Metastatic Bone Disease and Pathological Fractures
Metastasis is the process by which cancer spreads from its primary site of origin to other places in the body. Tumor cells escape from the primary tumor and travel in the blood stream or lymphatics to reach distal sites such as the skeleton.
Skeletal metastases from carcinomas are the most common malignant tumors involving bone, far more common than primary bone tumors. Solid organ cancers most likely to spread to bone include cancers of the breast, lung, thyroid, kidney, and prostate. Blood cell cancers such as lymphoma and multiple myeloma are also commonly detected in the skeleton.
Metastatic lesions are of course not made of normal bone tissue and therefore are at risk for a so-called pathological fracture. (The term “pathological fracture,” seemingly redundant, refers to fracture in a bone that is itself not normal, as discussed below.)
Typically, skeletal metastases are osteolytic (Figure 1); the tumor cells in the bone increase osteoclast activity, eroding the bone. This bone lysis can cause pain, increase the risk of fracture, and produce hypercalcemia as calcium is released from the breakdown of mineralized bone.
Lesions can also be osteoblastic, that is, characterized by increased bone formation. Osteoblastic metastases are common in prostate cancer. Metastatic lesions can also be mixed (i.e., osteoblastic and osteolytic), as may be seen with breast cancer. Though the risk of fracture is greatest with an osteolytic lesion, the bone architecture in osteoblastic or mixed lesions is also abnormal and thus prone to fracture as well.
If a lesion is painful (Figure 2) and fracture risk is low, external beam radiotherapy alone may be used to provide symptomatic relief. It is also possible for patients with cancer to present with diffuse skeletal pain without a focal lesion. For these patients, bisphosphonate medication can be effective.
If there is a focal lesion that is at high risk for fracture, or worse, has fractured already, orthopaedic surgical intervention will be needed.
Treatment of an impending or established pathologic fracture draws on many of the techniques that have been developed for the treatment of ordinary fractures in normal bone. There are, however, several important differences that must be kept in mind, including the following:
- Patients with pathologic fractures from cancer metastases are suffering from a progressive systemic disease. As such, clinical deterioration should be anticipated.
- Patients with metastases may be immunosuppressed – either by the cancer or its treatment.
- Wound healing is often compromised and requires special attention by surgeons regarding closure techniques and the obliteration of dead space.
- The timing of surgery, and the care needed before and after it, must be coordinated with medical and radiation oncologists, among other providers.
- Normal bone healing processes are largely absent. In addition, the tumor may be interposed between the ends of the fractured bone. Both factors point to a need for liberal use of bone cement at the time of surgery to fill in the gaps.
- The patient’s prognosis may influence treatment decisions. Specifically, it is usually beneficial to offer a patient with metastatic cancer a procedure with the shortest recuperation time. That is, it might be reasonable to consider a more extensive surgery as the initial procedure to minimize the risk of re-operation. Surgery for tumor metastases is guided by the axiom: “do the last surgery first.” (This principle also applies to treating fragility fractures in older patients without cancer.)
Diagnosis
Prior to treating a pathologic lesion in bone, it is essential to fully understand the lesion in question.
In a patient with numerous pre-existing bony metastases, it may be very reasonable to assume that a newly detected bone lesion is yet another a manifestation of the established disease. However, the first time a lesion is detected in bone, a tissue diagnosis of the lesion must be made by biopsy prior to definitive treatment, even if there is a prior diagnosis of a cancer (see Figure 3).
Consider, for example, a woman with known breast cancer who presents with a lytic lesion of the femoral shaft. It should not be assumed that the femoral lesion is a metastasis from the breast, even though breast cancer commonly spreads to the bone. Assuming without evidence that the bone lesion is a metastasis from the breast risks operating in what may turn out to be a sarcoma of the femur, for example, or a renal cell carcinoma. Notably, the standard operation used for a breast metastasis (the insertion of a nail) would spread sarcoma cells down the shaft of the bone and may lead to an extensive (and otherwise preventable) amputation. Likewise, operating on a renal cell cancer – a very vascular tumor – without appropriate precautions (such as pre-operative blood vessel embolization, as discussed below) may lead to massive blood loss.
All biopsy procedures must be preceded by a thorough history, physical exam, laboratory investigations (e.g. complete blood counts, platelets, coagulation studies, among others), and imaging to evaluate the local anatomy (see Figure 4).
Most importantly, the biopsy should only be performed by members of a team with the expertise and capabilities to properly evaluate and treat the tumor.
There are several ways to establish a histologic (tissue) diagnosis of a particular lesion in bone. For small, deep lesions which would require significant surgical dissection to reach, needle biopsies (see Figure 5) are a reasonable first choice. The major challenge with needle biopsy lies in obtaining a specimen sufficient for the pathologist to make a diagnosis.
If a needle biopsy cannot be performed, or if it does not provide a diagnosis, open biopsy may be considered. Open biopsies should be performed in a manner that does not interfere with any subsequent surgery. Thus, the surgeon should use the smallest possible incision and position it in line with any incisions that might be used in a future procedure. Meticulous hemostasis should be maintained, with all efforts taken to not contaminate other structures.
It is advisable to obtain a frozen section at the time of the open biopsy to ensure that sufficient tissue is available, even if a definitive diagnosis cannot be made on frozen section.
Adjuvant Treatment
In many instances, patients with skeletal metastases will benefit from adjuvant treatment, that is, a treatment beyond the primary therapeutics for the metastatic lesion itself. The adjuvant treatment typically employs chemotherapy or radiation.
Patients with metastatic disease will frequently be on chemotherapy protocols for their primary diagnosis prior to fracture. If so, the timing of the surgery should consider the effect of chemotherapy on marrow suppression and wound healing. Ideally, surgery would be deferred until blood counts have rebounded to safer levels.
It is essential that once a pathologic fracture is fixed, some treatment – chemotherapy or radiation – is given to prevent local recurrence or progression.
Radiation reliably limits tumor progression for most, but not all, metastatic lesions. Carcinomas and round cell tumors (e.g., lymphoma and plasmacytoma) account for the vast majority of metastatic lesions and are usually radiosensitive. Renal cell carcinomas are usually resistant to radiation. The radiation dose needed for control of metastatic lesions (~30 Gy) is sufficiently low as to not significantly impede wound healing.
Preoperative embolization can also be used to mitigate the problem of metastatic tumor vascularity. Metastatic renal cell carcinoma, for example, is notorious for its tremendous vascularity. It is very difficult and dangerous to operate in the presence of excessive bleeding. Thus, a patient with a known diagnosis of metastatic renal cell carcinoma should undergo preoperative embolization. Multiple myeloma/plasmacytoma and thyroid carcinomas can also be exceedingly vascular. When in doubt, requesting preoperative embolization is a safe option; the interventional radiologist will only take action if excessive vascularity is identified.
Prophylactic Fixation
Prophylactic fixation refers to operating on an impending pathologic fracture before it occurs to prevent the bone from actually breaking (Figure 6). However, the decision to operate can be complex. On the one hand, unnecessary surgeries should obviously be avoided. On the other hand, sustaining a fracture is painful, and avoiding that pain is beneficial. In addition, prophylactic fixation surgery is usually less extensive than surgery to fix an already-broken bone and is also likely to have a better outcome. Thus, shared decision making is imperative.
To help identify patients likely to benefit from prophylactic fixation surgery, the surgeon can calculate a “Mirel's score” (see Table 1). A score of 9 or above (on this 12-point scale) indicates a high risk of a lesion fracturing, hence representing an indication to fix the lesion prophylactically.
It is also reasonable to operate because of mechanical pain, that is, a marked increase in pain with load-bearing stress. Especially if an initial decision was made to not prophylactically fix a lesion, the onset of mechanical pain might prompt surgical treatment.
Surgical Considerations
Before surgery, a bone scan and complete radiographs of the affected bone should be obtained to detect any additional lesions. A new fracture just beyond the edge of a prior fixation is a surgical challenge best avoided. For this reason, a fixation device spanning the whole length of the bone, e.g., a long intramedullary nail, is often chosen.
Because patients with skeletal metastases usually have short life expectancies, it is particularly important that the surgeon establishes fixation that is strong enough for immediate weight bearing. “The surgical construction should be so strong that patients could push their stretchers back to the recovery room,” is the traditional teaching.
Pathologic fractures can be assumed to never heal normally, so there is no role for bone grafts or other biologic agents. Rather, all gaps should be filled with a generous application of bone cement to provide structural support.
Minimally invasive procedures have become popular for the treatment of ordinary fractures, but these techniques are less appropriate for pathological fractures. During surgery for a pathologic fracture, open reduction with wide exposure is often needed to understand the anatomy at the fracture site and to detect and fill gaps at the fracture site.
There are, unfortunately, instances in which the tumor has damaged the bone so much that there is inadequate bone to hold the fixation device. In those cases, use of a segmental replacement prosthesis should be considered. A prosthesis provides immediate structural integrity with much lower risk of failure (see Figure 7).
Surgeons should aim to perform the last operation first. A “perform the last operation first” rule does not, however, mean that excessive and unnecessary procedures are desirable: they are not. This rule does, instead, suggest that seemingly conservative surgery may be the riskier strategy if this minimalist approach is associated with a high risk of failure.
Miscellany
Pathological Fracture
By definition, a structure will fracture when it is subjected to a load which exceeds its strength. When bone is weakened by disease and the amount of force required to break it is reduced, the fracture is said to be a “pathological fracture.” In other words, a pathological fracture is one that results from a load that would not cause injury if the bone were of normal strength. The two most common causes of pathological fracture are tumors and metabolic bone diseases such as osteoporosis. In patients with cancer, a pathological fracture can occur because the bone is replaced by tumor. A tumor can also weaken the remaining bone due to the actions of hormones released by or in response to the tumor. Last, treatment of the tumor can also weaken the bone (e.g., drug therapies such as steroids).
Mirel’s score
Mirel’s score was published in 1989 based on retrospective observations of patients with known lesions that did not undergo prophylactic fixation. Patients were noted to either progress to fracture or not. The score was seen to have high sensitivity (91%) but low specificity (35%). In other words, a low score can be used as a screening tool to identify patients at low risk for fracture, but a high score will capture both high and low risk patients. Indeed, if the score were used alone, up to two-thirds of patients could receive unnecessary prophylactic surgery. Furthermore, although the site of the lesion is included in the score, further work elucidated that the site is in fact not an independent predictor of fracture. Another major limitation is that the score can only be used for long bone metastases and not very commonly found spinal lesions. It is likely that as imaging modalities improve and machine learning techniques are applied to large series of patients, future protocols will be both more sensitive and more specific than the Mirel score.