Lesions Characterized by Osteoid Deposition and Aggressive Radiology Located within Bone

Historical Overview

Although the term “sarcoma,” designating a fleshy tumor, was introduced by Galen, and tumors of the limbs were described by Hippocrates, osteosarcoma as a bone-forming primary malignancy was first recognized in 1805, both by Boyer in Philadelphia and Dupuytren in Paris. Both based their description on gross observation. The earliest focused review of osteosarcoma was presented in 1879 by Samuel Gross, who reported 28 cases of bone sarcomas, of which 16 produced either bony or cartilaginous matrix. Gross also recognized that the tumors were most common in the long bones of the lower extremity and had a tendency to metastasize to the lung. A “bone tumor registry,” the first tumor registry of any kind, was established in 1920 by Earnest Codman, James Ewing, and Joseph Bloodgood (representing Boston, New York, and Baltimore, respectively). Codman published observations on the collection in 1926, outlining 25 clinical, radiologic, and pathologic criteria for the diagnosis of osteosarcoma. Interestingly, the majority of specimens submitted to the registry were found to be metastatic carcinoma. The collection subsequently became part of the Armed Forces Institute of Pathology. Cade reported on 133 cases of osteosarcoma in 1955, with an emphasis on the efficacy of radiation therapy and documentation of treatment effect. He also noted that the majority of patients developed metastases after amputation and postulated microscopic systemic spread at the time of diagnosis.

The current classification of conventional osteosarcoma into osteoblastic, chondroblastic, and fibroblastic subtypes is based on the 1957 series of Coventry and Dahlin, expanded to 600 cases over a 55-year period in their 1967 update. Dahlin excluded from the series fibrosarcoma and chondrosarcoma, as well as surface osteosarcoma and tumors arising in special sites such as the jaw. Although many variants have since been described, this report is still the basis of modern classification.

In his original series of patients with osteitis deformans, Paget recognized that three of eight cases were complicated by the development of sarcoma. Subsequent series found that sarcoma associated with Paget disease is rare in individuals younger than 50 years of age but that the majority of osteosarcoma cases in those over 60 are associated with Paget disease.

Incidence and Demographics

Osteosarcoma is the most common primary bone sarcoma. It constitutes 20% of malignant bone tumors and is twice as common as chondrosarcoma and nearly three times as common as Ewing sarcoma. Nevertheless, the condition is uncommon, with fewer than 1000 new cases occurring each year in the United States. Osteosarcoma has a bimodal age distribution; most cases occur in childhood to young adult years (4.4 cases per million in patients younger than 24 years of age) and older patients (4.2 cases per million in patients older than 60 years of age). Osteosarcoma is rare in patients younger than 5 years of age. There is a male-to-female ratio of approximately 1.3 to 1 in both demographic groups. However, in the youngest patients (younger than 10 years of age), the reverse is true, and on average the onset of osteosarcoma is earlier in females, possibly because of the earlier age of pubertal growth. Osteosarcoma is about 1.2 to 1.4 times more common in African-American and Hispanic populations than in non-Hispanic Caucasian populations. A multi-institutional study found that osteosarcoma patients were significantly taller than controls, whereas no difference was found for Ewing sarcoma patients compared to controls. A similar observation has been made in osteosarcoma in dogs, where the incidence is much great in large breeds.

Tumors in the older incidence group are frequently secondary, with 20% of cases in patients older than 40 years and 50% of cases in patients older than 60 years arising in Paget disease. The risk of developing a secondary sarcoma is about 1% for all patients with Paget disease, as high as 10% for those with polyostotic disease, a 1000-fold greater risk than in the general population. Secondary osteosarcoma may also be associated with enchondromatosis, fibrous dysplasia, chronic osteomyelitis, and bone infarcts.

Tumors associated with previous radiation exposure, most commonly therapeutic for a prior malignancy, account for 3% of osteosarcomas. The mean interval from radiation exposure to diagnosis is 12 to 14 years, with a range from 4 to more than 40 years. Pediatric patients receiving radiation or alkylating agents have an increased risk of sarcoma that is dose dependent. Ewing sarcoma, which is treated with alkylating agents and higher doses of radiation, has a risk of secondary osteosarcoma that reaches 22% at 20 years post-therapy. Ingestion or administration of α- or β-particle emitting radionucleotides, such as cesium, radium, or thorium, is associated with osteosarcoma because many of these isotopes are concentrated in bone. Thorium-containing radiologic contrast media, theraepeutic radium injections, radium-containing elixirs, and glow-in-the-dark radium paint have all been associated with osteosarcoma. Several cases of sarcoma have occurred in the long-term follow-up of patients exposed to radiation from the Chernobyl nuclear reactor, including one case of osteosarcoma. There is little evidence that background environmental radiation increases the risk of osteosarcoma, although one study from Cornwall found levels of radon gas were significantly higher in the homes of osteosarcoma patients than in controls.

Localization and Clinical Manifestations

Although virtually any bone may be affected by osteosarcoma, the most common sites are the long bones of the extremities, with the femur, tibia, and humerus accounting for more than 50% of cases. The small bones of the hand and feet are rarely involved. In cases of osteosarcoma arising in Paget disease, tumors of the pelvis, skull, and humerus are common. Most lesions are metaphyseal (90%) or diaphyseal (9%), with epiphyseal lesions very uncommon.

Patients typically present with pain and a palpable mass, with pathologic fracture occurring in fewer than 10%. Skin changes, venous dilation, and bruits may be associated with more vascular lesions.

Paget disease may affect any bone but occurs frequently in the pelvis, spine, and skull, and it accounts for a significant share of osteosarcomas arising in these sites. Patients typically have a long history of Paget disease, with deformation of the involved bone and not infrequently present without new symptoms, and a new lytic and soft tissue mass are found radiographically. Pathologic fracture at presentation is uncommon.

Radiologic Features and Gross Pathology

Radiographic appearance is variable, depending on the rapidity of growth and the contribution of osteoblastic, chondroblastic, and fibroblastic elements. Most tumors show a mixture of lytic and sclerotic areas, with an indistinct interface with the surrounding bone ( Fig. 6-1 ). Cortical destruction is frequent, and more than 80% of cases have extraosseous extension, which in 90% of cases exhibits mineralization, often producing a “hair on end” or sunburst pattern perpendicular to the periosteum. At the interface of extraosseous tumor and normal bone, it is common to have a triangular area of periosteal elevation with matrix formation; the Codman triangle represents reactive periosteum. Computed tomographic (CT) imaging is more sensitive for the detection of small amounts of mineralized matrix and evaluating the status of the cortical bone. Magnetic resonance imaging (MRI) is vital for delineation of normal anatomic structures, soft tissue extension, joint space involvement, and evaluation of the marrow space for skip lesions and extent of tumor.

Paget disease is radiographically lytic, becoming irregularly mixed lytic and sclerotic with thickened trabeculae, cortical thickening, and bone expansion and deformity. Osteosarcoma complicating Paget disease usually presents with a soft tissue mass and periosteal reaction (see Fig. 6-1F ), although both may also be seen in Paget disease not complicated by malignancy.

Grossly, conventional osteosarcoma has a primary medullary component with erosion of the cortex and a large soft tissue mass ( Fig. 6-2 ). Depending on the proportion of osteoblastic, chondroblastic, and fibroblastic components, areas of the tumor may range in consistency from firm and sclerotic to gray and glistening to soft and fish-flesh–like. Mineralization tends to be greater centrally, with the periphery containing the least matrix. In sclerotic osteosarcoma, the tumor may be dense and ivory-like. Periosteal reaction at the periphery of the tumor may be prominent, corresponding to the radiographic Codman triangle.

In Paget disease–associated osteosarcoma, there is marked preexisting deformity with cortical thickening and lytic and sclerotic pagetoid bone, depending on the status of the disease. Destruction of the cortex and a soft tissue mass are often present, varying in consistency depending on the degree of matrix production.

Histopathology

On low power, an infiltrative growth pattern is present ( Fig. 6-3 ) within the medullary canal and cortex; tumor infiltrates preexisting bony trabeculae and Haversian canals, surrounding and trapping the native elements. Tumor usually extends through the periosteum and infiltrates skeletal muscle and soft tissue. Most tumors are predominantly osteoblastic, whereas chondroblastic and fibroblastic predominance is seen in about 10% of cases each ( Fig. 6-4 ). In all cases, osteoid matrix is produced by tumor cells. Osteoblastic tumors typically exhibit marked cytologic atypia, frequent, occasionally atypical, mitoses, and netlike osteoid matrix separating individual tumor cells. In hypocellular sclerotic lesions, or sclerosing osteosarcoma, broad areas of dense woven bone infiltrate and trap preexisiting native bone ( Fig. 6-5 ). Malignant osteoblastic cells entrapped in the matrix may display minimal pleomorphism, “normalizing” their cytologic appearance. A diagnosis of malignancy can be made based on the infiltrative pattern and radiographic features. Chondroblastic osteosarcoma has broad zones of occasionally myxoid cartilaginous matrix, simulating high-grade chondrosarcoma, but also produces osteoid matrix. Secondary ossification of cartilaginous matrix is not sufficient for the diagnosis of osteosarcoma. Fibroblastic osteosarcoma simulates an intermediate- to high-grade fibroblastic or myofibroblastic tumor and may have only sparse osteoid, occasionally present in broader trabeculae of woven bone.

Eighty percent of sarcomas arising in Paget disease are osteosarcoma, and the majority are osteoblastic (71%) or fibroblastic (20%), with chondroblastic (8%) occurring less frequently. Other histologies occur only rarely. Although the osteoblastic stage of Paget disease may be hypercellular, significant atypia is absent and bone is produced in trabeculae, in contrast to the sarcomatous component ( Fig. 6-6 ).

Differential Diagnosis

Osteosarcoma has an extremely variable histologic appearance depending on the dominant cell type and matrix, and the differential diagnosis is therefore broad. Clinical presentation and radiologic appearance are integral parts of assessing the lesion, and usually the index of suspicion is high even before the biopsy is performed. For osteoblastic lesions, the histologic differential diagnosis includes osteoid osteoma and osteoblastoma. Osteoma is small, cortically based and has a characteristic targetoid radiographic appearance, well-formed trabeculae with osteoblast rimming, and lacks cytologic atypia. Except for the rare intracortical osteosarcoma, location and radiographic appearance separate the entities. Osteoblastoma may have a more aggressive radiographic appearance with a less well-defined interface with normal bone. Histologically, the presence of trabeculae of woven bone with osteoblast rimming, vascular intervening stroma, and minimal atypia discriminate osteoblastoma from osteosarcoma. The rare osteoblastoma-like osteosarcoma displays increased atypia and fine lacy osteoid in the stroma between woven bone trabeculae ( Fig. 6-7 ).

An important differential diagnosis for chondroblastic osteosarcoma is chondrosarcoma. Histologically, the two can be indistinguishable except for the production of osteoid. For most patients, the young age and radiographic appearance of osseous matrix make the diagnosis of chondrosarcoma unlikely. If an initial biopsy on a patient younger than 20 years of age reveals only a malignant cartilaginous tumor, it is better to render a descriptive diagnosis and indicate that, taking into account the radiograph and clinical presentation, osteosarcoma is a much more likely diagnosis.

Two rare variants of osteosarcoma produce cartilaginous matrix but simulate benign lesions. Chondromyxoid fibroma (CMF)–like osteosarcoma lacks the radiographic sclerotic border usually seen in CMF; however this is also lacking in 10% of CMF patients ( Fig. 6-8 ). CMF-like osteosarcoma arises centrally, usually disrupts the cortex, and has soft tissue extension, whereas CMF is cortically based and rarely has a soft tissue component. Histologically, CMF-like osteosarcoma mimics the zonal appearance of CMF, with myxoid matrix containing stellate cells alternating with more cellular areas. Pleomorphism, mitotic activity, and the production of osteoid differentiate CMF-like osteosarcoma from CMF.

Chondroblastoma-like osteosarcoma is an extremely rare variant that occurs preferentially in the bones of the hands and feet at an average age of 40 years, as compared to chondroblastoma, which has peak incidence before closure of the epiphyses. Radiographically, most lesions are diaphyseal and have soft tissue extension, both unusual for chondroblastoma. Histologically, the tumor is composed of polygonal cells that simulate benign chondroblasts, scattered giant cells, and a sparse cartilaginous matrix that may display “chicken wire” calcification. Pleomorphism may be subtle, particularly because chondroblasts have a high nuclear-to-cytoplasmic ratio and frequently are dark and smudgy cytologically. An infiltrative growth pattern at the margin, soft tissue extension, and osteoid production all suggest osteosarcoma.

The differential diagnosis of fibroblastic osteosarcoma includes pleomorphic sarcoma (malignant fibrous histiocytoma) of bone, nonossifying fibroma, fibrous histiocytoma, and fibrous dysplasia. Although sometimes sparse, fibroblastic osteosarcoma produces osteoid matrix, in contrast to malignant fibrous histiocytoma. The radiograph of fibroblastic osteosarcoma is indicative of an aggressive lesion, and pleomorphism is not difficult to find.

Perhaps the most difficult differential in evaluating biopsies of osteosarcoma is fracture callus. The history of fracture is frequently not provided, the first biopsy specimen received often is of periosteum, and callus displays immature osteogenic and chondrogenic tissue that simulates malignancy. Fracture repair displays all the stages of normal wound healing, with the addition of the osteocartilaginous callus ( Fig. 6-9 ). The early changes involve granulation tissue and fibroblastic proliferation, followed by differentiation of periosteal and endosteal pluripotential cells into osteoblasts and chondroblasts. Histologically, the early callus simulates disorganized fetal cartilage and bone and can mimic the histology of conventional osteosarcoma or chondrosarcoma. Because injury is often ongoing, zones of more mature changes may alternate with more recent injury. Acute changes of hemorrhage and fibrin deposition are followed by neutrophils (less than 24 hours) and macrophages (2 to 3 days). Granulation tissue and proliferating myofibroblasts predominate until 7 days, when early osteoid formation is seen in the stroma. Woven bone and cartilage matrix are present by 10 to 14 days, followed by well-formed trabeculae of woven bone with osteoblast rimming by 2 to 3 weeks (see Fig. 6-6 ). Mitotic activity and cellularity are often high, and cytologic atypia in cartilage may be striking. Atypical mitoses and frank pleomorphism are not present in fracture callus.

Several histologic features help differentiate fracture callus from osteosarcoma. Callus has a zonal character, with areas of immature cartilage merging with woven bone and myofibroblasts, whereas osteosarcoma tends to be more diffuse. Maturing woven bone in fractures forms trabeculae with prominent osteoblast rimming, maturing to an “arches on arches” pattern of broad trabeculae of woven bone. Osteosarcoma produces lacelike osteoid between tumor cells and usually lacks well-formed trabeculae and osteoblast rimming. The matrix between trabeculae in a fracture is a mixture of vascular and reactive fibroblastic tissues.

Ancillary Diagnostic Studies and Genetics

Immunohistochemistry has limited utility in the diagnosis of osteosarcoma; the immunoprofile reflects the broad range of histologic appearance and includes S-100 protein, smooth muscle actin, CD99, osteonectin, and osteocalcin. Aberrant expression of cytokeratin has been reported, especially in tumors with epithelioid differentiation. Osteocalcin appears to have some utility in establishing bone lineage, with 70% sensitivity and 100% specificity. Immunohistochemistry for IDH1 is useful in the differentiation of chondrosarcoma from chondroblastic osteosarcoma.

Cytogenetic analysis is of limited use because there are no frequently recurring abnormalities and most osteosarcomas have complex and highly aneuploid karyotypes, including multiple chromosomal abnormalities. Amplification of 6p12-21, corresponding to the region containing the osteoblast differentiation gene RUNX2 , and of 8q21-24, which includes MYC , are each found in approximately 50% of cases.

Several syndromes confer a hereditary predisposition to the development of osteosarcoma and mirror mutations found in sporadic cases. Hereditary retinoblastoma patients, with a germline mutation in the cell cycle control gene Rb , have an increased risk of developing osteosarcoma as a secondary malignancy that ranges from 75-fold in patients treated by surgery alone to greater than 300-fold in those receiving radiation therapy—or a cumulative lifetime risk of 6% to 14% for all hereditary retinoblastoma patients. There is loss of heterozygosity of the Rb gene in 39% of sporadic osteosarcoma cases, apparently without an effect on prognosis.

Li-Fraumeni syndrome, an autosomal, dominantly inherited susceptibility to a variety of tumors, including sarcoma, is associated with mutation in p53 , a cell cycle and apoptosis control gene, in 70% of cases. Approximately 3% of osteosarcomas are associated with the syndrome, and the risk of developing sarcoma is 500 times that of the general population. Approximately 40% of sporadic cases have a loss of heterozygosity of p53 .

The RECQ DNA helicase gene family is involved in DNA repair and telomere maintenance. Mutations in three members of this group are associated with heritable genetic disorders that carry an increased risk of osteosarcoma. Seventy percent of patients with Rothmund Thomson syndrome (small stature, poikiloderma, and juvenile cataracts) have a mutation in the RECQL4 DNA helicase gene, and they have an associated 10% to 30% risk of developing osteosarcoma. Patients with this syndrome are highly sensitive to ionizing radiation and DNA intercalating drugs such as doxorubicin. Sporadic osteosarcoma is not associated with mutations of RECQL4 .

Bloom syndrome (short stature, micrognathism, photosensitivity, immune deficiency, and increased risk of multiple tumors) and Werner syndrome (progeria; cataracts; and increased risk of soft tissue sarcoma, melanoma, thyroid cancer, and osteosarcoma) are autosomal recessive syndromes caused by mutation in the BLM gene ( RECQL3 helicase) and WRN gene ( RECQL2 helicase), respectively. Both syndromes have marked genomic instability, with frequent chromosomal breaks, translocations, and telomere shortening. Lymphoma and leukemia are the most common malignancies in early life in Bloom syndrome, with carcinomas predominating in patients in their twenties and thirties. Osteosarcoma constitutes 2% and 5% of tumors associated with Bloom and Werner syndromes, respectively. As with RECQL4 , mutations in the RECQL2 or RECQ3 genes are not found in sporadic osteosarcoma. The syndromes suggest that the marked chromosomal abnormalities seen in sporadic osteosarcoma are related to faulty DNA repair, not to mutation of the RECQ family of helicase genes. Other studies have found increased RECQL4 gene expression in sporadic osteosarcoma and an association of RECQL5 polymorphisms with increased risk of osteosarcoma.

Fifteen to twenty percent of patients with Paget disease have a first-degree relative who also suffers from the disease, with an autosomal dominant pattern of inheritance. Up to 50% of familial cases and up to 15% of sporadic cases carry a mutation in the SQSTM1/p62 gene (5q35), which is known to indirectly affect receptor activator for nuclear factor (RANK) ligand signaling. Mice harboring a mutation in a ubiquitin-associated domain of SQSTM1 also develop Paget disease. Genome-wide studies have implicated seven other genes, including RANK and macrophage colony-stimulating factor. Osteosarcoma associated with sporadic Paget disease had a mutation of SQSTM1 in three of five cases in one study.

Therapy and Prognosis

Therapy in the prechemotherapy era was surgical, usually by amputation. Although local control was usually attained, 80% of patients succumbed to metastases. Adjuvant chemotherapy was introduced in the 1970s, and a randomized multidrug, multi-institutional study in 1986 reported a nearly 70% relapse-free survival compared to 17% for controls. Early trials of limb-sparing surgery were accompanied by a high local recurrence rate, but with the introduction of preoperative neoadjuvant chemotherapy in the 1970s and 1980s, limb-sparing surgery became the norm.

One of the most important indicators of prognosis is the response to neoadjuvant chemotherapy, or the pathologic assessment of percentage of tumor necrosis. The area of affected bone has usually been excised with soft tissue margins over areas of extraosseous extension. Following inking and sampling of soft tissue margins, the bone is skinned of soft tissue, split in the long axis, and made into a 3-mm thick parallel section. After fixation and decalcification, one complete face of the tumor is mapped and blocked in. Microscopic assessment of residual viable tumor is made, and cases with greater than 90% necrosis are considered to be responders and have an improved survival. Patients with nonresponding tumors usually receive a modified chemotherapy regimen. Patients with metastases at presentation and with predominantly chondroblastic histology are less responsive to chemotherapy. In spite of advances in chemotherapy, osteosarcoma arising in Paget disease has a dismal prognosis, with a 5-year survival of 10%.

Historical Overview

Hemorrhagic cystic tumors of bone were recognized in 1876 by Sir James Paget as representing a neoplasm of bone with a “blood cyst” forming as a secondary feature, and Gaylord in 1903 reported three cases of “so-called bone aneurisms” that had sarcomatous linings. However, Ewing was the first to use the term “telangiectatic osteosarcoma” when in 1922 he recognized these tumors as a variant of osteosarcoma. Geschickter and Copeland reported their experience with 88 cases of “osteolytic osteosarcoma,” malignant lesions that produced little matrix, in 1936. Although the series appears to include fibroblastic osteosarcoma and malignant fibrous histiocytoma of bone, several illustrations, including a low-power micrograph of blood spaces, are clearly telangiectatic osteosarcoma. The Mayo clinic experience in 1976 of 24 patients and the Memorial experience in 1982 of 124 cases are the two largest series.

Incidence and Demographics

Telangiectatic osteosarcoma is an uncommon subtype, constituting 4% to 10% of all osteosarcoma cases. It occurs most frequently in the second decade of life but otherwise has a similar demographic profile to conventional osteosarcoma.