist, with variable margins, each appropriate for different tumors with different
stages. There are four types of oncologic surgical procedures. (1) an intralesional
margin is one in which tumor is removed by curettage or in a piece-meal fashion.
Gross disease is frequently left in situ; therefore, this technique is generally
reserved for benign lesions. (2) A marginal zone of resection passes through
the pseudocapsule or reactive zone of the tumor. Residual microscopic disease
in the form of skip and satellite lesions may be left, accounting for a local
recurrence of 25 to 50 percent in malignant tumors treated by this method. (3)
A wide surgical resection takes out the tumor with a cuff of normal tissue beyond
the boundaries of the pseudocapsule. Skip lesions may be left, but the local
recurrence rate is less than 10 percent. Stages 1A and 1B tumors are most amenable
to this form of treatment. (4) A radical surgical margin includes the tumor
and the entire involved compartment, including the full extent of muscle, ligaments,
and connective tissues. This margin results in complete removal of the tumor
and any possible intracompartmental skip lesions. Functional limb salvage is
rarely possible after radical resection. Stages 2A and 2B lesions are best treated
by this method, although wide excision may be appropriate for certain tumors
that have shown adequate response to neoadjuvant chemotherapy or irradiation.
Stages 3A and 3B have metastases with 5-year survivorship approaching zero.
Treatment of these patients should be directed at palliation.
Principles of Adjuvant Therapy The role of multi-agent chemotherapy for the treatment of
musculoskeletal sarcomas has expanded over the last decade. The appropriate
utilization of these agents has allowed smaller margins of tumor resection while
reducing the rate of local tumor recurrence. This in turn has improved the prospects
of limb salvage and disease-free survival. Preoperative (so-called "neoadjuvant")
multi-agent chemotherapy are now commonly utilized, with proven efficacy, for
high-grade osteosarcoma, rhabdomyosarcoma, and Ewing’s sarcoma. Most chondrosarcomas
are not responsive to these agents or to irradiation. Most contemporary protocols
consist of neoadjuvant chemotherapy for 8 to 12 weeks, followed by postoperative
maintenance chemotherapy for up to one year. The adjunctive use of chemotherapy
has improved survival in stages 2A and 2B disease to as high as 40 to 60 percent
(compared to 20 percent without adjuvant therapy). In the presence of metastatic
disease, chemotherapy has been shown to prolong survival times but not increase
the rate of survival.
Radiation therapy has a role in the treatment of all soft tissue sarcomas, Ewing’s
sarcoma, myeloma, lymphoma, and metastatic disease. The radiation-induced fibrous
ring that forms around soft tissue sarcomas makes this an effective adjunct
to surgery for these malignancies. Local beam irradiation has limited systemic
effects; however, postirradiation sarcoma (in the form of osteosarcoma, malignant
fibrous histiocytoma, or fibrosarcoma) and pathologic stress fractures remain
potential complications.
