Use of Imaging Prior to Referral to a Musculoskeletal Oncologist
Developed by the Musculoskeletal Tumor Society
History of Growth: Soft Tissue Tumor
Moderate strength evidence supports that, in patients suspected of soft tissue tumor recurrence, an MRI of the tumor site can reliably identify neoplastic tissue and differentiate between solid and cystic areas.
Moderate Evidence Moderate Evidence
One aspect of a patient history that is important when evaluating a tumor of the bone or soft tissue is the general stability of the mass over time. Palpable masses that have been present and not enlarging for months or years are unlikely to represent a life-threatening malignancy, whereas tumors with rapid growth over a period of weeks may be concerning for an aggressive process. Much of the literature we found did not focus on the initial evaluation of a growing mass, but rather an attempt to distinguish recurrent tumor from a non-neoplastic process (post-operative scar, fluid collections, normal tissue). Although the clinical setting varied from our intended scenario, the question remained relevant, as the imaging was performed in attempt to determine the presence of a tumor in a patient with a concern for recurrent or residual sarcoma. One moderate quality study (Gingrich, 2017) reported on the ability of MRI to identify residual sarcoma after a prior resection and found 86.7% sensitivity, 57.9% specificity, and overall accuracy of 78.1%. One low quality study (Jiang, 2016) found that a soft tissue mass was a reliable indicator of tumor recurrence when an MRI was performed adjacent to a total joint arthroplasty, with 100% sensitivity and 96% specificity. One moderate quality study (Lehotska, 2013) used time-to-intensity curves to reflect the dynamic enhancement of soft tissue in contrast MRI and determined a positive predictive value of 95.7% and negative predictive value of 100% in their ability to diagnose recurrent sarcoma. One low quality study (Park, 2016) compared MRI to PET-CT and found that each could reliably detect soft tissue sarcoma recurrence and were statistically equivalent. They recommended MRI as the primary modality to investigate recurrence, with PET-CT as an additional option if the MRI was inconclusive.

In bone tumors, one moderate quality study (Pereira, 2014) reported that MRI was helpful and accurate at distinguishing solid and cystic components. The work group was concerned that a statement recommending MRI in all patients with a history of growth of a mass would result in a large number of unnecessary MRI scans. In our cumulative clinical experience, many patients report slow growth over time (a common history in benign entities such as lipomas) or may report a contradictory history of an enlarging mass which, by objective measures such as bony remodeling on conventional radiographs, is likely to be an inadvertent misrepresentation of tumor growth. Therefore, we recommend that an MRI be considered as an imperative study only when there is a clear history of rapid growth (such as a tumor doubling or tripling in size in a matter of weeks). Clinicians should use other measures, such as the appearance on conventional radiographs, presence of pain, size, and depth of the lesion as additional factors that can help with decision-making.
MRI: Use of Contrast
Strong evidence supports that a heterogenous signal in a contrast-enhanced MRI can assist in determining if a soft tissue tumor is benign or malignant.
Moderate Evidence Moderate Evidence
Although it is clear from the available literature and meta-analysis (2 high quality and 5 moderate quality studies) that the use of IV contrast assists in the differentiation between benign and malignant entities, a substantial amount of discussion was dedicated to the issue of how MRIs should be used as an initial imaging modality by referring practitioners. In most circumstances, a non-contrast study will provide adequate information to determine the underlying identity of a mass, specifically if the lesion is clearly consistent with a common benign entity, such as a lipoma or synovial cyst, or if there are abnormal characteristics consistent with a possible sarcoma, in which case referral to a specialty center is warranted and strongly recommended. The work group did not feel that a universal recommendation to perform contrast enhanced MRI in every patient was a judicious use of resources, but rather if contrast was deemed necessary by the treating cancer specialists, a limited contrast enhanced study could be performed at the discretion of the treating team on an individualized basis. Meta-analysis of 1 high quality and 4 moderate quality studies also showed that heterogeneous signal on contrast MRI has some value in determining whether a soft tissue tumor is malignant or benign.
CT Scans: Staging
In the absence of reliable evidence, it is the opinion of the work group that staging CT scans in the setting of a destructive bone lesion should be ordered by, or in consultation with, an oncology specialist.
Consensus Consensus
We did not find any acceptable investigations that directly addressed this question. However, it is well accepted, that a critical early imaging study is a CT scan that visualizes the chest, abdomen, and pelvis of the patient (Weber, 2010). This allows for assessment of common sites of origin of metastatic carcinoma (lung, breast, prostate, kidney, colon) and common sites of regional (axillary and inguinal lymph nodes) and distant (lung, liver, axial skeleton) disease. Contrast may be helpful to determine true pathologic lesions from other non-neoplastic conditions and should be used if there are no patient contraindications, such as a contrast allergy. It can be difficult to distinguish between the more common scenarios of metastatic carcinoma and multiple myeloma and the uncommon scenario of a primary sarcoma. However, the treatment of a primary sarcoma is vastly different than the treatment of metastatic carcinoma and multiple myeloma, and the early recognition of the underlying disease is critical for optimal treatment.

Therefore, we recommend that a staging CT scan is most appropriately ordered by an oncologic specialist, and encourage non-specialist practitioners to consider an early referral to or consultation with a specialty provider on suspicion of a bone or soft tissue malignancy prior to obtaining a CT chest/abdomen/pelvis. If there is no apparent site of primary carcinoma on the staging CT scan, or if the solitary destructive bone lesion is the only focus of additional disease, a referral to an orthopaedic oncologist is necessary prior to any biopsy or stabilization of the bone lesion to address the potential for a primary sarcoma.
History of Pain: Unknown Etiology
In the absence of reliable evidence, it is the opinion of this work group that, in the setting of a bone or soft-tissue tumor of unknown etiology with a complaint of pain at the site of the identified but undiagnosed tumor, CT of the chest/abdomen/pelvis, PET-CT, and Tc99 bone scan may assist with the diagnostic workup but should be utilized at the discretion of the treating oncologic specialists.
Consensus Consensus
In addition to a critical analysis of imaging studies, it is important to interview patients to determine their initial awareness of the condition, changes over time, and symptoms of presentation. Specifically, the presence or absence of pain can help determine the relative likelihood of an indolent or aggressive process. A physical exam is also necessary to determine alternative explanations for pain in the area of a bone or soft tissue lesion. It is not uncommon that unrelated symptoms due to arthritis, bursitis, and tendonitis can occur in the area of a lesion that is not the origin of the pain, but rather an incidental finding in close proximity. Therefore, pain by itself does not reliably indicate an aggressive process and a dedicated history and examination to investigate other potential causes is required.

These recommendations apply primarily to the scenario of pain that cannot be attributed to a competing explanation and is likely due to the underlying lesion. The majority of bone malignancies will cause pain, often described as unassociated with activity and present at rest and night. In the setting of a bone lesion of unknown etiology, the presence of pain suggests an active process that requires further investigation to determine the underlying biology. One moderate quality study (Barai, 2004) found that patients presenting with soft tissue tumors and reporting bone pain at distant sites of metastases reliably correlated to the presence or absence of metastatic sarcoma, which were detected by Tc99 bone scan. Among a population of patients mostly reporting bone pain, two moderate quality studies (Kotb, 2014 and Weger, 2013) found that MRI and radiographs can determine benignity of bone tumors with high accuracy but determined malignancy had a weaker association to the reference standard. Although the advanced imaging modality of choice is an MRI, an exception may be in the case of an obvious bone-forming lesion without a broken periosteal reaction on radiographs that is suggestive of an osteoid osteoma, in which case CT is the preferred imaging modality.
CT Scans: Staging
In the absence of reliable evidence, it is the opinion of the work group that CT chest/abdomen/pelvis scans performed in patients with a destructive bone lesion highly suspicious for metastatic disease of bone should use oral and IV contrast.
Consensus Consensus
We did not find any acceptable investigations that directly addressed this question. However, it is well accepted, that a critical early imaging study is a CT scan that visualizes the chest, abdomen, and pelvis of the patient (Weber, 2010). This allows for assessment of common sites of origin of metastatic carcinoma (lung, breast, prostate, kidney, colon) and common sites of regional (axillary and inguinal lymph nodes) and distant (lung, liver, axial skeleton) disease. Contrast may be helpful to determine true pathologic lesions from other non-neoplastic conditions and should be used if there are no patient contraindications, such as a contrast allergy. It can be difficult to distinguish between the more common scenarios of metastatic carcinoma and multiple myeloma and the uncommon scenario of a primary sarcoma. However, the treatment of a primary sarcoma is vastly different than the treatment of metastatic carcinoma and multiple myeloma, and the early recognition of the underlying disease is critical for optimal treatment.

Therefore, we recommend that a staging CT scan is most appropriately ordered by an oncologic specialist, and encourage non-specialist practitioners to consider an early referral to or consultation with a specialty provider on suspicion of a bone or soft tissue malignancy prior to obtaining a CT chest/abdomen/pelvis. If there is no apparent site of primary carcinoma on the staging CT scan, or if the solitary destructive bone lesion is the only focus of additional disease, a referral to an orthopaedic oncologist is necessary prior to any biopsy or stabilization of the bone lesion to address the potential for a primary sarcoma.
CT Scans: Prior Chest Radiograph
In the absence of reliable evidence, it is the opinion of the work group that it is not necessary to perform a chest radiograph prior to a chest CT in the staging of a bone or soft tissue malignancy.
Consensus Consensus
We did not find any acceptable investigations that directly addressed the question of whether performing a chest radiograph prior to a CT scan is warranted or not. The theoretical justification for performing a chest radiograph initially is that the results may influence the decision to obtain a subsequent CT scan. Our work group agreed that when the clinical presentation is concerning enough to justify a CT scan to evaluate for other sites of disease or metastatic spread regardless of the findings on a chest radiograph, as is the case with this scenario, a chest radiograph is of low utility and does not influence the decision to obtain a CT scan. In the clinical setting of a destructive bone lesion or soft tissue mass concerning for malignancy, visualization of the lungs is necessary to determine the presence of distant disease. Chest CT scans provide more detail than chest radiographs and are the study of choice for most practitioners. Because the chest CT and its scout image provide more detailed information, a chest x-ray prior to chest CT is redundant and unnecessary in this situation. If the treating cancer specialists anticipate post-treatment pulmonary surveillance with chest radiographs, a baseline chest radiograph may be useful as a comparison for future studies.
MRI: Magnet Strength
In the absence of reliable evidence, it is the opinion of the work group that a magnet of at least 1.5 Tesla should be used when imaging musculoskeletal neoplasms.
Consensus Consensus
No investigations directly compare the diagnostic performance of different magnet strengths on the same tumors, limiting the statements that can be made regarding whether increasing strength of the magnet improves diagnostic performance. However, strong evidence including several high and moderate quality investigations (Henninger, Crombe, Thornhill, Daniel, and Negendank) have demonstrated a strong sensitivity and specificity for differentiating between benign and malignant etiologies when imaging the tumor with a 1.5T magnet strength (1.5T magnets are widely available and are known to provide good quality images), when compared with the gold standard of histologic diagnosis. 1.5T was the most commonly used magnet strength in the literature, however, these several moderate strength studies demonstrated less accurate diagnostic results for 1.5T magnet strength compared to stronger magnets (Chen, Kalayanarooj).
MRI: Use of Contrast
In the absence of reliable evidence, it is the opinion of the work group that IV contrast does not offer any advantages for detecting tumor presence over a non-contrast study.
Consensus Consensus
Although it is clear from the available literature and meta-analysis (2 high quality and 5 moderate quality studies) that the use of IV contrast assists in the differentiation between benign and malignant entities, a substantial amount of discussion was dedicated to the issue of how MRIs should be used as an initial imaging modality by referring practitioners. In most circumstances, a non-contrast study will provide adequate information to determine the underlying identity of a mass, specifically if the lesion is clearly consistent with a common benign entity, such as a lipoma or synovial cyst, or if there are abnormal characteristics consistent with a possible sarcoma, in which case referral to a specialty center is warranted and strongly recommended. The work group did not feel that a universal recommendation to perform contrast enhanced MRI in every patient was a judicious use of resources, but rather if contrast was deemed necessary by the treating cancer specialists, a limited contrast enhanced study could be performed at the discretion of the treating team on an individualized basis. Meta-analysis of 1 high quality and 4 moderate quality studies also showed that heterogeneous signal on contrast MRI has some value in determining whether a soft tissue tumor is malignant or benign.
History of Pain: Tc99 Bone Scan
Limited evidence supports that a Tc99 bone scan may assist with obtaining a diagnosis or planning further diagnostic studies or treatment in patients with a bone tumor of unknown etiology and pain in the area of the tumor.
Limited Evidence Limited Evidence
In addition to a critical analysis of imaging studies, it is important to interview patients to determine their initial awareness of the condition, changes over time, and symptoms of presentation. Specifically, the presence or absence of pain can help determine the relative likelihood of an indolent or aggressive process. A physical exam is also necessary to determine alternative explanations for pain in the area of a bone or soft tissue lesion. It is not uncommon that unrelated symptoms due to arthritis, bursitis, and tendonitis can occur in the area of a lesion that is not the origin of the pain, but rather an incidental finding in close proximity. Therefore, pain by itself does not reliably indicate an aggressive process and a dedicated history and examination to investigate other potential causes is required.

These recommendations apply primarily to the scenario of pain that cannot be attributed to a competing explanation and is likely due to the underlying lesion. The majority of bone malignancies will cause pain, often described as unassociated with activity and present at rest and night. In the setting of a bone lesion of unknown etiology, the presence of pain suggests an active process that requires further investigation to determine the underlying biology. One moderate quality study (Barai, 2004) found that patients presenting with soft tissue tumors and reporting bone pain at distant sites of metastases reliably correlated to the presence or absence of metastatic sarcoma, which were detected by Tc99 bone scan. Among a population of patients mostly reporting bone pain, two moderate quality studies (Kotb, 2014 and Weger, 2013) found that MRI and radiographs can determine benignity of bone tumors with high accuracy but determined malignancy had a weaker association to the reference standard. Although the advanced imaging modality of choice is an MRI, an exception may be in the case of an obvious bone-forming lesion without a broken periosteal reaction on radiographs that is suggestive of an osteoid osteoma, in which case CT is the preferred imaging modality.
History of Pain: Contrast-Enhanced CT Scan
In the absence of reliable evidence, it is the opinion of this work group that contrast-enhanced CT scan of the site should be considered in patients with pain at the site of a bone or soft tissue mass when there are patient specific contraindications to MRI, such as a pacemaker or cerebral aneurysm clips.
Consensus Consensus
In addition to a critical analysis of imaging studies, it is important to interview patients to determine their initial awareness of the condition, changes over time, and symptoms of presentation. Specifically, the presence or absence of pain can help determine the relative likelihood of an indolent or aggressive process. A physical exam is also necessary to determine alternative explanations for pain in the area of a bone or soft tissue lesion. It is not uncommon that unrelated symptoms due to arthritis, bursitis, and tendonitis can occur in the area of a lesion that is not the origin of the pain, but rather an incidental finding in close proximity. Therefore, pain by itself does not reliably indicate an aggressive process and a dedicated history and examination to investigate other potential causes is required.

These recommendations apply primarily to the scenario of pain that cannot be attributed to a competing explanation and is likely due to the underlying lesion. The majority of bone malignancies will cause pain, often described as unassociated with activity and present at rest and night. In the setting of a bone lesion of unknown etiology, the presence of pain suggests an active process that requires further investigation to determine the underlying biology. One moderate quality study (Barai, 2004) found that patients presenting with soft tissue tumors and reporting bone pain at distant sites of metastases reliably correlated to the presence or absence of metastatic sarcoma, which were detected by Tc99 bone scan. Among a population of patients mostly reporting bone pain, two moderate quality studies (Kotb, 2014 and Weger, 2013) found that MRI and radiographs can determine benignity of bone tumors with high accuracy but determined malignancy had a weaker association to the reference standard. Although the advanced imaging modality of choice is an MRI, an exception may be in the case of an obvious bone-forming lesion without a broken periosteal reaction on radiographs that is suggestive of an osteoid osteoma, in which case CT is the preferred imaging modality.
History of Pain: Radiographs and MRI
Moderate evidence supports that both radiographs and MRI have weak sensitivity in determining malignancy but moderate to strong specificity in determining benignity of bone tumors in patients reporting pain.
Moderate Evidence Moderate Evidence
In addition to a critical analysis of imaging studies, it is important to interview patients to determine their initial awareness of the condition, changes over time, and symptoms of presentation. Specifically, the presence or absence of pain can help determine the relative likelihood of an indolent or aggressive process. A physical exam is also necessary to determine alternative explanations for pain in the area of a bone or soft tissue lesion. It is not uncommon that unrelated symptoms due to arthritis, bursitis, and tendonitis can occur in the area of a lesion that is not the origin of the pain, but rather an incidental finding in close proximity. Therefore, pain by itself does not reliably indicate an aggressive process and a dedicated history and examination to investigate other potential causes is required.

These recommendations apply primarily to the scenario of pain that cannot be attributed to a competing explanation and is likely due to the underlying lesion. The majority of bone malignancies will cause pain, often described as unassociated with activity and present at rest and night. In the setting of a bone lesion of unknown etiology, the presence of pain suggests an active process that requires further investigation to determine the underlying biology. One moderate quality study (Barai, 2004) found that patients presenting with soft tissue tumors and reporting bone pain at distant sites of metastases reliably correlated to the presence or absence of metastatic sarcoma, which were detected by Tc99 bone scan. Among a population of patients mostly reporting bone pain, two moderate quality studies (Kotb, 2014 and Weger, 2013) found that MRI and radiographs can determine benignity of bone tumors with high accuracy but determined malignancy had a weaker association to the reference standard. Although the advanced imaging modality of choice is an MRI, an exception may be in the case of an obvious bone-forming lesion without a broken periosteal reaction on radiographs that is suggestive of an osteoid osteoma, in which case CT is the preferred imaging modality.
Ultrasound: Benign Tumor
Moderate evidence supports that ultrasound helps to distinguish benign from malignant soft tissue tumors.
Moderate Evidence Moderate Evidence
Although frequently utilized prior to advanced imaging, standard ultrasound evaluation of concerning masses does not preclude subsequent advanced imaging. As a screening tool, the purpose of an ultrasound evaluation would be to identify which lesions need further imaging and which can be definitively diagnosed as benign. While mostly moderate quality evidence evaluations have shown reasonable psychometrics using advanced techniques in the 80-90% accuracy range (Belli 2000, Chen 2015, Chen 2009a, Lagalla 1998, and Nagano 2015), these studies did not address whether such evaluations could stand alone without an MRI or CT in a prospective manner. Part of the general usefulness of ultrasound is its availability and low cost; if a patient will likely ultimately need an MRI or CT regardless, the rationale for adding additional cost and time for ultrasounds needs further support. A meta-analysis of high and moderate quality studies conducted for this CPG showed a sensitivity of 0.84 and specificity of 0.84 for determining the malignancy of a lesion based on several ultrasound techniques (Chen 2015, Belli 2000, Chen 2009a, Lagalla 1998, Nagano 2015). Many authors reporting on the utility of ultrasound do so only as an adjunct rather than replacement for other advanced imaging (De Marchi 2003, Furuta 2016, Lagalla 1998, Nagano 2015), in which case the patientderived value needs to be elucidated. Miller et al (2015) noted that ultrasound studies were generally considered by orthopaedic oncologists to be unhelpful prior to referral. It may be possible in the future that advanced ultrasound techniques could be first line imaging, with MRI ordered by the referral center (De Marchi 2015, Loizides 2012).

It is the consensus recommendation that if a mass is less than 5cm, superficial, and not by critical structures (axilla, groin, popliteal fossa, over a subcutaneous bone) then a principled excisional biopsy without ultrasound evaluation is reasonable. Should a patient not desire removal but reassurance, ultrasound may be able to confirm cystic nature and allow observation in the absence of growth (Nagano 2015). Wagner et al (2013) noted high accuracy for lipomas with 96.9% specificity for superficial masses. In cases where the size or depth of the lesion cannot be determined by physical examination, ultrasound can provide anatomic location to guide further evaluation and treatment. It is the consensus recommendation that if a mass is greater than 5cm, or deep, or by critical structures then an ultrasound evaluation is unlikely to obviate the need for advanced imaging and may delay treatment or provide false reassurance. In particular circumstances, such as vascular malformations (Furta 2017), ultrasound can aid in making a diagnosis and avoiding a biopsy, but in this setting ultrasound could be ordered if desired by a referral center. Moderate and high-quality studies are evaluating means of distinguishing benign versus malignant soft tissue masses by ultrasound (eg., Pass 2017, Chen 2009 a, Chen 2009 b). However, it is the opinion of the work group that there is not yet sufficient sensitivity for malignancy or specificity for benignity for ultrasound evaluations to obviate the need for further advanced imaging for large or deep or precariously located lesions (Nagano 2015). In these suspicious circumstances, an ultrasound should not be required prior to obtaining an MRI. In other clinical situations, such as evaluating a possible soft tissue sarcoma recurrence, ultrasound may be an effective means of surveillance and directing a biopsy (Arya 2000). We did not find any literature discussing use of ultrasound in bone lesions and suggest that our recommendations apply only to soft tissue tumors.
Plain Radiographs: Initial Evaluation
In the absence of reliable evidence, it is the opinion of the work group that conventional radiographs are a reasonable diagnostic test and may be considered during the initial evaluation of a soft tissue tumor.
Consensus Consensus
One high quality study (Oudenhoven et al) found was a prospective series of 200 hand lesions with histology as the gold standard. Four moderate studies utilized radiographs in a similar way to evaluate bone tumors, and when combined with the high-quality study in meta-analysis, were shown to detect benignity and malignancy with high accuracy as compared to histology (76.5% sensitivity and 86.4% specificity). With respect to the diagnosis of soft tissue tumors of unknown etiology, there is scant published literature regarding the value of conventional radiographs of the tumor site to assist with obtaining a diagnosis or planning further diagnostic studies or treatment. In the absence of reliable evidence, it is the opinion of this work group that certain radiographic findings can be very helpful when present; such as phleboliths in hemangiomas, characteristic ossification patterns of myositis ossificans, mineralization within the substance of the tumor, density of the tumor, and cortical involvement of the underlying bone. However, many times conventional radiographs will not add any additional information regarding the identity of the tumor. Thus, our work group agreed that this test should be regarded as a justifiable, although not universally critical, diagnostic study at initial evaluation of soft tissue tumors.
Tumor Size: Bone or Soft Tissue
In the absence of reliable evidence, the work group recommends that, in aggressive appearing bone or soft tissue tumors, advanced imaging studies be requested with the guidance of an orthopedic oncologist or musculoskeletal radiologist.
Consensus Consensus
Size is an important feature noted by clinicians on initial evaluation of a bone or soft tissue tumor. For malignancy, increasing size of the mass is correlated with adverse outcomes such as local recurrence and diminished overall survival, implying a relationship with tumor biology. The importance of size is also reflected in tumor classifications, such as the widely-used American Joint Committee on Cancer (AJCC) staging system which includes the maximal dimension of soft tissue sarcoma (5 and 10 cm) and bone sarcoma (8 cm) as one of the few characteristics used to determine cancer stage. A unifying feature of aggressive neoplasia is growth over time. By this reasoning, larger tumors may be more likely to represent a malignancy and require an assertive imaging investigation.

Our review focused on literature that discusses the relationship of size to an underlying malignancy, and the use of advanced imaging modalities to determine the cause and formulate a treatment plan. There were 5 high and 11 moderate quality studies evaluating the use of MR imaging for a bone or soft tissue tumor of unknown etiology with a mass of a certain size or depth to assist with obtaining a diagnosis or planning further treatment. High strength studies have evaluated the ability of MR imaging to differentiate benign from malignant tumors in a variety of locations in the axial (Matsumoto 2016) and appendicular (Liu 2011) regions and soft tissue masses with a variety of sizes, appearances (cystic or solid [Harish 2006]) and tissue types (fatty [Rougraff 1997], neurogenic [Zhang 2015], etc). Two high quality studies (Matsumoto 2016 and Zhang 2015) and 6 moderate quality studies (Calleja 2012, Chen 2009c, Chung 2012, Datir 2008, Gruber 2016, and Sen 2010) found MRI to have a moderate to strong relationship to histopathological results in determining malignancy of soft tissue tumors with a size of 5cm or larger. MRI is first option for staging malignant bone tumors and for evaluation of all indeterminate soft tissue tumors. Other imaging modalities (CT of the site, PET/CT, Tc 99m Bone Scan) are used in specific cases and should be implemented by, or with the guidance of, the treating oncology team.
Plain Radiographs: Unknown Etiology
Moderate evidence supports using conventional radiographs in the initial evaluation of a bone tumor of unknown etiology.
Moderate Evidence Moderate Evidence
One high quality study (Oudenhoven et al) found was a prospective series of 200 hand lesions with histology as the gold standard. Four moderate studies utilized radiographs in a similar way to evaluate bone tumors, and when combined with the high-quality study in meta-analysis, were shown to detect benignity and malignancy with high accuracy as compared to histology (76.5% sensitivity and 86.4% specificity). With respect to the diagnosis of soft tissue tumors of unknown etiology, there is scant published literature regarding the value of conventional radiographs of the tumor site to assist with obtaining a diagnosis or planning further diagnostic studies or treatment. In the absence of reliable evidence, it is the opinion of this work group that certain radiographic findings can be very helpful when present; such as phleboliths in hemangiomas, characteristic ossification patterns of myositis ossificans, mineralization within the substance of the tumor, density of the tumor, and cortical involvement of the underlying bone. However, many times conventional radiographs will not add any additional information regarding the identity of the tumor. Thus, our work group agreed that this test should be regarded as a justifiable, although not universally critical, diagnostic study at initial evaluation of soft tissue tumors.
History of Pain: MRI
In the absence of reliable evidence, it is the opinion of this work group that an MRI of a bone or soft tissue tumor of unknown etiology should be considered, and is the preferred advanced imaging study, in patients with a complaint of pain at the site of the identified tumor.
Consensus Consensus
In addition to a critical analysis of imaging studies, it is important to interview patients to determine their initial awareness of the condition, changes over time, and symptoms of presentation. Specifically, the presence or absence of pain can help determine the relative likelihood of an indolent or aggressive process. A physical exam is also necessary to determine alternative explanations for pain in the area of a bone or soft tissue lesion. It is not uncommon that unrelated symptoms due to arthritis, bursitis, and tendonitis can occur in the area of a lesion that is not the origin of the pain, but rather an incidental finding in close proximity. Therefore, pain by itself does not reliably indicate an aggressive process and a dedicated history and examination to investigate other potential causes is required.

These recommendations apply primarily to the scenario of pain that cannot be attributed to a competing explanation and is likely due to the underlying lesion. The majority of bone malignancies will cause pain, often described as unassociated with activity and present at rest and night. In the setting of a bone lesion of unknown etiology, the presence of pain suggests an active process that requires further investigation to determine the underlying biology. One moderate quality study (Barai, 2004) found that patients presenting with soft tissue tumors and reporting bone pain at distant sites of metastases reliably correlated to the presence or absence of metastatic sarcoma, which were detected by Tc99 bone scan. Among a population of patients mostly reporting bone pain, two moderate quality studies (Kotb, 2014 and Weger, 2013) found that MRI and radiographs can determine benignity of bone tumors with high accuracy but determined malignancy had a weaker association to the reference standard. Although the advanced imaging modality of choice is an MRI, an exception may be in the case of an obvious bone-forming lesion without a broken periosteal reaction on radiographs that is suggestive of an osteoid osteoma, in which case CT is the preferred imaging modality.
MRI and CT Scans: Area to Visualize
In the absence of reliable evidence, it is the opinion of the work group that MRI or CT scans performed to visualize a soft tissue tumor should include a detailed assessment of the tumor and surrounding soft tissue, including complete visualization of enhancement along fascial planes and peritumoral edema.
Consensus Consensus
Although there is a paucity of reliable literature that directly addresses this question, there remains a long history of clinical acumen and associated recommendations from expert panels to justify visualization of the entire bone when performing an MRI to investigate a potentially malignant bone tumor. The American College of Radiology has created practice parameters to guide practitioners on the appropriate execution of MRI in the setting of bone tumors (https://acsearch.acr.org/docs/69421/Narrative/). The field of view should be chosen based on the size of patient and tumor, commonly requiring an adjustment of the field of view to visualize the entire bone to ensure the extent of intramedullary disease and presence of skip lesions are adequately addressed (Kager, 2006). This may require changes to the coil (e.g. a surface coil for a detailed evaluation of the tumor, with a change to a body coil for visualization of the proximal and distal extent of the bone) or possibly performing two separate studies. The sequences should provide multiple perspectives of the tumor and surrounding tissue (axial, coronal, and sagittal) that allow for complete visualization and planning for biopsy execution and operative strategy. The ordering of advanced imaging for a bone tumor may be an uncommon scenario for many practitioners not specialized in the diagnosis or treatment of neoplastic diseases, and we encourage consultation with or referral to dedicated musculoskeletal radiologists or treating specialists to guarantee the study is performed appropriately. The work group agreed that benign bone tumors and non-neoplastic abnormalities of the bone often do not require extension of the field of view outside of the area of concern, and further supports the recommendation of consultation with specialist practitioners when ordering the study to avoid over-imaging of tumors that are clearly benign. MRI is the preferred imaging study; however, a CT scan is acceptable when an MRI cannot be performed due to patient-specific contraindications (pacemaker, cerebral aneurysm clips).
Ultrasound in Large > 5 cm
In the absence of reliable evidence, it is the opinion of the work group that ultrasounds in large (>5 cm), deep soft tissues tumors are unlikely to adequately assess the benign or malignant nature of the lesion and should not be the imaging modality of choice.
Consensus Consensus
Although frequently utilized prior to advanced imaging, standard ultrasound evaluation of concerning masses does not preclude subsequent advanced imaging. As a screening tool, the purpose of an ultrasound evaluation would be to identify which lesions need further imaging and which can be definitively diagnosed as benign. While mostly moderate quality evidence evaluations have shown reasonable psychometrics using advanced techniques in the 80-90% accuracy range (Belli 2000, Chen 2015, Chen 2009a, Lagalla 1998, and Nagano 2015), these studies did not address whether such evaluations could stand alone without an MRI or CT in a prospective manner. Part of the general usefulness of ultrasound is its availability and low cost; if a patient will likely ultimately need an MRI or CT regardless, the rationale for adding additional cost and time for ultrasounds needs further support. A meta-analysis of high and moderate quality studies conducted for this CPG showed a sensitivity of 0.84 and specificity of 0.84 for determining the malignancy of a lesion based on several ultrasound techniques (Chen 2015, Belli 2000, Chen 2009a, Lagalla 1998, Nagano 2015). Many authors reporting on the utility of ultrasound do so only as an adjunct rather than replacement for other advanced imaging (De Marchi 2003, Furuta 2016, Lagalla 1998, Nagano 2015), in which case the patientderived value needs to be elucidated. Miller et al (2015) noted that ultrasound studies were generally considered by orthopaedic oncologists to be unhelpful prior to referral. It may be possible in the future that advanced ultrasound techniques could be first line imaging, with MRI ordered by the referral center (De Marchi 2015, Loizides 2012). It is the consensus recommendation that if a mass is less than 5cm, superficial, and not by critical structures (axilla, groin, popliteal fossa, over a subcutaneous bone) then a principled excisional biopsy without ultrasound evaluation is reasonable. Should a patient not desire removal but reassurance, ultrasound may be able to confirm cystic nature and allow observation in the absence of growth (Nagano 2015). Wagner et al (2013) noted high accuracy for lipomas with 96.9% specificity for superficial masses. In cases where the size or depth of the lesion cannot be determined by physical examination, ultrasound can provide anatomic location to guide further evaluation and treatment. It is the consensus recommendation that if a mass is greater than 5cm, or deep, or by critical structures then an ultrasound evaluation is unlikely to obviate the need for advanced imaging and may delay treatment or provide false reassurance. In particular circumstances, such as vascular malformations (Furta 2017), ultrasound can aid in making a diagnosis and avoiding a biopsy, but in this setting ultrasound could be ordered if desired by a referral center. Moderate and high-quality studies are evaluating means of distinguishing benign versus malignant soft tissue masses by ultrasound (eg., Pass 2017, Chen 2009 a, Chen 2009 b). However, it is the opinion of the work group that there is not yet sufficient sensitivity for malignancy or specificity for benignity for ultrasound evaluations to obviate the need for further advanced imaging for large or deep or precariously located lesions (Nagano 2015). In these suspicious circumstances, an ultrasound should not be required prior to obtaining an MRI. In other clinical situations, such as evaluating a possible soft tissue sarcoma recurrence, ultrasound may be an effective means of surveillance and directing a biopsy (Arya 2000). We did not find any literature discussing use of ultrasound in bone lesions and suggest that our recommendations apply only to soft tissue tumors.
Ultrasound in Small < 5 cm
In the absence of reliable evidence, it is the opinion of the work group that ultrasounds in small (<5 cm), superficial soft tissues tumors can help distinguish between benign lipomas, vascular malformations, cystic structures, and solid tumors that require further characterization.
Consensus Consensus
Although frequently utilized prior to advanced imaging, standard ultrasound evaluation of concerning masses does not preclude subsequent advanced imaging. As a screening tool, the purpose of an ultrasound evaluation would be to identify which lesions need further imaging and which can be definitively diagnosed as benign. While mostly moderate quality evidence evaluations have shown reasonable psychometrics using advanced techniques in the 80-90% accuracy range (Belli 2000, Chen 2015, Chen 2009a, Lagalla 1998, and Nagano 2015), these studies did not address whether such evaluations could stand alone without an MRI or CT in a prospective manner. Part of the general usefulness of ultrasound is its availability and low cost; if a patient will likely ultimately need an MRI or CT regardless, the rationale for adding additional cost and time for ultrasounds needs further support. A meta-analysis of high and moderate quality studies conducted for this CPG showed a sensitivity of 0.84 and specificity of 0.84 for determining the malignancy of a lesion based on several ultrasound techniques (Chen 2015, Belli 2000, Chen 2009a, Lagalla 1998, Nagano 2015). Many authors reporting on the utility of ultrasound do so only as an adjunct rather than replacement for other advanced imaging (De Marchi 2003, Furuta 2016, Lagalla 1998, Nagano 2015), in which case the patientderived value needs to be elucidated. Miller et al (2015) noted that ultrasound studies were generally considered by orthopaedic oncologists to be unhelpful prior to referral. It may be possible in the future that advanced ultrasound techniques could be first line imaging, with MRI ordered by the referral center (De Marchi 2015, Loizides 2012). It is the consensus recommendation that if a mass is less than 5cm, superficial, and not by critical structures (axilla, groin, popliteal fossa, over a subcutaneous bone) then a principled excisional biopsy without ultrasound evaluation is reasonable. Should a patient not desire removal but reassurance, ultrasound may be able to confirm cystic nature and allow observation in the absence of growth (Nagano 2015). Wagner et al (2013) noted high accuracy for lipomas with 96.9% specificity for superficial masses.

In cases where the size or depth of the lesion cannot be determined by physical examination, ultrasound can provide anatomic location to guide further evaluation and treatment. It is the consensus recommendation that if a mass is greater than 5cm, or deep, or by critical structures then an ultrasound evaluation is unlikely to obviate the need for advanced imaging and may delay treatment or provide false reassurance. In particular circumstances, such as vascular malformations (Furta 2017), ultrasound can aid in making a diagnosis and avoiding a biopsy, but in this setting ultrasound could be ordered if desired by a referral center. Moderate and high-quality studies are evaluating means of distinguishing benign versus malignant soft tissue masses by ultrasound (eg., Pass 2017, Chen 2009 a, Chen 2009 b). However, it is the opinion of the work group that there is not yet sufficient sensitivity for malignancy or specificity for benignity for ultrasound evaluations to obviate the need for further advanced imaging for large or deep or precariously located lesions (Nagano 2015). In these suspicious circumstances, an ultrasound should not be required prior to obtaining an MRI. In other clinical situations, such as evaluating a possible soft tissue sarcoma recurrence, ultrasound may be an effective means of surveillance and directing a biopsy (Arya 2000). We did not find any literature discussing use of ultrasound in bone lesions and suggest that our recommendations apply only to soft tissue tumors.
Tumor Size: Greater than 5 cm
Strong evidence supports the use of MRI imaging for a bone or soft tissue tumor of unknown etiology with a size greater than 5 cm to assist with obtaining a diagnosis and planning further treatment.
Strong Evidence Strong Evidence
Size is an important feature noted by clinicians on initial evaluation of a bone or soft tissue tumor. For malignancy, increasing size of the mass is correlated with adverse outcomes such as local recurrence and diminished overall survival, implying a relationship with tumor biology. The importance of size is also reflected in tumor classifications, such as the widely-used American Joint Committee on Cancer (AJCC) staging system which includes the maximal dimension of soft tissue sarcoma (5 and 10 cm) and bone sarcoma (8 cm) as one of the few characteristics used to determine cancer stage. A unifying feature of aggressive neoplasia is growth over time. By this reasoning, larger tumors may be more likely to represent a malignancy and require an assertive imaging investigation.

Our review focused on literature that discusses the relationship of size to an underlying malignancy, and the use of advanced imaging modalities to determine the cause and formulate a treatment plan. There were 5 high and 11 moderate quality studies evaluating the use of MR imaging for a bone or soft tissue tumor of unknown etiology with a mass of a certain size or depth to assist with obtaining a diagnosis or planning further treatment. High strength studies have evaluated the ability of MR imaging to differentiate benign from malignant tumors in a variety of locations in the axial (Matsumoto 2016) and appendicular (Liu 2011) regions and soft tissue masses with a variety of sizes, appearances (cystic or solid [Harish 2006]) and tissue types (fatty [Rougraff 1997], neurogenic [Zhang 2015], etc). Two high quality studies (Matsumoto 2016 and Zhang 2015) and 6 moderate quality studies (Calleja 2012, Chen 2009c, Chung 2012, Datir 2008, Gruber 2016, and Sen 2010) found MRI to have a moderate to strong relationship to histopathological results in determining malignancy of soft tissue tumors with a size of 5cm or larger. MRI is first option for staging malignant bone tumors and for evaluation of all indeterminate soft tissue tumors. Other imaging modalities (CT of the site, PET/CT, Tc 99m Bone Scan) are used in specific cases and should be implemented by, or with the guidance of, the treating oncology team.
MRI: Use of Contrast Benign or Malignant
Strong evidence supports that contrast enhancement on MRI can assist in determining if a soft tissue tumor is benign or malignant.
Strong Evidence Strong Evidence
Although it is clear from the available literature and meta-analysis (2 high quality and 5 moderate quality studies) that the use of IV contrast assists in the differentiation between benign and malignant entities, a substantial amount of discussion was dedicated to the issue of how MRIs should be used as an initial imaging modality by referring practitioners. In most circumstances, a non-contrast study will provide adequate information to determine the underlying identity of a mass, specifically if the lesion is clearly consistent with a common benign entity, such as a lipoma or synovial cyst, or if there are abnormal characteristics consistent with a possible sarcoma, in which case referral to a specialty center is warranted and strongly recommended.

The work group did not feel that a universal recommendation to perform contrast enhanced MRI in every patient was a judicious use of resources, but rather if contrast was deemed necessary by the treating cancer specialists, a limited contrast enhanced study could be performed at the discretion of the treating team on an individualized basis. Meta-analysis of 1 high quality and 4 moderate quality studies also showed that heterogeneous signal on contrast MRI has some value in determining whether a soft tissue tumor is malignant or benign. 
MRI and CT Scans: Area to Visualize
In the absence of reliable evidence, it is the opinion of the work group that MRI or CT scans performed to visualize a potentially malignant bone tumor should include a detailed assessment of the tumor and surrounding soft tissue, with additional sequences that visualize the entire bone compartment, from the proximal joint to the distal joint.
Consensus Consensus
Although there is a paucity of reliable literature that directly addresses this question, there remains a long history of clinical acumen and associated recommendations from expert panels to justify visualization of the entire bone when performing an MRI to investigate a potentially malignant bone tumor. The American College of Radiology has created practice parameters to guide practitioners on the appropriate execution of MRI in the setting of bone tumors (https://acsearch.acr.org/docs/69421/Narrative/). The field of view should be chosen based on the size of patient and tumor, commonly requiring an adjustment of the field of view to visualize the entire bone to ensure the extent of intramedullary disease and presence of skip lesions are adequately addressed (Kager, 2006). This may require changes to the coil (e.g. a surface coil for a detailed evaluation of the tumor, with a change to a body coil for visualization of the proximal and distal extent of the bone) or possibly performing two separate studies. The sequences should provide multiple perspectives of the tumor and surrounding tissue (axial, coronal, and sagittal) that allow for complete visualization and planning for biopsy execution and operative strategy. The ordering of advanced imaging for a bone tumor may be an uncommon scenario for many practitioners not specialized in the diagnosis or treatment of neoplastic diseases, and we encourage consultation with or referral to dedicated musculoskeletal radiologists or treating specialists to guarantee the study is performed appropriately. The work group agreed that benign bone tumors and non-neoplastic abnormalities of the bone often do not require extension of the field of view outside of the area of concern, and further supports the recommendation of consultation with specialist practitioners when ordering the study to avoid over-imaging of tumors that are clearly benign. MRI is the preferred imaging study; however, a CT scan is acceptable when an MRI cannot be performed due to patient-specific contraindications (pacemaker, cerebral aneurysm clips).
Cortical Irregularity/Periosteal Reaction
Moderate evidence supports the use of an MRI scan (or CT if MRI is not available) for evaluation of cortical irregularity or periosteal reaction in patients with a potentially malignant bone tumor.
Moderate Evidence Moderate Evidence
As aggressive tumors grow inside or adjacent to bone, eventually the bone cortex will be encountered and breached. Cortical destruction suggests an underlying malignancy or active process, and can be suspected on plain radiographs by identifying a clear cortical perforation, erosion of the cortex, or the host response to tumor invasion manifested as a periosteal reaction. When a cortical irregularity or periosteal reaction is noted, often further assessment is required to determine if the radiographic findings are due to a malignancy, benign tumor, or non-neoplastic condition such as a stress fracture. Two moderate quality studies (Einstien 2015 and Slavotinek 1991) found that plain radiographs, MRI and CT have demonstrated an excellent diagnostic performance in identifying the presence or absence of a periosteal reaction or cortical erosion in patients with malignant bone/soft tissue tumors as compared with the gold standard of histologic diagnosis. A CT scan may or may not provide additional clinical information, depending on the scenario. There is one high quality investigation (Schima 1994) demonstrating 100% sensitivity and 69% specificity when using MRI to determine whether joint invasion is present.
History of Growth: MRI
In the absence of reliable evidence, it is the opinion of this work group that an MRI should be considered, and is the preferred advanced imaging study, in patients with a clear history of rapid growth of a bone or soft tissue mass.
Consensus Consensus
One aspect of a patient history that is important when evaluating a tumor of the bone or soft tissue is the general stability of the mass over time. Palpable masses that have been present and not enlarging for months or years are unlikely to represent a life-threatening malignancy, whereas tumors with rapid growth over a period of weeks may be concerning for an aggressive process. Much of the literature we found did not focus on the initial evaluation of a growing mass, but rather an attempt to distinguish recurrent tumor from a non-neoplastic process (post-operative scar, fluid collections, normal tissue). Although the clinical setting varied from our intended scenario, the question remained relevant, as the imaging was performed in attempt to determine the presence of a tumor in a patient with a concern for recurrent or residual sarcoma. One moderate quality study (Gingrich, 2017) reported on the ability of MRI to identify residual sarcoma after a prior resection and found 86.7% sensitivity, 57.9% specificity, and overall accuracy of 78.1%. One low quality study (Jiang, 2016) found that a soft tissue mass was a reliable indicator of tumor recurrence when an MRI was performed adjacent to a total joint arthroplasty, with 100% sensitivity and 96% specificity. One moderate quality study (Lehotska, 2013) used time-to-intensity curves to reflect the dynamic enhancement of soft tissue in contrast MRI and determined a positive predictive value of 95.7% and negative predictive value of 100% in their ability to diagnose recurrent sarcoma. One low quality study (Park, 2016) compared MRI to PET-CT and found that each could reliably detect soft tissue sarcoma recurrence and were statistically equivalent. They recommended MRI as the primary modality to investigate recurrence, with PET-CT as an additional option if the MRI was inconclusive. In bone tumors, one moderate quality study (Pereira, 2014) reported that MRI was helpful and accurate at distinguishing solid and cystic components.

The work group was concerned that a statement recommending MRI in all patients with a history of growth of a mass would result in a large number of unnecessary MRI scans. In our cumulative clinical experience, many patients report slow growth over time (a common history in benign entities such as lipomas) or may report a contradictory history of an enlarging mass which, by objective measures such as bony remodeling on conventional radiographs, is likely to be an inadvertent misrepresentation of tumor growth. Therefore, we recommend that an MRI be considered as an imperative study only when there is a clear history of rapid growth (such as a tumor doubling or tripling in size in a matter of weeks). Clinicians should use other measures, such as the appearance on conventional radiographs, presence of pain, size, and depth of the lesion as additional factors that can help with decision-making.
Tumor Interface
Moderate evidence suggests that characterizing the tumor interface (borders and zone of transition) on MRI and CT may assist with obtaining a diagnosis or planning further diagnostic studies or treatment for bone or soft tissue tumor of unknown etiology.
Moderate Evidence Moderate Evidence
Seven studies were evaluated regarding the use of various imaging modalities for patients undergoing diagnostic work-up for a bone tumor of unknown etiology. There were 4 studies concerning MRI and 3 concerning combined modalities (MRI and CT, MRI and plain films). There were no articles on PET or Tc99 bone scan. The average number of patients per study was 57 (range=28-101). Literature pertaining to the use of MRI for differentiating benign and malignant tumors was diagnosis-specific. Choi et al (low quality) evaluated the ability of MRI to differentiate between enchondroma and low-grade chondrosarcoma in 34 patients. They concluded that, “MR imaging shows helpful features for differentiating low-grade chondrosarcoma from enchondroma.” De Beuckeleer et al (moderate quality) retrospectively reviewed 79 cartilaginous tumors. These included osteochondromas, enchondromas, low-grade chondrosarcomas, and high-grade chondrosarcomas. They concluded that MR features are highly specific but lack sensitivity. Yoo et al (high quality) retrospectively reviewed 42 chondrosarcomas: 28 low-grade and 14 high-grade. They determined that soft tissue mass formation favored high-grade lesions, and intratumoral fat was suggestive of low-grade lesions. Bernard et al (moderate quality) retrospectively compared cartilage cap thickness using CT and MRI to distinguish between osteochondromas and secondary chondrosarcomas; both studies were highly sensitive and specific. Henninger et al identified 28 patients in whom the diagnoses of osteomyelitis and Ewing sarcoma were both considered.

They concluded that STIR MRI sequences most reliably distinguishes between osteomyelitis and Ewing sarcoma. McCarville et al evaluated the use of MRI and CT to distinguish between osteomyelitis and Ewing sarcoma. They were unable to give imaging-based recommendations for diagnosis. Oudenhoven et al (high quality) evaluated the value of MRI in diagnosing bone tumors of the hand. MRI was found to confirm or enhance the diagnostic accuracy of plain radiographs. In conclusion, cross-sectional imaging of some kind (either CT or MR) is helpful in obtaining a diagnosis or planning further diagnostic studies or treatment for bone or soft tissue tumor of unknown etiology with radiographs that show a poorly defined interface with the tumor (e.g. permeative border or wide zone of transition). MRI can greatly enhance the diagnostic accuracy of plain radiographs in bony lesions of the hand. CT of the chest/abdomen/pelvis remains an essential aspect of tumor staging. This will reveal the primary site of metastatic bone tumors in many cases, as well determine the presence or absence of pulmonary metastatic disease in patients with sarcoma.

ACKNOWLEDGEMENTS

Guideline Work Group:
Benjamin J. Miller, MD
Patrick John Getty, MD 
Felasfa M. Wodajo, MD 
Kenneth R. Gundle, MD
Carlos M. Pereira Betancourt, MD
Ahmet Salduz, MD
Ana Cecilia Belzarena Genovese, MD
Mark D. Murphey, MD
Michael Mulligan, MD
Kurt R. Weiss, MD
Lukas M. Nystrom, MD
Matthew R DiCaprio, MD
Eric R. Henderson, MD
Catherine C. Roberts, MD

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