Version May 2024
INTRODUCTION — Most bone tumors are benign, although the true incidence of benign bone tumors is unknown because most are asymptomatic and are usually discovered as an incidental lesion. As a rough estimate, they may occur more than 100 times more often than primary malignant tumors of bone. (See "Nonmalignant bone lesions in children and adolescents".)
Primary malignant bone tumors are uncommon but are a significant cause of cancer morbidity and mortality, especially among young people. Although relatively rare in childhood, primary malignant bone tumors represent the sixth most common neoplasm in children, while in adolescents and young adults, they are the third most frequent, exceeded only by leukemias and lymphomas [1,2]. In the United States, it is estimated that approximately 3300 primary malignant bone tumors (excluding malignancies arising in the bone marrow) are diagnosed annually, and approximately half as many deaths result [3].
Primary malignant bone tumors are classified according to the morphologic features of the tumor cells and, partially, by the type of matrix produced by the tumor (table 1). For many of these tumors, most notably osteosarcoma and the Ewing sarcoma family of tumors (EFT), remarkable progress in surgical techniques and multidisciplinary management over the last 40 years has resulted in significant improvements in the likelihood of cure and limb salvage.
The initial work-up and staging evaluation of a patient with a suspected primary bone tumor, particularly the diagnostic biopsy, is a critical component of successful management. Here we will discuss the diagnostic evaluation and biopsy techniques for primary tumors of bone. The classification, epidemiology, and clinical features of specific types of bone tumors, and the evaluation and management of patients with complete and impending pathologic fractures in the setting of metastatic bone disease, myeloma, and lymphoma are considered elsewhere:
●(See "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis".)
●(See "Epidemiology, pathology, and molecular genetics of Ewing sarcoma".)
●(See "Clinical presentation, staging, and prognostic factors of Ewing sarcoma".)
●(See "Chondrosarcoma".)
●(See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)
CLINICAL PRESENTATION — Patients with a bone tumor (primary malignant or metastatic) typically come to medical attention because of localized pain or swelling of a few weeks' or months' duration. Trauma, often minor, may be the initiating event that calls attention to a benign or malignant bone tumor. However, benign bone tumors are most often asymptomatic. The pain associated with malignant tumors, which may be mild at first, may be aggravated by exercise and is often worse at night. A distinct soft tissue mass can sometimes be appreciated. When present, it is usually firmly attached to the bone and moderately to markedly tender to palpation.
The first diagnostic test to arouse suspicion for a primary malignant bone tumor is generally a plain radiograph of the affected area. At that point, a diagnostic evaluation is usually undertaken.
DIAGNOSTIC AND STAGING WORK-UP — When a bone tumor is suspected, the goals of the diagnostic evaluation are to establish the tissue diagnosis, evaluate disease extent, and assess the feasibility of surgical resection using the principles of limb-sparing surgery. (See "Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management".)
Imaging — A suspected bone tumor can be imaged using plain film radiographs, magnetic resonance imaging (MRI), and/or computed tomography (CT); each imaging modality has different benefits.
Plain film radiographs can often predict the probable histology of a potentially malignant bone lesion. However, the definition of tumor size and local intraosseous and extraosseous extent are most accurately assessed by MRI. MRI with intravenous gadolinium contrast administration can identify both hypervascular and necrotic areas within the tumor, which can assist with biopsy planning.
In general, CT scans are less useful than MRI for assessing primary bone tumors. CT of the primary tumor may be useful in the rare instance that a subtle pathologic fracture cannot be confirmed by plain film radiograph or MRI; intravenous contrast is not required to obtain this information. However, CT is the best method to evaluate the thorax for metastatic disease [4,5].
An important component of the initial radiographic evaluation is imaging of the entire involved bone to avoid missing skip metastases (ie, medullary disease within the same bone but not in direct contiguity with the primary lesion) [6,7].
Differential diagnosis — Differential diagnosis depends on recognition of the tissue type and the degree of aggressiveness. Tissue types that can usually be recognized on imaging are bone, cartilage, and fat. Recognition of fat within a bone lesion is generally a sign that it is benign. Aggressiveness can be estimated by the lesion size and the way it interacts with surrounding tissues (invasiveness).
●Osteosarcoma – Osteosarcoma is by far the most common primary malignant tumor arising in bone (myeloma excluded). Osteosarcoma, which is most common in the second and third decades of life, is usually a high-grade malignancy, although the low-grade central osteosarcoma and parosteal osteosarcoma are notable exceptions. (See "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis".)
Most often, osteosarcoma is located in the metaphysis of a long bone (figure 1 and figure 2) and usually has demonstrable internal bone formation. Tumor formation within the bone can be recognized by its amorphous "cloud-like" character. Its density never exceeds the density of normal cortex.
Characteristic features of conventional osteosarcomas (which account for the majority of cases) include destruction of the normal trabecular bone pattern, indistinct margins, and lack of endosteal bone response. There is usually a mixture of radiodense and radiolucent areas, with periosteal new bone formation and sometimes formation of Codman triangle (image 1). The associated soft tissue mass may be ossified in a radial or "sunburst" pattern. The degree to which the tumor is ossified is highly variable and roughly related to the degree of cellular differentiation. (See "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis", section on 'Differential diagnosis'.)
A primarily lytic osteosarcoma may be difficult to distinguish from Ewing sarcoma or other non-matrix forming tumors on imaging studies.
●Chondrosarcoma – Chondrosarcoma, a condition of middle aged and older adults, can be low, intermediate, or high grade. Cartilage can be recognized on imaging because it tends to grow in nodules, has a very high water content (making it bright on T2 weighted MRI and dark on CT scan), and deposits mineral in dense "rings and arcs," whose density can focally exceed cortical bone (image 2). As the grade of the tumor increases, the cartilage phenotype is less well recognized, and vascularity increases (consistent with CD31 and CD34 positivity) as the grade increases. Most chondrosarcomas arise in bone, but some have a soft tissue origin. (See "Chondrosarcoma".)
●Ewing sarcoma – Ewing sarcoma of the bone (as well as the other members of the Ewing family of tumors and all of the small round blue cell tumors) has a "permeative" or "moth-eaten" pattern on imaging with very poorly defined margins. The tumors can be large and frequently involve the diaphysis (figure 2 and image 3). The characteristic periosteal reaction produces layers of reactive bone, deposited in an "onion peel" appearance (image 4).
The cortex at the site of the lesion is often permeated by tumor, which extends into the soft tissues. The soft tissue component of the tumor rarely shows any calcification or ossification. Sclerosis of bone, if present, represents a secondary bone reaction rather than the primary bone formation that characterizes osteosarcoma. A pathologic fracture is present at diagnosis in 10 to 15 percent of cases. (See "Clinical presentation, staging, and prognostic factors of Ewing sarcoma", section on 'Radiographic studies'.)
Ewing tumors may resemble subacute osteomyelitis on imaging, and the clinical presentation may also be similar (ie, presence of fever and an elevated sedimentation rate, intense radiotracer uptake on bone scan) [8,9]. Aspiration of a tumor may yield purulent-appearing material; however, it will be sterile on culture.
●Other tumors – Other malignant tumors that should be considered in the differential diagnosis of a primary lytic lesion include fibrosarcoma (formerly referred to as malignant fibrous histiocytoma or, even more generally, a "spindle cell sarcoma" of bone (table 1)), which tends to resemble osteosarcoma but without ossification, metastasis from a non-bone tumor, solitary plasmacytoma of bone/multiple myeloma, and primary lymphoma of bone. (See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults", section on 'Differential diagnosis' and "Solitary plasmacytoma of bone".)
"Benign" bone tumors that can present as lytic lesions include hemangioma, various types of cystic tumors (including aneurysmal bone cyst and unicameral bone cyst), lipomas, eosinophilic granuloma, chondroblastoma, and giant cell tumor of bone. Destructive eosinophilic granulomas usually occur at a younger age and are not associated with a sizable soft tissue mass. (See "Giant cell tumor of bone" and "Nonmalignant bone lesions in children and adolescents" and "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Lytic bone lesions'.)
Evaluation of the rest of the skeleton — Radionuclide bone scans or total body 18-fluorodeoxyglucose positron emission tomography (FDG-PET) can evaluate the entire skeleton for the presence of multiple lesions (image 5 and image 6) [10]. Although radioisotope bone scans are more sensitive than plain radiography, some metastases may be missed [11]. The addition of single photon tomography (SPECT) may improve sensitivity [12,13].
Bone scans are also limited by a lack of specificity, with most false-positive results due to trauma, whether recalled by the patient or not. As a result, the diagnosis of metastatic bone disease usually requires radiographic confirmation, especially if the number of lesions is small (fewer than four) and/or limited to the ribs (image 7) [14]. The probability that an abnormal scan represents metastatic tumor is directly related to the number of abnormal foci.
There is growing consensus that PET scans represent an excellent approach to the clinical evaluation of bone metastases [10,15] and possibly the evaluation of a primary bone tumor. PET uptake correlates with the degree of cell metabolism and may be seen with many benign conditions. However, in some cases (eg, chondrosarcoma), the degree of uptake appears to be related to the histologic grade of malignancy. (See "Chondrosarcoma", section on 'Role of positron emission tomography'.)
For some malignancies (ie, lung and breast cancer), PET scans are more specific than bone scans for detection of bone metastases, although they are possibly less sensitive (especially for osteoblastic foci) and clearly more expensive. For patients with osteosarcoma, data are conflicting as to whether PET scans are superior to bone scans for detecting osseous metastases [15,16]. However, a major benefit of PET scans over bone scans in this disease is its ability to screen for distant metastases at sites other than bone [17,18]. (See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults", section on 'Bone scan' and "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults", section on 'Positron emission tomography (PET) scanning'.)
Guidelines from the National Comprehensive Cancer Network (NCCN) [19] suggest either PET or bone scan in the staging work-up of a primary bone tumor, and imaging guidelines from the Children's Oncology Group Bone Tumor Committee for both osteosarcoma and Ewing sarcoma recommend radionuclide bone scan and/or PET scan for whole-body staging. This subject is addressed in detail elsewhere. (See "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis", section on 'Evaluation for systemic disease' and "Clinical presentation, staging, and prognostic factors of Ewing sarcoma".)
Radiographic skeletal surveys are obsolete, except in multiple myeloma and possibly in patients with thyroid cancer, where the propensity for purely lytic bone metastases renders the bone scan insensitive to lesions at risk for a pathological fracture (table 2 and image 8 and image 9). A similar, but less frequent, lack of sensitivity for bone scanning is seen in renal cell, and head and neck cancer, in which lytic bone metastases predominate. (See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults", section on 'Skeletal survey'.)
Whole-body MRI has the potential to detect more lesions in the axial skeleton (particularly the spine) than bone scan, but it is generally not feasible in most centers due to time constraints. Whole-body diffusion-weighted MRI may provide significant advantages. MRI techniques are rapidly advancing and may replace other means of imaging bones, such as radionuclide bone scans, in the future. (See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults", section on 'Whole-body magnetic resonance imaging'.)
Low-dose whole-body CT can also be used to assess lytic lesions in patients with multiple myeloma, which is discussed separately. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'CT, MRI, and PET'.)
Staging system — The staging system used by the Musculoskeletal Tumor Society for primary bone sarcomas was developed by Enneking [20]. This system characterizes nonmetastatic malignant bone tumors by grade (low-grade [stage I] versus high-grade [stage II]) and further subdivides these stages according to the local anatomic extent (intracompartmental [A] versus extracompartmental [B]). The compartmental status is determined by whether the tumor extends through the cortex of the involved bone. Patients with regional nodal or distant metastases are categorized as stage III.
The American Joint Committee on Cancer (AJCC) adopted a tumor, node, metastasis (TNM) staging system in its 1997 fifth edition, and despite several modifications, it has not been in widespread use for bone sarcomas. Compared with earlier versions, the latest 2017 revision of the joint AJCC/Union for International Cancer Control (UICC) staging criteria has separate and distinct TNM classifications for primary tumors arising in the appendicular skeleton/trunk/skull/facial bones and those arising in the pelvis and spine (table 3) [21]. These staging criteria specifically define the extent of the primary tumor (T), the histologic grade of differentiation (G), and any spread to nodes (N) or distant sites (metastasis; M category). Regional nodal involvement from primary bone sarcomas is rare, and regional lymph node sampling/lymphadenectomy is usually not performed. As a result, the N stage is typically assigned clinically (cN), while the primary tumor is classified according to pathologic stage (pT, pG) after definitive surgery. The M category is stratified according to site (lung metastases [M1a] versus bone or other sites [M1b]) to reflect the poorer prognosis for nonpulmonary metastases.
It remains to be seen whether this most recent TNM modification will be more widely used than prior versions. The main clinical distinction is between localized versus metastatic disease.
INDICATION FOR BIOPSY — As noted above, the majority of patients with a primary malignant or metastatic bone tumor present with localized pain and/or swelling. The first diagnostic test to arouse suspicion for a bone tumor is generally a plain radiograph of the affected area. Depending on the clinical history and the degree of suspicion, a staging work-up may then be instituted (see 'Diagnostic and staging work-up' above) or a diagnostic biopsy considered. Bone biopsy is indicated in the following circumstances:
●Whenever there is significant doubt as to the diagnosis of a benign or malignant lesion
●When the histologic distinction among possible diagnoses could alter the planned course of treatment
●When definitive confirmation of the diagnosis is required before undertaking a hazardous, costly, or potentially disfiguring treatment
Doubtful diagnosis — A symptomatic lesion with demonstrable anatomical abnormality requires tissue diagnosis unless a specific entity can be confidently identified from the radiographic imaging studies. As an example, a radiographic diagnosis of "nonossifying fibroma" does not require a definitive tissue biopsy (image 10), while a nonspecific "benign-appearing bone lesion" may warrant biopsy confirmation.
For certain lesions, a definitive operative procedure can be planned without requiring a biopsy. As an example, the diagnosis of a low-grade parosteal osteogenic sarcoma is readily apparent on imaging studies in most cases (image 11). A preoperative biopsy may be avoided in such cases because of the difficulty in determining the appropriate biopsy site within the lesion and in obtaining tumor tissue in the characteristically hard thick bone. However, even for such lesions, preoperative biopsy is appropriate if the diagnosis is in doubt or if there is concern about the possibility of dedifferentiation to a higher-grade lesion, which would prompt more aggressive treatment. On imaging studies, areas of high-grade tumor involvement tend to be hypervascular and show the least amount of recognizable bone (less mineralized) (image 11).
Metastatic disease — A bone biopsy may sometimes be indicated to confirm the diagnosis of metastatic disease prior to definitive treatment with radiation or chemotherapy. (See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults", section on 'Diagnostic biopsy'.)
Metastases represent the most common bone tumor, particularly in older adults, and are the most frequent indication for a bone biopsy. Taken together, tumors of the breast, prostate, thyroid, lung, kidney, and pancreas account for more than 80 percent of primary tumors in patients presenting with metastatic bone disease. In children, neuroblastoma is the most frequent. (See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults", section on 'Epidemiology' and "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma", section on 'Metastatic disease'.)
If a primary tumor is known, a skeletal lesion with a typical appearance on imaging studies (either lytic or osteoblastic (table 2)) may be presumed to be metastatic, especially if there are multiple lesions. However, because of the dire prognostic implications of metastatic disease, the possibility that the finding could represent a benign lesion, and the outside possibility of a second occult primary malignancy, histologic confirmation of the initial site of metastasis is recommended. It is neither feasible nor desirable to confirm each metastatic lesion by biopsy. (See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults", section on 'Diagnostic biopsy'.)
An impending or complete pathologic fracture in a patient with a solitary bone lesion, with or without a history of cancer, should never be fixed without a tissue diagnosis. Should the lesion prove to be a primary mesenchymal malignancy (eg, osteosarcoma, chondrosarcoma), the surgical repair could jeopardize not only the opportunity for limb salvage, but also the possibility of cure. If the biopsy is to be done in advance by interventional radiology, discussion with the radiologist performing the biopsy is very important as the biopsy should be performed in a location that will permit excision of the biopsy tract should a primary sarcoma be diagnosed. Consultation with an orthopedic oncologist is advised if questions about the diagnostic biopsy arise. (See "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma", section on 'Diagnostic biopsy'.)
Planning the biopsy — The biopsy must be carefully planned to ensure that adequate diagnostic tissue is obtained without compromising the oncologic outcome. An incorrectly performed biopsy can jeopardize not only the opportunity for limb salvage, but also the possibility of cure [22-24]. As examples:
●The biopsy must be performed such that the entire biopsy tract can be easily excised during later definitive surgery. Certain benign bone tumors, such as giant cell tumor of bone, and certain malignant bone tumors, such as chordoma and chondrosarcoma, can seed the biopsy tract. Therefore, if not too morbid, the tract of the biopsy should be carefully removed without an effect on the final surgical approach; otherwise, there is a danger of tumor implantation in the scar (image 12A-B) [25,26]. The length of the biopsy incision should be kept to a minimum so that the final resection does not sacrifice excessive normal tissue and the wound is easily closed (picture 1).
●Open biopsies that are performed with a transverse rather than longitudinal incision may compromise more than one compartment, and the neurovascular bundle may also be contaminated. This may result in the need for amputation when a limb-sparing procedure might have been otherwise possible.
●Many bone tumors are hypervascular and can bleed profusely after even a small incisional biopsy. Careful hemostasis is mandatory since a hematoma can permit the spread of tumor cells into adjacent compartments, compromise the possibility of limb salvage, and increase the likelihood of a wound infection.
Biopsies should take place after the completion of the staging studies, and the surgeon, radiologist, and pathologist should review these studies in detail so that each member of the team is fully apprised of the diagnostic considerations. Since the site, approach, and method selected for biopsy are intimately connected to the planned operative procedure, the biopsy should generally be performed at the hospital where definitive surgery will be carried out.
The biopsy of a suspected primary neoplasm must yield enough tissue to permit complete histopathological evaluation, including grading. It is desirable for the biopsy to include the highest grade of tumor tissue found within the lesion, to the extent that it is possible, since this is what determines the final stage and, therefore, prognosis. As noted above, areas of high-grade tumor involvement tend to be hypervascular (ie, avidly enhance) and show the least amount of recognizable matrix (image 7). Areas of necrosis (ie, typically nonenhancing areas) seen on imaging studies should be avoided in particular because necrotic tissue can be histologically uninterpretable.
BIOPSY TECHNIQUES — A sample of the tumor can be obtained by either needle biopsy or open (operative) techniques.
In the future, we hope to be able to measure circulating tumor products, such as circulating tumor cells, circulating cell-free nucleic acids, tumor-derived exosomes, and metabolites, to not only help in the diagnosis of sarcoma but also to follow-up for tumor recurrence and/or progression [27].
Needle biopsy — Progress in imaging technology and needle guidance has made it possible to biopsy virtually all parts of the body safely and effectively. Advantages of needle biopsies are that they do not usually require general anesthesia or the operating room, are less expensive, and can be scheduled more readily than an operative biopsy. If the biopsy is performed with image-guidance, the needle can be directed to the lesion and its location documented.
The major disadvantages are the limited amount of tissue that is obtained for diagnostic studies (particularly with a fine needle rather than core biopsy) and the possibility of sampling error. The use of the largest possible core biopsy devices to sample the most promising portions of the tumor helps to minimize this problem. However, in view of the extensive adjunctive tissue studies that may be required for a definitive diagnosis (see 'Special specimen handling requirements' below), a needle sample may not be adequate, even if appropriately obtained.
Needle biopsies may be accomplished with a fine needle, producing a specimen for cytologic analysis, or with cutting needles of various calibers (core needle biopsy). They may be guided either by palpation ("blind") or by radiologic imaging, usually computed tomography (CT) or ultrasound.
It was previously thought that all needle biopsy tracts needed to be removed at the time of the definitive procedure, but observational data suggest that this is not the case, at least for most bone tumors [28].
However, there are certain tumors (eg, chordoma and giant cell tumor) that may seed the biopsy tract easily. For these specific histologies, we would recommend excision of the needle biopsy tract. (See 'Planning the biopsy' above.)
Fine needle aspiration biopsy — The fine needle aspiration (FNA) biopsy can be performed with or without image guidance. However, it is preferable to perform FNA under image guidance. FNA is an excellent method to confirm metastatic disease in bone and to document tumor recurrence. It is also suitable for diagnosis of infection, although identification of a specific organism in chronic osteomyelitis can be difficult by any method. In contrast, FNA is usually insufficient for making a primary diagnosis of a bone tumor because of the lack of tissue architecture and because it can only rarely provide information concerning tumor grade. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis".)
Core biopsy — Core biopsies without image guidance can be performed in the clinic setting if the mass is large and easily palpable, and this may result in considerable cost savings when compared with either image-guided or open biopsy [29]. However, it is important that the mass be relatively homogeneous since it is difficult to target a specific portion of a heterogeneous tumor. Core biopsy with image guidance (ie, fluoroscopy, ultrasound, CT, or magnetic resonance imaging [MRI]) provides the opportunity to selectively biopsy specific areas of the tumor.
While fluoroscopy and ultrasound are the least expensive and least time-consuming techniques, they each have significant limitations. Fluoroscopy is suitable only for bone lesions and does not provide information about the soft tissues through which the needle is being advanced. Ultrasound guidance is most suitable for soft tissue lesions and cannot be applied to all bones because of problems with penetration of the sound waves. Nevertheless, in one large series, 63 of 144 patients with a suspected primary bone tumor were considered suitable for an ultrasound-guided biopsy [30]. Compared with the final surgical result, the diagnostic accuracy was somewhat greater with ultrasound than with fluoroscopically guided biopsy (98 versus 88 percent).
CT is the most versatile of the imaging techniques, although it is relatively time consuming. The use of so-called "real-time" CT or CT fluoroscopy can minimize the time required. Almost any part of the body can be biopsied safely with CT guidance (image 13A-B), and specific areas of tumor can be targeted for biopsy. The accuracy rate ranges from 70 to >90 percent depending on whether a metastatic focus or a primary tumor is biopsied [31-34]. The introduction of three-dimensional (coaxial) needle guidance systems that make use of CT data is a more recent advance that appears highly promising [35,36].
Although MRI-guided bone biopsies appear to be accurate and safe [37,38], the requirement for open MRI systems (operating at relatively low field strengths), MRI-compatible non-ferromagnetic needles, and patient monitoring equipment limit the availability of this procedure. In addition, access to the patient is limited by the size of the magnet, adding to the difficulties of performing the biopsy and monitoring the patient. MRI is the most costly of the imaging modalities and is not in widespread use for biopsy guidance.
Technique
Fine needle aspiration technique — Material for cytological preparations can be obtained using any of the fine-caliber cutting needles (eg, the Chiba needle). Placing the needle into the tumor and moving it rapidly in and out in a piston-like movement while maintaining suction with a small amount of saline in a syringe will usually exfoliate a sufficient number of cells. The sample should be immediately spread on a slide and fixed to prevent air-drying.
Core biopsy technique — Side-cutting needles (eg, the Tru-Cut needle) result in well-preserved soft tissue samples. Newer automated spring-loaded biopsy devices (eg, the TEMNO device) come in a variety of gauges and have calibrated sheaths that allow them to be accurately placed at the appropriate depth. The length of the core sample can be adjusted on several of these devices to suit the size of the lesion. In our experience and that of others, these devices provide the best biopsy results for both soft tissues and lytic bone lesions [39]. The sample should be immediately fixed in 10% formalin for adequate preservation of the lesional cells. If lymphoma is in the differential diagnosis, the biopsy can be sent fresh for lymphoma work-up.
The presence of intact bone significantly influences needle choice and procedural technique. The needle may need to pass through dense bone in order to obtain a sample of nonossified tissue (eg, for a lytic bone marrow lesion), or sampling of a mineralized area may be required. When it is necessary to pass through dense bone (but not biopsy it), a drill may facilitate the procedure and be less painful for the patient compared with a trephine needle.
A hand-operated mechanical or battery-powered drill may be used [40,41], but a simple drill turned by the fingers is adequate in most cases. A particularly clever design is the Bonopty or Monopty drill (RADI Medical Systems, Uppsala, Sweden), which has an eccentric bit that produces a hole that is slightly larger than the drill diameter [42]. This permits a protective cannula to be introduced into the drill hole, and the anchored cannula then serves as a guide for the biopsy needle. This tool is particularly helpful for transpedicle biopsies of the spine [36]. The drill provides access through dense bone but does not produce a biopsy sample. It must be used in conjunction with a biopsy device, which could be either one of the automated systems (of appropriate gauge) or a simple fine gauge cutting needle (image 14). A new battery-powered drill system (OnControl bone access system, Vidacare Corporation) improves needle control and shortens procedure time [41].
If the tissue to be sampled contains a considerable amount of bone, a trephine needle (eg, an Ackermann or Jamshidi needle) may be helpful. In our experience, these needles work best in trabecular or partially destroyed bone, but do not penetrate intact cortex very readily.
As noted above, the transpedicular approach is useful for biopsies of the spine (image 15). This approach avoids the risk of damage to the spinal nerves but may not be suitable for some lesions (eg, if the pedicle is small or if the lesion cannot be reached) [43]. In expert hands, more than 50 percent of the vertebral body is accessible via a transpedicle approach [44].
Anesthesia — Most needle biopsies of bone can be performed with local anesthetic, either with or without conscious sedation. In general, malignant lesions, particularly metastatic foci, result in less procedural pain than benign lesions [45]. As a result, local anesthesia is adequate for the majority of cases, and conscious sedation is only occasionally needed. For young adolescents and children who are unable to cooperate because of anxiety, conscious sedation or even general anesthesia may be required.
The technique of local anesthetic injection is important as it can either reassure or alarm the patient about the remainder of the procedure. Anesthetic effectiveness is needed only over the width of the biopsy device; extensive infiltration of the skin and subcutaneous tissue is unnecessary and counterproductive. Xylocaine buffered with sodium bicarbonate may result in less pain upon injection than xylocaine alone. The beginning of the procedure should be delayed a few minutes after the anesthetic injection to allow time for the anesthetic effect to develop.
Accuracy of needle biopsy — The "success" of bone biopsy ranges from 90 to 95 percent for metastatic lesions, with lower rates (70 to 80 percent) reported for primary bone tumors and infectious lesions in most series [30-34,46-51]. Sclerotic lesions are more difficult to biopsy than lytic lesions, and accuracy rates for such lesions tend to be lower in many, but not all, series [33]. Causes of error in the biopsy of primary bone tumors include a nondiagnostic biopsy, biopsy histology that fails to match the resection specimen (discordance), and incorrect histologic grade of differentiation (sampling error).
Varying diagnostic rates are partly the result of differing definitions of "success." As an example, the pathologist's impression of "malignant cells" could be regarded as a successful result if all that is required is confirmation of a metastatic lesion; in contrast, such a reading would be inadequate to diagnose or classify a bone sarcoma.
One way of handling this dilemma is the concept of "effective accuracy," which is defined as the ability of the procedure to replace an open biopsy.
As examples:
●In one series, percutaneous needle biopsy was similarly accurate in identifying suspected metastatic lesions, musculoskeletal infections, and primary musculoskeletal tumors (82, 90, and 83 percent, respectively), but the effective accuracy was highest in identifying metastases, slightly lower for infections, and lowest for suspected primary tumors (77, 72, and 59 percent, respectively) [52]. The authors postulated that the diagnostic utility of a percutaneous biopsy was reduced to less than 20 percent for primary tumors because pathologists typically asked for more tissue to render a diagnosis in cases of a suspect primary lesion, requiring a repeat procedure.
●Another study evaluating the diagnostic utility of percutaneous biopsy to distinguish osteomyelitis from Ewing sarcoma found that percutaneous biopsies were less accurate than open biopsies in patients who were ultimately diagnosed with Ewing sarcoma [9]. Those authors recommended going directly to open biopsy rather than taking a wait-and-watch approach in such circumstances.
Data suggest that the effective accuracy of percutaneous biopsies is better in the diagnosis of metastatic lesions compared with primary tumors or musculoskeletal infections. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Bone biopsy'.)
Complications — Complications are rare with image-guided needle biopsy [53]. Some complications may occur with any procedure that breaks the skin (eg, infection, bleeding), while others are anatomically specific (eg, pneumothorax, nerve injury, airway compromise, damage to the great vessels).
Although it was previously thought that spinal biopsies have a higher risk of complications than biopsies of appendicular lesions, in two series with a combined 150 spinal biopsies, there was only one complication [47,48]. This patient, who had been ingesting significant quantities of aspirin for pain management, had a procedure-related hemorrhage. Inadequate hemostasis with hematoma can rarely be life-threatening but also, as noted previously, must be avoided due to adverse effects on outcome. (See 'Planning the biopsy' above.)
The use of large-caliber biopsy needles can be associated with a significant complication rate, especially in inexperienced hands. In one report of 82 patients undergoing CT-guided biopsy using a Craig needle, there were six complications, including one aortic puncture, two penetrations of the anterior vertebral cortex with hematoma, one wrong level, and two procedures aborted because of pain [54]. Ten procedures had to be repeated, three times in one case. This complication rate is unusual and not reflective of the experience at most centers.
As noted above, if an incisional biopsy produces a hole in the bone, it should be plugged or packed with polymethylmethacrylate cement to prevent hematoma and tumor spread. Another complication of open biopsy of a bone lesion is fracture; protected weight bearing or even prophylactic stabilization may be necessary following a biopsy. (See 'Operative biopsy' below.)
Operative biopsy — An operative or open biopsy is performed following standard skin preparation and draping. Antibiotics are not typically administered prior to the biopsy; they are not necessary as long as the standard sterile technique is used. Furthermore, since infection (osteomyelitis) can sometimes masquerade as a neoplastic process, the use of antibiotics may compromise the utility of cultures taken at the time of biopsy.
An incisional biopsy can be performed for primary bone tumors and, until recently, was more frequently done for primary bone tumors than an image-guided needle biopsy. Although excisional biopsies may be appropriate for small tumors involving the soft tissue (eg, subcutaneous dermatofibromas or lipomas), they are not advisable for lesions surrounding neurovascular structures or in locations deep to the fascia. In such cases, inappropriate excision may jeopardize definitive treatment.
If an open biopsy is performed, the incision should be placed in accordance with the planned surgical resection. If done properly, the primary tumor and the entire biopsy tract should be resected en bloc. Meticulous hemostasis and the judicious use of a drain are important to avoid the spread of hematoma-containing tumor cells. If a soft tissue mass is not present or material is nondiagnostic, a bone defect may be required to obtain tissue. If so, it should be a small, round or oval defect, and a polymethylmethacrylate plug should be used to close the hole in order to minimize hematoma. (See 'Planning the biopsy' above.)
SPECIMEN HANDLING
Fine needle aspiration — FNA biopsy yields cells or cell clusters that are suitable for cytological preparation, which can be done rapidly. Although the specific tissue diagnosis may require additional time and special processing, the presence of diagnostic material in the specimen can often be confirmed during the biopsy procedure. This permits additional "passes" to be performed as required and decreases the need for repeat procedures. However, as noted above, cytology is seldom adequate for the diagnosis of primary lesions. (See 'Fine needle aspiration biopsy' above.)
Frozen section preparation — Frozen section preparation of large core samples can be performed as for an operative specimen. However, analysis of tissue prepared in this way is less accurate than standard permanent fixation, and if the sample is small, it is preferable not to attempt a frozen section. Furthermore, the presence of bone within the sample interferes with optimum slide preparation, and decalcification may be required.
Special specimen handling requirements — The extensive pathologic evaluation that is often required to ascertain the correct diagnosis may require special handling for all or part of the specimen:
●"Touch preparations" stained with Wright's stain for certain hematologic malignancies.
●Decalcification to adequately process the biopsy.
●Cytogenetic (karyotyping), flow cytometric studies, and establishment of cell lines (in tissue culture media).
●Specialized immunocytochemical studies for diagnosis.
●Molecular analysis on formalin fixed paraffin embedded (FFPE) or frozen tissue (cryopreserved at -70°).
●Cytologic imprinting for fluorescence in situ hybridization (FISH) studies (alcohol-fixed and air-dried).
●A sample of tissue, aspiration of fluid, or swab should be sent for microbial culture if osteomyelitis is in the differential diagnosis.
●Ultrastructural examination by electron microscopy (in glutaraldehyde buffered solution) is seldom used as a diagnostic tool.
●If lymphoma is suspected, the hematopathologist should be alerted ahead of time for proper tissue handling. Samples should be collected in saline and sent to the laboratory where they can be triaged to flow cytometry, cytogenetic and molecular studies. It can be difficult to obtain diagnostic tissue from a lymphoma due to its susceptibility to severe "crush artifact." Multiple biopsies are often needed and even then may not yield a definitive diagnosis.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Bone cancer (The Basics)")
SUMMARY
●General principles – Primary malignant bone tumors are uncommon malignancies, but they are an important cause of cancer morbidity and mortality, especially among teenagers and young adults. (See 'Introduction' above.)
●Diagnostic and staging work-up – The goals of the preoperative evaluation are to establish the tissue diagnosis, evaluate disease extent, and assess the feasibility of a limb-sparing approach. (See 'Diagnostic and staging work-up' above.)
•Although plain radiographs can often predict the probable histology of a potentially malignant bone lesion, the definition of tumor size, and local intraosseous and extraosseous extent is most accurately achieved by magnetic resonance imaging (MRI).
•Computed tomography (CT) is the best method to evaluate the thorax for metastatic disease.
•Positron emission tomography (PET) scans are increasingly being used in place of radionuclide bone scans to evaluate the rest of the skeleton as well as other distant metastatic sites.
●Differential diagnosis – The radiographic differential diagnosis depends on recognition of the tissue type and the degree of aggressiveness (as determined by lesion size and relationship with the surrounding tissues [invasiveness]). Recognition of fat within a bone lesion is generally a sign that it is benign. (See 'Differential diagnosis' above.)
●Indications for biopsy – Bone biopsy is indicated in the following circumstances (see 'Indication for biopsy' above):
•Whenever there is significant doubt as to the diagnosis of a benign or malignant lesion
•When the histologic distinction among possible diagnoses could alter the planned course of treatment
•When definitive confirmation of the diagnosis is required before undertaking a hazardous, costly, or potentially disfiguring treatment
●Planning the biopsy – The biopsy of a suspected primary bone tumor must be carefully planned to avoid compromising the oncologic outcome. (See 'Planning the biopsy' above.)
●Biopsy techniques – Although a fine needle aspiration biopsy may be adequate for the diagnosis of a metastatic or recurrent bone lesion, core needle biopsy or an open biopsy is usually required for most primary bone tumors. Open biopsies are being done less frequently since most core needle biopsies can deliver sufficient tissue on multiple passes for all diagnostic studies. Given the heterogeneity of most sarcomas, the ability to guide the core needle to regions of more aggressive tumor is very important to accurately diagnose and grade the sarcoma. (See 'Biopsy techniques' above.)
●Specimen handling – The extensive pathologic evaluation that is often required to ascertain the correct diagnosis may require special handling for all or part of the specimen. This process can last one to two weeks depending on the number of tests necessary. Among patients undergoing an open biopsy, frozen section analysis is important in determining whether sufficient tissue has been acquired. (See 'Specimen handling' above.)
●Classification of bone tumors – Primary malignant bone tumors are classified according to their cytologic features and cellular products (table 1). (See "Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management", section on 'Histologic classification'.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Daniel Rosenthal, MD, and Miriam Bredella, MD, who contributed to an earlier version of this topic review.
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