Osteosarcoma Case File
Eugene C. Toy, MD, Andrew J. Rosenbaum, MD, Timothy T. Roberts, MD, Joshua S. Dines, MD
CASE 38
A 19-year-old woman presents to the office complaining of dull right thigh pain for the past 2 months. She denies any trauma or inciting events over that time. The pain was initially present only while walking and after other physical activities but has progressed and is present at rest. It now disrupts her sleep at night. She is otherwise healthy and denies any fevers, chills, weight loss, or night sweats. On physical exam, her right lower extremity is neurovascularly intact. Her knee has full range of motion, and there is no warmth or erythema. However, you do note mild swelling of her distal thigh and on palpation appreciate a mass in that region. An anteroposterior (AP) radiograph of the distal femur is shown in Figure 38–1 .
Figure 38–1. AP view of the distal femur. Many of the radiographic features of this osteosarcoma
mark it as a malignant tumor. The abnormal area of mottled lucent and sclerotic tumor in the
metaphysis fades gradually into the shadows of surrounding normal bone. It is difficult to see where
the tumor begins and ends; there is a large soft-tissue mass adjacent to the bone (M). The periosteum
has been unable to maintain a shell of mineralized new bone around this mass. The sclerotic
areas within the bone and the mineralized portions of the soft-tissue mass both have a relatively
amorphous, smudged appearance that is seen with calcified osteoid matrix. (Reproduced, with
permission, from Chen MYM, Pope TL, Ott DJ. Basic Radiology. 2nd ed. New York, NY: McGraw-Hill; 2011:Fig. 6-24.)
► What is the most likely diagnosis?
► What are the next steps in the workup?
► What is the treatment approach?
ANSWER TO CASE 38:
Osteosarcoma
Summary: This is a 19-year-old otherwise healthy woman who presents with a 2-month history of dull right thigh pain that was initially activity dependent but has progressed and is now most severe at rest, especially at night. She denies any fevers, chills, night sweats, or recent weight loss. A mass in her distal thigh is palpated on examination. An AP plain radiograph illustrates a soft-tissue mass adjacent to a mottled lucent and sclerotic lesion in the metaphysis of her right femur.
- Most likely diagnosis: Pathologic bone tumor, specifically osteosarcoma.
- Next steps in workup: Magnetic resonance imaging (MRI) of the right lower extremity, tissue biopsy, computed tomography (CT) scan of the chest, and a bone scan.
- Treatment approach: Multidisciplinary approach ultimately dependent on tumor grade and type of osteosarcoma.
ANALYSIS
Objectives
- Understand the important history, physical exam, and radiographic findings consistent with a diagnosis of osteosarcoma.
- Know the essential components of the workup for a musculoskeletal lesion, specifically an osteosarcoma.
- Appreciate the need for a multidisciplinary approach to treatment and how the Musculoskeletal Tumor Society Staging System (MSTS, Enneking) influences it.
Considerations
There are many important clinical, radiographic, and pathologic findings that will aid the orthopaedist in establishing the proper diagnosis in the setting of a likely musculoskeletal tumor, as in this case. Diagnosis begins with the history and physical exam. Concerning findings in this patient include her progression of pain symptoms, to the point where it awakens her from sleep, and the presence of a palpable mass. Age is another important consideration, especially for establishing an appropriate differential diagnosis. Furthermore, some tumors have a sex predilection; osteosarcoma is more common in males. Laboratory tests are not typically diagnostic for bone tumors, but may be helpful once a diagnosis is made. Imaging must begin with at least 2 plain radiographic views of the lesion. An MRI is typically obtained after and has become the imaging modality of choice for most musculoskeletal tumors. Nuclear imaging and CT are also performed for evaluation of metastases, staging, and surveillance. Biopsy of the lesion allows for histologic analysis, which determines tumor grade and significantly impacts treatment options and ultimate prognosis. After this workup, a multidisciplinary treatment plan can be developed in conjunction with both the oncologist and orthopaedic surgeon.
APPROACH TO:
Osteosarcoma
DEFINITIONS
CODMAN TRIANGLE: A radiographic finding of new subperiosteal bone created when a lesion elevates the periosteum away from bone. Although it can appear triangular, it is often a pseudotriangle on plain radiographs with a 2-sided appearance owing to tumor growing at a faster rate than the periosteum can expand.
MSTS (ENNEKING) STAGING SYSTEM: Most recognized staging system for malignant bone tumors. It is based on tumor grade (low, high), extent (intracompartmental, extracompartmental), and the presence or absence of metastases. In general, low-grade, localized tumors are stage I; high-grade, localized tumors are stage II; and metastatic tumors (regardless of grade) are stage III. Each stage is further categorized into type a and b subsets, representative of intra- versus extracompartmental disease, respectively.
LIMB-SALVAGE SURGERY: A constellation of surgical procedures designed to achieve removal of a malignant tumor and reconstruction of a limb with an acceptable oncologic, functional, and cosmetic result.
CLINICAL APPROACH
Osteosarcoma is the most common bone sarcoma, affecting approximately 560 children and adolescents annually in the United States. Its incidence peaks in the second decade of life and is most commonly seen at sites of rapid bone turnover, such as the distal femur, proximal tibia, proximal humerus, and proximal femur. Although most cases of osteosarcoma are sporadic, those that carry the retinoblastoma tumor suppressor gene (RB1) or who have Li-Fraumeni syndrome (p53 gene) are predisposed.
There are multiple subtypes of osteosarcoma, including low-grade, high-grade, and telangiectatic intramedullary variants, as well as parosteal, periosteal, and highgrade surface types. This discussion pertains to the classic, most common subtype, which accounts for approximately 80% of all osteosarcomas, the high-grade intramedullary osteosarcoma.
The history and physical exam are crucial in the initial diagnosis of osteosarcoma. A common presenting complaint is new-onset pain over several months duration; it may occur at rest, disrupt sleep, or only occur after physical activity. This complaint must be investigated with due diligence by the clinician. Pain associated with weightbearing or activity is typically due to an inflammatory process. However, pain at rest or at night is biologic pain possibly secondary to the growth of a lesion in bone. A patient with an osteosarcoma may also present with a palpable mass in the extremity that is painful. Symptoms such as fevers, chills, weight loss, and fatigue are late signs of disease.
After a physical exam, plain radiographs of the region in question must be obtained. An osteosarcoma classically arises from the metaphyseal region of a bone and appears as a mixed sclerotic and lytic lesion that can infiltrate bone and surrounding cortex, causing a periosteal reaction and soft tissue mass. A Codman triangle may be seen on radiographs ( Figure 38–2 ). Plain radiographs concerning for a malignant bone lesion require advanced imaging, such as an MRI, to evaluate for surrounding soft tissue, neurovascular, and bone marrow involvement, as well as skip lesions, which represent discontinuous metastases.
Figure 38–2. Osteosarcoma with Codman triangle, a new area of subperiosteal bone formed when a
tumor raises the periosteum away from the bone. (Reproduced, with permission, from Doherty GM.
Current Diagnosis & Treatment: Surgery. 13th ed. New York, NY: McGraw-Hill; 2010:Fig. 40-38.)
A biopsy of the lesion is required when the imaging, examination, and history are consistent with a pathologic process; it is the only definitive means of determining whether a tumor is benign or malignant. An orthopaedic oncologist must perform the biopsy, which, if improperly obtained, can compromise the ability to perform limb salvage procedures. Definitive osteosarcoma resection must include the biopsy tract, as it too can be contaminated with tumor cells. In the setting of osteosarcoma, histologic analysis often shows diffuse cellular atypia with nuclear pleomorphism and “lacey” osteoid matrix production.
Laboratory testing is not diagnostic for osteosarcoma, but does play a role in its workup and management. Before initiation of chemotherapy, laboratory values (ie, complete blood count with differential, basic metabolic profile, renal and liver function values) must be obtained to provide a baseline assessment of organ function. Additionally, elevated alkaline phosphatase (up to 2-3 times the normal value) and lactate dehydrogenase levels are considered poor prognostic factors.
Chest CT and bone scan evaluate for metastatic disease, which is the most important prognostic and staging factor in osteosarcoma. In approximately 10% of patients, pulmonary or lymph node metastases are detected at presentation. It is not uncommon for osteosarcoma to have early hematogenous metastases. Micrometastases, which are undetectable with conventional imaging, are likely present in the lungs in most patients on initial presentation and without appropriate treatment will become evident on imaging within 1 to 2 years. A bone scan will be “hot” in osteosarcoma, specifically in areas of tumor. Those areas of the body showing increased metabolic activity must be further evaluated with imaging.
The majority of patients with osteosarcoma present as having Enneking stage IIB disease at diagnosis. For most types, treatment is multimodal. Two to three cycles of neoadjuvant chemotherapy are commonly given before wide-margin surgical resection is performed, which involves achieving the largest possible margin without unnecessary functional sacrifice. Fortunately, approximately 90% of patients with osteosarcoma are able to undergo limb salvage procedures and do not require amputation. The excised segment of bone may be replaced with a prosthesis and/or allograft. Postoperative chemotherapy is also typically used. Radiation is not used in the treatment of osteosarcoma.
The overall 5-year survival rates of patients with osteosarcoma are 60% to 80%. With the initiation of neoadjuvant chemotherapy protocols, 5-year survival rates are almost 80% in patients with nonmetastatic disease and 10% to 20% in patients with metastatic disease. In addition to elevated alkaline phosphatase and lactate dehydrogenase, poor prognostic factors include metastatic disease at diagnosis, a poor response to chemotherapy (defined as < 90% necrosis of resected tumor), and pathologic fracture.
COMPREHENSION QUESTIONS
38.1 Which of the following most accurately lists the most common location of osteosarcoma in increasing frequency?
A. Proximal tibia < axial skeleton < proximal humerus < proximal femurB. Axial skeleton < proximal humerus < proximal femur < proximal tibiaC. Axial skeleton < proximal humerus < proximal tibia < proximal femurD. Proximal humerus < axial skeleton < proximal tibia < proximal femur
38.2 In addition to metastases, which of the following is also a poor prognostic indicator in the setting of osteosarcoma?
A. High alkaline phosphataseB. PainC. Low lactate dehydrogenaseD. A and B
38.3 A 14-year-old male presents with an 8-month history of increasing right knee pain and swelling. He is otherwise healthy, but is a known carrier of the retinoblastoma gene. A mass is found on the posterior aspect of his knee, and a biopsy is taken. If found to be an osteosarcoma, what would histologic analysis of the specimen likely show?
A. Densely packed uniform small blue-stained cells in sheetsB. Numerous multinucleated giant cellsC. Diffuse cellular atypia with nuclear pleomorphism and “lacey” osteoid matrix productionD. Cystic spaces filled with blood
ANSWERS
38.1 C. The distal femur is the most common location of osteosarcoma. This is followed by the proximal tibia, proximal humerus, and then the axial skeleton (ie, spine and sacrum).
38.2 A. Poor prognostic factors include elevated alkaline phosphatase and lactate dehydrogenase, metastatic disease at diagnosis, a poor response to chemotherapy (defined as < 90% necrosis of resected tumor), and pathologic fracture.
38.3 C. Histologic analysis of osteosarcoma often reveals diffuse cellular atypia with nuclear pleomorphism and “lacey” osteoid matrix production. Other malignant characteristics include stromal cells with atypia, a high nuclear to cytoplasmic ratio, and abnormal mitotic figures. A describes a Ewing sarcoma, B a giant cell tumor, and D an aneurysmal bone cyst.
CLINICAL PEARLS
► The history and physical exam are crucial in the initial diagnosis of osteosarcoma. ► MRI is effective at evaluating an osteosarcoma because it can clearly identify surrounding soft tissue, neurovascular and bone marrow involvement, and skip lesions, which represent discontinuous metastases. ► Chest CT and bone scan are used to evaluate for metastatic disease. ► The majority of patients with osteosarcoma present with Enneking stage IIB disease at diagnosis. ► Treatment commonly involves neoadjuvant chemotherapy, limb-salvage surgery, and postoperative chemotherapy. ► The overall 5-year survival rates of patients with osteosarcoma are 60% to 80%. |
REFERENCES
Leet, Arabella I. Chapter 64: Pediatric tumors and hematologic diseases. In: Aiona MD. OKU 10: Orthopaedic Knowledge Update . Rosemont, IL: American Academy of Orthopaedic Surgeons; 2011:827.
Messerschmitt PJ, Garcia RM, Abdul-Karim FW, Greenfield EM, Getty PJ. Osteosarcoma. J Am Acad Orthop Surg. 2009;17:515-527.
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