Metastatic bone disease

Main Points

Skeleton is the third most common site for metastasis.
Metastatic disease is the most common malignancy of bone.
Portends high morbidity and limited survival.
Seen in areas with hemopoetic marrow.
Classified as lytic, sclerotic and mixed.
Metastasis is a complex multistage event which involves 2way communication between the tumour cells and three different micro environments; the primary neoplasm, circulation and bone.

Introduction

Skeleton after the lungs and liver is the third most common site for metastasis. Metastatic disease is the most common malignancy of bone. Skeleton is a common site of metastasis for epithelial tumours. Presence of metastasis usually occurs in advanced disease and portends high morbidity and limited survival. They are usually multifocal and seen in areas with hemopoetic marrow. Most common cancers to present with skeletal metastasis are prostate, breast and lung. Two third of cancer patients may develop skeletal metastasis. In the 1970s the average survival of bone metastases was about 7 months . By 1990s this has increased to 2 years.
Bone metastasis have been classified as lytic, sclerotic and mixed. Irrespective of the radiologic appearances, the effect is a change in the bone architecture which predispose the patient to skeletal complications. Breast secondaries present with multiple lesions mainly in the axial skeleton; skull, spine, ribs, pelvis and proximal long bones. Ovarian and primary CNS tumours are less likely to metastasise to the skeleton.

Pathogenesis

The pathogenesis of skeletal metastasis is not fully understood. Sir Stephen Paget proposed the seed and soil theory; where tumour cells are the seeds and the bone is the soil. Metastasis is a complex multistage event which involves 2way communication between the tumour cells and three different micro environments; the primary neoplasm, circulation and bone. The tumour cells should escape into the circulation at the primary neoplasm, reach the bone, establish at the site, proliferate and produce metastatic lesions.
The genetic and molecular basis of metastasis is beginning to be understood. Distinct bone metastasis and poor prognosis genetic signatures have been identified. Bone metastasis signature genes include C-X-R chemokine receptor 4(CXCR4), connective tissue growth factor, IL11, MMP-1 and osteopontin genes. They encode surface and secretary proteins that participate in the multiple steps of homing, invasion, angiogenesis and proliferation.
The predilection of bone to metastasis may be due to many factors. The large sinusoids with sluggish blood flow may provide enough opportunity for tumour cells to bind. The continuous turn over in the hemopoetic marrow may provide abundant resources for the tumour cells to proliferate. Certain cells of the hemopoetic marrow with vascular endothelial growth factor receptor 1 may produce a premetastatic nidus in response to humoral factors secreted by the primary neoplasm. The cells of the nidus express cell surface ligands and receptors like fibronectin and integrins which help the migrating tumour cells to home in and proliferate. In addition various growth factors and cytokines may act as paracrine regulators during initial growth of metastasis.
Prostate cancers may produce osteoblastic and osteolytic secondaries. Osteoblastic prostate secondaries produce osteoprotegerin(OPG), BMP and TGF-B. Osteolytic prostate secondaries produce IL1, RANKL and TNF alpha. These factors act through osteoclasts to produce osteolysis. OPG/RANK/RANKL is the key pathway for osteoclast regulation. Wnt (wingless int) pathway, ET axis and BMP pathway are the key regulators involved in the establishment of osteoblastic secondaries.

Clinical Presentation

Patients may present with localised or diffuse bone pain, pathological fractures, neurological symptoms due to spinal cord involvement or swelling. Nocturnal pain and pain not entirely relieved by rest is the typical presentation. Ask for history of tobacco use, alcohol abuse, chronic infections especially viral, exposure to ionizing radiation, exposure to carcinogens and family history of malignancy. Advanced prostatic CA may present with anaemia and other features of bone marrow suppression and may die due to pancytopenia or disseminated intravascular coagulation. Serum alkaline phosphatase is often elevated in patients with bone metastasis.

Management Principles

Lesions may be lytic, sclerotic or mixed. More than 50% of cortex if destroyed is In patients with long bone lesions the risk of pathological fracture is assessed using Mirel’s criteria based on limb involved, type of lesion, extent of involvement and severity of pain. More than 8 points is suggestive of impending fracture.

Mirel’s Criteria

1. 2. 3.
Site Upper limb Lower limb Pertrochanteric
Type. Sclerotic. Mixed. Lytic
Extent. 2/3 diameter
Pain. Mild. Moderate. Activity related

Surgery is indicated in patients fit for for surgery and likely to survive for some period as metastatic pathological fractures even if stabilised, rarely unite. Surgery should aim for immediate weight bearing and should last the lifespan of the patient. Ideal fixation is by intramedullary fixation. A common practice is to support the whole bone by putting a long intra medullary rod and lock both the ends. If there is extensive involvement, adequate venting should be done through the distal part during reaming and nail insertion to prevent embolization. In extensive lesions, cement augmentation may be done. In periarticular lesions, plate fixation may be necessary. Fixation especially in the proximal femur has a high failure rate, cemented prosthesis (conventional or tumour prosthesis) have low failure rate. In very extensive lesions, modular megaprosthetic replacement may be needed. Surgery aims to relieve pain and improve function. These fractures rarely unite and chance of union is less for lytic lesions. Percutaneous cementoplasty may be done for painful lesions not responding to analgesic measures.
Spinal metastasis if they need surgery, usually will need decompression and stabilisation.
Bone scan is a very sensitive investigation to detect other lesions, but it is nonspecific. MRI and CT are more specific.
Adequate pain relief is an important consideration which may require narcotic agents. NSAIDs are very useful for bone pin if tolerated. Other measures useful for pain relief are chemotherapy, appropriate hormone blockade and radiotherapy. Radiotherapy is usually given in a single fraction and should include the operation field. Bisphosphonates are useful in preventing skeletal deterioration especially for breast cancer and myeloma. They are also useful in presence of hypercalcemia.

Copyright @Dr Rajesh Purushothaman, Associate Professor, Government Medical College, Kozhikode, Kerala, India

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