➢ Despite previous publications and educational efforts, poorly executed, inappropriate, and/or unplanned procedures remain exceedingly common in musculoskeletal oncology.
➢ Inappropriate biopsy and treatment have profound implications for subsequent definitive treatment and patient outcomes. Furthermore, the potential medicolegal implications of inappropriate diagnosis or treatment and delayed referral of musculoskeletal oncology patients are substantial.
➢ With knowledge of and adherence to specific tumor principles, non-tumor surgeons can avoid diagnostic and therapeutic pitfalls while appropriately treating many patients who have benign or metastatic disease.
Benign soft-tissue tumors, benign bone lesions, and metastatic disease of the skeleton are far more common than primary malignant lesions of bone and soft tissue1-3. As such, many non-tumor surgeons treat impending or overt pathologic fractures that are due to metastatic disease, osteomyelitis, and benign bone and soft-tissue tumors. The orthopaedic literature is replete with reports documenting treatment errors, cautionary case reports, and reports outlining the complications of inappropriate treatment of musculoskeletal oncology patients, with the general conclusion being that primary malignant tumors of bone and soft tissue should be treated at a specialty center4-7. Perhaps as a consequence of these all-too-frequent errors and complications, annual orthopaedic in-training and written board certification examinations place emphasis on musculoskeletal oncology (representing approximately 10% of the questions) that is disproportionate to the frequency with which sarcomas are encountered in general orthopaedic clinical practice8. Despite these prevalent educational efforts, management errors, inappropriate biopsies, and unplanned excisions continue unabated4-7,9-22. Acknowledging that many management errors are made by non-orthopaedic surgeons4,23, it is nonetheless clear that this educational emphasis has done little to benefit individual patients or to facilitate the necessary paradigm shift among extremity surgeons as a whole.
The purpose of this review is to highlight the pertinent literature in an effort to reiterate good management and referral principles, with emphasis on what not to do, the sequelae of management errors, and how to avoid oncologic catastrophes.
Common Pitfalls in (Suspected) Diagnoses
A few general principles are useful to help to guide the management of patients who have bone or soft-tissue lesions. Common pitfalls include the erroneous assumption that a lesion is benign or metastatic, inappropriate biopsy techniques, inappropriate incisions (e.g., incisions violating multiple compartments, incisions near neurological structures, and transverse incisions) or unplanned excisional biopsy, and the inadvertent intramedullary nailing of primary tumors. These errors, which can profoundly affect subsequent treatment options and patient outcomes and potentially can provoke medicolegal action, can be avoided by strict adherence to these basic tenets. These principles are discussed throughout the manuscript, but several points deserve mention here.
Most latent benign tumors of bone and soft tissue do not cause symptoms. For example, most enchondromas of the proximal part of the humerus are incidentally discovered24 and do not demonstrate overtly aggressive or concerning radiographic behavior such as deep endosteal scalloping (involving >50% of the thickness of the cortex), cortical erosion, nongeographic margins, periosteal reaction, or a soft-tissue mass. Alternate causes of symptoms (e.g., arthroses, muscle strains, ligament sprains, and other incidental trauma) can be identified in most cases.
Bone lesions that are clinically and radiographically benign do not necessarily necessitate referral to a musculoskeletal oncologist. Serial radiographic examinations are inexpensive and effective for documenting the lack of change or progression. As a general rule, aggressive benign and malignant tumors will change and progress over time, whereas benign latent tumors remain static or may even regress or consolidate. Patients with worsening symptoms or progressing lesions require immediate attention and prompt evaluation or referral.
There is also a common misconception that, because a soft-tissue lesion is well defined or discrete, it is unlikely to be either malignant or aggressive. This generalization is inherently flawed and has no role in the diagnostic algorithm for extremity tumors. In fact, a soft-tissue mass with an ill-defined radiographic or clinical border more commonly suggests benign aggressive lesions, such as fibromatosis, hemangiomas, early heterotopic ossification, or infection (Fig. 1), although certain sarcomas are also included in this differential diagnosis. Conversely, most soft-tissue sarcomas are well defined, are painless, occur deep to the fascia, present with a size of >5 cm, and are internally heterogeneous on magnetic resonance imaging (MRI). The discrete nature of a soft-tissue mass and the presence of well-defined borders thus provide no specific reassurance that the lesion is benign.
Determinate and Indeterminate Lesions
A select few bone and soft-tissue lesions can be effectively diagnosed on the basis of imaging alone. Papp et al. summarized the MRI findings associated with so-called “determinate” lesions that can be definitively diagnosed without tissue biopsy25. These lesions included lipoma, hemangioma, ganglion cyst, Baker cyst, hematoma, myositis ossificans, myonecrosis, neurofibroma, muscle tear, pigmented villonodular synovitis, bursitis, aneurysm, and/or pseudoaneurysm. It should be noted, however, that the list of determinate lesions is relatively short and the diagnosis of these lesions is dependent on the experience and expertise of the interpreting radiologist or orthopaedic surgeon.
Certain findings, therefore, should be interpreted with caution. For example, fluid-fluid levels are classically associated with aneurysmal bone cysts and soft-tissue cavernous hemangiomas, but a review of 700 bone and 700 soft-tissue tumors by Van Dyck et al.26 demonstrated that the fluid-fluid levels were not diagnostic of any one specific entity. Likewise, Ward et al.27 reviewed thirty-one soft-tissue tumors in patients who had presented with “hematomas,” twenty-three of whom had a history of antecedent trauma. In reality, twenty-seven of these tumors were soft-tissue sarcomas, three were soft-tissue metastases, and one was a lymphoma. With a mean delay in treatment of nearly seven months, the patients in this cohort were subjected to eleven attempted aspirations, ten irrigation and debridement procedures, and seven unplanned excisions. Presumed hematomas presenting without a history of anticoagulation, coagulopathy, or overt trauma should be viewed with suspicion and should either be monitored closely or referred for further evaluation, as hemorrhage may occur within sarcomas (Fig. 2).
Bone sarcomas can masquerade as acute osteomyelitis, and vice versa28. Certain permeative lesions that are characteristic of small-round-blue-cell tumors are often indistinguishable from infection on radiographs. One should therefore always follow the general rule to “culture what you biopsy and biopsy what you culture,” or, alternatively stated, “culture every tumor and biopsy every infection.”
Once a referral to a musculoskeletal oncologist is desired or initiated, attention to a few critical details can expedite and facilitate patient care, thereby avoiding treatment delays and patient frustration. First, early telephone or electronic mail consultation with the receiving orthopaedic oncologist or his or her team can avoid most subsequent difficulties. Bone lesions that are suspected to be malignant or aggressive require orthogonal radiographs and MRI of the lesion—and, in some cases, of the entire bone—with a tumor protocol that includes post-contrast sequences. Weight-bearing should be restricted prior to the referral visit in order to minimize the risk of pathologic fracture, which may adversely affect the rate of local recurrence, limb salvage, and, potentially, overall survival29-33. Staging studies generally can be ordered by the receiving tumor surgeon, and adjuvant therapy decisions should be made at the referral center in a multidisciplinary fashion.
An efficient and complete transfer of information is the best way to facilitate patient care. Again, early communication with the receiving tumor surgeon about new or potential referrals is encouraged and welcomed. All existing notes, radiographic studies, reports, and tissue specimens should be forwarded to the receiving physician. The inclination to omit questionable or potentially inappropriate treatment information or old imaging studies is understandable; however, the withholding or destruction of previous records and images may create the illusion that mismanagement has occurred even when the treatment to date has been entirely appropriate. Finally, full patient disclosure is highly recommended and has been shown to decrease the likelihood of lawsuits following medical errors34, should any have occurred.
Soft-tissue masses are more common than osseous lesions and are thus encountered more frequently. A systematic approach is recommended, with the history focusing on any known cancer diagnoses and treatment rendered, if applicable; the type and duration of symptoms, if any; the size and relative growth of the lesion over time; and the presence and location of any other masses. Of note, most soft-tissue sarcomas are painless and some sarcomas (e.g., synovial sarcomas) may have a long latency period with little or no growth over time; while the absence of progression or growth is generally reassuring, the evaluating surgeon should therefore be cautious in interpreting this finding as absolute evidence that the mass is not malignant. The physical examination should specifically include palpation of regional lymph nodes as well as a detailed, focused examination of the extremity in which the mass is located. The mass should be characterized as superficial or deep, movable or fixed, and soft or firm, and the presence or absence of overlying or generalized skin changes (e.g., café au lait spots) or ulcerations should be noted. Superficial masses should be assessed for transillumination. The presence of associated tenderness should be noted, as should neurologic signs or symptoms. A positive Tinel sign may be an indication of an underlying neurogenic tumor.
A standardized radiographic workup of soft-tissue lesions includes orthogonal radiographs of the mass. Many common soft-tissue masses have characteristic radiographic features, such as cavernous hemangioma (phleboliths) and synovial sarcoma (dystrophic mineralization), that are helpful for formulating a differential diagnosis. MRI of the entire compartment, including T1 and T2-weighted and contrast-enhanced imaging, is necessary for most soft-tissue masses, particularly large lesions (>5 cm) and those occurring deep to the fascia. Further advanced imaging, such as positron emission tomography, is of unproven value for the evaluation of soft-tissue masses and generally is not recommended for routine evaluation.
The term “unplanned excision” refers to cases in which presumed benign masses are excised without appropriate preoperative imaging, biopsy, and/or attention to operative margins12. In most cases, unplanned excisions leave macroscopic or microscopic residual tumor cells in the tumor bed4,9-13,15-18,20,21,35-38. Residual disease in the tumor beds of inadequately resected sarcomas is associated with higher rates of local recurrence5,9-11,13,17,20,38, which may affect patient survival4,9,11,39-42. Tumor bed excision requires the sacrifice of additional normal tissue and larger radiation fields as compared with planned wide excision, resulting in increased morbidity and the more frequent need for flap coverage and skin grafts17,20,43. Interestingly, in many studies, adjuvant radiation therapy has succeeded in improving local control but has failed to demonstrate a clear overall survival benefit44-47, suggesting that tumor burden manifesting as persistent or recurrent disease is not the sole determinant of metastatic potential. However, wide tumor bed excision and adjuvant radiation therapy following unplanned excision do not achieve rates of local control that are comparable with those following initial planned excision and treatment; thus, local recurrence rates are often increased following unplanned excision, independent of subsequent management4,5,17,18,20,38.
The effect on overall survival following unplanned excisions is difficult to elucidate clinically. The majority of series have demonstrated a trend toward decreasing survival in patients who underwent unplanned excision followed by re-excision and adjuvant radiation therapy in comparison with those who underwent primary wide excision, particularly after controlling for other variables and prognostics factors such as size, grade, and depth10,11,21. The single exception is a report on extremity soft-tissue sarcomas by Lewis et al.16. Although surgical margins were more likely to be negative in the re-excision group, those authors found no difference in the rates of local recurrence as well as a seemingly paradoxical survival benefit in the unplanned excision group. Critics of those results11,21,48 have cited referral bias as larger and deeper tumors with worse prognoses were more likely to be included in the primary excision group. In patients with superficial masses measuring <3 cm, unplanned excisions do not seem to affect oncologic outcome21.
When Is a Biopsy Indicated?
Biopsies are indicated when the diagnosis is unknown or when the surgeon suspects malignancy. Although most sarcomas are large (>5 cm) and deep to the fascia, as many as 33% are located in subcutaneous tissue49,50. As such, one should avoid the pitfall of considering a lesion to be benign simply because it is superficial. Nevertheless, in addition to all large (>5-cm) and deep lesions, indeterminate lesions that exhibit interval growth or increasing symptoms may warrant a biopsy.
Type of Biopsy
Open biopsies usually provide more tissue for analysis than needle biopsies do and may reduce interpretation errors compared with needle biopsies, especially fine-needle aspirations51-54. However, properly performed core needle biopsies can sample multiple areas within the same tumor and can yield several cores of tissue for analysis; these core needle biopsies are generally sufficient and remain the preferred biopsy technique at many facilities for the diagnosis of soft-tissue sarcoma55,56.
Excisional biopsy is an attractive option for superficial soft-tissue masses but should be approached with caution. Compared with incisional or needle biopsy, the indications for excisional biopsy are narrow and include only small (<3-cm), superficial lesions45,57. In this setting, a primary wide excision is recommended and all excised specimens should be sent for pathologic analysis. If a sarcoma is excised in a marginal or intralesional fashion, prompt referral for tumor bed excision and possible radiation therapy is indicated10-12,18-20,58.
Technical Aspects of Biopsy
The goal of the biopsy is to obtain adequate tissue for histologic and/or microbiologic diagnosis without compromising definitive resection or reconstructive procedures. Recommendations concerning the biopsy of suspected musculoskeletal sarcomas have been widely discussed4-7,22. An initial report by Mankin et al.6 demonstrated alarming rates of sampling errors, incorrect diagnoses, and inappropriate biopsy techniques, resulting in a demonstrable yet preventable deleterious effect on outcomes, including unnecessary amputation. Six recommendations were made to limit these disturbing occurrences. Unfortunately, subsequent studies demonstrated no improvement in practice habits, particularly in terms of the rates of diagnostic errors and disease-specific outcomes4,5,7,22,59.
The current guidelines for the biopsy of suspected musculoskeletal sarcomas are as follows7,59. First, a surgeon should not biopsy a lesion unless he or she is prepared and properly equipped to do so and plans to treat the lesion definitively. Referral to a center that is dedicated to the multidisciplinary treatment of sarcoma has been associated with improved functional outcomes and disease-related survival in several series60-68. Second, while increasing in popularity among tumor specialists, needle biopsies may result in more diagnostic errors than open biopsies do. However, experienced centers have reported accuracy rates of >92%, and adequate tissue can be obtained for ancillary studies such as immunofluorescence, flow cytometry, and cytogenetics. Third, biopsies are not simple procedures and require careful planning in order to (1) obtain a representative sample for analysis and (2) respect current and future planes of resection and potential reconstruction.
As referral may be neither timely nor feasible for all patients, extremity surgeons must be familiar with correct biopsy techniques. After the appropriate radiographic staging studies are complete, the biopsy is performed in the following fashion. The lesion is localized by means of palpation or fluoroscopy. The approach to the lesion should violate no more than one anatomic compartment and should not expose a joint or critical neurovascular structures69. An extensile limb-sparing incision overlying the lesion is drawn. The biopsy should be carefully placed, overlying the lesion, in line with the extensile incision. Sharp dissection is carried out down to the lesion, and, in order to minimize contamination, no soft-tissue flaps are developed6,52,59. Adequate, representative tissue is obtained and confirmed on frozen-section analysis. Tissue also should be sent for microbiologic analysis. Meticulous hemostasis is critical to avoid hematoma formation that could contaminate adjacent normal tissues. Drains, if used, should exit near to and longitudinally in line with the biopsy incision, and closure should be performed as close to the incision as possible, avoiding a retention-type suturing technique that may spread tumor cells and hematoma52,59. Adhering to these principles helps to ensure a correct diagnosis while not complicating later resection and/or reconstructive efforts. If the patient is referred to an interventional radiologist for a needle biopsy, close consultation is necessary to ensure adherence to the aforementioned considerations. If additional guidance is necessary or desired, the surgeon should not hesitate to contact an oncologic surgeon for advice or expedited referral.
In an attempt to improve cosmesis, it is tempting to excise superficial soft-tissue lesions through limited, often transverse, incisions along Langer lines. These incisions are routinely difficult to excise and sometimes are impossible to convert to the extensile exposures necessary for subsequent tumor resections (Fig. 3). This incorrect technique often results in additional morbidity in that it often necessitates flap coverage following definitive treatment. As such, transverse incisions should be avoided when biopsying or excising lesions of the extremities.
An exhaustive discussion of the radiographic features of all, or even most, benign and malignant bone tumors is beyond the scope of this article. However, a few key radiographic features are helpful for narrowing the differential diagnosis and guiding appropriate workup and treatment or serial radiographic observation. Benign lesions generally demonstrate geographic, often sclerotic, borders on radiographs70. Fading or ill-defined borders may be suggestive of malignant or locally aggressive lesions, particularly in classic locations (e.g., metaphyseal with subchondral extension for giant-cell tumors). A permeative or moth-eaten appearance of bone is highly suggestive of malignancy and is an indication for additional imaging and subsequent biopsy and culture, as are overt progressive bone destruction, progressive symptoms, visible active periosteal reaction, and any cortical breakthrough or overt soft-tissue mass. Within these guidelines, many benign lesions of bone (e.g., enchondroma, osteochondroma, geodes, fibroxanthoma, intraosseous ganglia, fibrous dysplasia) can be diagnosed on radiographs or advanced imaging studies without biopsy and observed.
New Bone Metastases
In terms of diagnostic accuracy, metastatic bone lesions deserve many of the same considerations as primary bone lesions. In fact, because patients with known visceral and other carcinomas are living longer71, several authors have encouraged orthopaedic surgeons to be more precise in their diagnosis when faced with treating new bone lesions72-75. The recommendations in this section therefore pertain predominantly to patients presenting with new bone lesions rather than to the more common patients with biopsy-proven, widespread metastases and impending or overt pathologic fractures. The workup should include a detailed history and physical examination, radiographs of the entire bone, radiographs of the chest, and, often, bone scintigraphy. Although core biopsies are most common, open biopsy, with adherence to the principles outlined above, may be performed by surgeons who are inexperienced with the technique and interpretation of core biopsies. Clayer and Duncan72, in a prospective analysis of fifty patients with known carcinomas, performed open biopsies of new bone lesions and identified a different diagnosis in 20% of patients. For a patient with metastatic disease resulting from an unknown primary tumor, computed tomography (CT) of the chest, abdomen, and pelvis should be included74.
The assumption that a new bone lesion is simply a progression of known or remote disease and thus requires no special workup is inherently flawed and could lead to inappropriate treatment, with catastrophic consequences. Importantly, impending, and even overt, pathologic fractures rarely represent operative emergencies, which would preclude an appropriate preoperative workup or intraoperative biopsy with frozen-section analysis. Inadvertent intramedullary fixation of primary osseous sarcomas requires, at best, resection and replacement of the entire involved bone (Fig. 4), and, at worst, disarticulation (Fig. 5) in order to achieve adequate local control76-79. These extreme local control measures are independent of the deleterious systemic effects of reaming a formerly localized sarcoma as embolization of intramedullary contents (in this case, tumor) with reaming is well documented in the orthopaedic trauma literature80,81.
Stabilization of Pathologic Fractures
Several treatment options exist for metastatic disease in long bones82-89. The decision to radiate and observe, stabilize, or resect lesions is influenced by the presence of impending versus overt fracture, residual bone stock, the physiologic status of the patient, and the anticipated response to local and systemic adjuvant therapy. For patients for whom radiation therapy combined with protected weight-bearing may not be optimal or feasible, the choices include conventional arthroplasty, endoprosthetic segmental replacement arthroplasty, and various means of internal or intramedullary fixation, often combined with polymethylmethacrylate (PMMA) cement augmentation. The appropriate technique is highly individualized and is predicated on the specific lesion, tumor location, and the estimated survival of the patient90; however, a discussion of certain principles unique to the operative treatment of metastatic lesions is therefore important.
Every effort should be made to minimize the spread of tumor cells. Although important in other diagnoses91, this concept is perhaps best illustrated in patients with solitary metastases resulting from renal cell carcinoma. Several authors have reported prolonged survival following wide excision of solitary metastases, with or without reconstruction, in comparison with that following intralesional treatments, including intramedullary nailing92-94. As such, wide excision of solitary metastases resulting from certain adjunct-resistant tumors (e.g., renal tumors, thyroid tumors, melanoma) should be considered whenever possible.
Intramedullary techniques, although popular for diaphyseal lesions, contaminate the medullary canal as well as the sites of nail insertion and locking screw insertion (Fig. 6). Contamination, particularly for larger, metaphyseal lesions, can be minimized by removing as much gross and radiographically evident tumor as possible before violating the remainder of the medullary canal. We prefer to do this at the time of open biopsy, immediately after receiving the frozen-section diagnosis. Once the tumor is intralesionally excised, the intramedullary nail, endoprosthetic stem, or plate can be inserted. The resulting osseous defect is then filled with PMMA cement (indicated for larger defects) to enhance immediate stability84. Postoperatively, the patient may bear weight as tolerated. Larger periarticular or metaphyseal lesions that are not amenable to intralesional techniques may, in fact, be better treated with wide excision and endoprosthetic reconstruction to maximize construct durability and longevity, particularly in the proximal parts of the humerus and femur87-89,95-98. Postoperative radiation therapy is recommended in the vast majority of cases, with or without chemotherapy, bisphosphonates, and targeted and/or hormonal therapies, in order to achieve reasonable local disease control and to help to prevent implant or bone failure (Fig. 7).
The resulting construct should outlast the patient. The goal of surgery, although palliative in many cases, is to relieve pain and to restore function for the maximum amount of time while minimizing morbidity. As such, the stability of the reconstruction should permit the patient to bear weight as tolerated immediately following the procedure. The value of surgical stabilization is well known in this patient population, and improved quality of life and/or performance status, decreased pain, improved mobilization, and ease of nursing care are predictable benefits68,99-101.
Prognostication and Implant Selection
Survival prediction in patients with skeletal metastases is notoriously difficult, and ongoing trials continue to offer new treatment options for this patient population102. At the same time, pathologic fracture-healing is unpredictable and fixation failures are common83,86-89,96. Operative treatment is generally not recommended for patients for whom the recovery and rehabilitation time is longer than the estimated survival90. Patients who are moribund with very limited life expectancy (less than three months) should be managed with conservative, palliative means or, in the presence of overt pathologic fracture, the least invasive technique (e.g., closed intramedullary nailing) that will relieve pain and, ideally, permit continued mobility or care. Those with an intermediate life expectancy (three to twelve months) typically require less invasive stabilization, thereby minimizing pain and convalescence and improving mobility and quality of life in the final months.
As implant failure directly correlates with the duration of patient survival after surgery88, it is critically important to identify patients who are likely to live more than one year, which has been reported as the median time to failure for intramedullary fixation for proximal femoral fractures96,98. As a result, this subset of patients requires more durable implants, such as endoprostheses that may be expected to last many years in most cases88,96-98.
Revision procedures are inevitable in this patient population but can be minimized by adhering to the general guidelines listed above. This approach, referred to as “one bone, one operation,” is preferable, rather than risking the need for a future, often far more extensive, revision procedure in a patient in whom the disease has likely progressed and whose functional status, prognosis, and physiologic reserve have concurrently deteriorated. As such, it is reasonable to manage patients who have impending and overt pathologic fractures, within the bounds of acceptable operative morbidity, as if the fracture may never heal and the patient may never die.
Adherence to basic oncologic principles and avoidance of the pitfalls discussed in this review will help many non-tumor surgeons to avoid oncologic mistakes. A high index of suspicion that an ostensibly benign bone or soft-tissue lesion may, in fact, be malignant is critical in this process. When in doubt, the surgeon should consult with or refer the patient to a musculoskeletal oncologist prior to any intervention. Relatively frequent referrals for second opinions are common, are necessary, and are greatly preferred to referrals following an inappropriate intervention.
Source of Funding: No external funding was utilized for this investigation.
Investigation performed at the Walter Reed National Military Medical Center, Bethesda, Maryland
Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
Disclaimer: The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the United States Army, United States Navy, or the Department of Defense.
- Copyright © 2013 by The Journal of Bone and Joint Surgery, Incorporated