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An approach to skeletal metastases

Description

Metastatic lesions are the most common malignancy in bone, vastly out numbering primary malignancies.  The treatment of skeletal metastasis varies depending on location, disability, life expectancy and the sensitivity of the primary tumor to chemotherapy and radiation.

Clinical Manifestations

Skeletal metastasis present most frequently as painful lesions and occasionally as pathologic fractures.  At times, skeletal metastases can be discovered as asymptomatic lesions as part of the initial staging of a primary lesion. The skeletal lesion or pathologic fracture can also be the initial presentation of the primary malignancy which has grown and metastasized without symptoms.

The pain from the skeletal lesions is often a deep seated pain which is constant.  There can be activity related pain, but this is often indicative of impending pathologic fracture as the physiologic load of mobility is nearing the fracture threshold of the abnormal bone.  This pain is relieved by narcotic pain medication and by weight bearing assist devices in the lower extremities.

Red flags

Patients with a known primary malignancy are often subject to intense diagnostic scrutiny, and therefore problems are not apt to be missed. There are a few scenarios that require additional vigilance:

  • Patients with a long latency between cancer diagnosis and appearance of skeletal lesion (ie, patients thought to be "cured" of a carcinoma or hematopoietic malignancy) should be evaluated with a biopsy of the skeletal lesion; the lesion may be a metastatic recurrence, but not necessarily so. Note also that the biopsy should be performed by an expert in case a sarcoma is discovered. (A poorly planned biopsy may contaminate clean tissues unnecessarily.)
  • Patients with large metastatic lesions may have an impending pathological fracture. These patients may benefit from having their fractures "fixed" before they occur, so called prophylactic fixation.

Epidemiology

There are 1.2 million new cases of cancer diagnosed each year in the US and bone metastases have been shown in up to 85% of cancer patients at autopsy. As such, there are potentially 1 million new cases of metastatic disease each year in the US alone. Most bone metastases are from breast, prostate and lung tumors. Melanomas and carcinomas of the kidney and thyroid are other common sources. The most common sites for metastasis are the spine, pelvis, ribs, sternum, femur and humerus (in that order of frequency).

Pathology and pathophysiology

The process of metastasis involves the escape of cells from the primary tumor; the survival of these cells in the circulation; and the implantation and proliferation of these cells in distal locations.

  • Cells that have the power to metastasize must lose their affinity with the primary tumor (for instance, there may be down--regulated expression of transmembrane cadherin (calcium-dependent adhesion) proteins).
  • Cells that metastasize can produce degradative enzymes that allows the tumor cells to intrude into the lymphatic or capillary network.
  • Bone, especially bone with rich hematopoietic marrow (eg vertebrae, pelvis and ribs) typically have sinusoids in which the blood circulates slowly, increasing the chance that a tumor cell will adhere to the bone surface and colonize it. Local production by the bone of various cell surface ligands and receptors further facilitate the process. Also, because bone is constantly remodeling itself, bone matrix houses many growth factors (eg, TGF-? and bone morphogenetic protein) which may be the source of tumor growth as well.

Tumor cells may preferentially stimulate either osteoclasts (which resorb bone) and osteoblasts (which sythesize new bone). Accordingly, lesions may be characterized as lytic or blastic, depending on whether bone destruction or formation is favored

Differential diagnosis

The basic questions in the differential diagnosis of a suspected metastatic lesion are: Is it a malignancy? And, If it is a malignancy, is a second primary tumor or is it from the original malignancy?

Because of the age of most patients with suspected metastatic lesions, multiple myeloma and other hematologic malignancies must always be suspected.  Not infrequently a biopsy is needed to confirm the diagnosis. This can be done at times with a fine needle aspirate.

If the patient does not have a known primary tumor, the most likely source of a bone lesion is myeloma, lymphoma or metastatic lung cancer. Among patients with known malignancies, breast and prostate cancer are most common-but these two rarely present first a bony metastasis.

Radiographic and laboratory findings

Laboratory findings are altered in the same fashion as the primary disease.  In addition, LDH may be increased as bone turnover increases.
Radiographic changes are in three types.  The reaction of the host bone to the tumor causes the different appearances.  The types are blastic (bone forming), lytic (bone resorbing) and mixed types.

The classic blastic metastasis is prostate cancer.  The lesions often appear as densely sclerotic lesions with fuzzy margins as they typically are slowly invading the host bone. Breast can also be blastic.

NEEDS FIGURE

Lung, renal and multiple myeloma are typically lytic lesions. Lytic lesions tend to have more infiltrative margins with soft tissue masses beyond cortical breakthrough if it has occurred.

NEEDS FIGURE

CT scan can show the extent of cortical involvement and often a soft tissue mass if evident.  MRI can show soft tissue mass, but can also be helpful showing bone marrow edema surrounding a lesion which can represent a stress reaction in an impending pathologic fracture.

Risk factors and prevention

Risk factors for the development of skeletal metastases are linked to the risks for individual primary tumors especially when an environmental or hormonal cause is identified and unable to removed by treatment.

Treatment options

The treatment of the systemic disease is the most important consideration for a patient with a skeletal metastasis.  There are a variety of treatment methods for addressing metastatic lesions. The goal of treatment is pain control and prevention (or remedy) of pathological fractures. At times, the pain produced from a lesion is the physical stress on the bone that is poised to break; preventing the fracture also addresses the pain issue.

  • No treatment can be appropriate for the end-stage patient who has an extremely low functional demand.
  • Non-operative treatments include bracing and irradiation.  Bracing can be useful for non-weight bearing long bones or vertebral lesions without instability in the setting of a primary disease which has a successful systemic strategy. Radiation makes sense, of course, only in tumors known to be radio--sensitive.
  • Operative interventions are used for fracture or impending fracture in the weight bearing long bones and to address instability or neural compression (myelopathy) in the spine.  Prophylactic surgery (ie before displacement occurs) is optimal. 

figure of impending fracture and its treatment would be helpful

Determining the probability that a lesion will indeed fracture (and the timing thereof) is difficult. Algorithmic approaches to selecting prophylactic surgery for extremity lesions have been attempted in various studies and remain controversial.  The following concepts are worthwhile guides:

  • Weight bearing bones (including the vertebrae) are more susceptible to pathologic fracture. 
  • Lytic lesions are structurally weaker than blastic lesions. 
  • Size matters: the more of the bone involved by the lesion, the greater the risk of fracture. The precise fraction the bone that signifies an unacceptable risk is not known, however.
  • Certain areas of bone, such as the peritrochanteric region of femur, that are exposed to great stress under ordinary usage, are more apt to fracture if a metastatic lesion is present.
  • Pain with ordinary usage (physiologic loading) is indicative of a stress reaction.

Outcomes

The outcomes for metastatic carcinoma are poor. That is because, by definition, skeletal metastasis represents widely disseminated disease.  The survival depends primarily in the success of systemic therapies on the whole body disease.  Thus metastasis in estrogen receptor positive breast cancer can be seen in a patient who will live a decade beyond diagnosis.  Outcomes for metastasis of unknown primary are similar to those of lung cancer with survival averaging 6-9 months. 

In one report of more than 1,000 patients treated surgically for skeletal metastasis, the mean survival was about 6 months, and the probability of 2 year survival was less than 20%, as shown

(Figure: The survival of 1028 cancer patients who underwent surgical treatment for fracture or impending fracture of either a long bone or pelvis, or for spinal metastases, redrawn from Bauer HCF. Controversies in the surgical management of skeletal metastases. Journal of Bone & Joint Surgery, British Volume 2005;87-B:608-17.)

Holistic medicine

 Patients who concede that their cancer may not be cure can elect to have palliative care only. This is quite different than hospice care, though both aim to improve the patient's quality of life. Hospice care addresses the comfort of patients who are dying. Palliative care focuses on symptom management, and may even include "aggressive treatment" such as surgical intervention for skeletal metastasis.

Miscellany

  • Acral metastases are most commonly from lung cancer
  • The life expectancy of a patient with a skeletal metastasis of unknown primary origin is most similar to non small cell lung cancer.
  • Thyroid and Renal metastasis are extremely vascular and should be embolized 24 hours prior to surgery

Key terms

Metastasis, carcinoma, met, mets, pathologic fracture, impending pathologic fracture

Skills and competencies

A medical student should be able to elicit the history and physical examination findings suggestive of a diagnosis of a primary malignancy in a patient with a radiograph suggestive of metastatic disease.
 
Students should be able to construct a conceptual framework for deciding treatment for metastatic disease, considering tumor biology, expected lifespan, adjuvant treatment effectiveness and effect on the lesion and host bone, and finally demonstrated disease impact of surgery.

Content

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