Introductory Course

  1. Welcome to our Bone Tumor Pathology site
  2. Approach to Bone Tumor diagnosis - Back to Basics
    1. General considerations
    2. Relevant clinical information
    3. Radiological correlation
    4. General histologic assessment of the lesion.

Welcome to our Bone Tumor Pathology site

Bone tumors represent a unique group of pathologic conditions for which little time is assigned during the training period in most Pathology residency programs.
This website is created to introduce trainees in Pathology to the basic concepts in diagnosis of bone tumors. It is structured to walk you through this difficult field in a stepwise manner by which you will familiarize yourself with the various common skeletal tumors and tumor-like conditions.
At this site you will find:
  • Overview of clinical, radiological and pathologic findings, characteristic of common bone tumors
  • Case studies with relevant radiological and pathologic images
  • Learn the importance and application of a combined clinico-radiologic-pathologic approach to Bone Tumor diagnosis.
Due to the limitations posed by the format of an online tutorial, the lesions discussed here are only those that are most common, and those that may present serious diagnostic difficulties. Obviously, the site is not meant to be all-inclusive and only serves a simple purpose of getting you started. For detailed information we would refer you to the following texts, which were used as sources for this website:
  1. Dorfman HD, Czerniak B: Bone Tumors. Mosby, Inc.1998
  2. Helliwell TR: Pathology of Bone and Joint Neoplasms. Philadelphia, WB Saunders Co.1999
  3. Mirra JM: Bone Tumors: Clinical, Radiologic and Pathologic Correlations. Philadelphia, Lea & Febiger 1989
  4. Fechner RE, Mills SE: Tumors of the Bones and Joints. Washington, DC: Armed Forces Institute of Pathology; 1993. Atlas of Tumor Pathology; 3rd series, No.8
  5. McCarthy EF, Frassica FJ: Pathology of Bone and Joint Diseases. Philadelphia, WB Saunders Co. 1998
  6. Unni KK(ed): Dahlin's Bone Tumors, 5th ed. Philadelphia, Lippincott-Raven 1996

Please read through the Introductory Course before moving on to the Case Studies section. Unknown Slides section (quiz) is available if you wish to test your knowledge. There is also a Search option, if you need to look up a specific entity.
We are glad to have you here, and we would appreciate your comments and suggestions. Good luck!

Approach to Bone Tumor Diagnosis

General Considerations:

Bone Tumors can be divided into primary and secondary. Secondary tumors can be further subdivided into
  • Metastatic tumors
  • Tumors resulting from contiguous spread of adjacent soft tissue neoplasms
  • Tumors representing malignant transformation of the pre-existing benign lesions.
Metastatic cancers are the most frequent malignant tumors found in bone. They are by far more common than primary bone tumors and are characterized by the following:
  • Predominant occurrence in two age groups: adults over 40 years of age and children in the first decade of life.
  • Multifocality and predilection for the hematopoietic marrow sites in the axial skeleton (vertebrae, pelvis, ribs and cranium) and proximal long bones. Metastases to long bones distal to the elbows and knees are unusual. Metastases to the small bones of the hands and feet are even rarer. Occasionally, metastases may appear as solitary lesions (particularly true for the lung, kidney and thyroid cancer).
Most common malignancies producing skeletal metastases:
Adults More than 75% of skeletal metastases originate from carcinomas of the prostate, breast, kidney, and lung. Also common are metastases from thyroid and colon cancers. And do not forget melanoma.
Children Neuroblastoma, rhabdomyosarcoma, and retinoblastoma
Radiographic appearance of the metastatic tumors can be
-Purely lytic (kidney, lung, colon, and melanoma)
-Purely blastic (prostate and breast carcinoma)
-Mixed lytic and blastic (most common appearance)
Primary bone tumors are characterized by the following:
  • Predominant occurrence in the first 3 decades of life, during the ages of the greatest skeletal growth activity. The commonest sites for many primary tumors, both benign and malignant, are in the distal femur and proximal tibia, the bones with the highest growth rate.
  • Relatively specific radiographic presentations. In some cases, the diagnosis can be confidently made based on the radiographic features alone.
  • Benign tumors are by far more common than malignant ones. Some of them are not true neoplasms, but rather represent hamartomas (eg., osteochondroma). The most common benign tumors are osteochondroma, non-ossifying fibroma, and enchondroma.
  • Some primary bone tumors are difficult to classify as benign or malignant. For example, giant cell tumor of bone is very aggressive locally but only rarely metastasizes.
  • Among primary malignant neoplasms, osteosarcoma and multiple myeloma have the highest incidence, followed by chondrosarcoma and Ewing's sarcoma.
Two important features of bone tumors:
  • The ability of some to dedifferentiate (eg., enchondroma or a low-grade chondrosarcoma transforming into a high-grade sarcoma)
  • Tendency of high-grade sarcomas to arise in damaged bone, at the sites of bone infarcts, radiation osteitis and Paget's disease.

Relevant clinical information
 AGE (probably the most important clinical clue).
Age group Most common benign lesions Most common malignant tumors
0 - 10 simple bone cyst
eosinophilic granuloma 		Ewing's sarcoma
leukemic involvement
metastatic neuroblastoma
10 - 20 non-ossifying fibroma
fibrous dysplasia
simple bone cyst
aneurysmal bone cyst
osteochondroma (exostosis)
osteoid osteoma
osteoblastoma
chondroblastoma
chondromyxoid fibroma 		osteosarcoma,
Ewing's sarcoma,
adamantinoma
20 - 40 enchondroma
giant cell tumor 		chondrosarcoma
40 & above osteoma metastatic tumors
myeloma
leukemic involvement
chondrosarcoma
osteosarcoma (Paget's associated)
MFH
chordoma
Summary: Primary osteosarcoma and Ewing's sarcoma are tumors of children and young adults. Occurrence of chondrosarcomas in children or Ewing's sarcoma in middle-aged patients is extremely unusual. In individuals older than 40 years, the commonest form of skeletal malignancy is metastatic cancer. Of the primary bone tumors in this age group, multiple myeloma and chondrosarcoma are most commonly encountered. Osteosarcomas in this age group are often secondary malignancies, which develop at the the sites of bone damage. Giant cell tumor, a locally aggressive lesion, almost exclusively occurs in skeletally mature patients, 20 to 50 years of age, with closed epiphyses. It is practically never seen in children or patients older than 60 years.
 PAIN  (although a non-specific symptom, it may help in differential diagnosis). Generally, benign non-growing lesions tend to be asymptomatic and represent incidental findings. Pain may be a symptom of:
  • Growing lesions. This category includes locally aggressive lesions (eg., aggressive osteoblastoma and GCT), and malignant tumors
  • Pathologic fracture complicating either benign or malignant tumor
  • Significant local tissue reaction to the tumor.

    The following clinical symptoms are worth remembering since they may help in the differential diagnosis:
    • Osteoid osteoma - small lesion, but highly irritative to adjacent tissues and typically causes intense night pain relieved by non-steroidal anti-inflammatory drugs. Osteoid osteomas may also occur close to the articular surface of a joint, causing severe inflammatory synovitis, which often obscures the presence of the tumor.
    • Enchondroma vs. chondrosarcoma, grade 1 - histologically, the distinction between a grade 1 chondrosarcoma and an enchondroma is extremely difficult, as histologic features overlap considerably. The distinction is based on the behavior of the lesion. One of the clues to clinical behavior is the presence of pain. Low-grade chondrosarcoma is a growing tumor and, therefore, presents with pain. Enchondromas tend to be asymptomatic, unless associated with a pathologic fracture.
 MULTIPLE LESIONS  Although both benign and malignant tumors may be multifocal, benign lesions tend to show symmetrical distribution.

Radiological Correlation
The following imaging studies are commonly used in evaluation of bone tumors:
PLAIN RADIOGRAPH is usually the first imaging technique for a suspected bone lesion since it is inexpensive and easily obtainable. It is also the best for assessment of general radiological features of the tumor.
COMPUTER TOMOGRAPHY is a method of choice when plain film assessment is difficult owing to the nature of the lesion (eg., permeative pattern of destruction) or anatomic site (eg., sacrum). In addition, CT is the best technique in assessment of matrix mineralization, cortical detail, and detection of the cystic and fatty lesions.
MRI is a method of choice for local staging. It is superior to CT in the definition of medullary and extracortical spread and of the relationship of the tumor to critical neurovascular structures. However, remember that the MRI appearances of the majority of bone tumors are totally non-specific. You need to examine plain films or CT films to define a neoplasm.
BONE SCINTIGRAPHY is a highly sensitive but relatively non-specific technique. Its main role is in detection of suspected metastases in the whole skeleton. It may also be helpful in the detection of osteoid osteomas ("double density sign" is present in about 50% of cases and is highly suggestive of this tumor).
Radiographic examination should answer the following questions:
  • What is the precise location of the lesion (type of bone and, if the long bone is affected, where exactly the lesion is centered - cortex or medulla; epiphysis, metaphysis or diaphysis)? Some tumors almost exclusively occur at specific sites; many oth ers favor certain locations.
  • Is there any evidence of underlying bone abnormality (eg., bone infarct, Paget's disease)? High-grade sarcomas tend to arise in damaged bone.
  • Is the lesion multifocal?
  • Does the tumor have a well-defined margin? Is there a rim of sclerotic bone? The presence of a well-defined margin and a sclerotic rim strongly suggests a benign non-growing lesion.
  • Is there evidence of significant cortical expansion or destruction? These findings are seen with locally aggressive or malignant tumors.
  • Is there an associated periosteal reaction and, if so, of what type? See discussion below.
  • Does the lesion produce mineralized matrix (osteoid or cartilage)?
  • Is there a soft tissue mass?
In many cases, the radiographic appearance of the lesion provides clues to its clinical behavior. It allows estimation of tumor growth rate and discloses expansive or infiltrative growth patterns characteristic of locally aggressive and malignant tumors.
 SKELETAL LOCATION  (while many lesions favor certain bones, some tumors almost exclusively occur at specific sites)
Lesions Most common skeletal sites
Ewing's sarcoma
Multiple myeloma
Leukemia/lymphoma
Metastatic cancers
 Hematopoietic marrow sites in the axial skeleton (vertebrae, ribs, sternum, pelvis, cranium) and proximal long bones (femur, humerus)
Non-ossifying fibroma Metadiaphyseal regions of the tibia and distal femur (80%) Does not occur in the flat bones, craniofacial bones, the spine, or the small bones of the hands/feet.
Simple bone cyst The vast majority of SBCs is found in the proximal humerus (55%) and proximal femur (20%).
Chordoma Base of the skull or sacrum (90%)
Adamantinoma Mid-shaft of tibia (90%), jaw bones
Chondroblastoma Long bones (knee area, proximal humerus)-70%
Giant cell tumor Knee area, distal radius (65%)
Enchondroma Small bones of the hands and feet (60%). This is in fact the commonest tumor at these sites.
Chondrosarcoma (primary, and to the less extent secondary) Tends to develop in the axial skeleton with 25% to 30% occurring in the pelvic bones
Fibrous dysplasia Femur, tibia, skull and ribs
Osteochondroma Knee area, proximal humerus, pelvis
Osteoblastoma Spine (30%), mandible, long bones
Aneurysmal bone cyst Any bone; common in the spine
Chondromyxoid fibroma Knee area (30%), pelvis, small bones of the feet
Hemangioma Spine, craniofacial bones
 SITE OF LONG BONE INVOLVEMENT 
(most primary bone tumors have favored sites within long bones; this may provide a clue to diagnosis).

Bone Contour
Epiphyseal lesions:
Chondroblastoma (Ch) and Giant Cell Tumor (GCT) are almost invariably centered in the epiphysis. Chondroblastoma is a rare tumor seen in children and adolescents with open growth plates. GCT is the most common tumor of epiphyses in skeletally mature individuals with closed growth plates. GCT often shows metaphyseal extension.
Metaphyseal intramedullary lesions:
Osteosarcoma is usually centered in the metaphysis. Chondrosarcoma and fibrosarcoma often present as metaphyseal lesions. Osteoblastoma, enchondroma, fibrous dysplasia, simple bone cyst, and aneurysmal bone cyst are common in this location.
Metaphyseal lesions centered in the cortex:
Classic location for a non-ossifying fibroma (NOF). Also, a common site for osteoid osteoma.
Metaphyseal exostosis:
Osteochondroma
Diaphyseal intramedullary lesions:
Favored location for Ewing's sarcoma, lymphoma, myeloma. Common for fibrous dysplasia and enchondroma.
Diaphyseal lesions centered in the cortex:
Adamantinoma, osteoid osteoma

 
 PATTERNS OF GROWTH and BONE DESTRUCTION 
Non-Ossifying Fibroma
  • Benign and non-growing (or extremely slowly growing) lesions are well circumscribed and show geographic pattern of bone destruction with a sclerotic rim. Geographic pattern refers to a well-defined area of lysis. The sclerotic rim is more commonly seen in the weight-bearing bones and represents bone reaction to the lesion. Its presence means that the bone has been given sufficient time to react. Some authors say that the sclerotic rim signifies benignancy to about 95%.
Aneurysmal Bone Cyst
  • If the lesion is growing more rapidly, it may still show a well-demarcated zone of bone destruction (geographic pattern), but it will lack a sclerotic rim. With continued growth, such lesions may show cortical expansion. Expansile growth pattern is defined as visible widening of the affected portion of bone. In many cases, an interrupted periosteal rim will surround the expanded portion of bone. This pattern may be seen in locally aggressive tumors and in low-grade malignancies.
Osteomyelitis
  • Rapidly growing lesions are poorly defined and may show aggressive, infiltrative patterns of bone destruction (permeative or "moth-eaten"). "Moth-eaten" pattern is defined as an ill-defined zone of multiple small radiolucencies that may coalesce.
Ewing's Sarcoma
  • Permeative pattern is characterized by numerous tiny radiolucencies in between the residual bone trabeculae. Due to the minute size of radiolucencies the lesion may be difficult to see and to delineate on the plain film. Generally, the more rapidly growing a lesion, the more difficult it is to see on plain film. "Moth-eaten" and permeative patterns are indicative of destruction involving both medullary and cortical bone. They are seen in high-grade malignant neoplasms and in osteomyelitis.
 TYPES OF PERIOSTEAL REACTION  The periosteum responds to traumatic stimuli or pressure from an underlying growing tumor by depositing new bone. The radiographic appearances of this response reflect the degree of aggressiveness of the tumor.
Osteoid Osteoma
  • Slow-growing tumors provoke focal cortical thickening (solid periosteal reaction, or "buttress")
Codman's triangle
  • Rapidly growing lesions penetrate through the cortex causing separation of the periosteum and formation of lamellated new bone. If the periosteum elevates to a significant degree, it can break forming an acute angle (Codman's triangle). This is seen in malignant bone tumors and in some other rapidly growing lesions such as aneurysmal bone cyst, or in reactive processes (osteomyelitis, and subperiosteal hematoma). Codman's triangle is usually free of tumor unless infiltrated through its open end or by transcortical growth.
Osteosarcoma
  • Other types of periosteal reaction in response to a rapidly growing lesion include "onion-skinning" and spiculated "hair-on-end" types.
Note that bone metastases usually do not provoke a periosteal reaction.
 PATTERNS OF MATRIX MINERALIZATION  Mineralization patterns (calcification or ossification) are helpful in identification of bone-producing and cartilage producing tumors.
Osteosarcoma
  • Osteoid. Malignant osteoid can be recognized radiologically as cloud-like or ill-defined amorphous densities with haphazard mineralization. This pattern is seen in osteosarcoma. Mature osteoid, or organized bone, shows more orderly, trabecular pattern of ossification. This is characteristic of the benign bone-forming lesions such as osteoblastoma.
Enchondroma
  • Chondroid. Radiologically, it is usually easier to recognize cartilage as opposed to osteoid by the presence of focal stippled or flocculent densities, or in lobulated areas as rings or arcs of calcifications. They are best demonstrated by CT. Whatever the pattern, it only suggests the histologic nature of the tissue (cartilage) but does not reliably differentiate between benign and malignant processes.

General Histologic Assessment of the Lesion
The following are the most important histologic features to consider:
  • Pattern of growth (eg., sheets of cells vs. lobular architecture)
  • Cytologic characteristics of the cells
  • Presence of necrosis and/or hemorrhage and/or cystic change
  • Matrix production
  • Relationship between the lesional tissue and the surrounding bone (eg., sharp border vs. infiltrative growth)
You should never try to make a diagnosis of bone tumor without integrating clinical, radiological, and histologic appearances. Biologically different types of tumors may have overlapping histologic features. Always obtain a list of differential diagnoses from a radiologist, make a habit of reviewing the films, and develop a good working relationship with an orthopedic surgeon. You are a part of a team.
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