Skip to content

Bone tumors: Pathology review



Musculoskeletal system


Pediatric musculoskeletal conditions
Musculoskeletal injuries and trauma
Bone disorders
Joint disorders
Muscular disorders
Neuromuscular junction disorders
Other autoimmune disorders
Musculoskeletal system pathology review

Bone tumors: Pathology review


0 / 9 complete

USMLE® Step 1 style questions USMLE

9 questions

A 67-year-old man comes to the clinic due to progressive fatigue and back pain over the past few months. Initially, the patient attributed the pain to strenuous work in the garden but decided to seek care when he noticed no improvement. The patient also noted a 10 lb (4.5 kg) weight loss without changes in his diet. Medical history is significant for smoking 1 pack of cigarettes per day for 35 years and diabetes mellitus type 2. Laboratory values are obtained and shown below:  

 Laboratory value  Result 
 Hemoglobin  11.2 g/dL 
 Mean corpuscular hemoglobin   90 fl 
 Creatinine   2.3 mg/dL 
 Total protein  9.5 
 Albumin  3.2 g/dL 
 Sodium   132 mEq/L 
 Potassium   4.2 mEq/L 
 Chloride   95 mEq/L 
 Calcium  12 mg/dl  

Radiograph of the spine reveals multiple areas of hyperlucency at the lumbar and thoracic regions. Which of the following is the most likely underlying cause? 


Content Reviewers:

Yifan Xiao, MD

While doing your rounds, you see two individuals. First is James, a 14-year-old boy who came in for chronic right knee pain, night sweats, and weight loss. He didn’t report falling or any other trauma to the region or any additional symptoms. On examination, his right knee is slightly larger than the left and, on palpation, a hard mass can be felt on the metaphysis of his right femur, close to the knee region. Then you see William, who’s 22 years old and complains of a 1-month history of bone pain along his left tibia, a problem which is worse at night. One interesting observation he made was that the pain responds well to Ibuprofen, a nonsteroidal anti-inflammatory drug. On examination, palpation reveals a bony mass on the anterior surface of the left tibial diaphysis. As expected, X-ray scans were obtained. They showed a distal sunburst appearance and Codman's triangle in James’ right femur, whereas William’s x-ray scans detected a small lesion under 2 centimeters with a radiolucent core on the anterior surface of his left tibia.

Now, both seem to have some type of bone tumor. But first, a bit of physiology. Even though the bones vary in size and shape, all bones are made of the same types of cells, and chief among them are osteoblasts which build up new bone, and osteoclasts which help with bone breakdown or resorption. Now in addition to these, there are some more primitive cells in the bone marrow called human mesenchymal stem cells and neuroectodermal cells, which can differentiate into many cell types including nerve, fat, bone, and cartilage cells. In terms of anatomy, looking at a long, bone like the femur, it has two epiphysis, which are the ends that contribute to joints with other bones. Between the two epiphyses, is the diaphysis, also called the bone shaft. In children and adolescents, there is an additional narrow portion between the epiphysis and the diaphysis called the metaphysis. The metaphysis contains the growth plate, the part of the bone that grows during childhood. In adults, the growth plate has ossified and fused with the diaphysis and the epiphysis.

Bone tumors form when bone cells divide uncontrollably and forms a mass or tumor. If the tumor remains confined and doesn’t spread into surrounding tissues, then it’s considered benign. But if the tumor invades into surrounding tissues and metastasizes or spreads through blood or lymph, then it’s considered malignant. Malignant tumors can either be primary which is when they arise from the bone cells, or secondary, which is when a tumor developed somewhere else in the body, like the breast, prostate, lungs, thyroid, and the kidneys, metastasized and spread to the bones.

So, let’s start with benign bone tumors. The most common one is osteochondroma, and it commonly affects males under age 25. Osteochondroma is thought to arise from the growth plate tissue, and it’s caused by mutations in the Exostosin 1, or EXT1 and Exostosin 2 or EXT2 genes. These genes encode proteins with the same names that help synthesize heparin sulfate, which regulates growth plate, growth. So, as a result, osteochondroma typically develops as a lateral bony projection, which contains a marrow cavity that is continuous with that of the underlying bone. This bony stalk is called an exostosis, and it has a cap, made mostly of hyaline cartilage. Now, given their growth plate origin, a high yield fact is that osteochondromas typically develop in the metaphysis of long bones, usually the distal femur and the proximal tibia. This type of tumor can sometimes undergo malignant transformation into chondrosarcoma, but this is uncommon.

Another benign tumor is the giant-cell tumor of the bone, more common in those 20 to 40 years old. The tumor consists of reactive osteoclasts-like cells, which have numerous nuclei, typically over 50, and of neoplastic mononuclear cells that express RANKL, a receptor that mediates osteoclast formation, differentiation, and survival. A well-known risk factor is having bon trauma like a fracture or radiation exposure. Now, this tumor typically arises in the knee region, in the epiphysis of the long bones, like the distal femur and the proximal tibia. And although it rarely becomes malignant, it is still considered a locally aggressive benign tumor.

Next we have osteoblastoma, which is more common in males, and osteoid osteomas, which is also more common in males, but it’s more frequent in those under 25 years of age. A high-yield concept is that both of these tumors arise from osteoblasts and they form a nidus, which is a disorganized mix of small blood vessels, tiny rods of bone called trabeculae, and unmineralized bony tissue called osteoid. In osteoblastomas, the nidi are larger, with a diameter of over 2 centimeters. In osteoid osteomas, the nidi are smaller than 2 centimeters in diameter and are often surrounded by a ring of sclerotic bone tissue. That ring of sclerotic tissue often produces prostaglandins, which are small molecules that trigger the sensation of pain. This explains why nonsteroidal anti-inflammatory drugs or NSAIDs that decrease prostaglandin production work so well in relieving the pain associated with this tumor. In contrast, in osteoblastoma, pain is unresponsive to NSAIDs. Osteoblastomas also tend to affect the vertebrae, where they cause bone erosion, whereas osteoid osteomas typically affect the cortex is of long bones like the tibia, and don’t usually erode the surrounding bone.

Osteomas are benign tumors that typically affect middle aged people. They consist primarily of well-differentiated mature, compact or trabecular bone and are typically found on the surface of facial bones. Something else interesting about them is that they are associated with Gardner syndrome, which is an autosomal dominant form of polyposis characterized by multiple polyps in the colon together with tumors outside the colon. Malignant transformation has not been reported in these tumors.

And, finally, chondromas are benign tumors of cartilage, with a lobular growth pattern. They arise from cells called chondrocytes, which produce and maintain the cartilaginous matrix, and are typically located within the medullary cavity of the small bones of the hands and feet.

Now, switching to malignant tumors. Remember that malignant metastasis to the bones are much more common than primary bone tumors; they have a predilection for the axial skeleton. For primary malignant bone tumors, osteosarcoma is the most common, accounting for around 20% of all bone cancer cases, especially in males under 20 years. It is not as prevalent in older individuals, where it usually develops secondary to predisposing factors, like Paget disease of bone, which is a condition where there’s abnormal bone remodeling; bone infarcts; familial retinoblastoma which is a childhood malignant tumor of the eye; and Li-Fraumeni syndrome, a condition in which there are a variety of cancers throughout the body. Osteosarcomas arise from osteoblasts, and the neoplastic cells are often different sizes, called pleomorphic, and they produce too much osteoid tissue. Some high-yield mutations associated with these pleomorphic osteoblasts include mutations in the pRB protein, also seen in familial retinoblastoma, and the p53 protein, which is also seen in Li-Fraumeni syndrome. Location-wise, the tumors often form in the metaphysis of long bones, especially in the knee region, because the cells there divide constantly. Osteosarcoma is very aggressive, with primary tumors having a better prognosis because they usually respond to treatment, whereas secondary osteosarcomas have much more reserved prognosis because they don’t typically respond well to chemotherapy or surgery.

Another type of malignant bone tumor is Ewing sarcoma, which is common in male caucasian adolescents under 15 years of age. Origin-wise, there is still some debate, but most seem to think the tumor arises from either neural crest cells or mesenchymal cells. Regardless of their origins, these malignant cells look like small, round, blue cells that resemble lymphocytes on microscopy, which is why Ewing's sarcoma needs to be differentiated from conditions with similar cells, like lymphoma and chronic osteomyelitis. Ewing sarcoma is associated with chromosomal mutations, specifically a translocation between the FLI1 gene on chromosome 11 and EWSR1 gene on chromosome 22. The EWSR1/FLI1 fusion results in the expression of an abnormal protein called the EWSR1/FLI1 fusion protein or simply the Ewing sarcoma protein. This protein causes defects in the differentiation process of human mesenchymal stem cells and neuroectodermal cells, resulting in Ewing sarcoma tumor cells. Ok, so the preferred location of this type of tumor is the diaphysis of long bones and the pelvic flat bones, especially the femur and the sacrum. Like most malignant tumors, Ewing's sarcoma is aggressive, resulting in early metastases, but the good news is that it responds well to chemotherapy.


Bone tumors can be either benign (non-cancerous) or malignant (cancerous), and can occur in any bone in the body. Bone tumors may be caused by several different factors, including genetics, infection, trauma, and exposure to radiation or certain chemicals.

Benign bone tumors include osteochondroma, giant-cell tumor, osteoid osteoma, and osteoblastoma. Malignant bone tumors include osteosarcoma, Ewing sarcoma, and chondrosarcoma

  1. "Robbins Basic Pathology" Elsevier (2017)
  2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
  3. "The WHO classification of bone tumors" Recent Results Cancer Res (1976)
  4. "Osteosarcomas of flat bones in adolescents and adults" Cancer (2000)
  5. "The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging" CA: A Cancer Journal for Clinicians (2017)
  6. "Bone scintigraphy and the added value of SPECT (single photon emission tomography) in detecting skeletal lesions." Q J Nucl Med (2001)
  7. "Principles and Practice of Pediatric Oncology" Lww (2015)
  8. "Benign tumours of the bone: A review" Journal of Bone Oncology (2015)
  9. "BENIGN BONE TUMORS AND TUMOR-LIKE BONE LESIONS: TREATMENT UPDATE AND NEW TRENDS" Revista Brasileira de Ortopedia (English Edition) (2009)
  10. "Malignant bone tumors" Instr Course Lect (2008)
  11. "Bone tumors: osteosarcoma and Ewingʼs sarcoma" Current Opinion in Pediatrics (2009)
  12. " Pathobiology and Diagnosis of Multiple Myeloma" Semin Oncol Nurs. (2017)
  13. "Multiple myeloma: from diagnosis to treatment" Aust Fam Physician (2013)