Bone tumors: Pathology review

Definitions & Key takeaways

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

Chapters:

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Case Study0:00–1:12

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.

Physiology1:12–2:19

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.

Pathology2:19–2:54

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.

Osteochondroma2:54–3:57

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.

Giant Cell Tumor3:57–4:43

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.

Osteoblastoma and Osteoi4:43–6:01

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.

Osteoma6:01–6:29

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.

Chondroma6:29–6:48

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.

Osteosarcoma6:48–8:25

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.

Ewing Sarcoma8:25–9:53

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.There’s also chondrosarcoma which tends to affect the elderly.

Chondrosarcoma9:53–10:10

Chondrosarcoma arises from mutated chondrocytes, and mainly affects the medullary cavity of the bones of the pelvis, but can also affect long bones, like the humerus and proximal femur.Regarding symptoms, bone tumors, especially osteosarcomas, commonly cause local symptoms like bone pain, swelling due to inflammation or the tumor growing in size, decreased range of motion, and pathologic fractures.

Symptoms10:10–11:07

Some unique symptoms are the pain in osteoid osteoma, which typically gets worse at night and improves with NSAIDs, while osteochondromas and osteoblastomas sometimes press against spinal nerves, causing numbness and limb weakness.
Additionally, they can cause avascular necrosis of the bone if the tumor starts pressing on a major blood vessel, which can worsen symptoms.
Malignant tumors tend to cause a chronic inflammatory response which leads to fever, night sweats, and weight loss. Bony tumors often metastasize to the lungs, so in that setting, there can be pulmonary symptoms like coughing and shortness of breath as well.
The diagnosis of bone tumors starts with medical imaging, with some tumors having a few classic X-ray findings that’s very high yield.

Diagnosis11:07–12:21

For example, osteochondroma causes exostoses, giant cell tumor forms multicystic bone lesions that look like soap bubbles, and osteoid osteoma is typically seen as a bony mass under 2 centimeters with a radiolucent core.
Osteosarcoma form lytic bone lesions, referred to as a sunburst appearance, because the radiating tumor streaks look like sun rays, or can cause the periosteum to lift, appearance which is called Codman’s triangle.
In Ewing sarcoma, X-ray shows lytic bone lesions referred to as onion skin appearance because the periosteum looks like a sliced onion bulb.
In chondrosarcoma, there are patchy lytic lesions that make the bone look like a “moth-eaten” piece of cloth. When radiographic findings raise suspicion for bone malignancy, laboratory studies like urinalysis, erythrocyte sedimentation rate, liver function testing, blood urea nitrogen, and creatinine level should be obtained to evaluate other systems and to look for signs of metastasis.Treatment depends on whether the tumor is malignant or benign.

Treatment12:21–12:38

Symptomatic benign tumors can be surgically removed to reduce pain and the risk of fractures, while malignant tumors are treated with radiotherapy, chemotherapy, and surgery, depending on the type and spread of the tumor.Now a final disorder that can cause bone tumors is multiple myeloma, which is the most common primary bone tumor in people 40-50 years.

Multiple Myeloma12:38–17:20

Multiple myeloma is a cancer of plasma cells in the bone marrow. Plasma cells start their journey as B lymphocytes in the bone marrow, which move to the lymph nodes where they mature into antibody-secreting plasma cells.
When this happens, adhesion molecules stimulate myeloma cells to migrate to the bone marrow and adhere to bone marrow stromal cells and the extracellular matrix.
This, in turn, stimulates bone marrow stromal cells to release cytokines, which promote osteoclast activity and impair osteoblast formation, resulting in bone destruction and hypercalcemia.
Another way myeloma cells cause damage is by secreting excess IgG or IgA, which have both a heavy and light chain. More rarely, the myeloma cells can only make the kappa or lambda light chains, and in that situation, the resulting protein is called the Bence-Jones protein, which can be a key clue on your exams!Now, a high yield concept is the clinical presentation of multiple myeloma, which can be summarized with the mnemonic CRAB.
“C” is for hypercalcemia, which results from increased osteoclast activity. Your exams might not just give you the lab finding, but instead give you some symptoms of hypercalcemia, such as abdominal pain, psychiatric changes, constipation or fatigue.
Okay, “R” is for renal disease, which can be caused by multiple mechanisms. First, the light chains can deposit in and obstruct the renal tubules, and this is called light chain cast nephropathy or myeloma kidney.
A second cause is type two renal tubular acidosis, or even hypercalcemia which may cause the formation of calcium phosphate kidney stones.
Third is by primary amyloidosis. In this type of amyloidosis, the immunoglobulin light chains leave the circulation and abnormally aggregate in various tissues, resulting in various clinical manifestations.
These include restrictive cardiomyopathy, a large tongue, also called macroglossia, and nephrotic syndrome to name a few.
“A” is for anemia, which causes fatigue and shortness of breath. Anemia occurs because the malignant cells infiltrate the bone marrow, and proliferate, crowding out the normal cells that form components of the blood.
Finally, “B” is for bone pain, which is due to increased osteoclast activity causing pathologic fractures and lytic bone lesions.
So, in your exams, look for an elderly individual with symptoms of anemia and chronic back pain. Other manifestations include spinal cord compression if the tumor infiltrates from the vertebrae, and frequent infections, because the immunoglobulins secreted by myeloma cells are not functional immunoglobulins and so they are not useful in fighting infections.
Also remember that a workup for multiple myeloma includes a complete blood count, which often shows normocytic normochromic anemia, and a peripheral smear, which can show a rouleaux formation due to IgG proteins attaching to red blood cell membranes, and then connecting with other red blood cell membranes, making the red blood cells stick to one other, causing them to look like a stack of coins.
Additionally, serum calcium levels, blood urea nitrogen, uric acid, and creatinine concentrations may be elevated. Serum and urine protein electrophoresis, or SPEP and UPEP, respectively, are important to see which M protein is predominantly being produced, and is seen as an M-spike.
SPEP detects most multiple myeloma patients that predominantly make IgG, followed by IgA, while UPEP is used to detect the minority of multiple myeloma individuals, who only make the Bence-Jones protein.
UPEP is needed because these light chains are rapidly filtered from the blood, so they may not be seen on SPEP. Next, beta-2 microglobulin, a component of the major histocompatibility class 1 antigens found on all nucleated cells, can be shed in the serum.
This is why it’s serum levels are checked in multiple myeloma, because the higher beta-2 microglobulins are, the higher the severity of the disease.
Then, a skeletal radiographic survey should be done to look for “punched out” lytic lesions, which are a classic finding you should remember!
Finally, another high yield fact is that a bone marrow aspiration and biopsy must be obtained, to look for more than 10% plasma cells which infiltrate into the bone marrow.
These plasma cells tend to give off a “fried egg” appearance.Alright, as a quick recap... benign tumors include osteochondroma which presents with exostoses; giant-cell tumor which has giant cells and looks like soap bubbles on X-ray; osteoid osteoma, characterized by a nidus less than 2 cm with a radiolucent core; osteoblastoma, whose nidus is greater than 2 cm; osteomas which consist primarily of well-differentiated mature, compact or trabecular bone, and chondromas which are benign tumors of cartilage, with a lobular growth pattern.

Review17:20–18:57

The primary malignant tumors include osteosarcoma, which is made of large pleomorphic cells and has a sunburst appearance on X-ray; Ewing sarcoma that has round blue cells, and a sliced onion appearance on X-ray; and chondrosarcoma which has large multinucleated chondrocytes and a moth-eaten appearance on X-ray.
Among the more important mutations, osteosarcoma is linked to RB1 and TP53 gene mutations, while Ewing sarcoma is thought to arise when there are EWSR1, and FLI1 genes mutation.
There’s also multiple myeloma, which is a cancer of plasma cells that cause bone destruction secondary to cytokine release.
Clinical presentation can be summarized with the mnemonic CRAB. “C” is for hypercalcemia, “R” for renal disease, “A” for anemia, and “B” is for bone pain.
A skeletal radiographic survey can show “punched out” lytic lesions and bone marrow biopsy can show more than 10% plasma cells with a “fried egg” appearance.Now, back to our cases.

Summary18:57–19:55

James is 14 years old and presents with rather nonspecific complaints like right knee pain, night sweats, and weight loss without any history of local trauma.
Examination shows a swollen right knee and a hard mass on the distal part of the right femoral metaphysis, which was accompanied by a sunburst appearance and Codman's triangle on x-ray.
Now, given his age, symptoms, and typical x-ray findings, we can assume that James has osteosarcoma. William, who is 22 years old, also presents with a chronic history of pain, this time along his left tibia, a problem which is worse at night but responsive to NSAIDs.
Examination revealed a bony mass on the anterior surface of the left tibial metaphysis, which was confirmed by an X-ray scan showing small lesion under 2 centimeters with a radiolucent core.
Giving the specific features of his age, his pain and tumor location, we can assume William’s diagnosis
Bone tumors: Pathology Review: Video and Anatomy | Osmosis