By Kristy Weber, MD
Chief, Division of Orthopaedic Oncology
Johns Hopkins University School of Medicine.
Release Date: February 28, 2006
Expiration Date: February 28, 2008
Dr. Weber has no significant financial interest or relationships to disclose.
It’s very nice to be here. My first rheumatology experience was here at Hopkins. That was awhile ago, but it was a great opportunity to learn more about the musculoskeletal system. Today I’m going to talk about treating metastatic bone disease, bench to bedside — with more on the bedside. I will talk about how to recognize some of the lesions that patients have, as well as some of the toys that we play with when we try to help patients with these problems, from an orthopaedic surgical standpoint.
The objectives are:
- To learn to recognize osteolytic and osteoblastic bone metastasis
- To understand the role of orthopaedic surgery in the treatment of patients with metastatic bone disease
- To understand that taking care of patients with metastatic bone disease requires a multidisciplinary team approach — working with medical oncologists, radiation oncologists, radiologists, pathologists, etc.
Metastatic bone disease has been around as long as cancer has been around. The scope of the problem is that every year more than 1.3 million new cancers are diagnosed — that is, cancer in general. About 50 percent of those have the possibility of spreading into the skeletal system, which is the third most common site, after the liver and the lung. It is the most symptomatic site, and there is an increase in the number of cases as time goes on because of a number of factors.
The pathogenesis of why tumor cells spread into the bone has been debated. In 1889, Paget discussed his seed and soil hypothesis. Why do breast cancer cells specifically go into the lung, or why do they spread into certain organs, whereas other cancers spread into completely different organs? He felt that it was the capacity of the tumor cell to secrete particular growth factors or cytokines that then found a fertile soil in the environment of the lung, liver, or other organ. The cell then has the right environment to grow in, whereas other environments might not be as conducive, might not have the right factors. In 1928, Ewing felt the reason that cancer cells spread to particular organs had to do with the blood supply, the circulation — whether it was the portal circulation, the systemic circulation or Batson’s plexus, which is a plexus of vessels in the lower portion of the spine and pelvis, valveless veins that allow retrograde flow. When someone has prostate cancer, often the metastases are focused around the pelvis and lower spine. Some people think that’s because of the vascular system in that area. The two theories are probably not mutually exclusive in why cells go to specific organs.
The schematic below shows the steps that have to happen.
The tumor cells are in the primary site, let’s say the kidney. New blood vessels must form for the tumor to grow. They have to be able to develop particular factors — be they proteases, metalloproteinases — to be able to break free through the basement membrane into the microvascular circulation. The cells spread to additional organs, and then have to have the right signals to be able to break out of the microvasculature and land in a particular organ matrix, and grow there. The vast majority, 99.99 percent of tumor cells, are eliminated by the body’s immune system so they never make it to the end organ. We talk about how cancers destroy bone in patients with metastatic bone disease. It’s not the tumor cells that destroy the bone; it’s the osteoclast. The tumor cells stimulate the osteoclast, the bone-resorbing cell, with mediators such as tumor necrosis factor, transforming growth factors, colony stimulating factors, prostaglandins, 1,25-dihydroxyvitamin D3, or parathyroid hormone-related protein. PTH-rP has been a very important factor looked at in breast cancer bone metastasis. These factors stimulate the bone resorption.
As for the clinical problems for patients with metastatic bone disease, pain is the major issue. Patients have a significant amount of pain. They can develop pathologic fractures if their lesions are large and destructive. If the lesions occur in the spine, neurological deficit is not uncommon. Patients are forced to be immobilized if they cannot walk due to lesions in the lower extremities. Anemia and hypocalcemia are some of the medical problems that occur when you have an extensive bone load of tumor. And, with involvement of the upper extremities, they often cannot use external aids that could help them walk. They cannot perform basic daily activities. Sometimes they cannot even do bed-to-chair transfers.
When we look at the primary lesions that most often spread into the bones, by far the most common are breast, lung, and prostate, but thyroid and kidney are also common. I used to say: “No, that does not go to the bone.” However, any cancer has the potential to get into the skeletal system. I have seen squamous cell cancer of the tongue and fallopian tube cancer with bone metastasis. I saw a patient at clinic one day who had pancreatic cancer. She had knee pain, and I was very slow to recognize that she had metastatic disease in the knee because I was just not thinking that pancreatic cancer would be a primary tumor likely to spread that way. When you are working with an older patient who has back pain, and a history of cancer, spine metastases should be considered. Other common sites of metastasis are the pelvis, ribs, skull, and the proximal long bones — something to keep in the back of your mind when you have a positive bone scan in those areas.
When you have a patient who has a lytic lesion or a destructive lesion in the skeleton and you do not know where it is coming from, medical history is the best way to focus your attention on what this might be. The pain pattern is very important. Patients who have cancer — and this goes for primary cancers or metastatic disease of the bone — have pain that is not relieved by anti-inflammatory medications. It is not relieved by rest if they have walked a long way. Cancer pain is constant. It happens at rest and, most importantly, it happens at night. If you have a patient who complains of pain in their extremities that won’t go away, that is something to be concerned about. A physical examination is also important — a routine examination to feel for masses, to feel for tender areas, to check the joint range of motion. Most tumors do not spread into a joint but near a joint, and can cause a joint effusion if it is near the end of the femur, at the upper part of the tibia, or around the shoulder. But generally, a joint effusion is not what we see in these particular patients but rather just pain, tenderness, and an inability to walk, a limp, or holding the arm in a protective fashion. Check for enlarged lymph nodes, and check the possible primary tumor sites. And with an older patient, it’s important to do a breast examination, a thyroid examination, and question the person about blood in the stool, blood in the urine, etc. Plain X-rays of the involved bone and the chest, a whole body bone scan, and a CT scan of the chest, abdomen and pelvis are the major tests used to screen for metastatic disease. We want to find where the primary lesion might be. These particular tests are going to identify almost all patients who have some type of primary cancer. Now, medical oncologists are very interested in using PET scans routinely on patients to try to identify where the disease is and identify if there is spread throughout the body. A biopsy is necessary if it is not obvious that the patient has widespread metastasis from a particular primary site.
Bone scans are not always positive. Bone scans, as you know, involve identifying intensity of bone response, or osteoblastic activity. An incredibly destructive lesion will not show up on a bone scan because it is so lytic that there is no osteoblastic response. And, remember that a negative bone scan does not help rule out multiple myeloma.
Metastases appear two ways on the plain radiographs: osteolytic or osteoblastic. Osteoblastic lesions induce bone formation and can produce sclerotic vertebral bodies. Shown below is a patient with metastatic breast cancer.
Prostate cancer metastasis are nearly always osteoblastic, and you will see dense lesions throughout the pelvis and lower spine. Breast cancer can be a mixed picture; we either see dense bone, or we can see lytic destruction, or we can see a mixed pattern. Much more common are the osteolytic metastases show below.
When you see an area in the bone that has a hole, the process has been underway for quite a while because 50 percent of the bone must be gone before you can notice it on an X-ray. Lung, thyroid, breast, kidney and less often GI and neuroblastoma are other examples. You can imagine that this can cause quite a problem at the level of the hip joint as it becomes weak and the person continues to put weight on it. We see fractures in the femoral neck in both osteoblastic and osteolytic metastasis.
The differential diagnosis of a destructive lesion in a patient over 45 years, then, begins with metastatic bone disease. It is much more common than anything else. Then come myeloma and lymphoma, which also can have lytic destruction. Much farther down the line are the primary tumors. Osteosarcoma, fibrosarcoma, and MFH are not seen very often in an older patient, but we do occasionally see them and they need to be in our memory bank. Then, there are post-radiation sarcomas, Paget’s disease related to sarcoma, hyperthyroidism, and insufficiency fractures.
As for imaging, plain X-rays are still the hallmark of what we use in orthopaedics. We get them in two planes — AP and lateral — and look at the entire bone. If a patient is having knee pain, the pain may be coming from a lesion at the hip, so we image the entire femur. Imaging also may include the bone scan, sensitive at detecting osteoblastic activity, and the MRI scan, which I find useful in evaluating the spine. CTs are getting remarkably better, but I generally do not use a CT scan other than to stage the visceral organs. I do not find it helpful in looking at metastatic bone disease except in the acetabulum. MRI still shows the marrow better than other imaging modalities. It is going to show compression upon the cord and the roots much better than a CT scan.
Shown below, we have a chest CT scan, an abdominal CT that shows a large kidney mass, and a bone scan with widespread metastasis.
Laboratory studies are not as helpful as the radiographs, but certainly need to be checked. We would routinely check the PSA, and we may have indication to check the thyroid function tests. A CBC is helpful because patients with multiple myeloma frequently are anemic; and the SPEP and UPEP, with various immunofluorescence studies to look for myeloma. Patients with renal cell carcinoma can have microscopic hematuria on a urinalysis. Calcium really is important only if it is incredibly high, which would signify later stage disease. Alkaline phosphatase is generally high when you have any type of destructive activity in the bone.
If the staging work-up of metastatic disease shows no primary lesion, it is most likely from the lung or the kidney. That has been borne out by some large studies.
Here are some clinical scenarios. Most commonly what we see in cancer patients who come to the clinic is that they have multiple bone lesions. The diagnosis is not really in question, and we generally are not looking to do biopsies of those bone lesions. More challenging are cancer patients with bone pain and normal X-rays. We need to look a little more carefully if they are complaining of back pain and they have a history of breast cancer. Are we missing a metastatic lesion? Do we need to get an MRI scan? We need to be a little bit more focused with our imaging studies. Some patients have bone pain because they are on Zometa® or they are on thalidomide or other agents that can cause bone pain. So there is not always a destructive lesion.
The other, even more concerning scenario is the patient without any history of cancer, but with a destructive bone lesion. We have to then decide if they have metastatic cancer or if they have a primary tumor, like an osteosarcoma or chondrosarcoma. The treatment from an orthopaedic standpoint, is very different. If you mistreat a primary bone lesion, you can actually compromise the patient’s limb or their life, so indeterminate lesions require a biopsy.
Below is an example of something that was not done well. This is a 72-year-old, three years post-prostatectomy.
There was elevated PSA and left hip pain. There is a lesion that has some matrix in it, and increased sclerosis. The surgeon felt that this, given the history, must be metastatic prostate cancer and so put in a short nail to try to stabilize the area, improve the pain, and decrease the risk of fracture. But, it turned out that this was a dedifferentiated chondrosarcoma. To be cured, a chondrosarcoma has to be resected with wide margins. So the surgeon just spread the tumor cells up and down the femur, and it has gone in through the gluteal muscles, so the patient, in order to have a curative procedure, now requires a hindquarter amputation. That was a mistake.
Biopsies used to be done in the operating room for the most part, but we have now shifted to image-guided needle biopsies. Now it just involves a local anesthetic plus sedation, if necessary. For bone biopsies, patients often need a bit of sedation as it’s not terribly comfortable putting the needle through the bone. Sometimes bone lesions have a very thin cortex or there is a soft tissue mass coming out of the bone, so it is not as uncomfortable. There also are FNA, or fine needle aspirations, and core needle biopsies, which take a bigger piece of tissue. This requires excellent musculoskeletal pathologists and excellent radiologists who are able to put the needle exactly where the lesion is and evaluate the tissue. They do it at JHH under either ultrasound for soft tissue masses, big thigh masses, etc., or they do it under CT guidance for the bones.
It’s important when talking about a biopsy to be certain of the diagnosis. The initial presentation of metastasis requires a complete work-up with biopsy. So, if it is the first time they present, and there is no diagnosis of cancer, you do need a biopsy. You cannot assume that it is a metastasis.
With metastatic cancer, the team approach to care is key. We do not operate in a vacuum. When we take care of cancer patients, we need to be attuned to their nutritional status and metabolic status. Controlling local symptoms is where we come in. The medical oncologists and our colleagues in interventional radiology and radiation oncology — we put our heads together to find what is best for each individual patient. There is no cookie-cutter approach to this because everyone has different needs at home, different activity demands, different projected life spans. There is better systemic therapy now for various cancers and better local control. We now have radioactive isotopes that we can use for bone metastasis, and we have radiofrequency ablation, where interventional radiologists place a probe within a small bone lesion, increase the temperature and basically fry the cancer cells. It is a way to decrease pain in patients, especially those who have not responded to radiation. And we can maintain the structural integrity, either surgically or with bisphosphonates.
From the orthopaedic standpoint, we have to decide when we should try to stabilize a weakened bone. If it’s obvious that a patient needs a surgical procedure to fix a broken bone and allow him to walk, that is not a difficult decision. But prophylactic internal fixation is so much better for the patient. If we have a good sense that a bone is going to break and can “fix” a patient with a rod inside the bone, they will recover more quickly. They have less pain, and can return more quickly to their primary treatment if you can repair the bone before it’s broken. That’s the trick.
You also have to think about the histology of the primary lesion. Someone with prostate cancer is probably less likely to fracture than someone with a large lytic renal cell carcinoma bone metastasis. Co-morbid conditions and predicted lifespan are also very important in deciding whether to take someone into the operating room.
The goals of surgery are primarily to relieve the patient of pain and, ideally, to allow them to get back to their daily activities, to allow them to be full weight-bearing or, at the very minimum, to facilitate nursing care. Therefore, when we decide whether to operate on a patient, the stability of the construct is very important. We have to decide what type of implant to use, taking into account what part of the body it’s going to be used in. We need to make sure that we don’t just fix the top part of the femur but that we fix the entire bone because someone could have a metastasis just below. We almost always stabilize the entire bone, and post-operative radiotherapy is incredibly important. When we stabilize people who have fractures in their skeleton, we are not curing the cancer. We are not even removing the cancer in the majority of cases; we are just stabilizing it. The cancer is still there. After the patient heals from surgery, we treat the patient with 10 days of external beam radiation therapy.
There has been an array of advances in the orthopaedic world: implants that go around the hip or the knee to replace a big segment of bone loss; there’s a cup that we can put in a hip socket, the acetabulum, and a spacer that we can use in the humerus. These have all evolved over time. Biomedical engineering is very active in coming up with new implants, better implants, stronger metals and the like. It used to be that these items were custom-made. You took measurements and told the factory you wanted something, say, 200 millimeters in length. Now it is all off the shelf. It is like building blocks: I need a 70 mm, 30 mm, and a 50 mm segment. And you just put them together in the operating room.
Below is an example of someone who had a renal cancer metastasis to the arm. A surgeon put a rod there, which we do for many cancers, such as breast cancer. But with renal cancer, it tends to continue to grow; medicines and radiation do not work very well.
This continued to get bigger and bigger, and ended up quite large. There’s significant tumor out in the soft tissues. We took out the whole section with the rod and put in a replacement segment at the top (this is the slide you’ve chosen). There was still disease there, but thinking this man was not going to survive very long, the lower humerus was left in so he could have a normal elbow. But he surprised us and continued living far after this procedure, to the point where he actually developed increased disease and an impending fracture. So, we went back in and replaced his entire arm; he has a total humerus replacement. He does not have great shoulder function, but he’s able to flex his elbow to 90 degrees and he seems to be doing quite well.
Sometimes you can actually put in a cadaver bone in combination with a metal prosthesis. We do not use this very often for patients who have a limited lifespan, but more in young people who have primary tumors that we can cure. The cadaver bone comes from the cadaver bone bank with the rotator cuff tendons intact. You can attach the patient’s tendons to those tendons enabling someone to raise their arm. However, it does not make sense to do this in someone who has a limited lifespan because of the lengthy time it takes for the bone to heal.
When you have something in the middle of the humerus, a metal rod, with cement around it can be used. Depending on the particular histology, if it has a chance of progressing, we will go in and scrape out all the gross tumor and fill it with cement. This provides a better construct, and sometimes the tumor is better controlled if you radiate microscopic disease rather than macroscopic disease. In the end of the humerus, down by the elbow, there are not as many good options. We can use flexible nails that go up from the bottom.
We can use plates and screws, but then I might worry about a bone metastasis occurring more proximal in the bone.
Or, if it is right at the elbow joint, we can do a segmental elbow replacement.
The acetabulum is probably the most difficult area we work with. It is a difficult area to reconstruct, and the lesions in this area can be quite large. This is very debilitating to the patient. We have to use three-dimensional imaging before planning surgery to know how much of the bone is destroyed.
Something I did not mention earlier is that thyroid cancer and kidney cancer are so vascular that the patient can die during surgery because of blood loss. When you have a tumor taking up a third of the pelvis, and you are scraping it out to put in your reconstruction, the tumor will continue to bleed because there is no blood vessel you can tie off. Therefore, we send these patients to interventional radiology to have the lesion embolized 24 hours before surgery. That way the blood loss is much more controllable.
Probably the most common area where lesions occur is around the femoral neck or the hip joint. With an elderly patient who has a hip fracture, you have to decide whether it was due to cancer or to osteoporosis. The way we fix these two particular fractures is extremely different, so it is very important to make that differentiation. Usually you can determine this on the X-ray. When patients have a broken hip due to osteoporosis and they come through the emergency room, they usually just get a couple of screws put in their hip, or a plate and screws, and that works. But it doesn’t work for cancer. Those constructs fail for people because the cancer continues to grow. In patients with cancer, we always replace the hip joint or the femoral head.
Technologically, things are evolving. There are new metals, like tantalum, or trabecular metal. It looks like the trabecula of a bone and allows bone ingrowth onto that metal. It is better than the porous coatings we previously used.
We have a couple of different ways to treat spine metastases. We try not to have people have major surgeries if they have limited lifespans. Some of the spine metastases involve the whole vertebral body and can involve taking out an entire segment of the spine. One thing to remember is that treating patients with radiation alone may be appropriate. If they have a progressive neural deficit, and their bone is broken into the canal, we usually do surgery because radiation is not effective. There also are a couple new approaches, called vertebroplasty and kyphoplasty, which involve injecting an acrylic cement to stabilize and reduce pain. You may have seen this technique in patients who have osteoporotic fractures, but there is also a role for these approaches in patients who have spine metastasis, especially multiple myeloma, who frequently have collapse of vertebral bodies. Injecting cement can stabilize the segment and provide pain control. And finally, interventional radiologists can do radiofrequency ablations in small areas around the pelvis to provide pain relief in very sick patients or patients who have not been able to be managed with radiation or maybe are not surgical candidates.
In closing, there are many approaches used in helping patients with metastatic bone disease, with stability and pain management being our primary goal. Each case is individual and care of these patients requires a multidisciplinary team approach.