MUSCULOSKELETAL ONCOLOGY: INTRODUCTION

Tumors of the musculoskeletal system are an extremely heterogeneous group of neoplasms consisting of well over 200 benign types of neoplasms and approximately 90 malignant conditions. The relative incidence of benign to malignant disease is 200:1. The tumors uniformly arise from embryonic mesoderm and are categorized according to their differentiated or adult histology. Current classification schemes are essentially descriptive. Each histologic type of tumor expresses individual, distinct behaviors with great variation between tumor types. Benign disease, by definition, behaves in a nonaggressive fashion with little tendency to recur locally or to metastasize. Malignant tumors or sarcomas, such as osteosarcoma and synovial cell sarcoma, are capable of invasive, locally destructive growth with a tendency to recur and to metastasize.

Neoplastic processes arise in tissues of mesenchymal origin far less frequently than those of ectodermal and endodermal origin. In 2004, soft-tissue and bone sarcomas had an annual incidence in the United States of more than 8600 and 2400 new cases, respectively. When compared with the overall cancer mortality of 563,000 cases per year in 2004, sarcomas are a small fraction of the problem. However, although a relatively uncommon form of cancer, these mesenchymal tumors behave in an aggressive fashion with reported current mortality rates in some series greater than 50%. According to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program, approximately 8600 new soft-tissue sarcomas developed in the United States in 2004 with over 3600 sarcoma-related deaths. The associated morbidity is much higher. These tumors inflict a tremendous emotional and financial toll on individuals and society alike. Furthermore, sarcomas are more common in older patients, with 15% percent affecting patients younger than 15 years and 40% percent affecting persons older than 55 years. Accordingly, as the population ages, as it is doing at a rapid rate, the incidence of these tumors will increase.

ETIOLOGY OF MUSCULOSKELETAL TUMORS

Tumorigenesis is a complex multiple-step process by which healthy tissue progressively transforms from a normal phenotype into an abnormal colony of proliferating cells. During this process, cells acquire genetic abnormalities in oncogenes, tumor suppressor genes, and other genes that directly or indirectly control proliferation. Such a process may progress beyond the controlled state of benign disease to become a dedifferentiated, aggressive, and immortal phenotype by genomic instability. It is this instability that allows the cell to progress to fulminant malignancy. DNA regulation and, correspondingly, integrity is ultimately lost and a cancer is born.

To appreciate how bone or soft-tissue tumors develop, one must have a basic understanding of the cell cycle during which cell division occurs. The cell cycle is divided into four distinct phases: G1 (gap 1), S (DNA synthesis), G2 (gap 2), and M (mitosis). DNA synthesis occurs during the S phase, with chromosomal separation and cell division occurring in the M phase. The majority of cell growth takes place during G1. The mature state for mesenchymal tissues is normally in a resting, nonproliferative phase designated G0. It is the factors that affect the exit of the cell from G0, with entrance into G1, that is the hallmark of neoplastic disease.

Control of the cell cycle is a function of numerous regulatory proteins and checkpoints. The checkpoints allow for the monitoring and correction in the genetic sequence. The proteins are encoded by two basic gene types: oncogenes (stimulatory) and tumor suppressor genes (inhibitory). The retinoblastoma (Rb) protein and its phosphorylation state are critically important in regulating cell cycle progression (from G1 to S phase). Therefore, the activation state of Rb is a highly regulated cellular event. In addition, multiple cyclins and cyclin-dependent kinases are being studied actively to elucidate their role in regulation of the cell cycle.

Oncogenes, encoding a variety of growth factors, promote progression of the cell through G1, effecting a mitogenic signal. Suppressor genes, such as wild-type TP53, act to arrest the cell cycle. Specifically, TP53 acts to stop the cell cycle at the G1/S border as a final attempt to abort proliferation. Other suppressor genes work earlier to keep reproduction at bay. A complex array of molecules can serve as either an induction or suppressor function. When this pathway is not orchestrated properly, a given cell obtains the potential for limited or even immortal proliferation. A normal cell progresses through a preneoplastic state on its way to becoming neoplastic via the accumulation of mutations. A critical step during tumor progression is the loss of suppressor gene function, which occurs by a variety of defects, including deletions, translocations, promoter silencing, loss of heterozygosity, point mutations, microsatellite changes, and telomeric associations. The degree to which the daughter cells dedifferentiate into a malignant phenotype is a function of the amount of genomic instability that arises with each subsequent mitosis. Mutation begets mutation as the checkpoints and regulatory machinery continually fail to repair the genetic code.

Factors that influence these mechanisms include both inheritable genetic conditions (eg, Li-Fraumeni syndrome, retinoblastoma) or environmental factors. It is well established that oncogenic viruses, radiation, and chemical carcinogens can affect these processes, ultimately compromising genomic stability.

The neoplastic process may arrest in the so-called benign state, with further genomic instability curtailed, or it can almost progress to a sarcomatous state. For example, if the cell type of origin is a lipocyte, then a lipoma or liposarcoma may develop. Furthermore, a liposarcoma can progress in its dedifferentiation such that its phenotype, as a high-grade lesion, minimally reflects its lipocytic origin. This possibility does not imply, however, that all benign lesions are necessarily at risk for malignant degeneration. It is not a surgical indication to remove a lipoma because of concern over developing a liposarcoma.

Although a plethora of molecular markers are being studied, understanding the details of genomic instability and subsequent tumor formation is lacking. The initiation of the neoplastic process and subsequent disease progression is a complex multistep process in gene expression and deregulation. There is no single pathway by which all neoplasms arise; instead, multiple genetic targets are altered in a variety of sequences with the common result of cellular proliferation that is tumorigenesis.

EVALUATION & STAGING OF TUMORS

History & Physical Examination

When evaluating a new patient with a possible tumor, the workup must commence with a thorough history and physical examination. Prior to ordering any diagnostic studies, particular questions must be answered, and the physical characteristics of the mass in question must be assessed. This procedure prevents unnecessary tests and better enables the physician to determine which tests will be most helpful in diagnosing the condition as well as facilitating therapeutic interventions if needed.

The clinical history is of paramount importance (Table 6–1). The age of the patient permits the generation of a list of potential diagnoses (Table 6–2), which, when combined with the history and a few additional studies, should permit establishing a diagnosis. The duration of symptoms, rate of growth, the presence of pain, and a history of trauma can help elucidate the diagnosis. A careful past medical history, family history, and review of systems must not be overlooked either.

A thorough physical exam is also critical (Table 6–3). The clinician must assess the location and size of the mass, the quality of the overlying skin, the presence of warmth, any associated swelling, the presence of tenderness, and the firmness of the lesion. Range of motion of all joints in proximity to the tumor, above and below, must be recorded as well as a complete neurovascular exam. An assessment of the related lymph node chains as well as an examination for an enlarged liver or spleen should be performed.

The clinician must also consider pseudotumors in addition to true neoplastic conditions. A history of trauma suggests a possible stress fracture or myositis ossificans as a diagnosis. The history of stress-related physical activity and the exact timing of symptom presentation and variations of symptoms with the passage of time are important considerations in establishing a differential diagnosis.

Imaging Studies

RADIOGRAPHY

Initial evaluation should begin with plain radiography. In every patient with a suspected tumor, orthogonal anteroposterior (AP) and lateral views of the affected area should be taken. This includes soft-tissue masses as well. In many cases, radiographic examination is diagnostic, and no further imaging studies are indicated. However, in the case of a more aggressive process, the diagnosis may be determined on the plain radiographs but further evaluation with advanced studies is usually indicated to determine the extent of local soft-tissue involvement as well as to assess the extent of disseminated disease (staging).

The initial radiographic images must be scrutinized. For bone lesions, the location within the bone (eg, epiphyseal, metaphyseal, or diaphyseal) facilitates the diagnosis. Epiphyseal tumors are usually benign. The more malignant primary sarcomas, such as osteosarcoma, are typically seen in a metaphyseal location; however, round cell tumors, such as Ewing sarcoma, multiple myeloma, and lymphomas, are usually medullary diaphyseal lesions. A tumor arising from the surface of a long bone may be a benign lesion, such as an osteochondroma, or it may be a low-grade sarcoma, such as a parosteal osteosarcoma.

Terms such as geographic, well circumscribed, permeative, and are used to describe the appearance of radiographic abnormalities. Geographic or well circumscribed implies that the lesion has a distinct boundary and is sharply marginated, suggesting a benign tumor (Figure 6–1). A poorly defined, infiltrative process is described as permeative or moth eaten and reflects a more aggressive processsuch as a malignancy (Figure 6–2), although aggressive but benign processes can have this radiographic quality as well (Figure 6–3). An exception to this rule is multiple myeloma, which frequently demonstrates a punched-out, well-demarcated appearance but in multiple locations.

With a careful history, physical, and appropriate radiographs, the physician can reach a working diagnosis of the lesion. Although benign and malignant tumors can mimic each other, some tumors can be ruled out on the basis of the history, the age of the patient, the location of the tumor (in which bone and where in the bone), and the radiographic appearance of the tumor, as shown in Tables 6-1, 6-2, 6-3, 6-4, 6-5, and 6-6. For example, a 20-year-old man with a 3-month history of pain in the knee is found to have an epiphyseal lesion in the distal femur. The lesion has a benign geographic appearance. If the tumor is benign, the criteria of the patient's age (see Table 6–2) eliminates only solitary bone cyst and osteofibrous dysplasia, but all other benign tumors remain possibilities. If the tumor is malignant, it is likely to be an osteosarcoma (various types), Ewing sarcoma, fibrosarcoma, vascular sarcoma, or, possibly, chondrosarcoma, according to the age criterion. The most common site for bone tumors is about the knee, especially the distal femur. The likely benign tumors are giant cell tumor, nonossifying fibroma, chondroma, osteochondroma, and chondroblastoma. The likely malignant tumors in this age group are osteosarcoma, Ewing sarcoma, fibrosarcoma, and, possibly, chondrosarcoma. Most malignant tumors are metaphyseal. Based on location in the bone (Table 6–4), the most likely benign tumors are chondroblastoma and giant cell tumor. Most malignant tumors are metaphyseal. The geographic appearance implies a benign radiographic appearance. Thus, the working diagnosis would be chondroblastoma or, possibly, giant cell tumor if the lesion were benign, whereas it would be osteosarcoma or chondrosarcoma if the lesion were malignant, which is less likely. In this age group, metastatic disease is very unlikely, but low-grade infection may mimic a tumor, particularly if the patient is immunocompromised, as can be determined from the patient's history. Table 6–5 indicates the most useful studies for further workup.

ISOTOPE BONE SCANNING

Technetium-99 radioisotope scans are used to assess the degree of osteoblastic activity of a given lesion (Figure 6–4). In general, they are quite sensitive, with a few exceptions, for active lesions of bone. Accordingly, technetium-99 scans are excellent screening tools for remote lesions (staging). The best indication for a bone scan is suspected multiple bony lesions, such as those commonly seen in metastatic carcinomas and lymphomas of bone. Isotope bone scanning is far simpler to perform, less expensive, and requires less total body irradiation than skeletal surveys. It is common practice to use serial isotope scans to follow patients with suspected metastatic disease and at the same time evaluate the effectiveness of their systemic therapy program.

Isotope scanning is also used in the staging process of a primary sarcoma such as an osteosarcoma to make sure the patient does not have an asymptomatic remote skeletal lesion. Technetium-99 scans are also useful in distinguishing blastic lesions of bone. Given that the study reflects metabolic activity, an enostosis (bone island) would not demonstrate significant increased activity compared with a blastic prostate metastasis. Inflammatory disease and trauma also show increased activity. It is important to note, however, that multiple myeloma and metastatic squamous cell carcinoma may not demonstrate technetium uptake (ie, a false-negative result). Skeletal surveys are preferable for screening for additional sites of involvement in such cases.

COMPUTED TOMOGRAPHY AND MAGNETIC RESONANCE IMAGING

Computed tomography (CT) remains a standard imaging procedure for use in well-selected clinical situations. Perhaps the best indication for CT is for smaller lesions that involve cortical structures of bone or spine (Figure 6–5). In such cases, CT is superior to MRI because the resolution of cortical bone using MRI is inferior. CT scan of the lung is the modality of choice for evaluating patients with sarcoma for possible lung metastases. Abdominal CT scan is invaluable in surveying for a primary tumor in patients who present with bone metastases. For tumors involving the pelvis and sacrum, CT can help elucidate the extent of bone involvement (Figure 6–6). In cases involving a soft-tissue lesion, MRI is far superior to CT unless there is a heavily calcified process.

MRI is the imaging modality of choice for evaluating bone marrow involvement as well as noncalcific soft-tissue lesions. The two most commonly used MRI sequences are the T₁-weighted and T₂-weighted spin echo (Figure 6–7). MRI can also demonstrate the normal anatomy of soft structures, including nerves and vessels, thereby nearly eliminating the need for arteriography and myelograms. Dynamic-enhanced MRI, with its ability to estimate tumor blood flow by examining the rate of contrast uptake and clearance, may serve as a predictor of clinical outcome or tumor response to chemotherapy.

Laboratory Studies

BIOPSY

The biopsy should usually be the final staging procedure. Although the biopsy can distort the imaging studies, such as MRI, pathologic evaluation and interpretation may require information provided by the prior workup. Complications relating to the biopsy are not infrequent. Accordingly, careful preoperative planning is imperative. The imaging studies aid the surgeon in selecting the best site for a tissue diagnosis. In most cases, the best diagnostic tissue is found at the periphery of the tumor, where it interfaces with normal tissue. For example, in the case of a malignant bone tumor, soft-tissue invasion is usually evident outside the bone, and this area can be sampled without violating cortical bone and thus without causing a fracture at the biopsy site. If a medullary specimen is needed, a small round or oval hole should be cut to decrease the chance of fracture. If the medullary specimen is malignant, the cortical hole should be plugged with bone wax or bone cement to reduce soft-tissue contamination following the procedure.

Obtaining an adequate specimen is critical. A frozen section determines if viable and adequate tissue were obtained. A few experienced tumor centers may make a definitive diagnosis based on a frozen section, allowing the surgeon to proceed with definitive operative treatment of the tumor. However, freezing artifact can cause overinterpretation of the material, so an aggressive resection should always be deferred until the permanent analysis is complete. Additional studies beyond conventional light microscopy, such as immunocytochemistries and cytogenetics, may also be necessary.

The placement of the biopsy site is a major consideration. If the surgeon is inexperienced and not familiar with surgical oncologic principles, a serious contamination of a vital structure such as the popliteal artery or sciatic nerve may occur. Such an error might necessitate an amputation instead of a limb-sparing procedure. To avoid this problem in the case of a suspected malignant condition, the surgeon who performs the biopsy should be the same surgeon who will perform the definitive operative procedure.

Transverse incisions should be avoided because removing the entire biopsy site with the widely resected subjacent tumor mass is difficult. Adequate hemostasis is mandatory to avoid formation of a contaminating hematoma. A drain may be helpful but frequently is unnecessary. If a drain is used, it must be placed in line with the incision.

Needle biopsies, either core or fine needle, can be used by experienced tumor centers, especially for lesions that are easily diagnosed, such as metastatic carcinomas or round cell tumors. Because the subtype of sarcoma is proving to be very important, architecture of the tumor is generally needed, which requires a core biopsy rather than a fine-needle aspirate. Core biopsies also allow the surgeon to sample various areas of the tumor to avoid sampling error in a heterogeneous tumor. In the case of a deep pelvic lesion or a spinal lesion, a CT-guided needle biopsy is ideal because it avoids excessive multicompartmental contamination.

In general, excisional biopsies are discouraged unless the lesion is particularly small (less than 2–3 cm) or in an area where a cuff of healthy uninvolved tissue of at least 1 cm can be removed as well. This technique ideally avoids a second procedure to remove the entire biopsy site if the lesion turns out to be malignant.

CULTURES AND SPECIAL STUDIES

The damage of biopsy specimens after retrieval can make it impossible to perform special studies such as immunohistochemistry, cytogenetics, flow cytometry, and electron microscopy. For this reason, the biopsy surgeon should consult with the pathologist before specimens are retrieved and handled. Furthermore, many current studies require fresh tissue (no formalin). It is also a good habit to obtain cultures for bacterial culture (anaerobic and aerobic) as well as fungal and acid-fast bacteria if clinical suspicion warrants.

Molecular diagnostics is on the verge of revolutionizing sarcoma diagnostics. Specific translocations were found in a variety of tumors (Table 6–7). Furthermore, therapeutics are beginning to be designed against specific molecular defects in malignancies. Gastrointestinal stromal tumor (GIST), a malignant mesenchymal tumor arising from the gastrointestinal (GI) tract, omentum, and mesentery, overexpresses a mutant form of c-kit. The KIT gene encodes a tyrosine kinase receptor for the growth factor named stem cell factor or mast cell growth factor. Therapy directed against c-kit is having an early and remarkable effect on the previously difficult treatment of malignancy. Similar pathways are being elicited in other sarcomas.

Staging Systems

After the appropriate studies are completed, staging begins. Staging refers to an assessment of the grade of the tumor and the extent to which the disease has spread. There are several staging systems, but all have the purpose of helping the physician plan a logical treatment program and establish a prognosis for the patient. The two major systems are discussed here.

SYSTEM OF THE AMERICAN JOINT COMMITTEE ON CANCER

The American Joint Committee on Cancer (AJCC) system (5th edition) is used by most surgical oncologists when dealing with soft-tissue sarcomas. It classifies sarcomas according to their histologic grade (low or high), depth (superficial or deep), and size (with large tumors more than 5 cm in greatest dimension). Adverse prognostic factors include large tumor size, deep location within the extremity, and high histologic grade.

SYSTEM OF THE AMERICAN MUSCULOSKELETAL TUMOR SOCIETY (ENNEKING SYSTEM)

Orthopedic oncologists generally prefer the Enneking system, which addresses the unique problems related to sarcomas of the extremities and applies to tumors of the bone as well as those of soft tissue. The Enneking system has a 3-point scale for classifying tumors as stage I, II, or III on the basis of their histologic and biologic appearance and their likelihood of metastasizing to regional lymph nodes or distant sites such as the lung. Stage I refers to low-grade sarcomas with less than 25% chance of metastasis. Stage II refers to high-grade sarcomas with more than 25% chance of metastasis. Stage III is for either low-grade or high-grade tumors that have metastasized to a distant site, such as a lymph node, lung, or other distant organ system.

The Enneking system further classifies tumors on the basis of whether they are intracompartmental (type A) or extracompartmental (type B). Type A tumors are constrained by anatomic boundaries such as muscle fascial planes and stand a better chance for local control of tumor growth with surgical removal than type B tumors do. A lesion contained in a single muscle belly or a bone lesion that has not broken out into the surrounding soft tissue would be classified as a type A tumor. A lesion in the popliteal space, axilla, pelvis, or midportion of the hand or foot would be classified as a type B tumor. Although compartmentalization of a tumor is an important concept, studies show that the size of the tumor rather than whether it is contained within a compartment is more prognostic. Larger tumors, greater than 5 cm, are prognostically unfavorable.

A low-grade fibrosarcoma located inside the fascial plane of the biceps muscle and having no evidence of metastasis would be classified as a stage IA tumor. A typical malignant osteosarcoma of the distal femur with breakthrough into the surrounding muscle as determined by MRI would be classified as a stage IIB lesion. If CT scanning revealed metastatic involvement of the lung, the osteosarcoma would then be classified as a stage IIIB lesion.

BENIGN BONE TUMORS

Benign bone tumors have certain characteristics that favor their diagnosis over malignant conditions. If the condition is benign, the patient is frequently asymptomatic, and the radiograph usually shows a well-defined geographic lesion with sclerotic reactive margins that suggest a long-standing process associated with slow growth potential. In contrast, if the condition is malignant, the patient usually complains of pain, and the radiograph commonly shows a more permeative lesion with lytic destruction and poorly defined margins that suggest rapid progression. In many cases, further studies such as MRI or bone isotope studies are not necessary for a typical benign tumor, such as fibrous dysplasia, enchondroma, or nonossifying fibroma. A system of staging exists for benign bone tumors. Stage 1 lesions are considered latent. They generally are asymptomatic but not always. Although they can progress, they usually resolve. Initially, these lesions should be observed. Stage 2 lesions are considered active. They tend not to resolve spontaneously and are less well demarcated than stage 1 lesions. They frequently require surgical intervention with aggressive treatment. Recurrence is not infrequent. Stage 3, or aggressive lesions, demonstrate extensive destruction. Treatment often requires wide en bloc resection.

The more common types of benign bone tumor seen by the practicing orthopedic surgeon are discussed in this section.

Benign Osteoid-Forming Tumors

OSTEOID OSTEOMA

The most common benign osteoid-forming tumor is the osteoid osteoma, accounting for 10% of all benign bone tumors. It is more common in males than in females, with a peak incidence in the second decade of life. The proximal femur is the most common site. Dull aching pain is the most frequent symptom. Symptoms are relieved with nonsteroidal antiinflammatory drugs (NSAIDs) secondary to a high concentration of prostaglandins in the nidus. Osteoid osteoma may have a unique pathogenic nerve supply as well, a unique finding among bone tumors.

The characteristic radiographic feature of the osteoid osteoma is the central lytic nidus that measures up to 1 cm in diameter. In the common cortical lesion (Figure 6–8), an extensive reactive sclerosis is evident, creating a fusiform bulge on the bone surface. However, if the nidus is more centrally located in metaphyseal bone, less sclerosis is seen and the radiographic appearance is less diagnostic. If the nidus is close to a joint or actually in the joint, as in the case of a femoral neck lesion, inflammatory synovitis results and suggests the diagnosis of a pyarthrosis or rheumatoid disease. Technetium bone scans are invariably positive. A CT scan is helpful to better anatomically locate the lesion in preoperative planning.

In the spine, the typical location for an osteoid osteoma is in the posterior elements, such as the lamina or pedicle. The lumbar spine is most commonly involved; the dorsal spine is the second most commonly involved. A secondary scoliosis may develop, with the convexity toward the lesion. Furthermore, if the nidus is in proximity to a nerve root, root irritation can develop. In the lumbar spine, this pain can present as sciatica and suggest the diagnosis of a herniated disk.

Previously, some investigators believed that the osteoid osteoma was an inflammatory process such as a Brodie abscess, which has a similar clinical and radiographic appearance. Currently, it is accepted that osteoid osteoma is a true osteoid-forming neoplasm and absent of lymphocytes or plasma cells. Histologically, the nidus shows aggressive but benign woven bone formation, with large numbers of osteoblasts and osteoclasts in a vascular fibrous stroma. No chondroid areas are seen.

Most cases of osteoid osteoma are stage 1 lesions and can be treated symptomatically with aspirin or NSAIDs. If the patient fails such treatment, surgical intervention is warranted. If surgery is undertaken, the entire symptomatic nidus must be eradicated. Removal of a large amount of the surrounding sclerotic bone should be avoided because it can severely weaken the bone and may result in a pathologic fracture. If the lesion is in cortical bone, adequate exposure is required so the surgeon can visualize the bulging cortex. Intralesional resection via the so-called burr-down technique is generally preferred over en bloc resection. The nidus can be identified visually by the hyperemic pink color in the reactive bone adjacent to it. Simple curettage of the nidus followed by high-speed burring to advance the margin another 2–3 mm is all that is necessary. If the lesion is not visible on the surface, as in the case of a medullary lesion, radiographic markers should be placed intraoperatively prior to placing the round cortical window. CT-guided radiofrequency ablation (RFA) is reported as an effective, less invasive method of treating osteoid osteoma. This method employs probes with high-frequency alternating current to induce ionic agitation and frictional heat to cause tumor necrosis. RFA is used extensively as a less invasive treatment modality with similar success rate as surgical excision.

OSTEOBLASTOMA

Osteoblastoma is a large osteoid osteoma that demonstrates a propensity for the posterior elements of the spine. The tumors are found more commonly in males than in females and occur in the same age group as osteoid osteomas. Osteoblastomas are less common than osteoid osteomas, accounting for 1% of all bone tumors. A few can be found in the metaphyses of long bone (raising suspicion about a possible osteosarcoma), and a few can be seen in the ankle and wrist areas. These lesions are usually stage 1–2 lesions.

Radiographically, the osteoblastoma has a more lytic and destructive appearance than the osteoid osteoma. Its nidus, which is greater than 1–2 cm, has a less sclerotic reactive bone at the periphery and may take on the appearance of an aneurysmal bone cyst. Histologically, the nidus of the osteoblastoma is nearly identical to that of the osteoid osteoma and shows excessive osteoblastic activity and osteoid formation with numerous giant cells in a vascular fibrous stroma.

In the spine area, the effects of osteoblastoma are similar to those of osteoid osteoma, with pressure on nerve roots causing pain down the leg or arm (Figure 6–9). In the thoracic area, a large lesion could result in cord compromise.

In patients with osteoblastomas, treatment usually consists of a vigorous curettage of the lesion, which may require a bone graft if instability results. Radiofrequency ablation may also prove useful in the management of this lesion.

OSTEOFIBROUS DYSPLASIA

Osteofibrous dysplasia is a rare condition that is seen almost exclusively in the tibia of children younger than 10 years. It is more common in boys than in girls and usually asymptomatic. It commonly affects the diaphysis and results in anterior cortical bowing. Osteofibrous dysplasia can occur in the fibula and even more rarely can be seen bilaterally. It is most likely a hamartomatous process and tends to involute spontaneously with skeletal maturity.

In osteofibrous dysplasia (Figure 6–10), the lytic changes seen in the anterior tibial cortex surrounded by sclerotic margins, thus creating a soap-bubbly appearance similar to the radiographic picture of both fibrous dysplasia and adamantinoma. Histologically, the lytic lesion shows a benign trabecular alphabet-soup pattern in a fibrous stroma. The histologic findings are similar to those in fibrous dysplasia, although the lesions of fibrous dysplasia lack the prominent surface layer of osteoblasts seen in osteofibrous dysplasia. These lesions are stage 1–2.

In a report of experience with 35 cases of osteofibrous dysplasia, investigators indicated that early attempts at curettage and grafting of the lesions resulted in a high failure rate because of recurrence. For this reason, they suggested waiting until patients reach the age of 15 years and their disease arrests spontaneously before proceeding with a definitive debridement and bone grafting.

Benign Chondroid-Forming Tumors

ENCHONDROMA

Enchondroma refers to a centrally located chondroma of bone. These tumors are relatively common lesions, accounting for greater than 10% of benign bone tumors. In 50% of cases, the tumor is found in the small tubular bone of the hands and feet. It arises in growing bones as a hamartomatous process but is frequently asymptomatic and may avoid detection until the patient reaches adulthood, at which time the lesion may be discovered in association with a pathologic fracture or as an incidental finding on a routine radiographic examination.

Radiographs of enchondromas show geographic lysis with sharp margination and central calcification (Figure 6–11). In the case of an enchondroma of the hand, the cortex is frequently thinned out with slight dilation. In contrast, with involvement of the large long bones, the lesion is centrally located with minimal evidence of cortical erosion or dilatation. Enchondromas are either stage 1 or 2 lesions.

Multiple enchondromatosis, or Ollier disease (Figure 6–12), is a rare nonfamilial dysplasia typically seen on half of the body and appears similar to fibrous dysplasia. This condition can be quite extensive, with significant involvement of metaphyseal areas resulting in bowing and shortening of the long bones. Such dramatic changes are rarely seen in cases of a solitary enchondroma. In patients with Maffucci syndrome, enchondromatosis is seen in association with multiple soft-tissue hemangiomas.

A large solitary enchondroma in a large bone converts to a low-grade chondrosarcoma in fewer than 5% of cases, and the conversion takes place during adulthood. A solitary enchondroma on the hand rarely converts to a chondrosarcoma. A secondary chondrosarcoma in enchondromatosis can arise in up to 20% of cases and may be related to inactivation of particular tumor suppressor genes.

There is no need to treat an asymptomatic patient with a solitary enchondroma of the hand or foot. If the patient has a pathologic fracture, it is best to allow the fracture to heal and then at a later date to perform a simple curettage and bone grafting procedure, which usually results in good function and a low chance of recurrence. Patients with Ollier or Maffucci disease must be followed carefully because of the increased risk of malignant degeneration.

PERIOSTEAL CHONDROMA

A benign chondroma seen on the surface of a bone is called a periosteal chondroma. Patients usually have more than one lesion, and the most common location is on the proximal humeral metaphysis. Radiographically, the lesions appear to lie on the cortical surface and appear to saucerize the underlying cortex (Figure 6–13). These lesions are stage 1–2. Periosteal chondromas can grow to a sizable mass, but anything larger than 4 cm suggests a peripheral primary chondrosarcoma.

Management of periosteal chondromas generally consists of observing the lesion at intervals to make sure it does not continue growing as the patient reaches adulthood. In cases in which simple local resection without bone graft is indicated, the procedure is associated with a low recurrence rate.

OSTEOCHONDROMA

The nonossifying fibroma of bone is the most common benign tumor of bone, and the solitary osteochondroma is the second most common. Like the enchondroma, the osteochondroma is a developmental, or hamartomatous, process that arises from a defect in the outer edge of the growth plate on the metaphyseal side and results in an exostosis that always points away from the joint of origin as the lesion moves away from the growth plate during the growing years.

The bony base of an osteochondroma is in direct communication with the medullary canal of the bone from which it arises. These lesions can be either pedunculated, as is commonly seen around the knee, or sessile, as is typically seen in the proximal humerus. There must be an associated cartilaginous cap on the bony base to make the diagnosis of osteochondroma (Figure 6–14). This cap has the histologic features of a normal growth plate during the growing years. However, osteochondroma growth plate activity subsides at the same time as the activity in the larger plate from which the osteochondroma arose.

A familial form of osteochondroma, called hereditary multiple exostosis (HME), is an autosomal-dominant disorder that is one tenth as common as solitary osteochondroma. Three genetic loci are associated with HME involving the tumor suppressor EXT genes (EXT1, EXT2, and EXT3). This condition can vary from quite mild to extensive involvement with symmetric limb shortening. Forearm involvement can be quite deforming. The metaphyseal portions of long bones are deformed and widened (Figures 6–15 and 6–16). The histologic findings in multiple exostoses are similar to those in solitary osteochondroma.

Conversion of solitary osteochondroma to chondrosarcoma occurs only during adulthood. The overall rate of conversion for all types of solitary lesions is quite rare. In HME, there is approximately a 1% chance of malignant conversion to secondary chondrosarcoma in the cartilaginous cap, especially in the larger, more proximal lesions.

Osteochondromas are stage 1 lesions. Most children and adults with a solitary osteochondroma are asymptomatic and therefore do not require surgical treatment. In some cases, the lesion may be palpable and irritating. Surgical removal is appropriate in these cases to address the symptoms only and not as a prophylaxis for chondrosarcomatous degeneration. In HME, symptomatic lesions are addressed surgically as needed. Corrective osteotomy is occasionally required because of angulatory deformity in the lower extremity. If a previously quiescent lesion begins to enlarge, in adults with either a solitary osteochondroma or with multiple exostoses, it should be removed. The surgical margin should be wide enough to include the entire cartilaginous cap because this is where malignant degeneration can occur.

CHONDROBLASTOMA

The term chondroblastoma suggests a benign cartilage-forming tumor, but in fact this epiphyseal lesion of childhood has a histologic appearance that is more typical of the benign metaphyseal-epiphyseal giant cell tumor of young adulthood. The chondroblastoma is approximately one fifth as common as the giant cell tumor. It differs from other bone tumors in that it is almost always associated with epiphyseal or apophyseal bone. The majority of cases arise in the second decade of life. Males are affected more often than females. The most common location is the outer portion of the proximal humeral epiphysis, but other common locations are the distal femoral and proximal tibial epiphyseal areas. Because of its proximity to a joint, chondroblastoma can present with a symptomatic joint effusion.

In cases of chondroblastoma, the radiograph demonstrates a lytic tumor with a sharp sclerotic margin and central stippled or flocculated calcification occurring in the chondroid portion of the tumor (Figure 6–17). As the growth plate closes, the tumor can expand gradually into the metaphyseal area, and it sometimes becomes quite aneurysmal, as in the case of a giant cell tumor. The chondroblastoma has the histologic appearance of a giant cell tumor, with numerous macrophages seen usually in areas of hemorrhage. The stromal cells of the chondroblastoma are polyhedral, like those of a giant cell tumor, but with associated halos that give the chondroblastoma a so-called chicken-wire appearance. Although chondroid metaplasia in the chondroblastoma is not easy to find, it must be present to firmly establish the diagnosis. Most chondroblastomas are stage 2 lesions, but some can be stage 3.

The spontaneous conversion of chondroblastoma to a malignant tumor is extremely rare. However, as with the case of giant cell tumors, conversion to sarcoma can occur following radiation treatment. Even though the chondroblastoma is considered benign, it is reported to metastasize to the lung on rare occasions. Nevertheless, it carries an excellent prognosis.

Treatment for chondroblastoma consists of aggressive intralesional resection with curettage; bone graft or bone cement (polymethyl methacrylate) may be used to reconstruct the defect. It is our experience that this suffices, with local recurrence less than 10%. Some authors, however, recommend more aggressive marginal or wide resection.

CHONDROMYXOID FIBROMA

The chondromyxoid fibroma, a very rare tumor, generally affects males in the second or third decade of life. The most common location of the tumor is the proximal tibial metaphysis, followed by the distal femur and the first ray of the foot. The tumor is slow growing and accompanied by mild pain symptoms.

Radiographs of chondromyxoid fibroma show a lytic tumor with sharp sclerotic margins and a pseudoloculated pattern resembling that of a bone cyst. The tumor is eccentrically located in metaphyseal bone with a slightly dilated and thinned-out cortex similar to that shown in Figure 6–18. Histologic findings include a strange but specific mixture of fibrous, myxomatous, and chondroid tissues, which could mistakenly suggest the diagnosis of a chondrosarcoma. The findings also commonly include giant cells, which may suggest the diagnosis of a chondroblastoma seen in epiphyseal bone. This stage 2 lesion is quite active locally, especially in children. With simple curettage and bone grafting, the recurrence rate can approach 25%. Aggressive marginal excision should be performed. The conversion of chondromyxoid fibroma to chondrosarcoma is extremely rare.

Benign Fibrous Tumors of Bone

FIBROUS CORTICAL DEFECT

Fibrous cortical defects, or cortical desmoids, are small hamartomatous fibromas seen almost exclusively in the metaphyseal areas of the lower extremities of growing children. They can be multiple, and as many as 25% of normal children demonstrate these asymptomatic lesions at 5 years of age. The lesions tend to disappear as the result of bone remodeling before skeletal maturity. If excessive stress is placed across the lesions, they can become symptomatic and can also cause findings of increased activity on an isotope bone scan.

In the case of fibrous cortical defects, microscopic studies show benign-appearing fibroblasts with an occasional area of histiocytes, foam cells, and benign giant cells. The radiographic appearance is so characteristic of this entity (Figure 6–19) that a biopsy is usually not necessary. These are stage 1 lesions and can generally be observed.

NONOSSIFYING FIBROMA

Just as the osteoblastoma is considered a larger or more extensive form of osteoid osteoma, the nonossifying fibroma is considered a larger form of the fibrous cortical defect. It is typically seen in the lower extremity of children. Because of its size, it may not entirely resolve by skeletal maturity and can persist into adult life. If the lesion is quite large, approaching 50% of the diameter of the bone, pathologic fracture may ensue. The fracture-healing process may facilitate resolution of the lesions. Careful consideration to fracture prophylaxis should be reserved for large lesions only in children older than 10 years. Nonossifying fibromas are stage 1 lesions, and neither they nor fibrous cortical defects require biopsy because their radiographic appearance is so characteristic.

With nonossifying fibroma, multiple lesions may take on the appearance of fibrous dysplasia and can be associated with café au lait skin defects. Large lesions in the proximal tibia can assume the appearance of a chondromyxoid fibroma (Figure 6–20). The lesions have a well-defined sclerotic margin and a pseudomultiloculated lytic center that gives them a soap-bubbly radiographic appearance. Histologically, they appear identical to fibrous cortical defects and are characterized by benign fibrous tissue speckled with areas of histiocytes, foam cells, and giant cells. As the lesion involutes in adulthood and the number of giant cells and histiocytes diminishes, large areas of cholesterol deposits become evident, which may suggest the diagnosis of a xanthofibroma or xanthoma of bone. Nonossifying fibromas are clearly separated from fibrous dysplasia by the absence of the metaplastic osteoid formation in the fibrous stroma.

FIBROUS DYSPLASIA

Fibrous dysplasia can present in a variety of ways: monostotic, polyostotic, and with or without associated syndromes (Figure 6–21). Most cases are diagnosed within the first three decades and have a distinct female predilection. The monostotic presentation is more common than polyostotic. This condition is a dysplastic anomaly of bone-forming mesenchymal tissue with an inability to produce mature lamellar bone. Accordingly, the bone is arrested in the woven state with a resultant proliferation of spindle cell fibroblasts. In the polyostotic form, it tends to involve one side of the body rather than bilaterally. Nevertheless, it can involve any bone of the body. The most common location is the proximal femur, where it results in the so-called shepherd's crook deformity. Other areas frequently involved include the tibia, pelvis, humerus, radius, and ribs.

In addition to bony involvement, patients can demonstrate café au lait skin pigmentation. These patches usually have a rough border, in contrast to the smooth border of those seen in neurofibromatosis. Patients with fibrous dysplasia may have associated endocrine problems. For example, 5% of patients with the polyostotic form of fibrous dysplasia also exhibit precocious puberty (McCune-Albright syndrome). Other associated endocrine abnormalities include hyperthyroidism, acromegaly, Cushing disease, and hypophosphatemic osteomalacia. Polyostotic fibrous dysplasia with soft-tissue myxomas is known as Mazabrand syndrome. Fibrous dysplasia can also involve the skull and jaw bones, mimicking ossifying fibroma of jaw bone.

In fibrous dysplasia, microscopic findings include an alphabet-soup pattern of metaplastic woven bone scattered through a benign fibrous tissue stroma. This woven stroma has an absence of osteoblastic rimming. Foam cells, giant cells, and cholesterol deposits can be seen. Large cystic areas and even areas of cartilage formation are commonly present.

The molecular basis for fibrous dysplasia is associated with mutations affecting the alpha subunit of G protein. These mutations affect cells of the osteoblastic lineage, resulting in decreased differentiation and increased proliferation. These mutations cause constitutive elevation of cAMP in fibrous dysplasia and thus alter cAMP target genes such c-fos, c-jun, IL-6, and IL-11.

Fibrous dysplasia tends to be active during the growing years and then burns out in adult life. Fewer than 1% of lesions convert to osteosarcoma, fibrosarcoma, or even chondrosarcoma. If conversion does occur, it almost always happens during adulthood. Generally, this disease is either stage 1 or 2.

In pediatric patients with active disease, curettage and grafting should be avoided because of high recurrence rates. The goals in treating pediatric patients should be the prevention and treatment of deformity, especially in the lower extremity. Most cases should become quiescent with skeletal maturity. If not, the best surgical treatment in adults consists of rigid fixation with an intramedullary implant with strut grafting as needed. The best surgical treatment in adults consists of the use of long autogenous fibular struts combined with autogenous cancellous bone graft. This treatment has a higher success rate in the adult group than in the pediatric group. Medical management with bisphosphonates is of benefit in some cases. Irradiation is contraindicated because it may lead to irradiation-induced sarcoma at a later date.

Cystic Lesions of Bone

SIMPLE BONE CYST

Simple bone cysts are a common pseudotumor of bone and the most frequent cause of pathologic fractures in children. Bone cysts typically affect patients between 5 and 15 years of age and occur more often in boys than in girls (2:1) with an incidence of 1 per 10,000 children per year. They are found in the proximal humerus in 50% of cases and in the upper femur in 25%. Patients are asymptomatic until a pathologic fracture occurs. Fractures seem to arise from the central metaphyseal side of an epiphyseal or apophyseal growth plate. The cystic process continues to grow away from the physis. When it remains in contact with the physis it is termed "active." When it separates it is termed "inactive."

Radiographs typically show a solitary cyst that is centrally located in the metaphyseal area and has marked thinning of the adjacent cortical bone and a pseudoloculated appearance (Figure 6–22). The bone cyst is filled with a clear serous fluid, and there is increased pressure during the active phase. The fact that this pressure gradually decreases as the cyst becomes inactive suggests a hydrodynamic mechanism.

The cyst cavity, lined with a fibrinous membrane that contains giant cells, foam cells, and a slight osteoid formation, is similar to the fibrous tissues seen in other fibrous bone lesions, including fibrous dysplasia. The periosteal covering in the area of a cyst is normal, and thus the pathologic fractures heal normally and in most cases do not require surgery. Unfortunately, the cyst usually persists after fracture union and requires further treatment. Bone-resorbing factors, such as matrix metalloproteinases, prostaglandins, IL-1, IL-6, tumor necrosis factor alpha (TNF), and oxygen free radicals, are demonstrated in the cyst fluid. Elevated nitrate and nitrite levels are also noted to be higher in the cyst fluid than in serum.

Before the mid-1970s, the standard treatment for a solitary bone cyst was aggressive curettage or even resection followed by bone grafting. In patients with active disease, the recurrence rate was 30–50%, and repeated grafting was frequently necessary. In patients with inactive disease, particularly those older than 15 years, the surgical results were much better and the recurrence rate was lower. Unicameral bone cysts are generally considered stage 1 lesions, but occasionally they may be stage 2. Currently, treatment is a function of location. In weight-bearing bones, such as the proximal femur, lesions should be treated aggressively. Initial management usually involves aspiration/injection with either bone marrow or corticosteroid. The injections are carried out with bone biopsy needles and are repeated three to five times at intervals of 2–3 months, depending on the radiographic response. The best results are when the patient is between 5 and 15 years of age, at which time the disease is active and macrophage activity is greatest in the cyst lining. Curettage and bone grafting may also be an effective modality. Demineralized bone matrix injected in combination with autogenous bone marrow shows encouraging results, with an approximately 20% recurrence rate and low morbidity.

Physicians should note that sarcomas can take on the radiographic appearance of a solitary bone cyst. For this reason, if needle aspiration does not reveal cystic fluid or if it is impossible to inject contrast material and obtain radiologic confirmation of the diagnosis, an open biopsy is indicated to rule out a sarcoma.

ANEURYSMAL BONE CYST

Aneurysmal bone cyst is a hemorrhagic lesion with many characteristics of a giant cell tumor but occurs only half as frequently. Although 75% of the cases of aneurysmal bone cyst occur in patients 10–20 years old, giant cell tumor is rare in patients younger than 20 years of age. Both aneurysmal bone cyst and giant cell tumor are more common in females than in males. The femur is the most frequently affected site, followed by the tibia, pelvis, and spine. In the spine, two thirds of aneurysmal bone cysts arise from posterior elements and one third arise from the vertebral body, whereas most giant cell tumors arise from the vertebral body.

Initially, the aneurysmal bone cyst appears on radiograph as an aggressive osteolytic lesion with extensive permeative cortical destruction that gives the impression of a malignant process such as Ewing sarcoma or hemorrhagic osteosarcoma. Next, a large aneurysmal bulge occurs outside the bone, with a thin reactive shell of bone forming at the outer edge. Less soap-bubbly pseudoseptation is seen in an aneurysmal bone cyst than in a solitary cyst (Figure 6–23).

At the time of biopsy, the aneurysmal bone lesion demonstrates large hemorrhagic cysts, but bleeding is modest. The hemorrhagic cysts are broken up by thick spongy fibrous septa that histologically contain great numbers of large giant cells and have thin osteoid seams. Even if a few mitotic figures are seen, the diagnosis of a benign lesion can remain. A carefully placed biopsy with multiple samples is needed to rule out other well-known skeletal tumors that may demonstrate an aneurysmal component. These include giant cell tumor, chondromyxoid fibroma, and malignant hemorrhagic osteosarcoma. Some authors believe there is no such entity as the aneurysmal bone cyst and that it is merely a morphologic variant of some other underlying neoplastic process. Like the solitary bone cyst, this cyst may have a hydraulic pressure origin that is secondary to hemorrhage and could be traumatically induced. However, abnormal cytogenetic findings were noted in aneurysmal bone cysts, which may suggest a distinct cellular pathogenetic etiology. Specifically, a t(16,17) translocation resulting in a CDH11-USP6 fusion gene product is frequently observed in aneurysmal bone cyst. Aneurysmal bone cyst is either a stage 2 or 3 lesion and frequently symptomatic.

If an aneurysmal cyst is left untreated, it may involute spontaneously, during which time it develops a heavy shell of reactive bone at the periphery. This involutional process can be hastened by surgical curettage and bone grafting. Radiation is no longer recommended. Another option for treating extremely large lesions is repeated embolization to reduce the rate of hemorrhagic expansion.

EPIDERMOID CYST

The least common bone cyst is the epidermoid bone cyst. This lesion is found either in the distal phalanx or in the skull. No other bone is affected. In the case of the phalanx, the cyst is usually the result of nail bed epithelium being driven into the subjacent distal phalanx by a crushing blow. The ectopic squamous epithelium produces a keratinized cavity that is filled with clear fluid and creates a surface erosion with a sclerotic reactive base (Figure 6–24). The bulbous cyst seen at the fingertip transilluminates with flashlight examination. Other conditions that might have a similar appearance are the glomus tumor and the enchondroma. The epidermoid cyst is treated with a simple curettage and, in some cases, a bone graft.

Giant Cell Tumor of Bone

Numerous types of tumors contain giant cells but are not true benign giant cell tumors. Most of the variants are seen in children and include aneurysmal bone cyst, chondroblastoma, simple bone cyst, osteoid osteoma, and osteoblastoma. The giant cell–rich osteosarcoma is the most malignant of the variants, and it is sometimes difficult to distinguish from an aggressive benign giant cell tumor. The giant cell reparative granuloma is a benign variant seen in jaw bones or hand bones and has more spindle cells than a classic giant cell tumor. The brown tumor of hyperparathyroidism is a nonneoplastic variant seen in both primary and secondary hyperparathyroidism. Only after all of the variant conditions are excluded can the diagnosis of benign giant cell tumor be made. Giant cell tumor of bone is now associated with overexpression of osteoprotegerin ligand (OPGL), an important stimulator of osteoclast differentiation, suggesting overactivity of osteoclast in the etiology of this neoplasm.

Between 5% and 10% of all benign bone tumors are true giant cell tumors, occurring most frequently in the third decade of life. They are more frequently found in females than in males. In approximately half of the cases, the tumor is found about the knee. The next most common locations are the distal radius and sacrum. The tumor is usually painful for several months prior to diagnosis and can cause a pathologic fracture. It can also cause a painful effusion because of its juxtaposition to a major joint. Giant cell tumors may present as either stage 2 or stage 3 disease and less frequently as stage 1. On radiograph, the lesion appears lytic in nature and is located in the epiphyseal-metaphyseal end of a long bone (Figure 6–25). The lesion grows toward the joint surface and frequently comes into contact with articular cartilage but rarely breaks into the joint.

Like the chondroblastoma, the benign giant cell tumor has a 1–2% chance of metastasizing to the lung. Recurrent tumors have a 6% chance. Accordingly, pulmonary staging is an importantcomponent in the initial evaluation and follow-up of giant cell tumor of bone. The prognosis for survival with this complication is favorable, and the tumors may resolve spontaneously. The benign giant cell tumor can later convert to a malignant condition such as an osteosarcoma or malignant fibrous histiocytoma. It is generally believed that this is secondary to treatment. A conversion rate of 15–20% is reported in patients who were treated previously with more than 3000 cGy of radiation, with conversion occurring 3 or more years after treatment. The conversion rate in patients who do not receive radiation therapy is less than 5%. This finding has come into question with newer radiation therapy modalities.

Until recent years, the standard treatment for giant cell tumor was curettage and bone grafting. The recurrence rate with this treatment was reported as up to more than 50%. Follow-up treatment consisted of an aggressive resection of the recurrent lesion and reconstruction with a large osteoarticular allograft, endoprosthesis, or an excisional arthrodesis. Currently, most surgeons elect an aggressive curettage, followed by high-speed burring and adjuvant phenol, hydrogen peroxide, or liquid nitrogen and by the subsequent packing of the defect with bone cement. With this new approach, the recurrence rate is between 10% and 25%. When giant cell tumor infrequently involves an expendable bone such as the proximal fibula or ilium, it should be primarily resected. En bloc resection continues to be used to treat multiple recurrent tumors, intensive soft-tissue involvement, or massively destructive cases. Embolization may also prove palliative or curative in unresectable cases. For advanced, multiply recurrent, or aggressive metastatic cases, investigators are developing experimental medical protocols. Close follow-up for locally recurrent disease and pulmonary involvement is critical. Surveillance should include a plain chest radiograph every 6–12 months for the first 2–3 years at least.

Hemangioma

Hemangioma of bone is a hamartomatous process that occurs more frequently in females than in males. It is most commonly found in vertebral bodies (Figure 6–26). It is found only rarely in the diaphysis of long bone. Hemangiomas of bone can be associated with hemangiomas of soft tissue. The spinal lesion is usually discovered as an incidental radiographic finding and demonstrates a characteristic vertically oriented honeycombed or moth-eaten appearance. On rare occasions, a lesion can cause cord compression that may require surgical resection. In such cases, preoperative angiography is critical in evaluating the vascular blood supply to the spinal cord. Alternatively an attempt at arterial embolization may prove successful and is less aggressive.

Gorham disease, characterized by massive osteolysis in children or young adults, is usually associated with the presence of benign cavernous hemangiomas or lymphangiomas of bone. This strange condition usually affects a particular area (such as the spine or the hip) but can involve multiple bones of that area and tends to resolve spontaneously.

MALIGNANT BONE TUMORS

Osteoid-Forming Sarcomas

Aside form multiple myeloma, osteosarcoma of bone is the most common primary malignant tumor of bone, constituting 20% of all primary malignancies of bone. In the United States, between 500 and 1000 new cases are diagnosed each year. The global incidence is felt to be between 1 and 3 per million people annually. There are currently many subtypes of osteoid-forming sarcomas, ranging from the extremely low-grade variants, such as the parosteal osteosarcoma, to the extremely high-grade variants, such as osteosarcoma secondary to Paget disease.

The molecular pathobiology of osteosarcoma is a subject of intense investigation. Several gene families were investigated as potential biomarkers of disease progression. Among these are genes involved in angiogenesis (eg, vascular endothelial growth factor, or VEGF), growth factors and their receptors (eg, transforming growth factor-beta, Wnt receptor LRP5, HER2), cytoskeletal protein (eg, ezrin), and cellular senescent protein (ie, telomerase).

This discussion begins with the more common, central form of sarcoma that is seen in children and known as classic osteosarcoma.

CLASSIC OSTEOSARCOMA

The classic form of osteosarcoma is typically seen in patients in their second or third decade, with a peak in the adolescent growth spurt. It occurs more frequently in males than in females and is found in the metaphyseal areas of long bones, with 50% of lesions seen about the knee joint (Figures 6–27 and 6–28). The distal femur is the most common site, followed by the proximal tibia and then the proximal humerus. It is rare to see osteosarcoma in small bones of the feet or hands or in the spine. When seen in the foot, it occur in the larger bones of the hindfoot. The prognosis is more favorable for a tumor in a small bone than for one in a large bone.

Most patients with classic osteosarcoma have symptoms of pain before a tumor mass is noticeable. A mass near a major joint may exist for several weeks or even as long as 4 months before a diagnosis is made. Dilated veins may be seen in the overlying skin. The radiographic findings include permeated lytic destruction of metaphyseal bone, with eventual cortical breakthrough into the subperiosteal space and subsequent formation of the Codman triangle at the diaphyseal end of the tumor. As the tumor continues to push its way into the extracortical soft tissue, a typical sunburst pattern neoplastic bone may be seen outside the involved bone.

In less than 2–25% of cases, an additional lesion may be found at a higher level in the femur. Such a so-called skip lesion may portend a worse probability of survival and should be considered a true metastatic focus (stage III [Enneking], stage IV [AJCC]). Approximately 50% of osteosarcomas are of the more typical osteoblastic type, followed by chondroblastic, with a small percentage of them fibroblastic. Whether the subtype portends a better or worse prognosis is controversial. Confounding variables such as multidrug resistance (p-glycoprotein expression) may be differentially expressed in different subtypes. P-glycoprotein overexpression itself bears a substantial relationship to clinical outcome.

Staging of osteosarcoma must include an MRI of the involved extremity (Figure 6–29). This technique offers excellent contrast of the extracortical portion of the tumor and at the same time gives good intramedullary contrast of the high-signal tumor next to a low-signal fatty marrow. The periphery of the tumor can readily be appreciated and represents the most anaplastic and rapidly growing part of the tumor. This region is the best tissue for a biopsy because it is easy to reach, soft enough for a diagnostic frozen section, and representative of the most aggressive portion of the tumor. Furthermore, the MRI provides the necessary anatomic data to determine the level of transection through the femur for a safe margin and to determine whether a limb-sparing procedure is feasible.

Before the advent of adjuvant multidrug chemotherapy, the treatment for osteosarcoma was radical amputation. Eighty percent of these patients proceeded to die from disseminated pulmonary disease. Today, with the combination of chemotherapy and surgical treatment, the prognosis for 5-year survival approaches 70%.

The drugs commonly used today include high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide. They are administered intravenously in cyclic intervals of 3–4 weeks for approximately 11–15 weeks prior to surgery. Surveillance imaging studies are performed during this period to assess possible reduction in tumor volume. Tumor necrosis secondary to neoadjuvant chemotherapy, determined at the time of tumor resection, is an important prognostic factor. Patients with greater than 90% tumor necrosis have a significantly improved 5-year survival rate, approaching 85%. Approximately half of patients demonstrate this response to current chemotherapy regimens. Furthermore, the postoperative drug regimen can be adjusted based on this evaluation.

In extremity osteosarcoma, limb-sparing surgery, with wide resection of the tumor, is the standard approach. Amputation is reserved for the exceptional or recurrent case. In less than 10% of cases, amputation is performed at a level approximately 5 cm above the upper pole of the tumor. Limb salvage techniques continue to evolve with reconstruction options including large prostheses, structural allografts, and composites reconstructions. Endoprosthetics are composed of modular components in various lengths, linked together with taper fittings (Figures 6–30 and 6–31). The intramedullary stems are of various diameters and lengths and usually cemented. The immediate functional results are excellent, with minimal early complications. However, subsequent loosening at 5–10 years occurs in as many as 15–30% of cases. Another limb-sparing procedure consists of the use of an osteoarticular allograft alone or in combination with a prosthesis. The major drawback with large bone allografts is a 10–15% chance of infection, nonunion, or stress fracture, especially in the immunosuppressed patient receiving chemotherapy. The use of an excisional arthrodesis was more popular in the past but is rarely elected today because patients have better function with a mobile joint.

Prior to the introduction of chemotherapy, the finding of a pulmonary metastasis portended a very poor prognosis. Today, however, in larger tumor centers where aggressive surgical approaches with multiple thoracotomies and continued chemotherapy are used, the 5-year survival rate is approximately 30%.

Molecular oncologic evaluation of osteosarcoma specimens is beginning to elucidate factors involved in its pathogenesis. The p53 suppressor genes have an increased mutation rate in osteosarcoma. However, wild-type TP53 and MDM2 assays in and of themselves are not of prognostic value. Loss of heterozygosity of the Rb gene is a predictive feature of osteosarcoma. The F33 isoform also demonstrates a strong correlation with osteosarcoma disease progression. ErbB-2(HER-2/neu), a protooncogene and transforming growth factor-beta, isoform 3 expression is also correlated with a worse prognosis in osteosarcoma patients. Controversy surrounds the significance of cytoplasmic versus membranous staining in HER-2/neu expression as relates to prognosis in osteosarcoma.

HEMORRHAGIC OR TELANGIECTATIC OSTEOSARCOMA

Telangiectatic osteosarcoma, an extremely lytic and destructive variant of classic osteosarcoma, is seen in the same age group and location. Its radiographic appearance is similar to that of an aneurysmal bone cyst, thereby making the diagnosis difficult (Figure 6–32). The pathologic specimen is hemorrhagic, with microscopic evaluation demonstrating the presence of malignant-appearing stromal cells with giant cells.

Because hemorrhagic osteosarcoma is a high-grade, purely lytic tumor, the incidence of pathologic fracture in the early course of the disease is high. If significant contamination of the adjacent neurovascular structures results, a pathologic fracture may necessitate amputation rather than limb salvage (Figure 6–33). This situation must be carefully evaluated with a preoperative MRI. Accordingly, in cases with significant risk for fracture during the preoperative treatment regiment, it may be appropriate to immobilize the involved extremity or proceed with limb-sparing surgery earlier than usual. Prior to the advent of aggressive multidrug chemotherapy, the prognosis for patients with hemorrhagic osteosarcoma was extremely poor. At present, however, it is the same as the prognosis for patients who have classic osteosarcoma and is treated with similar protocols.

PAROSTEAL OSTEOSARCOMA

Parosteal osteosarcoma is a low-grade variant arising in an exophytic pattern from the cortical surface of bone. There is no medullary involvement. It is low-grade with a 5-year survival rate in excess of 90% and a 10-year survival rate of 80%. It accounts for 3–4% of all osteosarcomas.

The tumor is composed of a spindle-cell fibroblastic component with well-developed bone trabeculae. There also may be areas of cartilage present. Osteoblasts are well differentiated, and few mitotic figures are present.

Parosteal osteosarcoma is more common in females than in males and affects a slightly older age group than classic osteosarcoma (see Table 6–2). It is a slow-growing tumor with minimal symptoms initially. It is metaphyseal in origin, with the vast majority of cases involving the posterior aspect of the distal femur (Figure 6–34).

Because the parosteal osteosarcoma is low grade, it does not respond well to either chemotherapy or radiation therapy. Therefore, the only treatment is wide surgical resection. This usually requires distal femoral removal, but in smaller cases side resection of the posterior cortex and tumor only may be feasible, sparing the knee joint. Nevertheless, a negative tumor margin is imperative. Otherwise, recurrence is likely. Recurrence may occur as late as 5–10 years because of the tumor's slow growth.

On occasion, low-grade parosteal osteosarcoma can dedifferentiate into a high-grade sarcoma. Such a lesion carries a similar prognosis to classic osteosarcoma.

PERIOSTEAL OSTEOSARCOMA

Periosteal osteosarcoma is another surface osteosarcoma of low to intermediate grade. This lesion represents less than 2% of all osteosarcomas. It arises beneath the periosteum, elevating it and inducing vigorous neoosteogenesis with a predominant chondroblastic differentiation. It is slightly more common in females, with a peak incidence in the second decade of life. It almost exclusively arises in the long bone. The lesion can mimic an aneurysmal bone cyst or periosteal chondroma radiographically (Figure 6–35).

Because of its low to intermediate grade, periosteal osteosarcoma is generally not treated with chemotherapy but may be in more advanced cases. Wide surgical resection is the modality of choice. Because periosteal osteosarcoma is a low-grade tumor, it carries a better prognosis than the classic osteosarcoma. Approximately 25% of patients succumb to metastatic disease within 2–3 years. The surgical treatment is usually a limb-sparing procedure, and because the tumor is more diaphyseal in location, the adjacent joints may often be spared.

SECONDARY OSTEOSARCOMA

Osteosarcoma can arise from benign disease through a process that may involve a second mutation and usually occurs at a later age (see Table 6–2). Among the benign conditions that can result in secondary osteosarcoma are Paget disease, osteoblastoma, fibrous dysplasia, benign giant cell tumor, bone infarction, and chronic osteomyelitis.

The classic example of a secondary osteosarcoma is seen in a small percentage of patients with Paget disease. Pagetic osteosarcomas, which represent approximately 3% of all osteosarcomas, are the most common osteosarcomas in the older (more than 65 years) age group. The most frequent location for pagetic osteosarcoma is the humerus, followed next by the pelvis and femur. The typical patient has a long history (15–25 years) of dull, aching pain associated with the inflammation of Paget disease before a new acute pain arises in an area of recent lytic destruction and the diagnosis of pagetic osteosarcoma is established (Figure 6–36). The prognosis for patients with pagetic osteosarcoma is extremely poor (5-year survival rate of approximately 8%). Because of the older age group involved, chemotherapy is usually not an option secondary to intolerance.

LOW-GRADE INTRAMEDULLARY OSTEOSARCOMA

Another rare and low-grade osseofibrous variant of osteosarcoma is the central or intramedullary form. Although this variant has a microscopic appearance similar to that of the parosteal osteosarcoma, it is usually located in metaphyseal bone about the knee joint in adults between 15 and 65 years of age. Males and females are equally affected. Radiographically, intramedullary osteosarcoma creates a sclerotic density in metaphyseal bone (Figure 6–37). Like the parosteal osteosarcoma, the low-grade intramedullary osteosarcoma carries an excellent prognosis and can be treated with local surgery alone.

IRRADIATION-INDUCED OSTEOSARCOMA

Radiation-induced osteosarcoma may arise after any form of significant radiation exposure (in excess of 30 Gy) (Figure 6–38). Onset is usually delayed an average of 15 years (range: 3–55). Other irradiation-induced sarcomas, besides the osteosarcoma type, include irradiation-induced fibrosarcoma and malignant fibrohistiocytoma. All of these secondary sarcomas are invariably high grade and carry a poor prognosis for survival, with a very high rate of metastasis.

MULTICENTRIC OSTEOSARCOMA

Multicentric osteosarcoma has two clinical presentations: (l) synchronous, occurring in childhood and adolescents, and (2) metachronous, occurring in adults. The synchronous type is a high-grade sclerosing intramedullary type, which is lethal. The adult form is less aggressive, with a lower histologic appearance, but prognosis remains grim (Figure 6–39).

SOFT-TISSUE OSTEOSARCOMA

Osteosarcoma can occur in muscle tissue outside bone and accounts for approximately 4% of all osteosarcomas (Figure 6–40). Soft-tissue osteosarcoma is rarely seen in patients younger than 40 years. The number of cases is equal in males and females, and the tumor is usually seen in large muscle groups of the pelvis and thigh areas.

Soft-tissue osteosarcoma must be differentiated from the more common myositis ossificans. Although soft-tissue osteosarcoma shows heavy mineralization in the central area (see Figure 6–40), myositis ossificans has a zonal pattern of ossification, with the mature dense ossification concentrating at the periphery of the lesion.

The treatment of the soft-tissue form of osteosarcoma is the same as for the high-grade osseous form and includes a wide resection and adjuvant chemotherapy. The prognosis is worse with the soft-tissue form of osteosarcoma, with a high rate of chemotherapy resistance.

Chondroid-Forming Sarcomas

Chondroid-forming sarcomas are a heterogenous group of neoplasms consisting of a cartilage-based histology. A cornerstone to the diagnosis of chondrosarcoma is the absence of osteoid formation. If any osteoid is present with a malignant stroma, the tumor is considered an osteosarcoma with chondroblastic features. It is important to make the distinction because chondrosarcomas behave differently from osteosarcomas. However, this can be a difficult task. The surgeon must consider the age of the patient and carefully assess the radiographic and histologic features to confirm the diagnosis.

PRIMARY OR CENTRAL CONVENTIONAL CHONDROSARCOMA

The typical primary chondrosarcoma is a low-grade tumor seen in adults between 30 and 60 years of age. The tumor is found more frequently in men than in women. Minimal symptoms of pain may occur over a period of several years before a radiograph is obtained. The pelvis and femur are the most common locations, followed by the rib cage, proximal humerus, scapula, and upper tibia. Primary chondrosarcoma is extremely rare in small bones, including the hand and foot. The metaphysis is the most common location in a long bone; however, a diaphyseal location is not unusual.

Approximately 85% of central chondrosarcomas are low-grade lesions with a typical matrix calcification that can be described as flocculated. The high-grade lesions are rare, and radiographically they lose their typical lobulated and calcific pattern and take on the appearance of a more permeative high-grade tumor, such as a malignant fibrous histiocytoma. At the same time, histologically the high-grade chondrosarcomas lose their chondroid matrix pattern, which is replaced with that of a more aggressive spindle-cell tumor.

The radiologic feature that clearly separates this lesion from a benign enchondroma is the permeative lysis seen in the surrounding cortex (Figure 6–41). Because of the weakened cortex, the patient usually complains of local pain not experienced with an enchondroma. Because most chondrosarcomas are low grade, they do not respond well to adjuvant irradiation or chemotherapy. Therefore, aggressive surgical management is imperative. However, optimal surgical management is controversial. Although wide en bloc resection is ideal from a margin standpoint, it can often produce considerable morbidity. On the contrary, aggressive intralesional resection (curettage) and margin expansion with an adjuvant therapy (eg, phenol or liquid nitrogen) can reduce morbidity and may provide equal local control. In fact, some authors found that for grade 1 chondrosarcoma the margin of resection is not significant in terms of local recurrence or disease progression.

In general, the prognosis for low-grade central chondrosarcoma is very good, with a low rate of pulmonary metastasis if the primary lesion is widely resected. Nevertheless, recurrences can occur late, even over 15 years later. For any intermediate- or high-grade chondrosarcoma, wide, en bloc resection is mandatory (Figure 6–42).

SECONDARY CHONDROSARCOMA

The vast majority of secondary chondrosarcomas arise from osteochondromas in patients afflicted with HME. Patients with solitary osteochondromas do not generally form secondary chondrosarcomas in their lesions, making prophylactic removal unnecessary and unwarranted unless the solitary lesion is otherwise symptomatic. Even in patients with HME, the rate of malignant degeneration is less than 1% and generally does not occur in patients prior to skeletal maturity. However, patients with secondary chondrosarcoma tend to be younger than those with primary chondrosarcomas (see Table 6–2). The lesions tend to be slow growing with minimal to mild symptoms. The most common site is the pelvis, followed by the proximal femur, proximal humerus, and ribs. Plain radiographs demonstrate a flocculated calcific pattern (Figure 6–43). Anything thicker than 1–2 cm should raise suspicion of a secondary chondrosarcoma. The overall prognosis for patients with secondary or peripheral chondrosarcoma is even better than that for patients with primary or central chondrosarcoma. Surgical removal, without violation of the cartilage cap, is the only effective treatment modality.

DEDIFFERENTIATED CHONDROSARCOMA

Dedifferentiated chondrosarcoma is the most malignant variant of chondrosarcoma, accounting for between 5% and 10% of all chondrosarcomas. It is heralded by the transformation of areas of conventional chondrosarcoma into malignant fibrous histiocytoma or osteosarcoma. Histologically, it is characterized by two distinct but neighboring areas of low- to intermediate-grade malignant chondroid tumor and heterogenous high-grade sarcoma. Dedifferentiated chondrosarcoma occurs in older patients, usually between 50 and 70 years of age. It is found in the same areas affected by central primary chondrosarcomas, including the pelvis, femur, and proximal humerus (Figure 6–44). Radiographs show areas of rarefication within the tumor with cortical attenuation. Pathologic fracture is not uncommon.

The prognosis in dedifferentiated chondrosarcoma is bleak, with the majority of patients developing and dying of metastatic disease within 1 year (historically, 1-year survival rate approached 10%). Chemotherapy and radiation therapy are less effective than in a malignant fibrous histiocytoma or osteosarcoma that arose de novo. Surgical resection remains the mainstay of treatment, with adjuvant modalities employed in younger patients.

CLEAR CELL CHONDROSARCOMA

Clear cell chondrosarcoma is a rare low-grade variant of chondrosarcoma. Clear cell lesions occur more often in males than in females and are usually seen in patients between 20 and 50 years of age. The vast majority of lesions are found in the femoral head (Figure 6–45). The radiographic appearance is one of a lytic tumor with sharp margination and a central matrix calcification, creating the appearance of a chondroblastoma. Although microscopic examination reveals the presence of some giant cells, as seen in a chondroblastoma, areas of low-grade chondrosarcoma are also evident in which no giant cells are seen. Even on gross examination, the clear cell chondrosarcoma does not look like a chondrosarcoma, which explains why it is frequently mistaken for a chondroblastoma in younger adult patients. The tumor cells have abundant glycogen, giving them their characteristic clear cell phenotype. Although no significant genetic alteration is found in clear cell chondrosarcoma, newer findings show that alkaline phosphatase activity may correlate with prognosis.

The treatment for clear cell chondrosarcoma is a wide excision and reconstruction. The prognosis with this type of treatment is good. In contrast, when lesions are mistaken for chondroblastomas and treatment consists of a simple curettage and bone grafting, the prognosis is poor and the recurrence rate is high.

MESENCHYMAL CHONDROSARCOMA

Another rare variant of chondrosarcoma is the mesenchymal chondrosarcoma. It is a highly cellular tumor composed of primitive mesenchymal cells with foci of cartilage differentiation. This tumor involves the soft tissue in a third of cases, occurs more frequently in females than in males, and is seen in young adults (see Table 6–2). The jaw is the most common location, followed by the spine and ribs, with very few cases noted in long bones.

Mesenchymal chondrosarcoma is a high-grade tumor with histologic features of low-grade chondrosarcoma. Heavily calcified areas, mixed with areas of malignant round cells, may give it the appearance of Ewing sarcoma or hemangiopericytoma.

Treatment consists of resection, with a wide margin if possible, and adjuvant chemotherapy and radiation therapy. Despite aggressive treatment, the prognosis is very poor, with a high incidence of pulmonary metastasis.

Round Cell Sarcomas

This so-called group of tumors is composed of distinct tumors that, other than their similar microscopic appearance using hematoxylin-eosin stain, are quite different. They behave and are treated in a variety of ways, given that each arises from a different cell type.

THE EWING FAMILY OF TUMORS

Ewing Sarcoma

Ewing sarcoma is a well-known clinical entity originally described by James Ewing as a diffuse endothelioma of bone. Since the time of his description, many theories have evolved regarding the tumor's true histogenesis. Based on electron microscopic and immunohistochemical findings, experts currently believe the tumor represents an undifferentiated member of the family of neural tumors distinct from neuroblastoma. Cytogenetic studies identified a chromosomal abnormality with a reciprocal translocation in chromosomes 11 and 22 seen in 90% of cases. This translocation is also seen in primitive neuroectodermal tumor (PNET) and Askin tumors. The breakpoints were cloned, and it is now known that the Ewing sarcoma and FLI1 genes are involved. The Ewing sarcoma gene encodes a homologous sequence to the RNA binding site in RNA polymerase II. The FLI product is a transcription factor. Accordingly, in the resultant fusion protein, the FLI1 transcription factor is placed under control of the Ewing sarcoma promoter. Two other translocations are also described in Ewing/PNET: t(21:22) and t(7:22).

In 90% of cases, Ewing sarcoma is found in patients between 5 and 25 years of age. If the patient is younger than 5 years, the most likely diagnosis is metastatic neuroblastoma. Males are affected more frequently than females and carry a worse prognosis. The pelvis is the most common location, followed by the femur, tibia, humerus, and scapula. However, because Ewing sarcoma is a myelogenous tumor, it can be found in any bone in the body.

Ewing sarcoma appears radiographically as a central lytic tumor of the diaphyseal-metaphyseal bone. It creates extensive permeative destruction of cortical bone, and as it breaks through under the periosteum, it takes on a typical onionskin, multilaminated appearance. Another radiographic feature is the reactive hair-on-end appearance created by bone forming along the periosteal vessels that run perpendicularly between the cortex and the elevated periosteum (Figure 6–46).

Ewing sarcoma can frequently masquerade as osteomyelitis because it is a high-grade lesion with resultant areas of necrosis, liquefaction may occur that may be mistaken for pus. Furthermore, patients frequently present with systemic symptoms of low-grade intermittent fever, elevated white cell count, and erythrocyte sedimentation rate (ESR).

Microscopically, small roundlike cells predominate in densely packed sheets. Formation of pseudorosettes may also be seen (in less than 20%). The rosette-like patterns are more frequently seen in PNET.

Ewing sarcoma is an aggressive malignancy with a high local recurrence and metastatic rate. Patients with locally resectable disease treated with multidrug chemotherapy have a 5-year survival rate of approximately 70%. Unfortunately, 15–25% of patients present with nonlocalized disease. For the patient who presents with advanced, metastatic disease, the 5-year survival rate is 30%. Resection of lung metastasis, if possible, does improve survival.

Ewing sarcoma is a radiosensitive tumor. Historically, this was a modality of choice employing 45–50 Gy over 5 weeks to treat local disease. Because of the not insignificant risk of secondary sarcomas, surgery was investigated as the primary modality for local control. If the margins are contaminated, local irradiation must still be used postoperatively. However, prospective well-controlled studies do not yet clearly establish that surgery significantly improves survival without radiation.

Primitive Neuroectodermal Tumor

PNET is the less common relative to Ewing sarcoma. Like Ewing, this tumor demonstrates expression of neural markers by immunocytochemistry. PNET also exhibits the t(11:22) translocation with the resulting EWS/FI1-fusion protein. In fact, because of such similarities, it is generally agreed that PNET and Ewing represent ends of a spectrum of disease.

By strict criteria, PNET is a rare tumor, representing approximately 10% of Ewing-like tumors. The demographics are identical to those of Ewing-like tumors. Treatment of PNET is similar to that of Ewing; however, the survival rate is slightly less. Accordingly, some authors feel it should be distinguished from Ewing.

LYMPHOMA

Lymphoblastic tumors are considered systemic neoplasms of the lymphatic organs, including the bone marrow, and they account for 7% of all malignant bone tumors. They can be roughly divided into Hodgkin lymphomas and non-Hodgkin lymphomas, both of which can affect bone. Of the two groups, the lymphomas associated with Hodgkin disease carry a much better prognosis. When they are found in bone, they tend to be localized and have a considerable blastic response, especially when involving the vertebra.

There are two main types of non-Hodgkin lymphomas. The type emphasized in this section is the primary lymphoma of bone, in which a localized lytic destruction occurs in a single bone, and the results of staging studies (including an isotope bone scan, a CT scan of the chest and abdomen, and marrow aspiration) all prove negative for other areas of involvement. The other type is the more generalized or systemic form of lymphoma, in which many lymphoid organs are involved, including the lymph nodes, liver, spleen, and bone. The prognosis is better for an isolated primary lymphoma of bone, but years later involvement may become generalized or systemic and carry a worse prognosis. This is similar to the case with plasma cell tumors, in which the findings in a patient can change from that of a solitary plasmacytoma with an excellent prognosis to that of the multiple myeloma form of the disease with a poor prognosis.

Primary lymphoma of bone, which was formerly called reticulum cell sarcoma of bone, accounts for approximately half of all lymphomas. To meet the criteria of being a primary bone lymphoma, there must be a 4–6-month interval from the onset of skeletal manifestations to the development of systemic disease. It occurs more frequently in males than in females, is usually found in patients older than 25 years, and affects the spine or pelvis in more than 50% of the cases. In the extremities, the femur is the most commonly involved area, followed next by the humerus and the tibia. Multiple skeletal involvement occurs in 10–40% of cases.

Radiographic findings in primary lymphoma include extensive lytic permeation of cortical bone, with minimal sclerotic response in diaphyseal, metaphyseal, and epiphyseal locations (Figure 6–47). MRI studies demonstrate that the actual marrow involvement is frequently more extensive than the cortical disruption seen on simple radiographs suggests.

The most common histologic types of lymphoma of bone are the large cell or mixed small and large cell types. The cells tend to demonstrate little cytoplasmic structure. However, the nuclear pattern shows indented and folded nuclear patterns and a prominent pink-staining nucleolus, which may help to distinguish it histologically from Ewing sarcoma. Immunohistochemical staining is often necessary to differentiate Ewing sarcoma from the B-cell and T-cell subtypes of lymphoma. In the case of lymphomas, the glycogen stain is usually negative, but the reticulum stain is often positive.

In primary lymphoma of bone, as in Ewing sarcoma, multidrug chemotherapy has greatly improved the 5-year survival rate, which now is approximately 70% for patients with either of these tumors. Like Ewing sarcoma, primary lymphoma of bone is highly sensitive to local irradiation. If the primary lymphoma is localized, a wide resection and limb-salvage reconstruction may be carried out, thereby avoiding the need for local irradiation and possibly effect a cure. However, if the involvement is more extensive, as is commonly the case, it is necessary to use intralesional techniques such as cemented intramedullary nails or a long-stem prosthesis and subsequently use whole bone irradiation, similar to the management of metastatic carcinoma with pathologic fractures. In cases of extensive systemic involvement, bone marrow transplantation can be used.

PLASMA CELL TUMOR

A bone tumor composed of malignant monoclonal plasma cells is referred to as a myeloma or plasmacytoma. It is rare for a patient to have a solitary myeloma or plasmacytoma. Tumors are almost always found on multiple bony sites, in which case the term multiple myeloma is used.

Myeloma

Multiple myeloma, which is the most common primary tumor of bone, accounts for 45% of all malignant bone tumors. It is the second most common hematopoietic malignancy. An estimated 90% of cases are in patients older than 40 years. It accounts for 1% of all malignancies in Caucasians and 2% in African Americans.

The disease is characterized by a triad of osteolytic punched-out lesions (multifocal) (Figure 6–48) neoplastic proliferation of atypical plasma cells and a monoclonal gammopathy. Diagnostic criteria are established for myeloma. Major criteria include plasmacytosis on biopsy of a lesion, marrow plasmacytosis, and an abnormal serum protein electrophoresis and light (Bence Jones) proteinuria. It causes bony destruction similar to that caused by lymphomas, with most lesions occurring in the trunk, hip, and shoulder areas. Many advances were made in the biology of myeloma in the last decade. The observation that myeloma cells enhance osteoclasts formation (through osteoprotegerin/RANKL [receptor activator of nuclear factor ] pathway) forms the basis for new treatment paradigms aimed at inhibiting RANKL and thereby decreasing osteolysis. A naturally occurring inhibitor of the Wnt signaling pathway called Dkk-1 is secreted by myeloma cells and promotes osteolysis.

Lesions are rarely found distal to the knee or elbow. Approximately 3% of patients with myeloma have a sclerotic form of the disease, which appears to carry a better prognosis and is associated with peripheral neuropathy. The serum protein electrophoresis shows an elevated monoclonal immunoglobulin on either the a or y spike. Bence Jones proteinuria is secondary to light-chain immunoglobulin spillover. Occasionally, electrophoresis of a urine sample yields positive results, whereas that of a serum sample yields negative results. In aggressive forms of myeloma, the extensive bone breakdown causes hypercalcemia, which can lead to a semicomatose state and over a long period results in nephrocalcinosis. Renal damage also results from protein plugging of the renal tubules and renal failure.

A marrow aspirate usually demonstrates the abnormal plasma cells. These cells show an eccentrically placed nucleus in a well-structured eosinophilic cytoplasm. Although normal B-cell–derived plasma cells produce antibodies, the abnormal B-cell–derived plasma cells produce immunoglobulin that is ineffective, which helps explain the increased infection rate in patients with myelomas. Patients may also demonstrate extraosseous infiltrates, with the majority seen in the upper airway and oral cavity. Amyloidosis may be seen concurrently in 10–15% of cases. A quarter of these have extensive cardiac involvement. In such cases the median survival is 4 months.

Plain radiographs show myeloma lesions to be sharply demarcated lytic lesions with minimal periostitis. Pathologic fixation is frequent. Bone scans have a high false-negative rate thought to be caused by almost exclusive osteoclast activity.

Less than 2% of myeloma cases demonstrate the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-component spike, skin changes, scleroses of bone).

Although treatment and prognosis have improved, myeloma remains a fatal disease, with more than 90% of patients dying within 2–3 years. Chemotherapy such as melphalan and cortisone may induce a transient remission in 50–70% of cases.

Local treatment of myeloma is similar to that of metastatic disease, with cemented intramedullary nails and prosthetic devices used after an intralesional debridement. The amount of bleeding at the surgical site is usually extensive, similar to that encountered with surgery for metastatic renal cell carcinoma and certain thyroid metastases. After surgery, the entire bone should be irradiated with 5500 cGy. Spinal lesions should be handled just like metastatic tumors, as discussed in a later section.

Solitary Myeloma

Solitary lesions are rare (Figure 6–49). By definition, there must be no marrow involvement. Seventy-five percent of these cases have an entirely normal serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP). The remaining 25% may have mild abnormalities. Vertebral involvement is the most common site. Patients also tend to be younger (less than 50 years). Unfortunately, 70% of these solitary cases develop multiple myeloma within 3 years. Until this happens, the treatment is only local, with a wide resection if possible or intralesional debridement and reconstruction followed by radiation therapy.

Fibrous Sarcomas of Bone

Malignant fibrous tumors of bone are clinically similar to the osteosarcoma, but they affect an older (more than 20 years) age group of patients and show a complete absence of tumor osteoid formation. The two major tumors in this category are the fibrosarcoma and the malignant fibrous histiocytoma.

FIBROSARCOMA OF BONE

Fibrosarcoma of bone is a malignant spindle-cell tumor seen in an older patient population with a peak incidence in the fourth decade. It is 10 times less frequent than osteosarcoma but tends to involve similar locations. The most common site of fibrosarcoma is the distal femur, followed next in order by the proximal tibia, pelvis, proximal femur, and proximal humerus. It is rarely seen in the spine, hand, or foot.

On radiograph, fibrosarcomas appear to be almost purely osteolytic and permeative, similar to lymphomas. For this reason, they are painful and can lead to a pathologic fracture. Microscopically, myofibroblastic differentiation with osteoid formation or histiocytes permits distinction from fibroblastic osteosarcoma and malignant fibrous histiocytoma (MFH) of bone. The low-grade form is characterized by malignant-appearing fibroblasts that form a large amount of collagen fiber, giving the appearance of an aggressive desmoplastic fibroma. The high-grade form is characterized by a more anaplastic fibroblast with a higher index of mitotic activity and less collagen fiber formation. It is common to see a basket-woven or storiform pattern in the microscopic picture.

The prognosis and treatment are directly related to the histologic grade of the tumor. Low-grade fibrosarcoma has a better prognosis than osteosarcoma does, but it must be treated by means of an aggressive and wide resection to avoid local recurrence. Because the low-grade form has a low mitotic index, adjuvant chemotherapy and radiation therapy are of little help. High-grade fibrosarcoma has a prognosis and a rate of metastasis that are similar to those of osteosarcoma, and it is usually treated in a similar manner with a combination of surgery and, if the patient is young enough to tolerate the systemic toxicity, adjuvant chemotherapy.

MALIGNANT FIBROUS HISTIOCYTOMA OF BONE

Prior to 1970, MFH was rarely diagnosed in bone but was commonly found in soft tissue. Now MFH is more common in bone than fibrosarcoma, but the two types of tumor run a similar clinical course. MFH of bone is seen in middle-age and older (see Table 6–2) adults, is more common in males than in females, and affects the same bony sites as the fibrosarcoma and osteosarcoma.

MFH is a purely lytic tumor that shows aggressive permeation of metaphyseal-diaphyseal bone, similar to the findings in lymphoma (Figure 6–50). Lytic destruction is diffuse, with no evidence of a periosteal response to blastic repair. Microscopic analysis of MFH usually shows the tumor to be high grade and have highly anaplastic fibroblasts mixed with malignant histiocytes and a few giant cells in a typical storiform pattern.

Because MFH is closely related to the high-grade fibrosarcoma, it carries a poor prognosis, with high rates of local recurrence and metastasis. The treatment program is therefore similar to that for high-grade fibrosarcoma and osteosarcoma, and it includes an aggressive wide resection and the use of adjuvant chemotherapy.

Adamantinoma of Bone

Adamantinomas account for only 0.33% of all malignant bone tumors; occur with equal frequency in males and females, usually during the second and third decades of life; are found in the tibia in 90% of cases; and are usually diaphyseal in location, frequently starting in the anterior cortex. The cause of adamantinoma remains unknown, although angioblastic synovial cells and epithelial cells were considered in the past. Newer investigations, including immunohistochemistry and electron microscopic studies, lend support to the hypothesis of an epithelial origin, which goes along with the histologic appearance of a basal cell carcinoma and might explain the common site of origin subcutaneously in the anterior tibial cortex. The name adamantinoma was given to the tibial lesion because its histologic appearance is similar to that of the adamantinoma of jaw bone (ameloblastoma), but the two entities have no other relationship clinically.

In patients with adamantinoma, the radiograph shows a benign tumor with a lytic central core that is surrounded by reactive sclerotic bone that typically bulges the anterior cortex and thus takes on the appearance of either fibrous dysplasia or osteofibrous dysplasia (Figure 6–51). One consideration in the differential diagnosis is that osteofibrous dysplasia is painless, whereas pain is a frequent symptom in adamantinoma. Another is that fibrous lesions of bone stop growing at bone maturity, whereas the adamantinoma continues on into adult life, at which point a biopsy of the progressive lytic portion of the disease should be performed. There have been cases of osteofibrous dysplasia combined with small areas of adamantinoma scattered in the benign osseofibrous tissue. Adamantinoma is also occasionally found in both the tibia and fibula, so the physician should look for multiple sites.

Microscopic findings include nests or cords of epithelial or angioid tissue growing in a fibrous tissue stroma, which can give adamantinoma the appearance of a low-grade angiosarcoma or a metastatic carcinoma.

Adamantinoma grows extremely slowly, over many years, but on occasion metastasizes to regional lymph nodes and the lung. For this reason, it should be treated by a wide resection, which in most cases is a segmental diaphyseal resection followed by an allograft reconstruction over an intramedullary nail. Because of the low-grade nature of this tumor, adjuvant irradiation or chemotherapy is rarely indicated. Even if pulmonary metastases occur, they can be resected, and there is a fairly good prognosis for survival.

Vascular Sarcomas of Bone

Vascular sarcomas are relatively rare. They include the hemangioendothelioma, angiosarcoma, and hemangiopericytoma of bone. The termshemangioendothelioma and angiosarcoma are frequently used synonymously; however, the first term refers to a low-grade tumor, and the second term usually suggests a higher grade lesion with a poorer prognosis. The vascular sarcomas have two different cell-line origins: endothelial cells for the hemangioendotheliomas, in contrast to hemangiopericytes for the hemangiopericytomas.

HEMANGIOENDOTHELIOMA

The hemangioendothelioma, which is more common in males than in females, is seen in a wide range of ages between the second and seventh decades. The femur, pelvis, spine, and ribs are the usual sites of origin, and the diaphyses and metaphyses of the long bones are also involved. One third of cases are multicentric, usually in the same bone or limb.

Radiographically, the lesion appears lytic, with surrounding sclerotic bone. The more anaplastic the disease process is, the less reactive bone is. The clinical picture varies widely, depending on the histologic grade of the tumor. The low-grade lesions look like benign hemangiomas, are slow growing, and carry an excellent prognosis. The high-grade lesions are fast-growing lytic lesions with a poor prognosis.

Treatment depends on the histologic grade. The low-grade lesions do well with simple curettement and bone graft, but the high-grade lesions require a more aggressive wide resection and reconstruction. Adjuvant chemotherapy and radiation therapy can be considered for high-grade lesions, especially in patients with multifocal disease.

HEMANGIOPERICYTOMA

The hemangiopericytoma is an extremely rare form of vascular sarcoma that also has a wide spectrum of clinical presentations, depending on the histologic grading. This tumor is the malignant counterpart of the glomus tumor, discussed later in the section on soft-tissue tumors. The hemangiopericytoma is a round cell tumor located outside the endothelial membrane of the vascular channel. This can be demonstrated clearly by a silver staining of the reticulum fibers lying between the inner endothelial cells and the outer hemangiopericytes.

Chordomas

Chordoma of bone is rare and accounts for 4% of malignant bone tumors. It takes its origin from the primitive notochord and has the clinical appearance of a chondrosarcoma. Chordomas affect males more frequently than females and are seen in patients between 30 and 80 years of age. Although 50% of the tumors are sacrococcygeal in origin, 37% arise in the sphenoccipital area, and the remainder arise from vertebral bodies of the cervical or lumbar spine. The cranial lesions are seen in a younger age group and carry a poor prognosis because of the dangerous location next to the brain, where surgical removal is difficult.

On radiograph, the chordoma appears as a centrally located lytic process that has minimal sclerotic response at the periphery and may show slight matrix calcification, as in a chondrosarcoma. If the sacrum is involved, the lesion is seen usually in the lower three sacral segments and presents as an extracortical lobulated mass both in front and behind the sacrum. Because of the slow tumor growth, pain may not occur early, but constipation can be an early symptom that results from pressure on the rectum. Because the true anatomic borders are not readily defined by routine radiography, it is best to image this tumor with CT or MRI (Figure 6–52). Microscopically, nests or cords of cells, sprinkled in a sea of mucinous tissue, give an appearance similar to low-grade chondrosarcoma. In most cases, large vacuolated cells appear like a signet ring and are referred to as physaliferous cells.

Treatment for the sacral lesions is an aggressive wide resection, which can be difficult because of excessive bleeding. Significant neurogenic bowel and bladder deficits can result. At the present time, it is common to use adjuvant radiation therapy to help reduce the chance of postoperative recurrence. Newer studies recommend using up to 5000 cGy preoperatively, followed with a boost of 1500 cGy postoperatively. If the surgeon is successful in obtaining clean margins, the local recurrence rate is approximately 30%. With contaminated margins, the recurrence rate climbs to 65%. Recurrence 10–15 years following surgery is common. Because of the low-grade characteristics of the chordoma, it is rare to see a pulmonary metastasis, even after a local recurrence following an inadequate local surgical resection.

BENIGN SOFT-TISSUE TUMORS

Soft tissue can be defined as nonepithelial, extraskeletal mesenchymal exclusive of the reticuloendothelial system and glia. This definition would include fat, fibrous tissue, muscle, and the relating neurovascular structures.

Benign soft-tissue tumors, by definition, represent a differentiated neoplastic process with a limited capacity for autonomous growth. They generally demonstrate a marginal capacity to invade locally with infrequent local recurrence. Because of the extensive numbers of benign soft-tissue tumors, discussion is limited here to the more common entities.

Lipomas

The lipoma is by far the most common soft-tissue tumor and has a large number of variants. Some examples include the superficial subcutaneous lipoma; the intramuscular lipoma; the spindle-cell lipoma; the angiolipoma; the benign lipoblastoma; and the lipomas of tendon sheaths, nerves, synovium, periosteum, and the lumbosacral area.

SUPERFICIAL SUBCUTANEOUS LIPOMA

The most frequently seen type of lipoma is the superficial subcutaneous type, which can be solitary or multiple. Subcutaneous lipomas occur with equal frequency in men and women and seem to arise spontaneously during the fifth and sixth decade of life. The most common locations are the back, shoulder, and neck.

On palpation this tumor is soft and ballotable. Although it is found more commonly in obese patients, the size of the lipoma does not correlate with the weight of the patient. Lipomas do not reduce in volume with weight loss. They generally grow to a limited size and sarcomatous degeneration does not occur. Surgical treatment is usually cosmetic in nature, and the recurrence rate is less than 5%.

INTRAMUSCULAR LIPOMA

The deep intramuscular lipoma is seen in adults between 30 and 60 years of age, affects men more frequently than women, and is commonly found in the large muscles of the extremities. The lesions are slow growing and painless. The intramuscular lipoma has a characteristic radiolucency that contrasts with the surrounding muscle (Figure 6–53). On MRI this tumor demonstrates a uniform high-signal image on the T₁-weighted spin-echo sequence. On gross examination, the tumor can appear quite infiltrative in surrounding muscle and has a faint yellow color on sectioning. Histologic studies show that the intramuscular lipoma, like the subcutaneous lipoma, is composed of benign lipocytes with small pyknotic nuclei that are difficult to see on the surface of the large fat-laden cell. When samples are taken for biopsy purposes, the pathologist must take care to rule out a low-grade, well-differentiated liposarcoma that can coexist with a benign lipoma. On rare occasions, a lipoma can have chondroid or osseous hamartomatous elements that have caused it to be classified as a mesenchymoma in the past. In other cases, evidence of hemorrhage or necrosis can be found in a lipoma and creates low-signal changes on the MRI that are similar to the changes seen in liposarcoma.

A marginal surgical excision is indicated for treatment of intramuscular lipoma. Local recurrence rates of 15–60% are reported.

SPINDLE-CELL LIPOMA

The spindle-cell lipoma is seen typically in the posterior neck and shoulder area in men between 45 and 64 years of age. On gross examination, the spindle-cell lipoma has the appearance of an ordinary lipoma but with areas of gray-white gelatinous foci streaking through it. Microscopic examination of these areas reveals the presence of benign fibroblasts. Thus, with imaging studies, dense areas are scattered throughout the normal radiolucent areas of a lipoma. On MRI, findings generally consist of a low-signal streaking through the typical high-signal pattern of a benign lipoma.

The treatment for this lesion is a simple marginal resection. The chance for local recurrence is minimal.

ANGIOLIPOMA

The angiolipoma (Figure 6–54) is a subcutaneous lesion seen in young (see Table 6–6) adults, usually on the forearm. Multiple lesions are frequently present and usually painful because of their vascularity. Grossly, the lobular lipoma demonstrates vascular channels.

Treatment of angiolipoma consists of marginal excision.

DIFFUSE LIPOMATOSIS

An extremely rare variant of the lipoma is diffuse lipomatosis, characterized by the presence of multiple superficial and deep lipomas that involve one entire extremity or the trunk and usually have their onset during the first 2 years of life. Histologically, an individual lesion in a patient with diffuse lipomatosis looks no different from a typical solitary lipoma. An involved limb may become massive in size, sometimes making it impossible to remove the fatty tumors surgically. If this is the case, amputation may be indicated.

LUMBOSACRAL LIPOMA

The lumbosacral lipoma occurs in the lumbosacral area posterior to a spina bifida defect. It is frequently associated with both intradural and extradural lipomas and thus can result in neurologic deficits. Although lumbosacral lipoma is generally considered a pediatric tumor, it can be seen in adults (Figure 6–55).

Surgical treatment consists of a marginal resection of the entire lipoma, including the portion arising from the vertebral canal and lumbosacral roots.

BENIGN LIPOBLASTOMA AND DIFFUSE LIPOBLASTOMATOSIS

The benign and diffuse types of lipoma are seen in the extremities of infants. The lesions, solitary or multiple, can be superficial or deep in muscle tissue. They demonstrate cellular immaturity, with lipoblasts similar to the myxoid form of liposarcoma. Even with the cellular aggressiveness of the lesions, the prognosis is excellent following simple surgical resection.

HIBERNOMA

Hibernoma, a rare lipoma usually seen in young (see Table 6–6) adults, commonly occurs in the scapular and interscapular regions, is painless and slow growing, and ranges between 10 and 15 cm in diameter. The hibernoma is composed of finely granular or vacuolated cells characteristic of brown fat and contains a considerable amount of glycogen. The treatment is marginal surgical resection with a low potential for recurrence.

Benign Vascular Tumors

Benign vascular proliferative tumors are the second most common benign tumor after lipomas. Three types of vascular tumors are discussed here: hemangiomas, lymphangiomas, and glomus tumors.

Like lipomas, angiomas occur in a wide variety of clinical conditions seen more often in females than in males. The most common type of angioma is the hemangioma, which can be a superficial cutaneous lesions or a deep and intramuscular one. The lymphatic counterpart of the hemangioma is known as the lymphangioma or hygroma. In most cases, the lesion is solitary or localized. If it is extensive and involves an entire limb, the term angiomatosis is used. Because most hemangiomas and lymphangiomas are congenital, the term hamartomatous or arteriovenous malformation is applied in their classification. Hemangiomas and lymphangiomas arise from developmental dysplasias of the endothelial tube, whereas glomus tumors and hemangiocytomas arise from hemangiopericytes, which are cells that lie outside the endothelial tube. Most vascular anomalies arise sporadically, but some familial, autosomal-dominant inheritance patterns are also described. Genetic analysis of these families identified specific gene mutations supporting the genomic role in the regulation of angiogenesis.

HEMANGIOMA

Hemangiomas are the most frequently seen tumors of childhood and account for 7% of all benign tumors.

Solitary Capillary Hemangioma

The most common type of hemangioma is the solitary capillary type, which appears as an elevated red to purple cutaneous lesion on the head or neck. The lesion occurs during the first few weeks after birth, grows rapidly over a period of several months, and regresses over a 7-year period in 75–90% of cases.

Because of the spontaneous regression, no treatment is needed in most cases. In the past, treatment consisted of cryosurgery, sclerotherapy, or irradiation, but frequently this treatment was worse than the disease itself. Today, lasers are used with good preliminary results. This may prove to be the treatment of choice in selected cases.

Cavernous Hemangioma

The cavernous hemangioma is larger and less common than the capillary hemangioma. The enlarged vascular spaces of the cavernous lesion give it the appearance of a cluster of purple grapes. It lies deep in the extremity, with common involvement of muscles and even the synovial membrane of the joints.

Imaging may be characteristic (Figure 6–56). In some patients with deep intramuscular forms of hemangioma, the skin shows no abnormalities and no phleboliths are apparent on radiograph. With MRI, deep intramuscular hemangiomas can be easily detected by the characteristic mixed-signal serpiginous pattern seen in the T₁-weighted image.

The muscle lesions are usually asymptomatic until intralesional hemorrhage occurs either spontaneously or after a minor injury. The pain symptoms are usually short lived but recur infrequently. In some patients, the pain is more severe and associated with muscle contracture and joint deformity. These patients may require surgical resection of the scarred-down lesion to allow for better joint function and to reduce the pain. In rare cases of multiple hemangiomas involving the entire limb, amputation may be indicated. Vascular embolization of the feeder vessels can be attempted but may lead to a significant compartment syndrome, with severe contractures or with loss of muscle strength and limitation of joint movement.

Arteriovenous Hemangioma

The arteriovenous hemangioma is seen in young patients (see Table 6–6) usually in the head, neck, or lower extremity. It is associated with significant arteriovenous shunting in the tumor, which creates increased perfusion. This results in increased local temperature, pain, and continuous thrill or bruit over the mass. In the extremity, it also results in an overgrowth of the limb.

If shunting is excessive, surgical removal of the hemangioma may be necessary to prevent increased pulse pressure from leading to high-output heart failure. Arteriograms are helpful in determining the degree of shunting prior to treatment. Embolization or surgical ligation of feeder vessels is frequently not a successful form of treatment.

Epithelioid Hemangioma (Kimura Disease)

This cutaneous hemangioma is found on the head or neck in women between 20 and 40 years old. It is associated with inflammatory changes and eosinophilia, and it sometime ulcerates. Its name is derived from the epithelial appearance of the endothelia-lined capillary structures.

Pyogenic Granuloma

The pyogenic granuloma is a polypoid capillary hemangioma that affects the skin or mucosal surfaces of males and females in all age groups. It may be associated with trauma and is found about the mouth, gingivae, or fingers. The lesions have a purple-red color, bleed easily, and ulcerate.

LYMPHANGIOMA

The lymphangioma is nothing more than an angioma composed of lymphatic endothelial tubes filled with lymphatic fluid, rather than being filled with blood, as the hemangioma is. Lymphangiomas can be localized, which occurs with the cystic hygroma, and they are usually seen about the head, neck, or axilla of young boys and girls (see Table 6–6). As with hemangiomas, the larger lymphomas are cavernous lesions seen in older patients with deeper involvement. In both lymphangioma and hemangioma, because of increased regional perfusion, bony overgrowth can occur (Figure 6–57).

GLOMUS TUMOR

The glomus tumor arises from the hemangiopericyte, which is a cell seen at the periphery of the capillary vascular network and normally involved with the regulation of blood flow through the capillary system. Microscopic examination of the tumor reveals large vascular spaces surrounded by a homogeneous field of round epithelioid hemangiopericytes, with no evidence of mitotic activity.

The glomus tumor is a pink lesion that measures less than 1 cm in diameter. It represents 1.6% of all soft-tissue tumors and occurs with equal frequency in men and women, usually between 20 and 40 years of age. Although the tumor is found most commonly in the subungual area of a digit, where it is readily visible, it also occurs subcutaneously on the hand, wrist, forearm, or foot, where it may be invisible and thus difficult to diagnose until localized lancinating pain leads to a surgical exploration. After the lesion is surgically removed, the pain subsides, and recurrence is unlikely.

Extraabdominal Desmoid Tumors (Aggressive Fibromatosis)

In comparison with the infantile fibrous lesions mentioned earlier, the desmoid tumor is seen in older children and young adults up through 40 years of age. Whereas abdominal desmoids are seen in the abdominal wall of women following pregnancy, the extraabdominal desmoids usually occur in men and are more common in proximal areas about the shoulder and buttock, followed next by the posterior thigh, popliteal area, arm, and forearm. In most cases, it presents as a solitary tumor. Multicentric involvement is seen at times, however, and can be associated with Gardner syndrome, which is characterized by polyposis of the large bowel and by craniofacial osteomas. In patients with familial adenomatous polyposis (FAP), an inherited disease caused by mutations in the APCgene, desmoids are a significant source of morbidity and mortality. The APC gene, located on chromosome 5, encodes for a 300-kDa protein, in which a germline mutation is an early event in tumor formation.

Desmoids are deep-seated tumors that arise from muscle fascial planes and infiltrate extensively into adjacent muscle tissue, tendons, joint capsules, and even bone. Compared with malignant fibrosarcomas, desmoids are poorly marginated and thus difficult to resect surgically. Desmoids can engulf surrounding vessels and nerves, whereas fibrosarcomas usually push these structures aside. A desmoid may cause local pain and grow quite rapidly, suggesting a malignant tumor. The desmoid tends to grow more longitudinally along muscle planes to a considerable size, frequently resulting in restricted joint motion about the shoulder, hip, or knee. Because the local aggressiveness of desmoids is so similar to that of malignant fibrosarcomas or malignant fibrous histiocytomas, some experts believe the desmoid may be a low-grade fibrosarcoma that has lost its potential to metastasize; however, molecular analyses may suggest otherwise.

On gross examination, a desmoid tumor is firm and heavily collagenized. Microscopically, it has a low mitotic index, similar to that of a plantar or palmar fibromatosis. Radiographically, a desmoid is noncalcified and appears dense in comparison with normal muscle. It is easily seen in soft window CT scanning. More exact presurgical imaging can be obtained with MRI (Figure 6–58). As with an abdominal desmoid, an extraabdominal desmoid physical injury may play a role in the activation of a preexisting oncogene located in the damaged fibroblast.

Desmoids are usually treated surgically with an aggressive wide resection similar to that used in treating a primary sarcoma. Even following a clean resection of the desmoid, the recurrence rate may approach 50%. For this reason, it is common to administer 50 Gy of radiation to the surgical site starting 2 weeks postoperatively. With radiation therapy, the recurrence rate decreases to 15%. In rare cases an amputation may be necessary after multiple recurrences. A few cases of spontaneous involution of desmoid tumors are reported after 40 years of age.

Based on clinical and experimental evidence, estrogen may play a role in the development of desmoid tumors. Accordingly, agents such as tamoxifen are being used in some centers because of their antiestrogen effects. NSAIDs were also implemented in attempts to treat aggressive cases. In selected patients with progressive disease, low-dose vinblastine and methotrexate chemotherapy may be used.

Benign Tumors of Peripheral Nerves

Benign tumors of peripheral nerve sheaths are common and take their origin from Schwann cells, which normally produces myelin and collagen fiber.

NEURILEMOMA

The neurilemoma (neurinoma or benign schwannoma) is the least common of the benign tumors of peripheral nerve sheaths. It usually affects individuals between 20 and 50 years of age and occurs with equal frequency in men and women. It has a predilection for spinal roots and for superficial nerves on the flexor surfaces of both upper and lower extremities. In most cases, the lesion is solitary, but multiple lesions are occasionally seen in Recklinghausen disease. The neurinoma is slow growing and rarely causes pain or a neurologic deficit.

Unlike the neurofibroma, which has a fusiform appearance, the neurilemoma is round (Figure 6–59). Microscopic studies reveal the presence of a characteristic Verocay body, which consists of palisading Schwann cells and is found in the fibrotic Antoni A substance of the tumor. Other areas reveal a more mucinous Antoni B substance. Neurilemomas may occur in an axial fashion involving spinal roots, often presenting as a dumbbell-shaped extradural defect (Figure 6–60). In comparison with the less restricted peripheral lesions, the nerve root lesions are more apt to cause pain associated with neurologic deficiency because of their bony constriction.

In some cases, simple excision of the neurilemoma is clinically indicated, which often can be performed without serious damage to the nerve. If the patient is asymptomatic, observation is appropriate because there is little chance for malignant degeneration.

SOLITARY NEUROFIBROMA

The solitary neurofibroma is a fusiform fibrotic tumor arising centrally from a smaller peripheral nerve (Figure 6–61). The tumor is seen with equal frequency in men and women, usually between 20 and 30 years of age. It is 10 times more common than the multiple form seen in Recklinghausen disease, is usually smaller, and carries less chance of malignant degeneration. Microscopic examination of the solitary neurofibroma shows interlacing bundles of elongated spindle cells with benign-appearing nuclei and occasionally with areas resembling the Antoni A tissue seen in the neurilemoma.

Treatment of the solitary neurofibroma consists of simple excision.

NEUROFIBROMATOSIS (RECKLINGHAUSEN DISEASE)

Recklinghausen disease is a familial dysplasia, inherited as an autosomal-dominant trait, with an incidence of approximately 1 in every 3000 live births. The disease usually begins during the first few years of life with the emergence of small café au lait spots. Over time, these lesions grow in number and size. Unlike the lesions seen in fibrous dysplasia, the lesions in Recklinghausen disease do not have rough edges. If a patient has more than six lesions that have smooth edges and are greater than 1.5 cm in diameter, the diagnosis of Recklinghausen disease is certain.

Later in life, the patient develops multiple neurofibromas, each of which appears as a soft cutaneous nodule (Figure 6–62). This pedunculated skin lesion, which is called fibroma molluscum, can be large and pendulous. More pathognomonic of the disease is the plexiform neurofibroma, which appears in larger nerves and can involve an entire extremity (see Figure 6–62). When the overlying skin of an extremity is loose and hyperpigmented, the condition is called elephantiasis neuromatosa, or "elephant man syndrome." (It is now thought that John Merrick, the so-called elephant man, was actually affected by Proteus syndrome.) Among the bony changes seen in Recklinghausen disease are angular scoliosis, spinal meningocele, scalloping of the vertebra, pseudarthrosis of the tibia, and osteolytic lesions in bone.

A major threat to the patient's life is that a malignant schwannoma will develop from one of the large and deep neurofibromas. This occurs at a later age in 3–5% of patients.

Intramuscular Myxomas

The intramuscular myxoma is a rare tumor seen in patients older than 40 years and affecting the large muscles about the thighs, shoulders, buttocks, and arms. It is a slow-growing well-marginated tumor that has the gelatinous physical quality of a ganglion cyst or myxoid liposarcoma. The intramuscular myxoma causes no pain and can grow to greater than 15 cm in diameter. Although it appears radiolucent on CT scan, MRI demonstrates an intermediate signal on the T₁-weighted image and an extremely high signal on the T₂-weighted image. Multiple myxomas are associated with polyostotic fibrous dysplasia.

The intramuscular myxoma can be resected marginally. After this procedure, the recurrence rate is extremely low.

MALIGNANT SOFT-TISSUE TUMORS

Sarcomas are capable of invasive, locally destructive growth with a tendency to recur and to metastasize. All sarcomas do not behave the same, however. Some sarcomas, such as dermatofibrosarcoma protuberans, rarely metastasize. Malignant fibrous histiocytoma, in contrast, does so with alacrity.

FIBROHISTIOCYTIC TUMORS

Until recently, MFH was the most common soft-tissue sarcomas seen in adults (Figure 6–63). Strangely, although more frequently encountered than other adult soft-tissue sarcomas, the cell type(s) of origin remain unclear. Current debate is centered on whether MFH is a distinct entity or a diverse group of sarcomas that on histologic evaluation appear similar. The latest World Health Organization classification for sarcomas no longer includes MFH as a distinct entity. The current nomenclature for the majority of MFH is undifferentiated pleomorphic sarcoma.

Storiform Pleomorphic

Storiform pleomorphic is the most common subtype of MFH. It occurs more frequently in men than in women, primarily affecting individuals between 50 and 70 years of age. Usually it is a deep lesion found in the large muscles about the thigh, hip, and retroperitoneal areas. The tumor may be asymptomatic.

On gross examination, the tumor appears multinodular and may demonstrate several separate satellite lesions in the same muscle belly, especially at the superior and interior poles. It may be necrotic and ranges in color from dirty gray to a reddish tan. Microscopy demonstrates that it is composed of malignant fibroblasts mixed with anaplastic and pleomorphic histiocytes.

The prognosis and treatment vary, depending on the size and location of the tumor. The overall local recurrence potential is 45%, with a 40% incidence of metastasis to the lung and with a 10% incidence of regional lymph node involvement. Tumors smaller than 5 cm in diameter and found in a subcutaneous location in the distal body parts carry a good prognosis, with a 5-year survival rate of 80%, whereas tumors that are 5 cm or more in diameter and located deep in a more proximal muscle group carry a poor prognosis, with a 5-year survival rate of only 55%.

Although the treatment depends on the clinical situation, it generally consists of an aggressive wide resection after careful preoperative staging, including an MRI of the primary and CT scan of the chest. Amputation is rare, with limb salvage possible in the majority of cases.

The use of adjuvant radiation therapy is important in reducing the local recurrence rate. Most clinicians administer 55 Gy to a wide area, followed by a boost to 65 Gy aimed at the surgical site. An attempt is made to leave a longitudinal strip of tissue out of the field of radiation to reduce the chance of postirradiation edema distal to the treatment site. Some centers advocate preoperative and postoperative radiation with 50 Gy given before resection and approximately 15 Gy postoperatively. Some institutions employ preoperative radiation exclusively. Local recurrence rates are generally between 5% and 25%.

The use of adjuvant chemotherapy is more controversial. Because limited data suggest that chemotherapy results in a significant improvement in survival and because most patients are older individuals who cannot tolerate the high-dose protocols, medical oncologists are divided on whether to advocate the use of chemotherapeutic agents in the treatment of MFH.

Myxoid

The myxoid type is the second most common type of MFH and is seen in the same age group of patients and the same locations as the pleomorphic type. On gross examination, myxoid MFH has a multinodular and translucent or gelatinous appearance similar to the appearance of a myxoid liposarcoma or a benign myxoma of muscle. Because of its gelatinous nature, myxoid MFH has a greater chance for local contamination and thus has a higher local recurrence rate than pleomorphic MFH. However, the metastasis rate in cases of myxoid MFH is approximately 25%.

Giant Cell

The giant cell type of MFH also affects older patients and is seen in large muscle groups, but it is hemorrhagic and carries a 50% chance of pulmonary metastasis.

Inflammatory

The inflammatory type of MFH affects the older age groups, is more common in the retroperitoneal areas, and has a 50% metastasis rate.

DERMATOFIBROSARCOMA PROTUBERANS

Dermatofibrosarcoma protuberans, a low- to intermediate-grade fibrohistiocytic tumor, is unique because of its nodular cutaneous location. It is seen more commonly in males than females and occurs in young or middle-age (20–40 years) adults. It is typically located about the trunk and proximal extremities. Antecedent trauma is recorded in 10–20% of cases. Dermatofibrosarcoma protuberans begins as a painless subcutaneous nodule or nodules and slowly develops into an elevated multinodular plaque (Figure 6–64). Microscopic examination of the lesion reveals the same storiform or basket-weave pattern of a benign or malignant fibrous histiocytoma but with a very low mitotic index. The pattern tends to infiltrate extensively into surrounding subcutaneous fat and skin, which accounts for the high local recurrence rate, sometimes reported to approach 50%.

Characteristic cytogenetic abnormalities are described with characteristic features such as reciprocal t(17;22)(q22;q13) or, more commonly, supernumerary ring chromosomes containing sequences from chromosomes 17 and 22.

Surgical treatment, consisting of an aggressive resection, is associated with a lower recurrence rate of 20%. Because of the low mitotic index, radiation therapy is not usually indicated, and the chance of pulmonary metastasis is only 1%.

FIBROSARCOMA

Fifty years ago, fibrosarcoma was considered the most common of the soft-tissue sarcomas, secondary to imprecise pathologic classification of MFH, certain liposarcomas, rhabdomyosarcoma, leiomyosarcomas, and malignant peripheral nerve sheath tumors. Currently, fibrosarcoma is considered one of the least common soft-tissue sarcomas. The diagnosis is reserved for those tumors in which the histology demonstrates a uniform fasciculated growth pattern of spindle cells (malignant fibroblasts). It is clinically similar to MFH, occurs with nearly equal frequency in men and women, is found in patients between 30 and 55 years of age, is sometimes slow growing and painless, and tends to affect deep fascial structures of muscle about the knee and thigh, followed next by the forearm and leg.

On gross examination, fibrosarcoma appears as a firm and lobulated lesion that has a yellowish white to tan color. The lesion may demonstrate a few calcific or osseous deposits on radiographic exam. Microscopy reveals spindle, uniformly shaped fibroblasts that have varying degrees of mitotic activity. Fibrosarcomas contain no malignant histiocytes.

The treatment and prognosis depend on the grade of tumor in a particular patient. Low-grade fibrosarcoma is nearly the same tumor as a benign desmoid tumor and has an extremely low rate of metastasis. However, high-grade fibrosarcoma requires an aggressive wide surgical resection, along with radiation therapy, and has a pulmonary metastasis rate of 50–60%. Lymph node involvement is rare. The use of chemotherapy is considered controversial in patients with fibrosarcoma, as it is in patients with MFH.

LIPOSARCOMAS

Liposarcoma is the second most common soft-tissue sarcoma after MFH. Like MFH, liposarcoma is a tumor of older (40–60 years) patients and can be large and deep seated. Four types of liposarcoma are discussed in the following sections. The well-differentiated type and the myxoid type are associated with a low chance for lung metastasis, whereas the round cell and the pleomorphic types tend to behave more aggressively.

Well-Differentiated Liposarcoma

This very low grade tumor affects individuals who are 40–60 years of age and occurs more frequently in men than in women. It grows extremely slowly and reaches a large size without causing pain. The deep-seated tumor is found in the retroperitoneum, buttock, or thigh. In some cases of well-differentiated liposarcoma, findings include inflammation and sclerosis.

On gross examination, this tumor has a fatty lobulated appearance similar to a benign lipoma. Even under the microscope, many large areas of the tumor appear benign. However, with proper sampling, the pathologist will find a few areas of lipoblast activity to suggest the diagnosis of a liposarcoma. MRI findings are sometimes difficult to distinguish from a large deep lipoma (Figure 6–65).

In cases of well-differentiated liposarcoma, a conservative wide resection is performed to avoid local recurrence. Adjuvant radiation therapy is not helpful, and chemotherapy is never used. The chance of metastatic disease is very low, and the prognosis for survival is excellent.

Myxoid Liposarcoma

Myxoid liposarcoma is the most common fat sarcoma, accounting for 40–50% of all liposarcomas. The myxoid type is low to intermediate grade and seen in older patients (see Table 6–6). The clinical presentation is similar to the well-differentiated liposarcoma.

Gross examination of a myxoid liposarcoma reveals a lobulated pattern with some areas that appear similar to those of a lipoma but with other myxomatous areas. Microscopic examination shows myxoid tissue with areas of signet ring lipoblasts. It is common to find a delicate pattern of capillaries running through the myxoid areas. MRI frequently demonstrates a heterogeneous high- and low-signal pattern typical of myxoid liposarcoma but not present in cases of benign lipoma (Figure 6–66).

Characteristic translocations are also seen in myxoid liposarcoma. The predominant type is t(12;16)(q13;p11); however, t(12;22)(q13;q12) is also described.

Multifocal myxoid liposarcoma is also described. Consideration for additional advanced axial imaging should be entertained with this histologic subtype.

Although myxoid liposarcoma carries a very good prognosis, the tumor should be removed with wide margins, and adjuvant radiation therapy should be given. Chemotherapy is not indicated.

Round Cell and Pleomorphic Liposarcoma

These high-grade liposarcomas are seen in the same locations and age group as the well-differentiated and myxoid subtypes. But unlike the latter, the round cell and pleomorphic types are fast-growing tumors that may be painful.

In cases of round cell or pleomorphic liposarcoma, the lesion does not have a fatty appearance on gross examination but instead looks more like an MFH or a fibrosarcoma. Moreover, on MRI, the lesion appears more like an MFH, with a low-signal pattern in the T₁-weighted image and a high-signal pattern in the T₂-weighted image. Microscopically, the round cell type of liposarcoma shows areas of uniformly shaped round cells similar to those found in Ewing sarcoma or lymphoma and also shows areas of myxoid tissue. In the pleomorphic type of liposarcoma, large and bizarre giant cells occur similar to those found in the pleomorphic type of MFH and rhabdomyosarcoma.

In round cell and pleomorphic liposarcoma, there is an early and high rate of pulmonary metastasis. Accordingly, the prognosis for survival is poor. Thus, the treatment should include aggressive resection, adjuvant radiation therapy as necessary, and chemotherapy in selected patients.

RHABDOMYOSARCOMAS

Rhabdomyosarcomas account for 20% of all soft-tissue sarcomas. The embryonal and alveolar types of rhabdomyosarcoma affect pediatric patients, and the rarer pleomorphic type affects adults.

Embryonal Rhabdomyosarcoma

The embryonal type is seen in patients from birth to 15 years of age and encountered more frequently in boys than in girls. It is most common in the head and neck area. The so-called botryoid form is seen as a cluster of grapes under mucous membranes in the vagina, bladder, or retroperitoneal area. Histologically, it is a round cell tumor like Ewing sarcoma, but some rhabdomyoblasts with cross striations are present in a few areas.

Embryonal rhabdomyosarcoma is treated with local surgical resection plus preoperative and postoperative chemotherapy consisting of vincristine, dactinomycin, cyclophosphamide, and doxorubicin given in cyclic courses during a 2-year span. If the surgical margins are contaminated, local radiation therapy is used. With this program, the 5-year survival rate is 80%. Prior to the advent of chemotherapy, it was only 10%.

Alveolar Rhabdomyosarcoma

This type of rhabdomyosarcoma affects individuals between 10 and 25 years of age and is found more commonly in males than in females. Besides affecting the head and neck, it can be seen in the extremities, especially the thigh and calf. Microscopic examination of the lesion reveals a typical alveolar pattern of round cells, with fewer rhabdomyoblasts seen in this type of rhabdomyosarcoma than in the embryonal type. This type of rhabdomyosarcoma is associated with the fusion genes PAX3-FKHR and PAX7-FKHR. Although not definitive, the presence of the translocation t(2;13)/PAX3-FKHR may be an adverse prognostic factor, with molecular screening being implemented in the future. Currently, the treatment is the same as for the embryonal type, but the prognosis is a bit worse.

Pleomorphic Rhabdomyosarcoma

In the 1940s, pleomorphic rhabdomyosarcoma was a popular histologic diagnosis and MFH was a rare one. Based on today's criteria, most of the old cases classified as pleomorphic rhabdomyosarcoma would now be classified as MFH. Currently, the pleomorphic type of rhabdomyosarcoma is the rarest type.

Pleomorphic rhabdomyosarcoma is a high-grade tumor that affects middle-age and older adults and is seen most commonly in the large muscle groups of the proximal extremities, usually the lower extremities. Microscopic examination of the tumor reveals large atypical giant cells, along with racket- or tadpole-shaped malignant rhabdomyoblasts that stain positive for glycogen, actin, and myosin. The tumor carries a poor prognosis and is associated with a high rate of metastasis to the lung. The treatment for pleomorphic rhabdomyosarcoma is similar to that for MFH and consists of a wide local resection and adjuvant radiation therapy. Chemotherapy is rarely indicated.

LEIOMYOSARCOMA

Leiomyosarcoma is a very rare soft-tissue tumor whose cell type of origin is smooth muscle. It is seen in the middle-age (see Table 6–6) adult and is much more common in women than in men. Its usual locations, in order of frequency, are retroperitoneal, intraabdominal, cutaneous, and subcutaneous. In some cases, the lesion has a venous wall origin and is found in the vena cava or large vessels of the leg. On microscopic examination, leiomyosarcoma can demonstrate a palisading, orderly fascicular pattern similar to a malignant schwannoma. A specific immunohistochemical staining for actin may be helpful in the differential diagnosis.

The prognosis and the treatment for leiomyosarcoma are similar to those for fibrosarcoma. However, leiomyosarcomas of venous wall origin have a worse prognosis because they are difficult to resect and have a high rate of pulmonary metastasis.

SYNOVIAL SARCOMAS

Synovial sarcoma (Figure 6–67) is the fourth most common soft-tissue sarcoma. It is seen in young adults between 15 and 35 years of age and affects males slightly more than females. The name of this tumor suggests a synovial cell origin, but only 10% of synovial sarcomas are found in a major joint. Nevertheless, they frequently arise from juxtaarticular structures, especially around the knee, and they can also arise from tendon sheaths, bursal sacs, fascial planes, and deep muscles. Synovial sarcomas can be seen about the shoulder, arm, elbow, and wrist and are the most common soft-tissue sarcoma in the foot.

Synovial sarcomas initially grow slowly and cause pain in approximately half of the affected patients. The tumors may appear after an injury, and because dystrophic calcification or even heterotopic bone formation is seen in half of the cases, the tumors are assumed to be a benign process for 2–4 years before a diagnostic biopsy is performed.

Microscopic examination of the tumor shows a typical biphasic pattern composed of epithelium-like cells that form nests, clefts, or tubular structures surrounded by malignant fibroblastic spindle cells. The epithelium-like cells produce a mucinous material that suggests a synovial cell origin, although this origin is unlikely. A monophasic form of synovial sarcoma is described and reported to consist of a dominant fibroblastic or epithelial cell pattern. If the lesion shows no biphasic component, however, it is difficult to confirm the diagnosis of synovial sarcoma.

Molecular characterization of this tumor reveals a particular translocation, t(X;18), representing the fusion of SYT (at 18q11) with either SSX1 or SSX2 (both at Xp11). Both SYT and SSX appear to be transcription regulation factors whose fusion product is seen in the majority of synovial sarcomas.

Despite the slow growth of synovial sarcoma, the 5-year and 10-year survival rates are only 50% and 25%, respectively. In cases in which the tumors are heavily calcified, the 5-year survival rate is 80%. Because of the poor prognosis, the treatment plan should include aggressive wide resection, along with both radiation therapy and chemotherapy. Lymph node involvement is seen in 20% of affected patients and may require a surgical excision followed by local radiation therapy.

MALIGNANT PERIPHERAL NERVE SHEATH TUMOR

A malignant peripheral nerve sheath tumor can arise from a preexisting benign solitary neurofibroma but more frequently arises from the multiple lesions of neurofibromatosis type 1. In both cases, the tumor mass is usually larger than 5 cm in diameter and may arise from a large deep neurogenic structure such as the sciatic nerve (Figure 6–68) or one of the spinal roots. Smaller nerves, even cutaneous branches, however, can give rise to these sarcomas. Malignant degeneration from a solitary neurofibroma usually occurs after 40 years of age with a 5-year survival rate of 75%. In contrast, patients whose schwannoma arose from the lesions of neurofibromatosis type 1 are generally younger and have a 5-year survival rate of 30%. Surgical treatment consists of a wide resection if possible. Adjuvant radiation and chemotherapy are used in selected cases.

MALIGNANT VASCULAR TUMORS

Kaposi Sarcoma

Of the malignant vascular tumors, Kaposi sarcoma is the most common with four specific subtypes: (1) chronic, (2) lymphadenopathic, (3) transplant associated, (4) AIDS related. It is found directly beneath the skin, generally in the lower extremity of adults, is seen more often in men than in women, and is endemic in central Africa. The cutaneous lesions seen frequently in the foot and ankle area are purplish in color and are nodular (Figure 6–69). Microscopic examination of Kaposi sarcoma shows an aggressive vascular pattern with rare mitosis. However, over a period of many years, the tumor progresses into a full-blown angiosarcoma or fibrosarcoma. It is associated with AIDS and other immunosuppressive disorders and is also seen with lymphomas and multiple myeloma. Although the behavior of Kaposi sarcoma is a function of the immunologic status of the patient and other variables, the overall mortality rate is 10–20%.

Angiosarcoma

Soft-tissue angiosarcoma is rare, accounting for less than 1% of all sarcomas. Although angiosarcomas are usually cutaneous lesions and tend to affect men more than women, they sometimes take the form of a deep tumor, and they are typically seen in the upper extremities of women who have chronic lymphedema following radical breast surgery and radiation therapy. Histologic examination of angiosarcoma shows anaplastic endothelial cells surrounded by reticulum fiber. Prognosis for the older patient is poor. Smaller lesions in younger (less than 50 years) patients have a distinctively better outcome. The treatment is wide resection, sometimes with radiation therapy.

Hemangiopericytoma

This rare perivascular tumor arises from pericytes. Pericytes are highly arborized perivascular cells that line capillaries and venules. The lesion, which affects male and female adults with equal frequency, is usually found deep in muscle bellies and generally located in the thigh or retroperitoneal area of the pelvis. Microscopic examination of the malignant hemangiopericytoma reveals tightly packed cells with round nuclei with moderate amounts of cytoplasm with poorly defined borders. The bifurcating sinusoidal vessels have a typical staghorn appearance. Cytogenetic analysis reveals multiple chromosome translocations including t(12:19) and t(13:22). Treatment consists of a wide surgical resection, followed by local radiation therapy. Some authors recommend preoperative embolization or afferent vessel ligation (or both) intraoperatively.

MISCELLANEOUS SOFT-TISSUE SARCOMAS

The remaining soft-tissue sarcomas are rare and only a brief description of their clinical patterns is summarized.

SOFT-TISSUE CHONDROSARCOMA

There are three types of soft-tissue chondrosarcomas.

Myxoid Chondrosarcoma

The myxoid chondrosarcoma is sometimes referred to as a chordoid sarcoma because it looks like a chordoma. It is a slow-growing tumor seen in adults, usually in deep structure of the leg. It has a myxoid appearance, does not calcify, and is low grade. Like the chordoma, the myxoid chondrosarcoma responds only to surgical removal.

Mesenchymal Chondrosarcoma

This tumor affects individuals between 15 and 40 years of age, is found deep in the lower extremity and neck areas, is fast growing, and carries a poor prognosis because of the high risk of pulmonary metastasis. Calcification may be seen on radiograph, and microscopic examination reveals round cells scattered in a chondroid matrix. Treatment consists of a wide resection in conjunction with chemotherapy and radiation therapy.

Synovial Chondrosarcoma

The conversion of a synovial chondromatosis to a malignant synovial chondrosarcoma is an extremely rare phenomenon. It can occur with lesions of the hip or knee region in older (more than 60 years) adults.

EWING SARCOMA

Extraskeletal Ewing sarcoma can be found in individuals between 10 and 30 years of age and is usually located in the paravertebral area, thorax, or deep muscle area of the lower extremity. It is a fast-growing tumor with minimal pain symptoms. It carries the same prognosis as its counterpart in bone and is treated with the same combination of surgery, chemotherapy, and radiation therapy.

ALVEOLAR SOFT PART SARCOMA

This round cell sarcoma affects more females than males, is usually found in patients between 15 and 35 years of age, and arises in the deep muscle tissue of the lower extremity, usually the thigh. Alveolar soft part sarcoma is a slow-growing tumor but carries a poor prognosis because of early pulmonary metastasis. The tumor has increased vascularity and is thought to originate from a neurogenic stem cell. It derives its name from its alveolar pattern, which is seen on microscopic examination and can cause this tumor to be mistaken for an alveolar form of rhabdomyosarcoma. A cytogenetic, unbalanced abnormality, t(x;17)(p11.2;q25), is described. Treatment of alveolar soft part sarcoma consists of a wide surgical resection plus radiation therapy and chemotherapy.

EPITHELIOID SARCOMA

Although this superficial skin lesion is seen most commonly in the palm of the hand, it can also be found on the dorsum of the forearm or on the plantar aspect of the foot. It is a slow-growing tumor that affects patients between 20 and 30 years of age, causes minimal pain symptoms, and is associated with ulceration.

Because epithelioid sarcoma has a whitish color that under the microscope demonstrates cords of epithelium-like cells, it can be mistaken for a synovial sarcoma. Moreover, because of its firm multilobulated presentation, the epithelioid sarcoma may be mistaken for a plantar of palmar fibromatosis (Figure 6–70).

Epithelioid sarcoma spreads as a lumpy nodularity along tendon sheaths or fascial planes and frequently involves local lymph nodes. Local surgical resection is followed by a high local recurrence rate, and a late pulmonary metastasis is common. For this reason, early treatment should consist of an aggressive wide surgical resection.

CLEAR CELL SARCOMA

The clear cell sarcoma is thought to be a deep, noncutaneous variant of the well-known cutaneous melanoma. It is extremely rare, affects women more often than men, and commonly occurs between 20 and 40 years of age. It arises in tendon sheaths and fascial planes, most frequently in the foot and ankle but also in the knee and arm. Clear cell sarcoma starts slowly as a painless lump and has a high potential to spread to local lymph nodes. The lesion in many cases demonstrates evidence of melanin and melanosomes and may be of neural crest origin. The microscopic clear cell appearance can cause this sarcoma to be confused with epithelioid sarcoma and synovial sarcoma.

The prognosis is poor because of a high rate of pulmonary metastasis. This tumor may spread via lymphatics as well. Treatment consists of early aggressive wide resection and may include chemotherapy and local radiation therapy.

MANAGEMENT OF CARCINOMA METASTASIZED TO BONE

Incidence & Natural History of Metastases

COMMON METASTATIC CARCINOMAS AND AREAS OF SKELETAL INVOLVEMENT

Metastatic involvement of the musculoskeletal system is one of the most significant clinical issues facing orthopedic oncologists. The number of patients with metastasis to the skeletal system from a carcinoma is 15 times greater than the number of patients with primary bone tumors of all types. Approximately a third of all diagnosed adenocarcinomas include skeletal metastases, resulting in approximately 300,000 cases per year. Furthermore, 70% of patients with advanced terminal carcinoma demonstrate bone metastases at autopsy. The carcinomas that commonly metastasize to bone are prostate, breast, kidney, thyroid, and lung carcinomas. One study showed that nearly 90% of patients with these types of carcinoma had bone metastases. Among the carcinomas that less commonly metastasize to bone are cancers of the skin, oral cavity, esophagus, cervix, stomach, and colon.

The spine is the most frequent area of bone metastasis. Other common skeletal sites include the pelvis, femur, rib, proximal humerus, and skull, in that order. Metastatic lesions are rarely found distal to the elbow or knee. If lesions are found in these areas, the lung is the most common source. Solitary bone lesions comprise only approximately 10% of cases of bone metastasis.

CLINICAL COURSE OF METASTASES

The mechanism of metastases is accounted for in a modified "seed/soil" theorem. Less then 1 in 10,000 neoplastic cells that escape into the circulation from the primary site are able to set up a metastatic focus, a complex multistep process by which the cell must first break free. This is a function of degradativeenzymes such as collagenases, hydrolases, cathepsin D, and proteases. Once the cell invades the vascular channel, it circulates through the body. It is theorized that the cell is protected by a fibrin platelet clot. However, clinical trials with heparin do not show a significant change in metastatic outcome. Local factors such as integrins are instrumental in attracting the circulating metastatic cell to a particular remote tissue site. Once within the new tissue, the metastatic cell releases factors such as tumor angiogenesis factor, inducing neovascularization, which in turn facilitates growth of the metastatic focus.

Patients with advanced metastatic disease frequently experience dysfunction of their hematopoietic and calcium homeostases systems. Patients may develop a normochromic, normocytic anemia with leukocytosis. In response to the anemia, the increased production of immature cells is noted on the peripheral blood smear. This is termed the leukoerythroblasticreaction. Hypercalcemia may result in up to 30% of cases with extensive metastases. This is most frequently seen in myeloma, breast cancer, and non–small cell lung cancer.

Blastic metastases are frequently painless and associated with a lower incidence of pathologic fracture because the bone is not as severely weakened (Figures 6–71 and 6–72). Not all tumors that metastasize from the prostate to the bone are blastic. The lytic variants are painful and can cause pathologic fractures.

Most tumors that metastasize from the breast to the bone are blastic, but some demonstrate mixtures of blastic and lytic areas in the same bone. By taking serial radiographs and noting the appearance of bone metastases, it is possible to follow the progress of treatment consisting of systemic therapy with hormones or chemotherapeutic agents plus local radiation therapy. A favorable response may show a gradual conversion from a lytic to a blastic appearance as the pain decreases.

Bone destruction in lytic lesions is a response by native osteoclasts to the tumor. Neovascularity is common. Among the tumors that are characteristic for this hemorrhagic response are thyroid carcinomas (Figure 6–73), renal cell (Figure 6–74), and multiple myeloma. Before a surgical intervention, it is beneficial to perform a prophylactic embolization of the area to reduce perioperative bleeding. If a lesion is unexpectedly found to be aneurysmal at the time of surgical exploration, it is best to debulk the friable tumor mass rapidly down to normal bone and then pack the area until it can be stabilized with bone cement.

Diagnosis

GENERAL APPROACH

A methodical approach is mandatory in the workup of a patient with presumed metastatic disease to bone to locate the primary tumor. A thorough biopsy and physical examination must be completed prior to laboratory and radiographic analysis. Eight percent of patients may have their primary carcinoma detected on physical exam. Laboratory analysis should include complete blood count, ESR, renal and liver panels, alkaline phosphate, and serum protein electrophoresis.

Radiographic examination should follow with a plain chest radiograph and radiographs of known involved bones. Approximately 45% of primaries are detected in the lung on the chest radiograph. The workup should also include a staging bone scan. If this is negative, myeloma should be suspected. Furthermore, a lesion at a more convenient biopsy site may be found. Bone scan is also more sensitive than plain radiographs in detecting early lesions. CT scans of the chest, abdomen, and pelvis should be performed. Lung CT can detect up to 15% of primaries missed on the plain radiograph.

These studies in conjunction with a well-planned biopsy detect the majority of cases. Routine radiographic screening studies in search of early metastatic disease are not very helpful (Figure 6–75). Lytic changes become evident on routine radiographs only when cortical destruction approaches 30–50% (Figure 6–76).

Treatment & Prognosis

NONSURGICAL TREATMENT

Nonsurgical management of metastatic carcinoma to bone includes observation, radiation treatment, and hormonal/cytotoxic chemotherapy. Radiation is reserved for palliative management. Each patient must be carefully evaluated as a candidate for radiation therapy. The histologic type of disease, extent of disease, prognosis, marrow reserve, and overall constitution must be assessed.

After sustaining a pathologic fracture secondary to metastatic carcinoma, the average survival time is 19 months. Each histologic type has varying lengths of survival (prostate, 29 months; breast, 23 months; renal, 12 months; lung, 4 months). Furthermore, each type of carcinoma exhibits varying radiosensitivity. Prostate and lymphoreticular types demonstrate excellent sensitivity. Breast is intermediate, and renal and gastrointestinal are poor. When used, appropriately 90% of patients gain at least minimal relief, with up to two thirds obtaining complete relief. Seventy percent of patients who are ambulatory retain this function after radiation therapy to the lower extremities. Systemic radioisotopes may also be used. Strontium-89 mimics calcium distribution in the body and shows promise in clinical applications.

When a patient has sustained a true pathologic fixation (rather than an impending lesion) surgical stabilization is usually indicated with subsequent radiation therapy. Because of poor bone quality, augmentation of fixation with bone cement may be necessary.

Hormonal therapy has an important role in the management of metastatic breast and prostate cancer. Fortunately, these agents are easy to administer and have few side effects.

For breast cancer, medical hormonal manipulation can be done by use of antiestrogens, progestins, luteinizing hormone-releasing hormone, or adrenal-suppressing agents. Tamoxifen is effective in 30% of all breast cancer cases but increases to 50–75% of cases when the tumor is known to be estrogen receptor, progesterone receptor positive. Surgical ablation (oophorectomy) may also have a role in certain cases.

For prostate cancer, reduction in testosterone levels via bilateral orchiectomy or administration of estrogens or antiandrogens may produce dramatic results in certain cases. Estrogens are no longer used as a first agent because of the risk of cardiovascular complication.

Cytotoxic chemotherapy is used in adenocarcinoma treatment quite extensively. In older (more than 60 years) patients with advanced disease, however, the side effects of the drugs may be too severe.

SURGICAL TREATMENT

The goals for surgical intervention in the patient with metastatic carcinoma to bone are relief of pain; prevention of impending pathologic fixations; stabilization of true fixations; enhancement of mobility, function, and quality of life; and perhaps improvement of survival. It is generally agreed that a patient must have a life expectancy of at least 6 weeks to warrant operative intervention. Special considerations to surgical management include noting that bone quality is attenuated and healing will be delayed if even possible. Cancer patients, irrespective of their age, may have increased difficulty protecting their fixation device/prothesis secondary to systemic debilitation. Accordingly, rigid fixation, with polymethylmethacrylate (PMMA) augmentation as needed, is mandatory.

Hip

Seventy-five percent of all surgery for cancer that has metastasized to bone is performed in the hip area (Figure 6–77). Prior to 1970, surgeons attempted to stabilize these fractures with conventional hip nails or Austin Moore prostheses, but results were poor because of deficient local bone stock. After 1970, with the advent of bone cement as an adjuvant form of therapy, these same devices could be used, with improved results in most cases, along with local radiation therapy starting 2 weeks after the surgery. This technique allowed for early ambulation with less pain. However, as time passed and survival times increased, more failures were noted after 1–2 years with the hip nail and cement technique. For this reason, most surgeons currently use a cemented bipolar hemiarthroplasty for the femoral neck fractures and a longer stem calcar replacement hemiarthroplasty for the intertrochanteric fractures. Before these procedures are performed, it is wise to evaluate the entire shaft of the femur and the supraacetabular area for other lytic lesions that might require a longer stem femoral component for the shaft or a modified cemented acetabular component with a total hip replacement for acetabular lesions.

In many cases, the diagnosis of metastasis to the proximal femur is made before a fracture occurs. In these cases, it is the responsibility of the orthopedic surgeon to decide whether the patient should receive some form of internal stabilization prior to radiation therapy. A CT scan of the involved area helps make this decision. Criteria for the performance of a prophylactic stabilization procedure include the following: (1) 50% cortical lysis, (2) a femoral lesion greater than 2.5 cm in diameter, (3) an avulsion fracture of the lesser trochanter, and (4) persistent pain in the hip area 4 weeks following the completion of radiation therapy. These criteria are not perfect, however, and large errors arise in estimation of the load-bearing capacity of the bone.

Supraacetabular Area

In the case of a small supraacetabular lesion with intact cortical bone, a cemented cup with a total hip system is generally most appropriate. Augmentation of the fully cemented reconstruction with threaded Steinmann pins or similar anchoring screws may be necessary in advanced cases (Figure 6–78). The principles of treatment are always the same, irrespective of the extent of disease: aggressive intralesional curettage of the area back to healthy bone, followed by the placement of large (4.76 mm) threaded Steinmann pins into the sacroiliac area. The pins are placed with an initial foundation batch of cement, leaving them exposed for a second batch of cement, on top of which the cup is placed. A routine femoral component is then cemented.

Femoral Shaft

Diaphyseal lesions that affect the femur but spare the peritrochanteric area are best handled with some form of intramedullary nail (Figure 6–79). Fixation of the entire femur, including the peritrochanteric area, with a reconstruction type nail is preferable in the event the disease progresses within the bone. Current intramedullary fixation devices often do not need cement augmentation. However, in cases of severe bone deficiency, PMMA introduction, either directly into the defect or indirectly at the nail insertion site, is preferable.

Humerus

The principle for the management of metastatic disease to the humerus is no different from that for the femur. In the case of diaphyseal lesions, surgeons either use a conventional intramedullary rod or they plate the lesion. PMMA may be used with either technique.

In the case of the proximal humerus involving a large amount of the humeral head and neck, it is frequently necessary to cement a long-stem prosthesis (Figure 6–80). Just as with the proximal femur, in the proximal humerus there is no need to widely resect the tumor, and the rotator cuff is usually left intact.

Spine

In most cases of metastasis to the spine, the patient's pain can be managed adequately with local radiation therapy and medication. However, in cases of mechanical collapse associated with bony protrusion into the vertebral canal and cord compromise, surgical decompression and stabilization are frequently indicated. In the past, most of these problems were treated with posterior decompression by laminectomy alone. The results were poor because the spine was further destabilized, which resulted in increased kyphosis and anterior cord compression. With advances in the area of spinal instrumentation, the treatment shifted toward a more aggressive anterior decompression and stabilization if the patient's general condition allows. Even in cases in which the patient's general health does not tolerate the larger anterior approach, a less aggressive alternative might include posterior decompression supplemented by posterior spinal fixation.

The midthoracic spine is the most common area for paraplegia secondary to metastasis because of the narrow vertebral canal at this level of the spine. The ideal surgical approach to the problem in a patient with a reasonable prognosis consists of an anterior thoracotomy and anterior decompression by vertebrectomy, followed by anterior stabilization. As an alternative approach in a patient with a worse prognosis and a circumferential cord compression, a posterior decompression stabilization can be considered (Figure 6–81).

The second most common site for cord compression is the thoracolumbar region. The anterior reconstruction is the same in the thoracolumbar area as in the midthoracic area. A posterior stabilization may be advisable, especially in cases in which the prognosis is good.

The cervical spine is the least likely area for surgical treatment, mainly because the vertebral canal is wide at this level and cord compromise is uncommon. If surgery is needed, an ideal reconstruction is an anterior decompression and stabilization.

Radiation therapy is required postoperatively with all of these reconstructions. The use of bone graft is therefore undesirable because of inhibited osteoblastic healing.

DIFFERENTIAL DIAGNOSIS OF PSEUDOTUMOROUS CONDITIONS

In addition to benign, malignant, and metastatic neoplasms, a group of pseudotumors masquerade as bone and soft-tissue tumors. These lesions actually appear with greater frequency than either primary bone or soft-tissue tumors.

Stress-Reactive Lesions

The most common pseudotumors are those related to either bone or soft-tissue injury.

STRESS FRACTURE OF BONE

Stress fractures are common in young (less than 30 years) athletic individuals and can produce radiographic features that might suggest the diagnosis of a bone-forming sarcoma or Ewing sarcoma. It is important to obtain a careful history from patients regarding their physical activity both at work and at play. There will be no history of a single injury if the bone symptoms are caused by repetitive impact loading stress such as occurs with working out for cross-country running. The stress fracture usually occurs several weeks after a sudden increase of physical activity for which the patient is not properly conditioned. This is a common situation in the military, particularly during initial training.

Stress fractures are commonly located in the metaphyseal-diaphyseal areas of long weight-bearing bones. Early radiographs frequently appear normal before periosteal new bone begins to form. The most sensitive early diagnostic tool is a bone scan, which can appear hot or abnormal in the case of stress fractures, neoplasms, and infections. The MRI is sensitive to early fluid shifts in the periosteum overlying a stress fracture, but it is also sensitive to neoplastic and infectious conditions. One of the best methods to help rule out tumors and infection is to simply stop all physical stress to the injured bone for a period of 4 weeks. In patients with stress fracture, the pain should resolve spontaneously during this period, and a follow-up radiograph taken after this period reveals a typical fusiform circumferential periosteal callous formation. In patients with a tumor or infection, the pain persists, and the radiographic signs of permeative osteolysis predominate, in which case a biopsy and culture are indicated.

At times, the clinical picture of a stress fracture is confused by the preexistence of a benign stress raiser, such as a nonossifying fibroma or fibrous cortical defect (Figure 6–82).

In older patients, especially in postmenopausal women, stress fractures can occur with minimal physical activity. The circumstances under which the fracture occurred might not come out in a routine history. A common location of osteoporotic stress fractures is in the sacrum (Figure 6–83).

MYOSITIS OSSIFICANS

Another common stress-reactive pseudotumor seen in the extremity is myositis ossificans, which occurs most frequently in the lower extremity in young men. The quadriceps muscle is commonly involved because of direct blows or tearing injury to this muscle. The pseudotumor mass may not arise for several months after the injury and may not be related to a specific injury. In older (more than 40 years), more sedentary patients, there may be no history of stress injury.

Early radiographs may not reveal soft-tissue calcification. With maturation, ossification occurs in the traumatized muscle fascial planes, which may suggest the diagnosis of a synovial sarcoma or other calcifying sarcoma. If the myositis pseudotumor is attached to the subjacent bone, it can mimic a parosteal osteosarcoma (Figure 6–84).

Infectious Diseases

Bacterial, viral, tuberculous, or fungal infections of the bone or soft tissue can frequently mimic a neoplastic process. This is particularly the case with infections that are not highly virulent, do not create systemic symptoms or a febrile response, and do not cause a large alteration in acute-phase reactant laboratory work. If a tender mass is present on examination and a bone or soft-tissue tumor is suggested by imaging studies, a biopsy may be indicated and should include a tissue culture to make the correct diagnosis. Inflammatory pseudotumors can be seen in any age group but are more common in children and frequently affect the lower extremity.

BACTERIAL INFECTION

Bacterial infections of bone can take on the appearance of a round cell tumor such as Ewing sarcoma in children or lymphoma in adults (Figure 6–85). In contrast, tuberculous and fungal infections are less inflammatory and thus have more localized, well-marginated lesions that take on the imaging appearance of a benign tumor.

TUBERCULOUS OR FUNGAL INFECTION

A tuberculous or fungal infection of the spine or extremity can present as a pseudotumor in children or young adults, especially in Asian or Mexican patients (Figure 6–86). The incidence of tuberculous and fungal infections, which are low-grade infections that typically have an insidious onset, is also increased in patients with AIDS.

CAFFEY DISEASE

Caffey disease can mimic a neoplastic process. It is an idiopathic form of periostitis that is seen in infants younger than 6 months and affects the extremities, shoulder girdle, and mandible (Figure 6–87). It may have a viral origin and is currently much rarer than it was 30 years ago. The bony changes are osteoblastic and could suggest the diagnosis of an osteosarcoma, which is rare in infants. Caffey disease is self-limiting and usually clears spontaneously without disability.

Metabolic Disorders

BROWN TUMOR OF PRIMARY HYPERPARATHYROIDISM

Brown tumor is the most common metabolic disorder that mimics a neoplastic process in bone. The lytic giant cell lesions occur symmetrically in metaphyseal-epiphyseal bone as the result of increased parathyroid hormone production by a solitary parathyroid adenoma, by hyperplastic parathyroid glands, or by a solitary parathyroid carcinoma. Brown tumors occur three times more often in females than in males and are usually seen between 15 and 70 years of age. They are most common in the ends of the long bone, followed next in frequency in the pelvis, long bone diaphysis, maxillary bone, cranium, rib, and hand. Brown tumors are rarely seen in the spine. Symptoms of pain are related to the local bone destruction, but widespread pain may result from generalized osteomalacia. The hyperparathyroid condition can lead to weight loss, psychologic disorders, gastrointestinal disorders, renal stones, polyuria, and polydipsia.

The radiographic features of the brown tumor in bone include a round lytic area that may be multicentric and may suggest the diagnosis of metastatic carcinoma, multiple myeloma, or histiocytic lymphoma (Figure 6–88). In the case of a solitary lesion, it may suggest the diagnosis of a nonossifying fibroma, fibrous dysplasia, giant cell tumor, or aneurysmal bone cyst. At the time of biopsy, the brown tumor has the reddish brown appearance of a giant cell tumor. Microscopically, it looks like a giant cell tumor except that the background stromal cells are more fibroblastic and the bone trabeculae demonstrates abnormally thick and poorly mineralized osteoid seams. Because of the marked similarity between the brown tumor and the giant cell tumor, clinicians should routinely order an analysis of serum calcium, phosphorus, and alkaline phosphatase levels in all patients with bone lesions that produce giant cells.

In patients with brown tumors, the treatment consists of removing the source of the excessive parathyroid hormone. After this, the bony defects usually heal spontaneously. Bone grafting is rarely required. Although the secondary hyperparathyroidism seen in renal failure patients does not usually develop into brown tumors, it does produce pseudotumorous calcification in soft tissue, a condition similar to tumoral calcinosis, which is discussed later in this section.

PAGET DISEASE

Paget disease is frequently included in discussions of metabolic bone disorders, although the demonstration of cytoplasmic and nuclear inclusion bodies in osteoclasts of pagetic bone similar to paramyxovirus infections may suggest a viral origin. Most clinicians are familiar with the late changes in Paget disease, which include the bowing of long bones and the finding of dense blastic changes on radiographic examination. However, many are unfamiliar with the early lytic phase of Paget disease when the radiographic findings are more suggestive of metastatic carcinoma, histiocytic lymphoma, primary sarcoma, or even primary hyperparathyroidism (Figure 6–89).

GAUCHER DISEASE

Gaucher disease is a rare familial disorder in which accumulation of glucocerebroside causes enlargement of the liver, spleen, and marrow tissues. The marrow infiltration in children and young adults causes a gradual loss of bone that can mimic a neoplastic condition. The most common areas involved include the distal femur, tibia, humerus, vertebral column, skull, and mandible. Isolated focal destructive changed with endosteal scalloping and moth-eaten patterns may suggest the diagnosis of metastatic disease, myelomatosis, primary sarcoma, or fibrous dysplasia (Figure 6–90).

Hemorrhagic Conditions

PSEUDOTUMOR OF HEMOPHILIA

A hematoma in the soft tissue or bone under the periosteum may be difficult to distinguish from a tumor. Hematoma formation is frequently precipitated by some form of trauma, and the bones most commonly involved are the femur, pelvis, tibia, and small bones of the hand. It is rare to see multiple lesions. The bony lesions can be central or eccentric. The finding of lytic destruction followed by sclerotic reaction at the periphery may mimic the radiographic picture of an aneurysmal bone cyst or a giant cell tumor. In the hand bones, the osseous pseudotumors take on the appearance of a giant cell reparative granuloma or an osteoblastoma. The subperiosteal lesions bulge into the surrounding soft tissue and show reactive periosteal new bone formation and subjacent cortical erosion that may mimic Ewing sarcoma or hemorrhagic osteosarcoma (Figure 6–91).

INTRAMUSCULAR HEMATOMA

Another hemorrhagic disorder that can produce a pseudotumor of soft tissue is the intramuscular hematoma. It is similar to the soft-tissue pseudotumor of hemophilia but without a bleeding abnormality. Intramuscular hematomas are almost always related to blunt trauma, but they occasionally result from a traction injury that may subsequently produce myositis ossificans. There may be no superficial signs of bruising in the overlying skin, and sometimes the hematoma grows in size at a later date, even as long as several years after the initial injury. The radiographic examination is of little help because no calcification or bony abnormality is evident. The MRI is the best imaging study, but unfortunately, the appearance of an intramuscular hematoma on MRI can mimic that of a deep soft-tissue sarcoma such as a malignant fibrous histiocytoma (Figure 6–92).

Ectopic Calcification

Ectopic calcification in soft tissue has many causes, most of which are related to chronic degenerative disorders in collagenous structures such as tendons or ligaments about a joint. However, in cases in which the dystrophic calcification is associated with a soft-tissue mass, the clinician must rule out the diagnosis of a soft-tissue sarcoma such as synovial sarcoma.

TUMORAL CALCINOSIS

Tumoral calcinosis, seen about the hip, shoulder, and elbow, is characterized by extensive calcium phosphate deposition in a benign fibrous mass. It is an idiopathic condition that affects patients between 10 and 30 years of age and occurs more frequently in males than in females. Multiple lesions occur, and the lesions cause minimal pain and tenderness.

In cases of tumoral calcinosis, the extensive central fluffy calcification might suggest the diagnosis of a synovial sarcoma, soft-tissue chondrosarcoma, or tuberculosis (Figure 6–93). At biopsy, a chalky white paste exudes from a spongelike fibrous mass. Microscopic findings include extensive amorphous calcium phosphate deposits in a fibrous stroma speckled with macrophages and inflammatory cells. If the pseudotumor is not completely removed, a recurrence is very likely.

A similar condition is seen in patients with renal osteodystrophy with secondary hyperparathyroidism, and the mechanism for the deposition in this case is a high level of calcium phosphorus production.

COMPARTMENT SYNDROME

The ischemic calcification and even ossification that occur in traumatic compartment syndromes in the lower extremity can often mimic a tumor. The initial injury is usually a crushing type that causes increased compartment pressure from muscle swelling. This pressure eventually leads to ischemic necrosis of the compartment muscle, which several years later becomes calcific or even ossified. Because the muscle appears firm and calcified on radiographic examination, the clinician may not relate the finding to an old injury and may suspect a calcifying sarcoma such as synovial sarcoma. The most common place for this pseudotumor is in one of the muscle compartments of the leg, and it causes stiffness and muscle weakness at the ankle and foot area (Figure 6–94). This process can mimic soft-tissue calcifications secondary to a neoplastic process (Figure 6–95).

Dysplastic Disorders

Many developmental or dysplastic conditions can create bony abnormalities, which, on radiographic examination, can mimic a bone tumor. These are usually focal defects in enchondral bone formation that result from a failure to remodel primary woven bone forming at the metaphyseal end of the physis.

OSTEOMA

Osteoma commonly occurs in the skull or maxilla and is composed of dense unorganized woven bone seen just beneath the cortex. There is no lytic component in or around the dense bone, and no symptoms are associated with the presence of osteomas. Because the lesions are commonly seen in the metaphyseal areas about the knee, the clinician may become concerned about the diagnosis of an early osteosarcoma. However, the lack of periosteal response and minimal uptake on an isotope bone scan help rule out sarcoma (Figure 6–96). In such cases, there should be no concern about future problems from the lesion, and usually no intervention is necessary.

BONE ISLAND

The bone island is an even more sharply marginated dysplastic process than the osteoma. It is most commonly located in the pelvis. It can mimic a blastic metastatic lesion in patients with prostate cancer. However, with a bone island, as with an osteoma, the bone scan shows minimal and very focal activity, and the CT scan and MRI show no reaction in the surrounding marrow. Figure 6–97 shows the findings of a bone island through the pelvis of a 35-year-old man.

Bone Infarcts

The two types of bone infarcts that can mimic bone tumors are the metaphyseal type and the epiphyseal type. They can be idiopathic in origin or secondary to increased alcohol consumption or corticosteroid use.

METAPHYSEAL BONE INFARCT

The most common bone infarct is in the metaphyseal region, which is typically seen about the knee, hip, and shoulder in adults. Radiographically, the infarct can mimic a low-grade cartilaginous tumor such as an enchondroma. An infarct presents with a sclerotic honeycombed pattern (Figure 6–98), whereas a cartilaginous lesion presents with central flocculated calcification (Figure 6–99).

EPIPHYSEAL BONE INFARCT

Although epiphyseal bone infarcts have the same etiology as those in the metaphysis, these are most commonly found in the femoral condyles and the proximal femoral and humeral epiphyses. In these locations, the lytic change seen in the epiphyseal bone can mimic a chondroblastoma. The differential diagnosis can be difficult before the appearance of a crescent sign or other radiographic signs of subchondral collapse that usually rule out the chondroblastoma (Figure 6–100).

Histiocytic Disorders

LANGERHANS CELL HISTIOCYTOSIS

Sometimes inappropriately called histiocytosis X, Langerhans cell histiocytosis can present in a variety of ways. Previously considered distinct diseases, including eosinophilic granuloma, Hand-Schüller-Christian disease, and Letterer-Siwe disease, they are now considered part of the same spectrum of histiocytosis presentation. Of these, the localized granulomatous form, which is called eosinophilic granuloma or Langerhans cell granulomatosis, is the one that mimics a tumor radiographically. Eosinophilic granuloma is seen twice as often in boys as in girls and commonly occurs between 5 and 15 years of age. It is usually monostotic but in 10% of cases involves two or three separate areas. It is a histiocytic process of unknown cause but may have a viral origin. It causes local inflammatory pain and may result in low-grade fever associated with an elevated sedimentation rate. Although the most common location of eosinophilic granuloma is the skull, it is also seen in the rib, pelvis, maxilla, vertebral body (vertebra plana), clavicle, and scapula, listed in the order of frequency. Besides affecting flat bones, it can arise in the diaphysis of long bones, followed next by the metaphysis, and it is least common in the epiphysis.

Eosinophilic granuloma can be extremely permeative and destructive, especially in long bones (Figure 6–101) and vertebrae (Figure 6–102), thereby mimicking a more aggressive process, such as Ewing sarcoma, metastatic neuroblastoma, or osteomyelitis. It can also produce a so-called onionskin periostitis of the type seen in Ewing sarcoma. The lesion has a more aggressive pattern in younger children and later becomes more focal and granulomatous. Microscopic findings include large pale-staining histiocytes speckled with small bright-staining eosinophils and an occasional giant cell.

Eosinophilic granulomas tend to involute spontaneously without treatment, and therefore treatment should be conservative. Simple curettement and corticosteroid injections are beneficial. In difficult areas such as the spine or pelvis, low-dose radiation treatment (10 Gy) can be considered. In more disseminated cases that do not respond to simple treatment, low-dose chemotherapy is appropriate.

PIGMENTED VILLONODULAR SYNOVITIS

Although this form of synovitis can mimic a histiocytic tumor, it is thought to be a nonneoplastic condition involving histiocytic proliferation. It occurs in the subsynovial tissue about major joints of the lower extremity in patients between 20 and 40 years of age. The knee joint is the most common site of involvement, followed next by the hip, ankle, and foot. Involvement of the upper extremity is rare.

The histopathology of pigmented villonodular synovitis is similar to that of a giant cell tumor of the tendon sheath, which presents with soft-tissue tumors about the ankle and on the fingers of the hand. The usual situation involves spontaneous swelling of one knee secondary to synovial hypertrophy. The swelling can grow gradually to a massive amount and be associated with intermittent hemarthroses. The inflamed synovium can cause juxtaarticular erosion into bone at the point of attachment of the joint capsule, as is seen in any chronic proliferative synovitis, including hemophilia and coccidioidomycosis.

In fewer than 10% of cases, pigmented villonodular synovitis is more localized and presents as a focal soft-tissue mass high in the suprapatellar pouch or in the popliteal space, and no generalized swelling of the knee occurs. In these cases, the mass can mimic a soft-tissue sarcoma such as a synovial sarcoma (Figure 6–103). Cortical erosion with secondary bony changes can also be appreciated frequently (Figure 6–104).