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Metastatic tumours of bone
ORTHOPAEDICS I: GENERAL PRINCIPLES
Metastatic tumours of bone
tumours of bone; this article specifically deals with the basic science, clinical features and treatment of metastases.
Alexandra K Freeman
Epidemiology
Vaiyapuri P Sumathi
Metastases affecting bone are far more common than primary bone tumours. In the UK in 2011, 331,000 new cases of cancer were diagnosed, and it is thought that up to 70% of these patients will develop metastatic bone tumours. Bone metastases are common in late-stage disease but certain cancers are ‘osteotropic’ (have an affiliation to bone). Autopsy studies have shown that 70% of patients with breast and prostate carcinoma develop skeletal metastases, numbers are less but still significant in thyroid (40%), renal (35%), bronchus (35%) and rectal (10%) carcinoma. Although bowel, rectal and bladder carcinoma have a lower rate of metastasis to bone, due to the much higher incidence of these cancers, bone metastases from these tumours are common. The skeletal system is the third most common site for metastatic tumour spread, after the lungs and liver. Most secondary bone tumours are found in middle-aged and older patients, with 75% of metastases affecting those over the age of 50 years. The most commonly involved bone sites are those with persistent red marrow, such as the vertebrae, proximal femur, ribs, sternum, pelvis and skull. The vertebrae are affected by 50e70% of metastases, but only 10% of these ever become symptomatic. About 70% vertebral deposits occur in the thoracic spine (T4e7), 20% are found in the lumbar spine and rest in the cervical spine. Multiple spinal deposits are found in half of patients, with the anterior portion of the vertebral body being most commonly affected, followed by the pedicle or lamina. The site prevalence depends, in part, on the primary source of the tumour. For example, widespread skeletal metastases are common in lung cancer primary due to its tendency to spread via the systemic arterial blood supply. Breast carcinoma is the commonest cause of metastatic deposits, and causes 50% of pathological fractures that are due to metastases. Prostate carcinoma is the second most common site of origin, but is less likely to cause pathological fractures, as metastases tend to be osteosclerotic. Renal cell carcinoma metastases can occur many years after the primary tumour, necessitating long-term follow-up, and bone metastases are the presenting feature in 15% of renal tumours.
Lee Jeys
Abstract Metastatic tumours of the bone are the most common types of bone cancer. Autopsy studies have shown that 70% of patients with breast and prostate carcinoma develop skeletal metastases. The most commonly involved bone sites are those with persistent red marrow, such as the vertebrae, proximal femur, ribs, sternum, pelvis and skull. The precise mechanism of metastases to bone is unclear, however, the understanding of the molecular biology of metastases is becoming increasingly important in providing new therapeutic targets. Treatment of bone metastases is multi-modal and may include medications, radiotherapy or surgery. Bone metastases can cause many complications and have significant morbidity. Traditionally, the presence of a metastatic bone deposit has been seen as a terminal event. With the increased survival and improved treatment of patients with carcinoma, long-term survival with metastatic bone disease is possible and treatment can prolong life, or even be curative. Implants used in reconstruction need to be sufficiently robust to survive the patient, and the expertise of reconstruction available within tertiary bone tumour units is increasingly required.
Keywords Bone; carcinoma; metastasis; outcome; secondaries; treatment
Metastatic tumours of bone are tumours that spread to bone from another primary site in the body. Histologically, they often resemble the cells of the tumour from which they originated, but sometimes they are poorly differentiated and the primary tumour site cannot be determined. Metastasis is the ultimate phase in the multistage process of tumour progression and is the major cause of death in cancer, however, improvements in treatment are allowing long-term survival of patients with metastatic bone disease, and may even be curative. In view of increased survivorship following surgery, the implants used in reconstruction need to be sufficiently robust to out-live the patient, and the expertise within tertiary bone tumour units on the gold standard reconstructive techniques is increasingly required. The investigation and staging of secondary tumours has been dealt with in a previous article by the authors on primary
Pathogenesis of bone metastases The precise mechanism of metastases to bone is unclear but consists of a multistep process that involves interaction between tumour cells and normal host cells. The biology of bone metastases is complex and involves: breaking free from the extracellular matrix of the primary tumour; being transported in the blood or lymphatic system; avoiding detection and destruction by the immune system; exiting the blood or lymphatic system; and proliferating in an environment which is removed from their original location. The host environment has to be rich in nutrients and oxygen and so the metastatic cells must recruit blood vessels (neoangiogenesis) in order to allow continued growth of the secondary tumour. Tumours can spread by direct tumour invasion (e.g. soft tissue sarcoma directly invading bone), via the bloodstream or via the lymphatics.
Alexandra K Freeman MBChB BSc (Hons) is an Academic Foundation Year 2 Doctor at the Royal Orthopaedic Hospital, Birmingham, UK. Conflicts of interest: none declared. Vaiyapuri P Sumathi FRCPath is a Consultant Histopathologist at Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK. Conflicts of interest: none declared. Lee Jeys MB ChB MSc (Orth Eng) FRCS (Tr & Orth) is a Consultant Orthopaedic Oncology Surgeon at the Royal Orthopaedic Hospital, Birmingham, UK. Conflicts of interest: none declared.
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Ó 2015 Published by Elsevier Ltd.
ORTHOPAEDICS I: GENERAL PRINCIPLES
Theories of mechanisms of macroscopic tumour spread Two main theories exist to explain possible mechanisms of distant spread of tumour and it is most likely that a combination of factors are responsible.
increased bone formation. Mixed lesions are caused by a combination of both osteolytic and osteoblastic processes. Several other factors are also involved in the metastatic process, but are not specific to bone metastasis, such as matrix metalloproteinase (MMP) maspin, integrin, e-cadherin and vascular endothelial growth factor (VEGF). In metastatic bone disease the normal balance of formation of new bone by osteoblasts and resorption of old bone by osteoclasts becomes imbalanced, leading to the development of lesions that are osteolytic, osteoblastic or a combination of both. Analysis of osteolytic bone metastases indicates that the bone destruction is mediated by the osteoclast rather than directly by the tumour cells. These observations suggest a vicious cycle driving the formation of osteolytic metastases: tumour cells secrete factors stimulating osteoclasts through adjacent bone marrow stromal cells; osteoclastic resorption in turn releases growth factors from the bone matrix; finally, locally released growth factors activate the tumour cells. This vicious cycle model has now been confirmed at the molecular level. In particular, TGF b is abundant in bone matrix and released as a consequence of osteoclastic bone resorption. Bone-derived TGF b plays an integral role in promoting the development and progression of osteolytic bone metastases by inducing tumour production of PTHrP, a known stimulator of osteoclastic bone resorption. In breast cancer cells TGF b appears to stimulate PTHrP secretion by a post-transcriptional mechanism through both Smad and p38 mitogen-activated protein (MAP) kinase signalling pathways. Osteolytic metastases can be suppressed in vivo by inhibition of bone resorption, blockade of TGF b signalling in tumour cells, and by neutralization of PTHrP. Other factors released from bone matrix may also act on tumour cells in bone, and in turn stimulate bone resorption, following the vicious cycle paradigm established for TGF b and PTHrP. Studies have shown that tumour cancer cells interact with osteoblasts or stromal cells to induce osteoclast formation by increasing RANKL expression in several ways. RANK, RANKL and osteoprotegerin (OPG) are the regulatory triad in the differentiation, activation and survival of osteoclasts. RANK is a receptor on the surface of the osteoclast and RANKL is a member of the tumour necrosis factor (TNF) family of cytokines that binds to its receptor RANK to stimulate osteoclast differentiation and activation. RANKL and OPG form a ligandeligand inhibitory pair which modulates RANK signalling in osteoclasts and their precursors. It is likely that increased bone resorption around cancer cells in the bone results from increased RANKL expression. Mice studies have shown that in-vivo neutralization of RANKL by OPG results in complete protection from paralysis and marked reduction in tumour burden in bones, but not in other organs. Factors such as PTHrP regulate the expression of OPG and RANKL. Cancer cells can express or upregulate the expression of these factors, of which OPG and RANKL will lead to bone resorption. In this process, treatment possibilities arise, for example, by blocking RANKL signalling within OPG treatment. This can protect against bone destruction, and may inhibit tumour growth in bone. The clinical application of this is the increasing use of bisphosphonates (which block RANKL) to reduce skeletal events in metastatic bone disease.
Soil hypothesis (Paget): in 1889 British surgeon Stephen Paget (son of Sir James Paget) popularized a theory published previously by Fuchs, of ‘the seed and the soil’ hypothesis. This suggested that malignant cells escaping from the tumour (the ‘seeds’) colonize those tissues (the ‘soils’) that are favourable for them because of mutual compatibilities. Paget imagined that breast tumours metastasize to bones and liver, rather than the spleen, because bone marrow and liver tissues provide optimal conditions for the multiplication of breast cancer cells. Circulation theory (Ewing): proposed in 1928 by James Ewing, of the New York Memorial Hospital, stating that the distribution of metastases depends principally on the routes of dissemination of the tumour. He observed that colonic tumours metastasize principally to the liver because the liver is the first organ visited by the circulating blood coming from the intestines. The preferential deposition of primary tumour cells in the vertebrae, with relatively scarce visceral involvement, was also noted. This can be explained by Batson’s valveless venous plexus from around the vertebrae that communicates with the pelvis and proximal halves of the upper and lower extremities, but excludes the chest, portal and caval systems. It is postulated that the spread of malignant cells through this plexus is likely to occur through retrograde spread, as a result of a Valsalva manoeuvre, from the sites of primary tumours. The unique ability of lung lesions to shed tumour cells directly into the arterial circulation causes the spread of tumour cells to tissues far and wide in the body, including to the bones of the hands and feet, with 50% of all metastases to the hands coming from primary lung tumours. Molecular mechanisms in bone metastases The bone matrix provides a unique and fertile microenvironment for the proliferation of tumour cells. The interaction between tumour cells and bone stroma that initiate the cycle of bone destruction and tumour growth are critical aspects of the metastatic process. The exact pathogenesis or biology of bone metastasis is still not well understood. There are several important factors in the development of osteolytic bone metastases. Some of the major contributors are: parathyroid hormone-related protein (PTHrP e which is an important cause of hypercalcaemia of malignancy and bone resorption); transforming growth factor b (TGF b); interleukin11 and interleukin-6 (which have been shown to simulate bone resorption and may induce osteolysis). Other factors include calcitonin receptors, osteopontin and silo protein, tumour necrosis factor a, prostaglandins, receptor activator of nuclear factor-K B ligand (RANKL), macrophage colony-stimulating factor (M-CSF) and human platelet-derived growth factor (PDGF). Osteoblastic metastatic lesions arise from uncoupled increase in bone formation and reduced bone resorption. TGF b, bone morphogenetic protein (BMP), and insulin growth factors stimulate the differentiation and activity of osteoblasts, leading to
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Figure 1 Metastatic breast carcinoma. Macroscopy of the proximal femur shows multiple fleshy deposits.
Pathology of bone metastasis
cases, use of immunohistochemical stains is essential to differentiate from primary bone sarcoma (Figures 3 and 4).
Macroscopic features Metastatic tumours to the bone tend to be poorly circumscribed and grow in an invasive, permeative manner with indistinct borders. The consistency is variable, depending on the amount of bone and desmoplastic stromal reaction produced in response to the tumour. Osteoblastic metastases appear greyish-white and firm, whilst renal cell carcinoma produces soft, haemorrhagic and necrotic deposits (Figures 1 and 2).
Clinical features Pain Unlike chest and liver metastases, bone metastases are the most common cause of cancer-related pain, and half of all patients with solid tumours that metastasize to bone experience one or more skeletal events during the course of their treatment. Problems related to bone metastases account for over a third of all nights spent in hospital in advanced breast cancer care. Pain is thought to be caused by stretching of the overlying periosteum and/or stimulation of nerves in the endosteum, resulting in gradually progressive, dull, non-mechanical pain. Structural weakening of the vertebrae can lead to collapse, causing subsequent back pain (although pain is present in only
Microscopic features Metastatic tumours often recapitulate the original tumour. Thyroid, renal cell and squamous cell carcinomas retain morphological similarities to the primary tumour. Occasionally, poorly differentiated carcinomas, in particular renal cell carcinoma and lung carcinoma, may exhibit a sarcomatoid pattern. In such
Figure 2 Metastatic renal cell carcinoma. Gross photograph of a distal femur with metastatic renal cell carcinoma showing a haemorrhagic fleshy tumour.
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or the spinal cord. About 50% of cases have motor or sensory dysfunction and around 50% have bladder or bowel dysfunction. If cord compression is left untreated, progressive motor weakness will occur leaving the patient unable to walk, and around 15% will become paraplegic. Impending cord compression is a surgical emergency and patients with symptoms of cauda equina (saddle anaesthesia and altered bowel/bladder function) require an urgent MRI and referral for radiotherapy or surgery before neurological compromise becomes irreversible. Hypercalcaemia This occurs in 10% of patients with bone metastases and is more common in osteolytic tumours. Symptoms include fatigue, depression, confusion, anorexia, vomiting, pancreatitis and polyuria. Urgent treatment is required, with rehydration, and bisphosphonates or calcitonin, to prevent complications such as cardiac arrhythmias and coma. Figure 3 Haematoxylin and eosin metastatic breast carcinoma. Microscopic photograph of an osteoblastic metastasis of carcinoma from the breast.
Treatment options for metastatic bone disease The majority of patients with metastatic bone disease will not require any surgical intervention, the mainstay of treatment being bisphosphonates and radiotherapy. The principles of treatment are to control local symptoms, maintain function, prevent pathological fractures, improve or maintain mobility, relieve pain, and improve quality of life. The complexity of these cases requires a multi-disciplinary approach to management, which may include a specialist bone tumour unit.
54% of patients with this complication). Non-mechanical, night and radicular pain should alert the clinician to the need for further investigation. Pathological fracture Osteolytic lesions are most at risk of pathological fractures, and up to half of these are due to breast cancer metastases. The mechanism of injury should be identified, as the fractures often occur with minimal force or torsional stresses. If the deposit affects less than 50% diameter of the bone, fractures occur most commonly under loading. If the lesion affects more than 75% of the diameter, fractures can occur with simple torsion. The mechanical properties of the implant used to treat the pathological fracture should be durable enough to load-bear for the likely survival time of the patient, as only one-third to one-fifth of pathological fractures unite, despite adjuvant therapy
Medical treatment Analgesia is an essential aspect of treatment for patients suffering with bone pain; combinations of simple, opiate and adjuvant analgesia may be required. Non-steroidal anti-inflammatory drugs have been shown to significantly reduce cancerrelated pain, particularly when used in conjunction with opiate-based analgesia.1 Bisphosphonates are a class of drugs that work by inducing osteoclast apoptosis, thereby reducing the lytic activity of bone metastases. Administration of these drugs reduces the number of skeletal events, and may also have an effect on metastatic spread.2 Data from preclinical studies suggest that bisphosphonates, in addition to inhibiting osteoclast activity, may also have anti-tumour activity and prevent bone metastasis, though the exact mechanism remains unclear. There is likely an indirect effect provoked through the inhibition of bone resorption, the inhibition of angiogenesis and the stimulation of the immune system, but there may also be a direct effect through the inhibition of tumour cell invasion, proliferation and adhesion to bone. More recently evolving research into the use of nanotechnology to allow targeted delivery of bisphosphonates to bone has shown promising results.3 The nano-particles act as a transporter to deliver bisphosphonates to their site of action with minimal systemic breakdown, thus allowing more targeted therapy with fewer side effects. Further studies are needed before the true clinical value is known.
Neurological symptoms Vertebral metastases are common and 5% of those affected will suffer neurological symptoms due to compression of nerve roots
Chemotherapy, hormonal and biological drug therapies may be indicated in the treatment of bone metastases, especially from breast (tamoxifen), prostate (anti-androgens) and renal cell
Figure 4 Haematoxylin and eosin metastatic renal cell carcinoma. Histology of metastatic renal cell carcinoma with clear cell features.
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carcinoma (sunitinib). Current imaging modalities do not accurately determine the response of bone metastases to these treatments; however, with developments in PET scanning and MRI, this is likely to improve. These treatments are not without side effects; osteoporosis is one such effect that may further compound the risk of pathological fractures.
Mirel scoring system Variable
Site Upper limb Pain Mild Lesion type Blastic Size <1/3 diameter
Immunotherapy is a novel treatment for bone metastases and promising early results are emerging. A phase two trial examining the use of AGS-003 immunotherapy in addition to sunitinib for patients with metastatic renal cell carcinoma has shown survival to be significantly increased.4 Another promising cytokine for immunotherapy is PTHrP which, when neutralized with antibodies, is proven to reduce the development of bone metastases in animal models. With increasing knowledge about the pathology of metastatic disease in the bone, more opportunities will arise for cytokine and antigen-specific immunotherapies.
Score 2
Score 3
Lower limb Moderate Mixed 1/3e2/3 diameter
Trochanteric On weight bearing Lytic >2/3 diameter
Table 1
than, or equal to, 7 with a low risk and those greater than, or equal to, 8 with a high risk. A score of 9 relates to a 33% risk of fracture, compared to a 4% risk for a score of 7 (Table 1). Surgery can involve either stabilization of the lesion with an intermedullary nail (sometimes augmented with bone cement), plate fixation, or excision and reconstruction with an endoprosthesis. If the mean survival of the patient is expected to be greater than 12 months then a total joint replacement should be used to reduced the risk of revision surgery.
Radiotherapy Radiotherapy is commonly used to provide symptomatic relief for painful bone metastases. It causes irreversible damage to the cellular DNA, preventing cell division and ultimately causing cell death. Palliative radiotherapy varies from conventional radiotherapy, by utilising much higher doses of radiation. There are various palliative radiotherapy modalities possible, including external beam radiation therapy to local fields, hemi-body irradiation and internal radiotherapy (for example radionuclide therapy or radioimmunotherapy). Radiation to local fields can be given in single or multiple fractions, and most studies have found multi-fractionated radiation to be marginally superior to radiation in single fractions. Radiotherapy can provide pain relief in up to 70% of patients with bony metastases, and almost 30% can expect complete pain relief at 1 month. Radiotherapy may also act to control a tumour in the short term, however, complications (including tissue fibrosis) can make subsequent surgery more difficult, therefore its use should be restricted to the palliative setting.
To attempt curative resection: excision of solitary bone lesions has been shown to improve survival. An isolated bone metastasis from renal cell carcinoma, for example, should be treated as a primary bone tumour, with wide local excision and reconstruction, if required. To prevent or relieve spinal neurological compromise: surgery is increasingly being used to treat intractable pain, progressive neurological defects, radioresistant tumours and ‘threatened’ spinal cords. Spinal surgical techniques include vertebrectomy, reconstruction with cages and stabilization with rods/pedicle screw systems. Radiological intervention New interventional radiological techniques can help to stabilize metastases and prevent pain. Embolization of vascular metastases, particularly in renal lesions, can be used preoperatively to aide surgical resection or reduce the size of the tumour. Percutaneous ablative technologies include cryoablation, microwave ablation, ethanol ablation and focused ultrasound; all are under investigation for use in bone metastases and studies show variable success.6 Stabilization of bone lesion with percutaneously injected bone cement under image guidance is a novel technique being used for palliation of vertebral and sacral lesions.
Radioimmunotherapy The use of radioimmunotherapy is still under evaluation, although some benefit in metastatic bone disease has been demonstrated.5 In radioimmunotherapy, an antibody labelled with radionuclide is used to deliver high loads of radioactive isotope to tumour cells. It is useful in the presence of multiple metastases and where radiotherapy has been previously tried with little effect. The advantage over radiotherapy is that it provides targeted treatment not simply anatomically, but directly to the rapidly dividing bone cells. It should be administered early in the treatment of bone metastases, as this has been shown to provide a greater oncolytic effect and improved survival.
Outcomes and prognostic factors Skeletal metastatic deposits were historically considered to be the harbinger of incurable disease. Patients with a pathological fracture were thought to have a life expectancy measured in weeks. Current 5-year survival rates for patients with metastatic bone disease from thyroid (well differentiated only), prostate, renal, breast and lung primaries are 44%, 33%, 25%, 22% and 2%, respectively. For patients with solitary renal carcinomas, surgical excision with wide margins can be curative and these should, therefore, be treated in the same way as primary bone tumours. Short-term survival for patients with bone metastases from lung carcinoma remains poor, with a median survival less than 3 months.
Surgery Surgery for bone metastases is used for three main reasons. To prevent pathological fractures: the treatment of impending fractures can reduce stress and trauma caused by a fracture, treat symptoms and optimize subsequent management. The Mirel scoring system assesses the likelihood of a pathological fracture occurring based on site, size, lesion type and pain. Scores of less
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5 Chiacchio S, Mazzarri S, Lorenzoni A, et al. Radionuclide therapy and integrated protocols for bone metastases. Q J Nucl Med Mol Imaging 2011; 55: 431e47. 6 Kurup AN, Callstrom MR. Ablation of skeletal metastases: current status. J Vasc Interv Radiol 2012; 21: S242e50.
An important prognostic factor for patients with metastatic disease to the bone is the presence of metastases elsewhere, which will negatively affect survival. In a study examining predictors of skeletal complications in patients with metastatic breast cancer, 81% of the patients with bone-only disease at first relapse developed skeletal complications, compared to 60% of the women with bone and extra-osseous metastases. Several studies have looked for correlations between extent of skeletal spread and survival in patients with prostate cancer. Whilst some variability in survival according to number and distributions of skeletal lesions has been identified, results have shown limited significance.
FURTHER READING Berrettoni BA, Carter JR. Mechanisms of cancer metastasis to bone. J Bone Joint Surg Am 1986; 68: 308e12. Boruban S, Sancak T, Yildiz Y, Saglik Y. Embolisation of benign and malignant bone and soft tissue tumours of the extremities. Diagn Interv Radiol 2007; 13: 164e71. €rr HR, Mu €ller PE, Lenz T, Baur A, Jansson V, Refior HJ. Surgical treatment Du of bone metastases in patients with breast cancer. Clin Orthop Relat Res 2002; 396: 191e6. McQuay HJ, Carroll D, Moore RA. Radiotherapy for painful bone metastases: a systematic review. Clin Oncol 1997; 9: 150e4. Mirels H. Metastatic disease in long bones. A proposed scoring system for diagnosing impending pathologic fractures. Clin Orthop Relat Res 1989; 249: 256e64. Rougraff BT, Kneisl JS, Simon MA. Skeletal metastases of unknown origin. A prospective study of a diagnostic strategy. J Bone Joint Surg Am 1993; 75: 1276e81. Sasaki A, Boyce BF, Story B, et al. Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice. Cancer Res 1995; 55: 3551e7. Schaberg J, Gainor BJ. A profile of metastatic carcinoma of the spine. Spine 1985; 10: 19e20. Unni KK. Dahlin’s bone tumors: general aspects and data on 11,087 cases. 5th edn. Philadelphia: Lippincott-Raven, 1996.
Conclusions Bone metastases are a common event in the cancer patient’s journey, and are significantly more common than primary bone tumours. They cause many complications and have significant morbidity. Treatment is multidisciplinary in nature and the most common modalities have been discussed in this article. With ever increasing survival due to improved oncological treatments, definitive surgical reconstruction with endoprostheses, usually within tertiary bone tumour units, is becoming increasingly indicated. As research into the pathology of bone metastasis continues, treatment options for this condition are evolving, and it is likely that morbidity and mortality will continue to improve.A REFERENCES 1 McNicol E, Strassels SA, Goudas L, et al. NSAIDs or paracetamol, alone or combined with opioids, for cancer pain. Cochrane Database Syst Rev 2005; 25: CD005180. 2 Pavlakis N, Schmidt R, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev 2005; CD003474. 3 Wenyi G, Chengtie W, Jiezhong C, Xiao Y. Nanotechnology in the targeted drug delivery for bone diseases and bone regeneration. Int J Nanomedicine 2013; 8: 2305e17. 4 Amin A, Dudek A, Logan T, et al. Prolonged survival with personalized immunotherapy (AGS-003) in combination with sunitinib in unfavourable risk metastatic RCC (mRCC). J Clin Oncol 2013; 6 (abstr 357).
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Acknowledgement The authors acknowledge the contribution made by Nienke Legdeur, from the University of Amsterdam, Netherlands, to the previous version of this article.
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Ó 2015 Published by Elsevier Ltd.
Metastatic tumours of bone
tumours of bone; this article specifically deals with the basic science, clinical features and treatment of metastases.
Alexandra K Freeman
Epidemiology
Vaiyapuri P Sumathi
Metastases affecting bone are far more common than primary bone tumours. In the UK in 2011, 331,000 new cases of cancer were diagnosed, and it is thought that up to 70% of these patients will develop metastatic bone tumours. Bone metastases are common in late-stage disease but certain cancers are ‘osteotropic’ (have an affiliation to bone). Autopsy studies have shown that 70% of patients with breast and prostate carcinoma develop skeletal metastases, numbers are less but still significant in thyroid (40%), renal (35%), bronchus (35%) and rectal (10%) carcinoma. Although bowel, rectal and bladder carcinoma have a lower rate of metastasis to bone, due to the much higher incidence of these cancers, bone metastases from these tumours are common. The skeletal system is the third most common site for metastatic tumour spread, after the lungs and liver. Most secondary bone tumours are found in middle-aged and older patients, with 75% of metastases affecting those over the age of 50 years. The most commonly involved bone sites are those with persistent red marrow, such as the vertebrae, proximal femur, ribs, sternum, pelvis and skull. The vertebrae are affected by 50e70% of metastases, but only 10% of these ever become symptomatic. About 70% vertebral deposits occur in the thoracic spine (T4e7), 20% are found in the lumbar spine and rest in the cervical spine. Multiple spinal deposits are found in half of patients, with the anterior portion of the vertebral body being most commonly affected, followed by the pedicle or lamina. The site prevalence depends, in part, on the primary source of the tumour. For example, widespread skeletal metastases are common in lung cancer primary due to its tendency to spread via the systemic arterial blood supply. Breast carcinoma is the commonest cause of metastatic deposits, and causes 50% of pathological fractures that are due to metastases. Prostate carcinoma is the second most common site of origin, but is less likely to cause pathological fractures, as metastases tend to be osteosclerotic. Renal cell carcinoma metastases can occur many years after the primary tumour, necessitating long-term follow-up, and bone metastases are the presenting feature in 15% of renal tumours.
Lee Jeys
Abstract Metastatic tumours of the bone are the most common types of bone cancer. Autopsy studies have shown that 70% of patients with breast and prostate carcinoma develop skeletal metastases. The most commonly involved bone sites are those with persistent red marrow, such as the vertebrae, proximal femur, ribs, sternum, pelvis and skull. The precise mechanism of metastases to bone is unclear, however, the understanding of the molecular biology of metastases is becoming increasingly important in providing new therapeutic targets. Treatment of bone metastases is multi-modal and may include medications, radiotherapy or surgery. Bone metastases can cause many complications and have significant morbidity. Traditionally, the presence of a metastatic bone deposit has been seen as a terminal event. With the increased survival and improved treatment of patients with carcinoma, long-term survival with metastatic bone disease is possible and treatment can prolong life, or even be curative. Implants used in reconstruction need to be sufficiently robust to survive the patient, and the expertise of reconstruction available within tertiary bone tumour units is increasingly required.
Keywords Bone; carcinoma; metastasis; outcome; secondaries; treatment
Metastatic tumours of bone are tumours that spread to bone from another primary site in the body. Histologically, they often resemble the cells of the tumour from which they originated, but sometimes they are poorly differentiated and the primary tumour site cannot be determined. Metastasis is the ultimate phase in the multistage process of tumour progression and is the major cause of death in cancer, however, improvements in treatment are allowing long-term survival of patients with metastatic bone disease, and may even be curative. In view of increased survivorship following surgery, the implants used in reconstruction need to be sufficiently robust to out-live the patient, and the expertise within tertiary bone tumour units on the gold standard reconstructive techniques is increasingly required. The investigation and staging of secondary tumours has been dealt with in a previous article by the authors on primary
Pathogenesis of bone metastases The precise mechanism of metastases to bone is unclear but consists of a multistep process that involves interaction between tumour cells and normal host cells. The biology of bone metastases is complex and involves: breaking free from the extracellular matrix of the primary tumour; being transported in the blood or lymphatic system; avoiding detection and destruction by the immune system; exiting the blood or lymphatic system; and proliferating in an environment which is removed from their original location. The host environment has to be rich in nutrients and oxygen and so the metastatic cells must recruit blood vessels (neoangiogenesis) in order to allow continued growth of the secondary tumour. Tumours can spread by direct tumour invasion (e.g. soft tissue sarcoma directly invading bone), via the bloodstream or via the lymphatics.
Alexandra K Freeman MBChB BSc (Hons) is an Academic Foundation Year 2 Doctor at the Royal Orthopaedic Hospital, Birmingham, UK. Conflicts of interest: none declared. Vaiyapuri P Sumathi FRCPath is a Consultant Histopathologist at Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK. Conflicts of interest: none declared. Lee Jeys MB ChB MSc (Orth Eng) FRCS (Tr & Orth) is a Consultant Orthopaedic Oncology Surgeon at the Royal Orthopaedic Hospital, Birmingham, UK. Conflicts of interest: none declared.
SURGERY 33:1
34
Ó 2015 Published by Elsevier Ltd.
ORTHOPAEDICS I: GENERAL PRINCIPLES
Theories of mechanisms of macroscopic tumour spread Two main theories exist to explain possible mechanisms of distant spread of tumour and it is most likely that a combination of factors are responsible.
increased bone formation. Mixed lesions are caused by a combination of both osteolytic and osteoblastic processes. Several other factors are also involved in the metastatic process, but are not specific to bone metastasis, such as matrix metalloproteinase (MMP) maspin, integrin, e-cadherin and vascular endothelial growth factor (VEGF). In metastatic bone disease the normal balance of formation of new bone by osteoblasts and resorption of old bone by osteoclasts becomes imbalanced, leading to the development of lesions that are osteolytic, osteoblastic or a combination of both. Analysis of osteolytic bone metastases indicates that the bone destruction is mediated by the osteoclast rather than directly by the tumour cells. These observations suggest a vicious cycle driving the formation of osteolytic metastases: tumour cells secrete factors stimulating osteoclasts through adjacent bone marrow stromal cells; osteoclastic resorption in turn releases growth factors from the bone matrix; finally, locally released growth factors activate the tumour cells. This vicious cycle model has now been confirmed at the molecular level. In particular, TGF b is abundant in bone matrix and released as a consequence of osteoclastic bone resorption. Bone-derived TGF b plays an integral role in promoting the development and progression of osteolytic bone metastases by inducing tumour production of PTHrP, a known stimulator of osteoclastic bone resorption. In breast cancer cells TGF b appears to stimulate PTHrP secretion by a post-transcriptional mechanism through both Smad and p38 mitogen-activated protein (MAP) kinase signalling pathways. Osteolytic metastases can be suppressed in vivo by inhibition of bone resorption, blockade of TGF b signalling in tumour cells, and by neutralization of PTHrP. Other factors released from bone matrix may also act on tumour cells in bone, and in turn stimulate bone resorption, following the vicious cycle paradigm established for TGF b and PTHrP. Studies have shown that tumour cancer cells interact with osteoblasts or stromal cells to induce osteoclast formation by increasing RANKL expression in several ways. RANK, RANKL and osteoprotegerin (OPG) are the regulatory triad in the differentiation, activation and survival of osteoclasts. RANK is a receptor on the surface of the osteoclast and RANKL is a member of the tumour necrosis factor (TNF) family of cytokines that binds to its receptor RANK to stimulate osteoclast differentiation and activation. RANKL and OPG form a ligandeligand inhibitory pair which modulates RANK signalling in osteoclasts and their precursors. It is likely that increased bone resorption around cancer cells in the bone results from increased RANKL expression. Mice studies have shown that in-vivo neutralization of RANKL by OPG results in complete protection from paralysis and marked reduction in tumour burden in bones, but not in other organs. Factors such as PTHrP regulate the expression of OPG and RANKL. Cancer cells can express or upregulate the expression of these factors, of which OPG and RANKL will lead to bone resorption. In this process, treatment possibilities arise, for example, by blocking RANKL signalling within OPG treatment. This can protect against bone destruction, and may inhibit tumour growth in bone. The clinical application of this is the increasing use of bisphosphonates (which block RANKL) to reduce skeletal events in metastatic bone disease.
Soil hypothesis (Paget): in 1889 British surgeon Stephen Paget (son of Sir James Paget) popularized a theory published previously by Fuchs, of ‘the seed and the soil’ hypothesis. This suggested that malignant cells escaping from the tumour (the ‘seeds’) colonize those tissues (the ‘soils’) that are favourable for them because of mutual compatibilities. Paget imagined that breast tumours metastasize to bones and liver, rather than the spleen, because bone marrow and liver tissues provide optimal conditions for the multiplication of breast cancer cells. Circulation theory (Ewing): proposed in 1928 by James Ewing, of the New York Memorial Hospital, stating that the distribution of metastases depends principally on the routes of dissemination of the tumour. He observed that colonic tumours metastasize principally to the liver because the liver is the first organ visited by the circulating blood coming from the intestines. The preferential deposition of primary tumour cells in the vertebrae, with relatively scarce visceral involvement, was also noted. This can be explained by Batson’s valveless venous plexus from around the vertebrae that communicates with the pelvis and proximal halves of the upper and lower extremities, but excludes the chest, portal and caval systems. It is postulated that the spread of malignant cells through this plexus is likely to occur through retrograde spread, as a result of a Valsalva manoeuvre, from the sites of primary tumours. The unique ability of lung lesions to shed tumour cells directly into the arterial circulation causes the spread of tumour cells to tissues far and wide in the body, including to the bones of the hands and feet, with 50% of all metastases to the hands coming from primary lung tumours. Molecular mechanisms in bone metastases The bone matrix provides a unique and fertile microenvironment for the proliferation of tumour cells. The interaction between tumour cells and bone stroma that initiate the cycle of bone destruction and tumour growth are critical aspects of the metastatic process. The exact pathogenesis or biology of bone metastasis is still not well understood. There are several important factors in the development of osteolytic bone metastases. Some of the major contributors are: parathyroid hormone-related protein (PTHrP e which is an important cause of hypercalcaemia of malignancy and bone resorption); transforming growth factor b (TGF b); interleukin11 and interleukin-6 (which have been shown to simulate bone resorption and may induce osteolysis). Other factors include calcitonin receptors, osteopontin and silo protein, tumour necrosis factor a, prostaglandins, receptor activator of nuclear factor-K B ligand (RANKL), macrophage colony-stimulating factor (M-CSF) and human platelet-derived growth factor (PDGF). Osteoblastic metastatic lesions arise from uncoupled increase in bone formation and reduced bone resorption. TGF b, bone morphogenetic protein (BMP), and insulin growth factors stimulate the differentiation and activity of osteoblasts, leading to
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Figure 1 Metastatic breast carcinoma. Macroscopy of the proximal femur shows multiple fleshy deposits.
Pathology of bone metastasis
cases, use of immunohistochemical stains is essential to differentiate from primary bone sarcoma (Figures 3 and 4).
Macroscopic features Metastatic tumours to the bone tend to be poorly circumscribed and grow in an invasive, permeative manner with indistinct borders. The consistency is variable, depending on the amount of bone and desmoplastic stromal reaction produced in response to the tumour. Osteoblastic metastases appear greyish-white and firm, whilst renal cell carcinoma produces soft, haemorrhagic and necrotic deposits (Figures 1 and 2).
Clinical features Pain Unlike chest and liver metastases, bone metastases are the most common cause of cancer-related pain, and half of all patients with solid tumours that metastasize to bone experience one or more skeletal events during the course of their treatment. Problems related to bone metastases account for over a third of all nights spent in hospital in advanced breast cancer care. Pain is thought to be caused by stretching of the overlying periosteum and/or stimulation of nerves in the endosteum, resulting in gradually progressive, dull, non-mechanical pain. Structural weakening of the vertebrae can lead to collapse, causing subsequent back pain (although pain is present in only
Microscopic features Metastatic tumours often recapitulate the original tumour. Thyroid, renal cell and squamous cell carcinomas retain morphological similarities to the primary tumour. Occasionally, poorly differentiated carcinomas, in particular renal cell carcinoma and lung carcinoma, may exhibit a sarcomatoid pattern. In such
Figure 2 Metastatic renal cell carcinoma. Gross photograph of a distal femur with metastatic renal cell carcinoma showing a haemorrhagic fleshy tumour.
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or the spinal cord. About 50% of cases have motor or sensory dysfunction and around 50% have bladder or bowel dysfunction. If cord compression is left untreated, progressive motor weakness will occur leaving the patient unable to walk, and around 15% will become paraplegic. Impending cord compression is a surgical emergency and patients with symptoms of cauda equina (saddle anaesthesia and altered bowel/bladder function) require an urgent MRI and referral for radiotherapy or surgery before neurological compromise becomes irreversible. Hypercalcaemia This occurs in 10% of patients with bone metastases and is more common in osteolytic tumours. Symptoms include fatigue, depression, confusion, anorexia, vomiting, pancreatitis and polyuria. Urgent treatment is required, with rehydration, and bisphosphonates or calcitonin, to prevent complications such as cardiac arrhythmias and coma. Figure 3 Haematoxylin and eosin metastatic breast carcinoma. Microscopic photograph of an osteoblastic metastasis of carcinoma from the breast.
Treatment options for metastatic bone disease The majority of patients with metastatic bone disease will not require any surgical intervention, the mainstay of treatment being bisphosphonates and radiotherapy. The principles of treatment are to control local symptoms, maintain function, prevent pathological fractures, improve or maintain mobility, relieve pain, and improve quality of life. The complexity of these cases requires a multi-disciplinary approach to management, which may include a specialist bone tumour unit.
54% of patients with this complication). Non-mechanical, night and radicular pain should alert the clinician to the need for further investigation. Pathological fracture Osteolytic lesions are most at risk of pathological fractures, and up to half of these are due to breast cancer metastases. The mechanism of injury should be identified, as the fractures often occur with minimal force or torsional stresses. If the deposit affects less than 50% diameter of the bone, fractures occur most commonly under loading. If the lesion affects more than 75% of the diameter, fractures can occur with simple torsion. The mechanical properties of the implant used to treat the pathological fracture should be durable enough to load-bear for the likely survival time of the patient, as only one-third to one-fifth of pathological fractures unite, despite adjuvant therapy
Medical treatment Analgesia is an essential aspect of treatment for patients suffering with bone pain; combinations of simple, opiate and adjuvant analgesia may be required. Non-steroidal anti-inflammatory drugs have been shown to significantly reduce cancerrelated pain, particularly when used in conjunction with opiate-based analgesia.1 Bisphosphonates are a class of drugs that work by inducing osteoclast apoptosis, thereby reducing the lytic activity of bone metastases. Administration of these drugs reduces the number of skeletal events, and may also have an effect on metastatic spread.2 Data from preclinical studies suggest that bisphosphonates, in addition to inhibiting osteoclast activity, may also have anti-tumour activity and prevent bone metastasis, though the exact mechanism remains unclear. There is likely an indirect effect provoked through the inhibition of bone resorption, the inhibition of angiogenesis and the stimulation of the immune system, but there may also be a direct effect through the inhibition of tumour cell invasion, proliferation and adhesion to bone. More recently evolving research into the use of nanotechnology to allow targeted delivery of bisphosphonates to bone has shown promising results.3 The nano-particles act as a transporter to deliver bisphosphonates to their site of action with minimal systemic breakdown, thus allowing more targeted therapy with fewer side effects. Further studies are needed before the true clinical value is known.
Neurological symptoms Vertebral metastases are common and 5% of those affected will suffer neurological symptoms due to compression of nerve roots
Chemotherapy, hormonal and biological drug therapies may be indicated in the treatment of bone metastases, especially from breast (tamoxifen), prostate (anti-androgens) and renal cell
Figure 4 Haematoxylin and eosin metastatic renal cell carcinoma. Histology of metastatic renal cell carcinoma with clear cell features.
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carcinoma (sunitinib). Current imaging modalities do not accurately determine the response of bone metastases to these treatments; however, with developments in PET scanning and MRI, this is likely to improve. These treatments are not without side effects; osteoporosis is one such effect that may further compound the risk of pathological fractures.
Mirel scoring system Variable
Site Upper limb Pain Mild Lesion type Blastic Size <1/3 diameter
Immunotherapy is a novel treatment for bone metastases and promising early results are emerging. A phase two trial examining the use of AGS-003 immunotherapy in addition to sunitinib for patients with metastatic renal cell carcinoma has shown survival to be significantly increased.4 Another promising cytokine for immunotherapy is PTHrP which, when neutralized with antibodies, is proven to reduce the development of bone metastases in animal models. With increasing knowledge about the pathology of metastatic disease in the bone, more opportunities will arise for cytokine and antigen-specific immunotherapies.
Score 2
Score 3
Lower limb Moderate Mixed 1/3e2/3 diameter
Trochanteric On weight bearing Lytic >2/3 diameter
Table 1
than, or equal to, 7 with a low risk and those greater than, or equal to, 8 with a high risk. A score of 9 relates to a 33% risk of fracture, compared to a 4% risk for a score of 7 (Table 1). Surgery can involve either stabilization of the lesion with an intermedullary nail (sometimes augmented with bone cement), plate fixation, or excision and reconstruction with an endoprosthesis. If the mean survival of the patient is expected to be greater than 12 months then a total joint replacement should be used to reduced the risk of revision surgery.
Radiotherapy Radiotherapy is commonly used to provide symptomatic relief for painful bone metastases. It causes irreversible damage to the cellular DNA, preventing cell division and ultimately causing cell death. Palliative radiotherapy varies from conventional radiotherapy, by utilising much higher doses of radiation. There are various palliative radiotherapy modalities possible, including external beam radiation therapy to local fields, hemi-body irradiation and internal radiotherapy (for example radionuclide therapy or radioimmunotherapy). Radiation to local fields can be given in single or multiple fractions, and most studies have found multi-fractionated radiation to be marginally superior to radiation in single fractions. Radiotherapy can provide pain relief in up to 70% of patients with bony metastases, and almost 30% can expect complete pain relief at 1 month. Radiotherapy may also act to control a tumour in the short term, however, complications (including tissue fibrosis) can make subsequent surgery more difficult, therefore its use should be restricted to the palliative setting.
To attempt curative resection: excision of solitary bone lesions has been shown to improve survival. An isolated bone metastasis from renal cell carcinoma, for example, should be treated as a primary bone tumour, with wide local excision and reconstruction, if required. To prevent or relieve spinal neurological compromise: surgery is increasingly being used to treat intractable pain, progressive neurological defects, radioresistant tumours and ‘threatened’ spinal cords. Spinal surgical techniques include vertebrectomy, reconstruction with cages and stabilization with rods/pedicle screw systems. Radiological intervention New interventional radiological techniques can help to stabilize metastases and prevent pain. Embolization of vascular metastases, particularly in renal lesions, can be used preoperatively to aide surgical resection or reduce the size of the tumour. Percutaneous ablative technologies include cryoablation, microwave ablation, ethanol ablation and focused ultrasound; all are under investigation for use in bone metastases and studies show variable success.6 Stabilization of bone lesion with percutaneously injected bone cement under image guidance is a novel technique being used for palliation of vertebral and sacral lesions.
Radioimmunotherapy The use of radioimmunotherapy is still under evaluation, although some benefit in metastatic bone disease has been demonstrated.5 In radioimmunotherapy, an antibody labelled with radionuclide is used to deliver high loads of radioactive isotope to tumour cells. It is useful in the presence of multiple metastases and where radiotherapy has been previously tried with little effect. The advantage over radiotherapy is that it provides targeted treatment not simply anatomically, but directly to the rapidly dividing bone cells. It should be administered early in the treatment of bone metastases, as this has been shown to provide a greater oncolytic effect and improved survival.
Outcomes and prognostic factors Skeletal metastatic deposits were historically considered to be the harbinger of incurable disease. Patients with a pathological fracture were thought to have a life expectancy measured in weeks. Current 5-year survival rates for patients with metastatic bone disease from thyroid (well differentiated only), prostate, renal, breast and lung primaries are 44%, 33%, 25%, 22% and 2%, respectively. For patients with solitary renal carcinomas, surgical excision with wide margins can be curative and these should, therefore, be treated in the same way as primary bone tumours. Short-term survival for patients with bone metastases from lung carcinoma remains poor, with a median survival less than 3 months.
Surgery Surgery for bone metastases is used for three main reasons. To prevent pathological fractures: the treatment of impending fractures can reduce stress and trauma caused by a fracture, treat symptoms and optimize subsequent management. The Mirel scoring system assesses the likelihood of a pathological fracture occurring based on site, size, lesion type and pain. Scores of less
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5 Chiacchio S, Mazzarri S, Lorenzoni A, et al. Radionuclide therapy and integrated protocols for bone metastases. Q J Nucl Med Mol Imaging 2011; 55: 431e47. 6 Kurup AN, Callstrom MR. Ablation of skeletal metastases: current status. J Vasc Interv Radiol 2012; 21: S242e50.
An important prognostic factor for patients with metastatic disease to the bone is the presence of metastases elsewhere, which will negatively affect survival. In a study examining predictors of skeletal complications in patients with metastatic breast cancer, 81% of the patients with bone-only disease at first relapse developed skeletal complications, compared to 60% of the women with bone and extra-osseous metastases. Several studies have looked for correlations between extent of skeletal spread and survival in patients with prostate cancer. Whilst some variability in survival according to number and distributions of skeletal lesions has been identified, results have shown limited significance.
FURTHER READING Berrettoni BA, Carter JR. Mechanisms of cancer metastasis to bone. J Bone Joint Surg Am 1986; 68: 308e12. Boruban S, Sancak T, Yildiz Y, Saglik Y. Embolisation of benign and malignant bone and soft tissue tumours of the extremities. Diagn Interv Radiol 2007; 13: 164e71. €rr HR, Mu €ller PE, Lenz T, Baur A, Jansson V, Refior HJ. Surgical treatment Du of bone metastases in patients with breast cancer. Clin Orthop Relat Res 2002; 396: 191e6. McQuay HJ, Carroll D, Moore RA. Radiotherapy for painful bone metastases: a systematic review. Clin Oncol 1997; 9: 150e4. Mirels H. Metastatic disease in long bones. A proposed scoring system for diagnosing impending pathologic fractures. Clin Orthop Relat Res 1989; 249: 256e64. Rougraff BT, Kneisl JS, Simon MA. Skeletal metastases of unknown origin. A prospective study of a diagnostic strategy. J Bone Joint Surg Am 1993; 75: 1276e81. Sasaki A, Boyce BF, Story B, et al. Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice. Cancer Res 1995; 55: 3551e7. Schaberg J, Gainor BJ. A profile of metastatic carcinoma of the spine. Spine 1985; 10: 19e20. Unni KK. Dahlin’s bone tumors: general aspects and data on 11,087 cases. 5th edn. Philadelphia: Lippincott-Raven, 1996.
Conclusions Bone metastases are a common event in the cancer patient’s journey, and are significantly more common than primary bone tumours. They cause many complications and have significant morbidity. Treatment is multidisciplinary in nature and the most common modalities have been discussed in this article. With ever increasing survival due to improved oncological treatments, definitive surgical reconstruction with endoprostheses, usually within tertiary bone tumour units, is becoming increasingly indicated. As research into the pathology of bone metastasis continues, treatment options for this condition are evolving, and it is likely that morbidity and mortality will continue to improve.A REFERENCES 1 McNicol E, Strassels SA, Goudas L, et al. NSAIDs or paracetamol, alone or combined with opioids, for cancer pain. Cochrane Database Syst Rev 2005; 25: CD005180. 2 Pavlakis N, Schmidt R, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev 2005; CD003474. 3 Wenyi G, Chengtie W, Jiezhong C, Xiao Y. Nanotechnology in the targeted drug delivery for bone diseases and bone regeneration. Int J Nanomedicine 2013; 8: 2305e17. 4 Amin A, Dudek A, Logan T, et al. Prolonged survival with personalized immunotherapy (AGS-003) in combination with sunitinib in unfavourable risk metastatic RCC (mRCC). J Clin Oncol 2013; 6 (abstr 357).
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Acknowledgement The authors acknowledge the contribution made by Nienke Legdeur, from the University of Amsterdam, Netherlands, to the previous version of this article.
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