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Introduction
Bone is one of the most common anatomic sites for metastases, along with the lungs and liver, and metastases are the most commonly diagnosed neoplasms encountered in the skeleton. Metastases are far more frequent in bone than are primary bone neoplasms. Although carcinomas of all types account for most metastatic deposits in the adult skeleton, melanomas, sarcomas, and even germ cell tumors may also metastasize to bone. In most instances, patients develop multiple bone metastases, and usually the presence of a tumor elsewhere is known, so the diagnosis is obvious. However, solitary metastases from occult primaries can be confused clinically and radiographically with primary bone tumors. More than 80% of all bone metastases originate in the breast, lung, prostate, thyroid, or kidney. In children, bone metastases can be seen in patients with neuroblastoma, rhabdomyosarcoma, and osteosarcoma.
About 70% of bone metastases affect the axial skeleton, and the remainder involve the appendicular skeleton. In all bones, metastases preferentially involve areas with red bone marrow. Because of this, metastases occurring in the long bones most often involve the metaphyseal region. In general, metastatic carcinoma reaches the bones through the complex venous and arterial systems. Bone is richly vascular, and a significant proportion of the body’s vasculature is found in the skeletal system. Additionally, the vertebral plexus of veins is valveless, and the retrograde venous pressure is often increased in the abdominal and chest regions. This enables a retrograde flow of blood to bypass the caval system and easily reach the bones of the vertebral column.
Autopsy reports detailing large series of patients have shown that, with careful gross and microscopic examination, skeletal metastases can be documented in at least 30% of patients who die of carcinoma, with particular carcinomas such as breast and prostate cancer present in nearly 85% of patients who undergo postmortem examination. These findings are supported by bone scintigraphy studies, which suggest that approximately 85% of patients with the most common carcinomas have skeletal involvement.
This chapter will discuss the clinical, radiographic, and pathologic features of metastatic disease in the skeleton.
Clinical Features
Patients may present with signs and symptoms related to metastatic bone lesions before a primary tumor has come to clinical attention. Severe pain or a pathologic fracture is commonly the presenting complaint. Tenderness, swelling, and pain are typical presenting symptoms of skeletal metastases, but patients may also have signs or symptoms related to bone marrow dysfunction. The symptoms are insidious in onset and gradually increase in intensity over weeks to months, often preceding changes that are recognizable on conventional radiographs. Abrupt onset of symptoms (typically severe pain) is usually associated with pathologic fracture ( Fig. 25.1 ). In general, the presence of skeletal metastases is a sign of disseminated multisystem disease, and other organs are likely to be involved. However, in a minority of patients, a solitary metastatic focus in the skeleton can be the only identifiable site of the disease. When a patient presents with a skeletal metastasis and has no known cancer history, a careful clinical and radiographic examination, along with laboratory studies, will often identify the source for the metastasis.
Radiologic Features
Metastatic tumor in bone typically presents as a destructive focus that has an aggressive pattern of bone destruction. Cortical disruption, extension into soft tissue, and periosteal new bone formation can be present. Many metastatic bone lesions are osteolytic in nature, but some metastatic tumors can provoke an osteoblastic reaction with new bone formation and appear to be a sclerotic lesion. Occasionally, focal osteosclerosis is seen within lytic lesions, and therefore some skeletal metastases produce a mixture of radiolucent and osteoblastic appearances. Tumors with a tendency to produce purely osteoblastic metastases are prostatic carcinoma, carcinoid tumor and other neuroendocrine neoplasms, and breast carcinoma ( Fig. 25.2 ). The mechanism for blastic metastases is thought to involve both systemic and local factors that induce osteoblast proliferation, including transforming growth factor (TGF)-β, fibroblast growth factor, and bone morphogenetic proteins. Likewise, the mechanism of bone resorption is thought to be related to the stimulation of osteoclast formation via parathyroid hormone, vitamin D 3 , interleukins, and other factors activating the RANK-RANKL pathway. Aside from those listed above, most other metastases result in osteolytic lesions.
Multiple lesions are a radiographic hallmark of metastatic skeletal disease. Although any skeletal site can be affected by metastasis, most lesions involve the axial skeleton and proximal parts of the appendicular skeleton. Consequently, such bones as the vertebrae, pelvis, ribs, skull, sternum, proximal femur, and humerus are most frequently involved. These sites correspond to areas that contain hematopoietic marrow, which has a rich sinusoidal vascular network. This feature and the presence of venous plexus connected with abdominal and thoracic organs may promote metastasis in these regions. Metastases that predominantly involve fatty marrow distal to elbow and knee joints and the mandible are unusual in adults.
Occasionally a single metastatic focus of carcinoma can be present. In some patients, it can be a presenting sign of a clinically silent primary tumor that, most often, is located within the thoracic or abdominal organs. Although solitary skeletal metastasis can be a presenting sign in any type of common carcinoma, it is most frequent in carcinomas of the kidney, lung, breast, pancreas, thyroid, and colon. Rarely, bilateral symmetric metastases involving the left and right sides can be present. Bilateral, symmetric, osteoblastic metastases can simulate osteopoikilosis. Small tubular bones of the hands and feet are rarely affected by metastasis. In some instances, metastatic lesions may have a radiographic appearance suggesting a benign condition or a primary bone lesion ( Fig. 25.3 ).
The bone(s) involved and the character of the changes seen radiographically are helpful in predicting the site of the primary neoplasm. Thyroid carcinoma often metastasizes to the bones of the shoulder girdle, skull, ribs, and sternum, whereas carcinoma of the kidney tends to involve the skull, sternum, flat bones of the pelvis, humerus, and scapula. Bone metastases peripheral to the knees or elbows are rare, but they certainly occur, as distally as the terminal phalanges, which may occur with pulmonary carcinomas ( Fig. 25.4 ).
Conventional radiographs are not particularly sensitive in identifying early metastatic lesions in the skeleton. Radioisotope scanning can demonstrate abnormal uptake of bone-seeking isotope approximately four months on average before a lesion can be identified on plain radiographs ( Fig. 25.5 ). Radioisotope scans, however, are not specific, and they identify an increased turnover state associated with osteoblastic activity rather than the proliferation of tumor cells. Therefore, they may not detect metastatic tumors that are primarily associated with bone destruction and minimal or no osteoblastic activity. Diffusion-weighted magnetic resonance imaging and whole body FDG-PET/computed tomography scans have been shown to be very sensitive and accurate in identifying metastatic deposits in bone from a variety of sources ( Fig. 25.6 ).
Periosteal bone proliferation may rarely accompany a metastatic lesion. This is more likely to occur in certain blastic metastases such as those caused by prostate carcinoma. Exuberant new bone formation can also occur because of a pathologic fracture associated with metastatic carcinoma and lead to diagnostic confusion with osteosarcoma.
Pathologic Features
Gross Features
The gross appearance of metastatic carcinoma involving bone is generally non-specific. Radiolucent metastases may be similar in appearance to non-matrix forming primary bone sarcomas (e.g., undifferentiated pleomorphic sarcoma) ( Fig. 25.7 ), and osteoblastic metastases can mimic osteosarcoma. Most metastases are centered in the medullary cavity; however, certain metastatic carcinomas, such as those of pulmonary origin, may preferentially involve the cortex.
Microscopic Features
The microscopic appearance of metastatic carcinoma, sarcoma, or melanoma is generally similar to that of the primary lesion. Therefore, metastases of renal, thyroid, and colorectal origin, as well as squamous cell carcinomas from any primary site, are typically straightforward to identify based on their histologic appearance alone. When a primary source for a metastasis is already known, the morphologic appearance of the metastatic deposit and the primary can be compared, and a diagnosis easily rendered, even in cases where the histologic features are unusual. When the primary site is not known or a prior tissue sample is not available for review, immunohistochemical evaluation is necessary to characterize the metastatic carcinoma (see below).
Sarcomatoid carcinomas, often originating in the kidney or thyroid, can lack overt epithelial differentiation and closely mimic primary spindle cell sarcomas of bone. Fortunately, it is uncommon for sarcomatoid carcinomas to metastasize to bone prior to the discovery of the primary lesion. Likewise, metastatic carcinomas that induce a marked osteoblastic reaction can be confused with epithelioid osteosarcoma, which can be immunoreactive for EMA and keratins. Finally, metastatic malignant tumors – including carcinoma and melanoma – can be accompanied by a prominent population of osteoclasts and simulate a giant cell tumor.
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