Osteosarcoma Paleopathology Presentation
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  • Before I get into what osteosarcoma is, I’m doing to have a brief review of what cancer in general is. And then go through an extremely brief history of our knowledge of cancer and review some important terms.Then I will go over what osteosarcoma is, a differential diagnosis, and the clinical perspective.Finally, I will discuss how studying osteosarcoma in the archaeological record can help researchers answer questions about cancer.
  • Cancer is not just one disease, but a group of diseases.Cancer develops when cells in a part of the body begin to grow out of control. There are many, many types of cancer, but they all are a result of uncontrollable growth of abnormal cells. Normal cells grow and eventually die. When they get damaged they die and don’t continue to divide. Cancer cells, on the other hand, continue to form new abnormal cells. Cancer cells develop because of damage to their DNA.
  • Metastasis is when cancer spreads from the part of the body where it developed (called its primary site) to other parts of the body. The malignant tissue then continues to grow in the new area and replaces normal tissue, leading to systemic failure and eventually death.A type of primary bone cancer is what I’ll be focusing on, rather than metastatic cancer. Primary means that it is cancer that starts in the bone.
  • Here’s how the process works. The top of this figure is how cells normally replicate. When the cell gets damaged beyond repair, the cell dies and is replaced by another healthy cell.Cancerous cells have damaged DNA, but they don’t die. They keep dividing and growing and won’t stop. The extra cells form a mass of tissue, which is what creates a tumor.
  • The presence of a tumor doesn’t automatically make it cancer, though.Benign tumors aren’t cancerous, can often be removed, and usually don’t come back after removal. It’s an abnormal growth, but the key difference is that benign tumors do not spread to other parts of the body.Malignant tumors, on the other hand, can invade nearby tissues and spread.Cancer spreads to other tissue through surrounding tissues, the lymph system, or through the blood stream. Malignant cells break off the tumor and enter these bodily systems and that is how metastatic cancers can reach other areas of the body.
  • The history of cancer is actually long. The Greeks were the first to identify the disease.The name “cancer” comes from Greek descriptions. Hippocrates was said to use the word carcinos, which in Greek means crab, to describe the shape of lesions that he saw. The word carcinos lead to the word carcinoma used by the Romans, which is the medical term we still use for malignant tumors of the soft tissue. The word oncos, the basis of the word oncology, also derives from Greece.The Greek and Roman physicians described a number of tumors and swellings researchers now believe were descriptions of cancer.However, there are very few descriptions and most are ambiguous. Carcinoma could have been used to describe any type of swelling, not just tumors. Basically any neoplastic lesion or swollen area of the body might be referred to as cancer in these ancient descriptions.Other descriptions of disease that may be cancer exist in several other cultures, with slightly more definite evidence found in Egypt and Peru. Again, these descriptions were mostly vague and would describe mainly tumors. And it wasn’t until the last 200 years that we started to really notice or understand what cancer was. The word “cancer” is very old, but our scientific understanding of the disease is relatively not.
  • In Egypt, a bunch of preserved medical texts on papyrus were discovered. They were purchased by Edwin Smith in Luxor, Egypt in 1862, and published by Georg Ebers in 1872. These papers date back to around 1538 BCE. In these texts there were stories of a mysterious “eating” disease that would attack bodily organs, with some descriptions of breast and uterine cancer. They contained suggestions for different treatments to prevent the “eating” with spells and fumigation (using gas and smoke). This is actually a picture of the text discussing cancer.The Greeks used surgical treatments, basically just cutting off and cauterizing tumors, and some topical treatments such as honey, burnt lead, calamine, milk, and other available ingredients.As far as we know, traditional treatments such as these would be all that you would have up until the advent of modern medicine. Some physicians in the middle ages, such as John of Arderne and Guy de Chauliac in the 1300s, wrote accounts of mysterious lesions and carcinoma with some possibly quarantining cancer victims when lesions were mistaken for contagious diseases. Later accounts have also been found from the Renaissance and late 1700s, but it was not very well understood. Cancer wasn’t really recognized or specifically acknowledged in most historical documents.
  • It wasn’t until the 1800s that people started to make a connection between tumors and individuals getting sick and dying, and leaps in our scientific understanding of cancer were made around the turn of the 20th century. Campbell Greig De Morgan was a British surgeon that first proposed that cancer started as a tumor and then spread to other parts of the body. He even suggested that cancer can spread through the lymphatic system, which we know to be true today.Theodor Boveri was a German biologist and the first to suggest that cancer has a genetic origin. He suggested that a tumor begins with a single cell in which the chromosomes are somehow damaged, causing the cell to divide uncontrollably.Marie Curie, the famous physicist and chemist, pioneered research on radioactivity. She was the first to use radiation on cancerous cells, and it was in around 1910 that radiation therapy was first used on cancer patients.
  • Now we know a (very) brief history of our understanding of cancer, and we know that cancer results from damaged DNA, but how does DNA get damaged? First, people can inherit damaged DNA, which explains family histories of certain types of cancer.And second there are environmental causes that have been linked to the development of cancer. Such as radiation, viruses, and toxins. Essentially, if it can damage the DNA of cells there may be a risk of abnormal development.However, the direct causes of many types of cancer are still unknown. For example, the causes of osteosarcoma are not known, although some have been hypothesized.
  • What is osteosarcoma?Osteosarcoma is perhaps the most common type of primary bone cancer (cancer that starts in bone cells).But overall primary malignant tumors in bone are rare! With only around 1500 cases reported in the US each year, as opposed to over 1 million new cases of lung cancer (one of the most common types of cancer) each year.Another name for the disease is osteogenic sarcoma. The word sarcoma means that it occurs in the musculoskeletal system (in bone or cartilage).Other cancers that may start in bone include Ewing’s sarcoma and multiple myeloma. Osteosarcoma is more common, accounting for about 40-60% (depending on the source) of primary bone cancers. It also accounts for 7% of juvenile cancers and 19% of all tumors in bone.However, those numbers should give you an idea of how rare bone cancer in general is, if osteosarcoma is the most common and yet only about 1500 new cases are reported each year.
  • Osteosarcoma originates in the growth plate, extending into the cortex of the bone and outward into the soft tissues. Here is an example of the femur with the growth plates outlined. The metaphyseal side would be this side, not the epiphyses.It usually starts in the osteoblasts, which if you remember are the cells that create new bone. Here is a picture of osteoblasts, the black bar is pointing towards them.Again, this type of cancer is a sarcoma, the malignant version of the disease. A chondroma would be the benign version. So if you see “osteochondroma” anywhere, that’s not the same thing.
  • This is sadly a cancer that affects the young, usually kids and teenagers. It is a cancer that is associated with growth periods, and nearly always happens during puberty. Basically what is thought to happen is that during puberty some bone cells are mutated or damaged and when they are activated to grow those cells keep growing and growing and growing and become cancer. That’s the theory based on the very strong association with growth. The exact nature of osteosarcoma is still somewhat mysterious.Males are more often affected, probably because they typically have a longer period of skeletal growth than females.
  • Other risk factors for developing osteosarcoma include radiation therapy. Male teenagers and adolescents that have had past treatment with radiation have an increased risk of developing osteosarcoma. Ironically some anti-cancer radioactive drugs are also a risk factor as well. Genetics may also have an influence. Some genes have been found that might be related, but cancer researchers are still working on definitively finding a genetic relationship.And osteosarcoma has been found in patients with Paget’s disease. In fact, adults with Paget’s can develop this type of cancer. From what I found, osteosarcoma is so rare that in order to develop it as an adult the individual essentially has to have Paget’s (in other words, some sort of growth disorder because of this type of cancer’s strong relationship with skeletal growth).
  • Osteosarcoma is typically associated with certain areas of the skeleton.Most common around the Distal femur,Proximal tibia, and humerus.Around the knee area is most common – 60%Humerus – 10%Proximal femur – 15%Mandible – 8%And this distribution is actually the same in other animals susceptible to osteosarcoma. Mainly the proximal and distal portions of the long bones.Because it is so strongly associated with these areas of the skeleton, a tumor on these areas (mainly around the knee) can be used in differential diagnosis for osteosarcoma.
  • For the diagnosis of osteosarcoma, there needs to be a production of bone where “Osteoblast-like” tumor cells produce calcified tissue.The bone formed by the tumor may appear “sunburst,” which is very indicative of osteosarcoma. If you remember from the neoplasms lectures Dr. Hamilton showed us, that’s the “hair on end” periosteal reaction that makes it looks like spines are shooting out of the bone. The appearance of Codman’s triangle is also diagnostic of osteosarcoma. Codman’s triangle is where in radiographs you can see a triangular area where the periosteum is raised up by a bone tumor.Symptoms for living patients can include intense swelling over a bone, extreme pain, and a pathological fracture. And when osteosarcoma progresses it usually metastasizes to the lungs (oddly enough) and other bones.
  • Of course, there are many, many tumors that are possible in bone. Here is an image that compares an osteosarcoma tumor to other lesions. As you can see, what sets this tumor apart from the others is that it’s around the growth plate, it builds up bone (it’s not a lytic lesion), and it has a “sunburst” shape with a possible Codman’s triangle.
  • After biopsy confirms the presence of osteosarcoma, there are 4 main treatments available. Surgery to excise tumors is the first option if the tumor is localized. This may require amputation, but new surgical techniques have made it so that the bone doesn’t always need to be removed. Generally amputation is reserved for when the cancer has progressed and it’s too late to save the limb. Chemotherapy and radiation therapy are when drugs or radiation are used to kill cancer cells. And samarium is a radioactive drug that targets bone cells specifically, but it kills the bone marrow, requiring a transplant of marrow or stem cells. Obviously you can imagine how all of these options can be traumatic for a child or teenager with osteosarcoma.
  • I’m going to quickly go through how a modern case of osteosarcoma would be identified and treated.We have here a 17 year old male. For about 3 years he noticed a bump near his knee, but ignored the bump for that time. However, the bump started to grow exponentially and he entered the hospital, saying that he now felt extremely intense pain.X-ray and biopsy confirm osteosarcoma. Note the “sunburst” pattern on the radiograph.
  • I have a gross picture here, just to warn you. There was a picture of the actual femur and I wanted to show what it actually looked like after removal, so that’s why I’m including it. But it’s gross. You can really see how big the tumor actually was. That is the distal portion of the femur, and most of that is actually calcified under the tissue. Following this, the patient was fitted with a false metal femur and started on chemotherapy. Luckily today there are many more options for osteosarcoma treatment and amputees.
  • What are the odds of survival with a diagnosis of osteosarcoma? The disease is highly malignant and cause an early death for teenagers. It also progresses very rapidly. As you saw in the case study, the patient had a mysterious bump for about 3 years but it never bothered him. It was only when it started growing out of control that he went into the hospital, and by then it was too late to save the femur but at least it was localized so treatment could be started. Metastasized osteosarcoma can lead to death fairly quickly. The actual rate of survival depends on several factors, the more important being if the cancer cells have metastasized or not. There is generally a 20% 5 year survival rate for those that are treated with surgery alone. That rate goes up to around 70% with chemotherapy is combined with surgery. That 70% rate is compared to around 15% in the 1960s, so it’s become much better for osteosarcoma patients over the past few decades. However, if the cancer has already metastasized at the time chemotherapy starts, then the survival rate drops to about 15-30%. As you can imagine, without these modern treatments and surgery, survival rates would have been extremely low in the past.
  • Now that we’ve talked about the clinical side of cancer, I’m going to move more into archaeology and what osteosarcoma can tell us about the evolution of cancer. There is a popular theory that age at death, diet, and environment contributed to a substantial rise in the incidence of cancer in humans. In other words, the way we live our lives now directly contributed to our current rates of cancer.Cancer rates are associated with age. This is a figure of cancer rates in the Netherlands, but several other charts I found from other countries including the United States looked very similar. I liked this one because it separated out rates by gender, so it’s a bit more information. The X-axis is age, and the Y axis is prevalence (incidence per 100,000 people). As you can see, childhood cancers are extremely rare, and the number of incidences of cancer go up with age. So there is definitely an association with age, which makes sense when you think back to that cell division figure I showed you at the beginning. Errors in DNA can occur during replication. Each time a cell divides there is a risk of something going wrong in the DNA of those cells. Older individuals have had cells that have been dividing for longer, there’s an increased risk of errors in the DNA, and therefore an increased risk of cancer. In past populations, it would make sense that cancer wouldn’t show up as often if life expectancy was lower than it is today.
  • So, knowing that there is that trend, is cancer a “new” disease? There is certainly an increasing incidence rate of cancer today. Cancer in general is the 2nd leading cause of death, with Cardiovascular disease as #1.There are very few definite references in the historical record to cancer. As I went over, there have been some descriptions by the ancient Greeks and Egyptians and some in medieval times, but over all there have been very few accounts and the accounts that do exist are very general and vague. (Was that swelling from a bone fracture or was it we think of as cancer?)So what do the bones say? What has been found in the archaeological record? One researcher counted about 176 cases of probable skeletal malignant neoplasms, primarily metastatic neoplasms (so not osteosarcoma). That’s including all bone tumors. Although, who knows if that includes the more ambiguous neoplasms or tumors from all skeletal collections. It is also generally very difficult to diagnose a neoplasm as malignant with only skeletal remains. Evidence of cancer does exist in animal fossils (I even found one science article where a set of paleontologists claimed to have found osteosarcomatumors in dinosaur bones), non-human primates, there is possibly a Neanderthal case, but it’s debatable, and in modern humans. Some neoplasms of the soft tissue have also been found in mummified tissue in Chile and Egypt. But in general even the most common of benign tumors are rare.
  • By this point you’ve probably wondered why out of all the types of cancer out there I would choose to focus on osteosarcoma. Well, osteosarcoma is important to paleopathology for two main reasons. The first is that it is a cancer of the bone, obviously. Specifically these cancer cells produce bone. Meaning that tumors are likely to last through taphonomic processes.The second reason is that it occurs in young individuals. Meaning it shouldn’t matter that life expectancy was lower in the past, because this is a disease that typically shows up in adolescence. That means that paleopathologists should still be able to find cancer in the archaeological record.Overall, this can help answer questions about the possible evolution of cancer.
  • So what have anthropologists found then? Here are a few examples.Aufderheide and colleagues found a femur in pre-Columbian Peru that was what can be considered a classic case with a sunburst pattern on a femur.Suzuki also found evidence of osteosarcoma on an individual in pre-contact Hawaii.Brothwellfound osteosarcoma around the knee of a young Saxon from southern England way back in 1967, and that diagnosis has apparently held up despite all the changes that paleopathology has gone under over the past few decades.Strouhal and colleagues also found a medieval site in Czech Republic that had crania that were fairly indicative of osteosarcoma. Supporting evidence of osteosarcoma during the middle ages.Overall, there have been possibly diagnoses in Egypt, Peru, and Europe, with one or two cases in other areas of the world. Some of these diagnoses have been debated, but others are most likely osteosarcoma because they fit all of the criteria of being located around the metaphyseal growth plate, producing bone, and having the distinctive “sunburst” pattern.Overall there have been very few cases found. Because most of those cases have been found in association with complex societies (dynastic Egypt, medieval Europe, and ancient Peru) there has been speculation that malignant cancers, such as osteosarcoma, show up more in hierarchical societies. There may be something about environment, population genetics, or class structure that encouraged the development of cancer in those cultures. However, it’s hard to say that, because there have been so few cases found. The fact that there haven’t been many cases has been convincing evidence that cancer was very rare in the past.
  • Remember that osteosarcoma affects young individuals and should show up in the record despite differences in life expectancy. And if that is so, that even cancers like osteosarcoma are extremely rare, then perhaps the increase of cancer that we’re seeing in recent decades is actually more due to our environment (increased exposure to carcinogens!) rather than just living longer.
  • Malignant neoplasms in general are rare in the archaeological record.And osteosarcoma is even more rare, therefore we would probably need thousands of well-preserved skeletons of teenagers in order to have a representative sample of osteosarcoma in a time period. As you recall from our discussions of the Osteological paradox, just because something is not in the archaeological record doesn’t necessarily mean that it didn’t exist. Although most paleopathologists seem convinced that the absence of cancer in collections is still more than what would be expected, we don’t know how representative of a sample the skeletal collections are.And as we have learned throughout the semester, differential diagnosis is improving and in the past diagnostic methods may have not been sufficient to diagnose cancer in osteological remains.And of course there may be insufficient data.Finally, as far as historical records are concerned, in ancient societies not all social classes may have had equal access to doctors and medical treatment, meaning that physicians in the past were not likely to record descriptions of the health of all portions of the population. Also, a lot of records and historical writings that have been said to describe cancer have been dismissed as too vague. But physicians in the past were probably not equipped to understand the influence of a tumor on health or necessarily pay any particular attention to lesions.
  • Cancer is not a “new” disease BUT it was most likely extremely rare for most of our history (although we can’t know that for sure).Even osteosarcoma is rarely found in the archaeological record, despite the fact that bones with the disease should be expected considering that this is not a disease that is associated with old age.Increase in cancer rates is most likely a new concern as a result of not only an increase in life expectancy but also changes in our environment. Historical accounts in this century support this conclusion, because even several decades ago cancer was relatively unheard of. And other evidence, such as the fact that a high prevalence of cancer is not limited to countries with the highest life expectancy rate today and countries with similar life expectancy rates may have completely different cancer rates, plus the type of cancer that is prevalent seems to vary by country for some reason – In other words it’s thought the environment plays a really big role in the development of cancer.
  • Paleopathology has the potential to greatly contribute to the study of cancer.Are environmental causes the reason why cancer is so prevalent today?

Osteosarcoma Paleopathology Presentation Osteosarcoma Paleopathology Presentation Presentation Transcript

  • Osteosarcomain Paleopathology
    Joanna K. Suckling
    Anth5374 · Paleopathology
    April 20, 2011
  • Outline
    What is cancer?
    History
    What is osteosarcoma?
    Diagnosis
    Why look for osteosarcoma in the archaeological record?
    Conclusions
  • What is Cancer?
    The uncontrolled growth of abnormal cells in the body.
    Normal cells  Grow, divide, and die.
    Cancer cells  Grow and divide.
    Develop because of damage to DNA
  • What is Cancer?
    Metastasis
    When cancer cells travels to other parts of the body, grow, and replace normal tissue.
    Primary bone cancer
    When cancer starts in the bone.
  • Cancer in Antiquity
    Greeks first to identify cancer
    Hippocrates “Father of Medicine”
    Descriptions of disease that may be cancer exist in several cultures (Egypt, Peru, etc.)
    Little understanding until the past 200 years
  • Ancient Treatments
    Egypt
    Papyrus Ebers describe spells and fumigation to prevent “eating” of body tissues
    Greece
    Surgical treatments
    Topical treatments
  • History
    Campbell Greig De Morgan (1811-1876)
    Idea that cancer spreads from a tumor to other parts of the body (1871-1874)
    Theodor Boveri (1862-1915)
    Proposed genetic basis of cancer (1902)
    Marie Curie (1867-1934)
    First non-surgical treatment for cancer (~1910)
  • What causes cancer?
    Genetics
    Environment
    Radiation
    Viruses
    Chemicals and toxins
    Anything that can damage DNA!
  • What is osteosarcoma?
    One of the most common malignant neoplasms of bone
    But one of the more uncommon types of cancer
    ~1500 reported each year in the US
    Sometimes known as “osteogenic sarcoma”
    40-60% of primary malignant tumors in bone are osteosarcoma
    7% of adolescent cancers
    19% of all tumors in bone
  • What is osteosarcoma?
    Develops from the metaphyseal growth plate and extends into the bone cortex
    Usually starts in osteoblasts
  • What is osteosarcoma?
    Usually affects juvenile individuals (< 20)
    Occurs during growth periods
    Males more often affected
  • Other Risk Factors
    Radiation therapy
    Medications
    Genetics
    Paget’s disease
  • Diagnosis
    Production of osteoid
    “Osteoblast-like” tumor cells
    “Sunburst”
    Codman’s Triangle
    Swelling over a bone
    Pain
    Pathological fracture
  • Differential Diagnosis
  • Modern Treatment
    Four standard options:
    Surgery
    Chemotherapy
    Radiation therapy
    Samarium
  • Modern Case Study
    17 year old male
    Growing mass on the leg
    Pain
    • X-ray and biopsy confirm osteosarcoma
  • Modern Case Study
    Emergency above knee amputation
    Patient started on chemotherapy
    Image removed
  • Survival?
    Malignant
    Early death
    Bone cells can release hormone-like factors that cause cancer cells to grow faster (American Cancer Society 2008)
    Rate depends on treatment plan and metastasis
    20% survival with only surgery
  • Is cancer a “new” disease?
    Popular theory that age at death, diet, and environment contributed to a substantial rise in the incidence of cancer
  • Is cancer a “new” disease?
    Industrialized nations: 2nd leading cause of death
    Very few references to cancer in antiquity
    Few definite examples in archaeology
    ~176 total?
    Mostly metastatic (not primary sarcoma)
    Evidence of cancer does exist in animal fossils, non-human primates, possibly Neanderthal, and modern humans.
  • Why look for osteosarcoma in the archaeological record?
    Important to paleopathology:
    Produces bone
    Likely to survive!
    Occurs most often in young individuals
    Should appear in populations despite shorter life expectancy
  • Physical Evidence of Osteosarcoma
    Femur found in Peru(Aufderheide et al. 1997)
    Hawaii (Suzuki 1987)
    Europe (Brothwell 1967; Strouhal et al. 1997)
    Possibly Egypt, Spain, Germany, Poland, and France
    Very few cases!
  • The Increase of Cancer Incidence?
    Osteosarcomaaffects young individuals
     Should show up in the record despite differences in life expectancy!
    Perhaps the increase of cancer that we’re seeing in recent decades is more due to our environment rather than solely living longer.
  • But wait…
    Explanations for rarity:
    Osteosarcoma is rare in general
    Lack of sufficient diagnostic methods in the past
    Insufficient data
    In past societies not all social classes may have had equal access to care
    Not all cases recorded or recognized
  • Conclusions
    Cancer has always affected humans
    BUT it was most likely really rare
    (Can’t know that for sure!)
    Osteosarcoma is rarely found
    Increase in cancer rates is most likely a new concern, resulting from increases in life expectancy and changes in our environment
    Historical accounts in this century support this conclusion
  • Conclusions
    … But the debate continues.
    Need more data!
    Better diagnoses
    Paleopathology has the potential to contribute to the study of cancer.
  • References
    American Cancer S. 2008. Bone metastasis : what you need to know-- now. Atlanta, Ga.: American Cancer Society.
    Aufderheide A, Ragsdale B, Buikstra J, Ekberg F, and Vinh TN. 1997. Structure of the radiological "sunburst" pattern as revealed in an ancient osteosarcoma. JOURNAL OF PALEOPATHOLOGY 9:101-106.
    Aufderheide AC. 2003. The scientific study of mummies. Cambridge, UK; New York: Cambridge University Press.
    Boveri T. 2008. Concerning the Origin of Malignant Tumours by Theodor Boveri. Translated and annotated by Henry Harris. J Cell Sci 121(Supplement_1):1-84.
    Bronner F, and Farach-Carson MC. 2009. Bone and cancer. London: Springer.
    Brothwell DR, and Sandison AT. 1967. Diseases in antiquity; a survey of the diseases, injuries, and surgery of early populations. Springfield, Ill.: C.C. Thomas.
    Capasso LL. 2005. Antiquity of cancer. International journal of cancer Journal international du cancer 113(1):2-13.
    Dorfman HD, and Czerniak B. 1998. Bone tumors. St. Louis: Mosby.
    Halperin EC. 2004. Paleo-Oncology: The Role of Ancient Remains in the Study of Cancer. Perspectives in Biology and Medicine 47(1):1-14.
    Mirabello L, Troisi RJ, and Savage SA. 2009. Osteosarcoma incidence and survival rates from 1973 to 2004. Cancer 115(7):1531-1543.
  • References
    Mould RF. 1998. The discovery of radium in 1898 by Maria Sklodowska-Curie (1867-1934) and Pierre Curie (1859-1906) with commentary on their life and times. The British journal of radiology 71(852):1229-1254.
    Ortner DJ. 2003. Identification of pathological disorders in human skeletal remains. Amsterdam; London: Academic.
    Pinhasi R, and Mays S. 2008. Advances in human palaeopathology. Chichester, England; Hoboken, NJ: John Wiley & Sons.
    Roberts CA, and Manchester K. 2007. The archaeology of disease. Ithaca, N.Y.: Cornell University Press.
    Strouhal E, Vyhnanek L, Horackova L, Benesova L, and Nemeckova A. 1997. A Case of Osteosarcoma in a Late Medieval-Early Modern Skull from Kyjov (Czech Republic). INTERNATIONAL JOURNAL OF OSTEOARCHAEOLOGY 7(1):82-90.
    Suzuki T. 1987. Paleopathological study on a case of osteosarcoma. American journal of physical anthropology 74(3):309-318.
    http://www.cancer.gov/cancertopics/pdq/treatment/osteosarcoma/patient
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