Bones and Joints

Clinical Features

• Male predominance (2:1 to 3:1)

• Age ranges from second decade to elderly, with most cases occurring in fourth and fifth decades

• Occurs most commonly in skull bones, including mandible, maxilla, frontal sinuses, ethmoid sinuses, paranasal sinuses, orbital bones, and calvarium; rarely involves the clavicles and long bones

• May be asymptomatic or, if in sinuses, may present with signs of obstruction, including sinusitis and nasal discharges

• Orbital tumors may produce diplopia, exophthalmos, and blindness

Radiographic Findings

• Radiodense, circumscribed surface, or intramedullary mass usually without destructive features

Gross Pathology

• Nodular or dome-shaped, dense cortical bone

Histopathology

• Consists of dense lamellar bone with or without haversian canals and usually without a medullary component ( Figure 16.1 )

  

• When a medullary component is present, it is represented by hematopoietic tissue or fibroadipose tissue; the process extends up to uninvolved bone and does not blend in with the adjacent normal bone

Special Stains and Immunohistochemistry

• Noncontributory

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

Clinical Features

• Male-to-female ratio of 3:1

• Usually occurs in second or third decade

• Most commonly occurs in the leg, usually in the proximal femur

• May involve tibia, vertebra (arch more so than body), and small bones of foot and hand

• Typically intracortical tumors

• Classic clinical presentation includes progressive pain that is greater at night and is relieved by aspirin

• Depending on the site, other symptoms may develop

  • Vertebrae: peripheral nerve compression and painful scoliosis owing to muscle spasms (symptoms of intravertebral disk disease)

  • Upper and lower extremities: peritumoral muscular atrophy

  • Epiphyseal tumors: skeletal asymmetry, arthritis, and joint effusions

Radiographic Findings

• Routine radiographs reveal a small, round, central area of radiolucency (nidus) surrounded by sclerosis

• Nidus is usually cortical in location and may exhibit central ossification

• When plain radiographs fail to reveal the tumor (about 25%), tomograms, bone scans, computed tomography (CT), or magnetic resonance imaging (MRI) may be necessary

Gross Pathology

• Dense sclerotic bone surrounds a central nidus that is round, red, soft, and friable; nidus may be granular if ossified

• Typically less than 1 cm

Histopathology

• Central nidus is composed of interlacing thin bone trabeculae or woven bone with variable degrees of mineralization ( Figure 16.2 )

  

• Trabeculae may vary in thickness

• Prominent benign osteoblastic rimming of the trabeculae and multinucleated osteoclast-like giant cells are present within intervening fibrovascular stroma

• Outside the nidus is an abrupt zone of fibrovascular tissue surrounded by sclerotic compact lamellar bone

• No cartilage in the tumor unless there has been a fracture at the tumor site

• No hematopoietic tissue or adipose tissue within the tumor

Special Stains and Immunohistochemistry

• In short decalcified biopsies, FosB proto-oncogene, AP-1 Transcription Factor Subunit (FOS) immunohis- tochemistry can be used to diagnose osteoid osteoma and osteoblastoma, as overexpression is seen in the majority, while being rare in their mimics

Other Techniques for Diagnosis

• Osteoid osteoma is shown to harbor FOS (87%) and FosB proto-oncogene, AP-1 Transcription Factor Subunit (FOSB) (3%) rearrangements

• Preoperative tetracycline allows osteoblastic incorporation in the nidus, which is fluorescent under ultraviolet light

• Preoperative intravenous technetium-99 m with specimen autoradiography is another technique that may be used to identify a small nidus when curettage is used

• May express c-fos and c-jun by immunohistochemical analysis; some cases have demonstrated partial deletion of the long arm of chromosome 22 (22q13.1)

Differential Diagnosis

Clinical Features

• Male predominance, with a male-to-female ratio of 2:1 to 3:1

• Occurs in first through fourth decades, with most occurring in second and third decades

• Predilection for the vertebral column (arch) and sacrum followed by the mandible and craniofacial bones; the next most common sites are the extremities, where it follows a distribution similar to that of osteoid osteoma

• Typically intramedullary

• Localized pain may be present, but not with the intensity of an osteoid osteoma

• Vertebral tumors may produce scoliosis, muscle atrophy, and neurologic deficits

Radiographic Features

• Round, well-demarcated, expansile, radiolucent zone with a peripheral rim of sclerosis (sclerosis may not be as extensive as in osteoid osteoma)

• Central radiolucent zone (nidus) is greater than 1.5 cm; central stippled calcifications may be present

• Tumor may be surrounded by an area of new bone formation

• About one fourth may exhibit cortical destruction with periosteal new bone formation, suggesting a malignant tumor (osteosarcoma)

• Secondary aneurysmal cyst formation may be present

Gross Pathology

• Features similar to osteoid osteoma; however, these tumors are larger (>1.5 cm)

• Central nidus is red, soft, and friable; if calcified, the nidus may be yellow and gritty

• Cortical bone may be destroyed or thin, and there may be hemorrhagic cysts within the nidus, representing secondary aneurysmal cyst formation

Histopathology

• Irregular interlacing network of osteoid with prominent osteoblastic rimming and features of woven bone ( Figure 16.3 )

  

• Osteoid may be fine and lacelike with variable mineralization

• Osteoblasts have benign cytologic features

• Osteoblasts may exhibit abundant mitotic activity but no atypical forms

• Osteoid is separated by fibrovascular stroma containing multinucleated osteoclast-like giant cells

• Appears well circumscribed, with tumor osteoid merging with adjacent uninvolved bone

• Large blood lakes representing secondary aneurysmal cystic changes may be seen

• Cartilage is usually not present in the tumor, although rare cases have been reported

• Osteoblasts may have epithelioid features represented by large cells with abundant eosinophilic cytoplasm and enlarged nuclei containing large nucleoli

  • When epithelioid cells exceed 75% of the osteoblast population, the diagnosis of aggressive osteoblastoma should be made, which denotes an increased risk for recurrence, although no cases of metastases are reported

• Rare tumors may contain bizarre, cytologically atypical multinucleated giant cells without mitotic activity (these tumors may be designated bizarre osteoblastoma or pseudomalignant osteoblastoma )

Special Stains and Immunohistochemistry

• In short decalcified biopsies, FOS immunohistochemistry shows as overexpression in the majority

Other Techniques for Diagnosis

• Osteoid osteoma and osteoblastoma are shown to harbor FOS (87%) and FOSB (3%) rearrangements

Differential Diagnosis

Clinical Features

• Slight male predominance, with a male-to-female ratio of 1.5:1

• Bimodal age distribution, with most cases occurring in second decade; a second, smaller peak occurs in patients older than 50 years

• Represents the fourth most common cause of malignancy in the pediatric age group

• Patients with hereditary retinoblastoma are at increased risk for developing an osteosarcoma

• Other conditions that may be associated with the development of osteosarcoma: Li-Fraumeni syndrome, Ollier disease, osteoblastoma, fibrous dysplasia, Paget disease of bone, hereditary multiple exostosis, previous radiation or chemotherapy, hypoplastic or aplasia of thumbs, Werner syndrome, and Rothmund-Thomson syndrome

• Occurs in parts of the skeleton with the highest growth rates

• Predilection for the distal femur, proximal tibia, and proximal humerus

• Approximately 50% of cases occur in the region of the knee

• Typically presents with a history of short-term (several weeks to several months), mild, intermittent pain

• Affected area may be swollen and tender to palpation, and the overlying skin may exhibit telangiectasia and be warm

• Serum alkaline phosphatase may be elevated

Radiographic Features

• Classically shows a large lytic, sclerotic, or mixed lytic-sclerotic mass arising in medullary bone of the metaphysis that extends through the cortex and creates a soft tissue mass

• Variable mineralization within the tumor, which causes cloudy opacities

• Outer cortical surface exhibits prominent periosteal reaction represented by Codman triangle, sunbursts, or onion-skinning

• CT and MRI are used for staging (intramedullary involvement, presence of skip lesions in marrow, and soft tissue involvement)

Gross Pathology

• Resected specimens exhibit an intramedullary metaphyseal mass that has usually penetrated through the cortex and invades into soft tissue ( Figure 16.4A )

  

• Marrow extension of the tumor proximally is usually seen, and there may be skip lesions in which normal marrow separates islands of tumor

• Gross characteristics of the tumor are heterogeneous and variable, depending on the stromal component

  • Highly ossified areas are yellow to white and hard

  • Chondroid areas are lobulated, translucent, and light gray to white

  • Osteoblastic areas are firm, white to yellow, and sometimes gritty

  • Fibroblastic areas are soft and fleshy

  • Tumor may contain areas of necrosis, hemorrhage, and cystic changes

Histopathology

• Microscopic features may vary considerably in different areas of a tumor

  • Tumor is basically composed of sarcomatous, spindle-shaped cells exhibiting evidence of tumor osteoid production (see Figure 16.4B )

  • Sarcomatous stroma is hypercellular and may exhibit osteoblastic, chondroblastic, fibroblastic, or malignant fibrous histiocytoma-like differentiation

  • Cells usually have obvious cytologic malignant features, including brisk mitotic activity with atypical forms

  • Some cells may exhibit epithelioid features

• Tumor osteoid is represented by eosinophilic, amorphous, fibrillary deposits between individual tumor cells or small aggregates of tumor cells

• Early tumor osteoid forms a lacelike pattern around tumor cells, whereas the more advanced type is mineralized and has the appearance of woven tumor bone

• As tumor cells become incorporated with tumor osteoid, they tend to become smaller; this feature is regarded as normalization

• Some tumors exhibit prominent chondroblastic differentiation requiring careful search for tumor osteoid

• Fibroblastic areas may exhibit a herringbone pattern; diligent search for tumor osteoid is sometimes required

• Some tumors may have large numbers of osteoclast-like giant cells and are designated as giant cell–rich osteosarcoma

• Some tumors may contain foci rich in vascular structures with an hemangiopericytoma-like pattern

• Small cell variant

  • May have features suggestive of Ewing sarcoma/primitive neuroectodermal tumor (PNET), mesenchymal chondrosarcoma, and lymphoma and require immunohistochemistry for differentiation

  • Presence of tumor osteoid

  • Rare cases of small cell variant share genetic features of Ewing sarcoma/PNET

• Preoperative chemotherapy may result in tumor necrosis represented by acellular tumor osteoid, acellular chondroid tissue, fibrosis, or hyalinized vascular stroma; preoperative chemotherapy is considered effective when greater than 90% of the tumor is necrotic

Special Stains and Immunohistochemistry

• SATB2: recently discovered osteoblast transcription factor (nuclear stain) critical for osteoblast lineage commitment

• SATB2 immunohistochemistry can be useful in the diagnosis of osteosarcoma when histologic features of matrix are equivocal (i.e., osteoid vs hyalinized collagen) and when biopsy only samples tumor with undifferentiated appearance

Other Techniques for Diagnosis

• DNA ploidy analysis usually shows prominent aneuploid clones

  • Conversion from pretreatment aneuploidy to predominant diploidy after chemotherapy correlates with subtotal or total necrosis of the tumor

• One case of the small cell variant of osteosarcoma reportedly demonstrated chromosome translocation t(11;22)(q24;q12) typical of Ewing sarcoma/PNET; however, subsequent studies have not replicated this result

• Hereditary form shows a loss of function of the RB gene; in nonhereditary form, there may be mutation of the TP53 gene (about 20% of cases)

Differential Diagnosis

Clinical Features

• Male-to-female ratio is 2:1

• Most occur in second decade

• Accounts for about 4% of all osteosarcomas

• Similar distribution as conventional intramedullary osteosarcoma

• Predominantly affects distal femur, proximal tibia, and proximal humerus

• Similar symptoms to conventional osteosarcoma, except it is more likely to present as a pathologic fracture (25% of cases)

Radiographic Findings

• Recognizable as a completely lytic lesion involving the metaphysis with infiltrating destructive margins

• May cause cortical expansion of the bone

• Periosteal new bone formation may be represented by onion-skinning or Codman triangle

• Some cases may exhibit benign features and mimic an aneurysmal bone cyst

Gross Pathology

• Hemorrhagic mass that may be multicystic and necrotic

• No areas of fleshy, sarcoma-like tissue or sclerotic areas

Histopathology

• Multiple cystlike spaces resembling an aneurysmal bone cyst, except that the septa of the cysts contain stromal cells (mononuclear and multinucleated) with cytologically malignant features intermixed with benign osteoclast-like giant cells ( Figure 16.5 )

  

• Mitotic features are present, including atypical forms

• Sometimes the malignant stromal cells are floating in the center of the hemorrhagic cysts; identification of the stromal cells may be difficult, requiring multiple sections

• Tumor osteoid can be difficult to identify; it is usually focal and found in a delicate lacelike pattern

Special Stains and Immunohistochemistry

• SATB2 immunohistochemistry can be useful in the diagnosis when histologic features of matrix are equivocal (i.e., osteoid vs. hyalinized collagen) and when biopsy only samples tumor with undifferentiated appearance

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

Clinical Features

• Also known as “juxtacortical osteosarcoma”

• Slight female predominance, with a male-to-female ratio of 1:1.5

• Occurs predominantly in third decade

• Involves metaphyses of long bones with approximately three fourths of cases involving the distal posterior femur, with the proximal tibia as the second most common site

• Clinically presents as a painless mass of long duration (slow growing); pain may occur late in the course but is not typical initially

• May also present as an inability to flex the knee

Radiographic Features

• Radiodense, bosselated, or mushroom-shaped mass arising on the surface of a bone (outside of periosteum); in long-term lesions, tumor may encircle the bone

• A separate lucent zone between the tumor and the cortex known as a string sign may be seen

• No evidence of periosteal bone reaction

• Peripheral lucent areas may represent a cartilaginous cap

• Central lucent areas may represent high-grade sarcoma or dedifferentiated tumors

• CT or MRI may be necessary to visualize lucent areas

Gross Pathology

• Well-ossified mass that appears attached to the cortical surface of the bone

• Cartilaginous cap may be present and there may be soft foci, which should be sampled; these foci may represent high-grade sarcomatous regions or dedifferentiated tumor

Histopathology

• Tumor osteoid is arranged in parallel arrays and separated by a hypocellular fibroblastic stroma that exhibits minimal cytologic atypia and minimal mitotic activity without atypical forms ( Figure 16.6 )

  

• Islands of cartilaginous tissue and a cartilaginous cap may be present

  • Chondrocytes are atypical and do not exhibit orderly arrangement

  • Atypia is mild and reminiscent of chondrocytic atypia seen in enchondromas

• No evidence of periosteal new bone formation

• Areas of dedifferentiated high-grade sarcoma may be seen (about 15% of cases)

• No fatty or hematopoietic marrow is seen in association with the tumor

Special Stains and Immunohistochemistry

• SATB2 immunohistochemistry can be useful

Other Techniques in Diagnosis

• Cytogenetic studies: a ring chromosome may be seen

Differential Diagnosis

Clinical Features

• Slight male predominance, with a male-to-female ratio of 1.7:1

• Typically occurs in second to third decades (later than a conventional osteosarcoma appears and sooner than a parosteal osteosarcoma appears)

• Most occur in the diaphysis and metaphysis of the tibia and femur

• Patients present with pain, swelling, and tenderness; symptoms often present for less than 1 year

• Rare (<2% of all osteosarcomas)

Radiographic Findings

• Represented by a surface radiolucent tumor containing a spiculated pattern of calcifications that are oriented perpendicular to the long axis of the primary bone

• May see cortical thickening or erosion

• Periosteal reaction may be present

• No medullary involvement

Gross Pathology

• Lobulated surface mass having a cartilaginous appearance

• Cortical erosion may be seen, but the tumor does not extend into the medullary cavity

Histopathology

• Malignant osteoid must be present (may only be focal), but the predominant pattern of tumor is represented by lobulated chondromatous tissue with cytologic features of grade 2 or 3 chondrosarcoma

• Tumor is located on the surface of the bone and may extend into soft tissue

• High-grade anaplastic sarcomatous spindle cell component may separate lobules of the malignant chondroid component

• Periosteal bone formation may be present, and there may be cortical erosion, but the tumor does not involve the medullary cavity

Special Stains and Immunohistochemistry

• SATB2 immunohistochemistry can be useful in the diagnosis of osteosarcoma when histologic features of matrix are equivocal (i.e., osteoid vs. hyalinized collagen) and when biopsy only samples tumor with undifferentiated appearance

Other Techniques for Diagnosis

• Cytogenetics: usually diploid

Differential Diagnosis

Clinical Features

• Very rare tumor, with male-to-female ratio of about 3:1

• Occurs predominantly in third and fourth decades

• Distal and midfemur, proximal humerus, and proximal fibula are most common sites

• Pain and swelling are most common symptoms, with duration from less than a year to many years

• Similar prognosis to conventional intramedullary osteosarcoma, but poorer prognosis than parosteal osteosarcoma

Radiographic Features

• Exhibits a surface mass with features similar to those of periosteal osteosarcoma, except the mineralization pattern is similar to that of conventional osteosarcoma, revealing a fluffy, cumulus cloud appearance

• May be cortical destruction, periosteal reaction, and focal medullary involvement

Gross Pathology

• Large, lobulated surface mass with variable consistency ranging from soft to firm

• Should not significantly involve the medullary region

• May be hemorrhagic

Histopathology

• Histologically high-grade osteosarcoma with features similar to those of conventional intramedullary osteosarcoma, but lacks significant medullary involvement

Special Stains and Immunohistochemistry

• SATB2 immunohistochemistry can be useful in the diagnosis when histologic features of matrix are equivocal (i.e., osteoid vs. hyalinized collagen) and when biopsy only samples tumor with undifferentiated appearance

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

Clinical Features

• Male-to-female ratio is about 1:1

• Most cases occur in third and fourth decades; this variant of osteosarcoma can occur in older age groups

• Patients present with a history of pain for many months up to several years; usually no complaint of swelling

• Most common sites include mid- and distal femur and proximal and midtibia

• Some patients may have been previously diagnosed with fibrous dysplasia

Radiographic Features

• Large, poorly marginated intramedullary mass that either is sclerotic or exhibits trabeculations

• Usually no evidence of periosteal reaction

• Medullary tumor may extend along the length of the bone to the subarticular bone

• May have cortical destruction with formation of a soft tissue mass

Gross Pathology

• Tumors are gritty, gray, medullary masses that may have fibrous and fleshy areas

• Cortical destruction may be seen, and the tumor may extend the length of the bone with poor demarcation between tumor and uninvolved medullary bone

• Mean size about 9 cm

Histopathology

• Similar to parosteal osteosarcoma and can also mimic fibrous dysplasia

• Well-differentiated intramedullary fibro-osseous process represented by irregular bony trabeculae separated by fibrous spindly stroma

• Spindle cells are fibroblastic-like and have elongated nuclei with nucleoli

• Nuclei exhibit minimal atypia and infrequent mitoses; atypical mitoses are rare to absent

• Rare chondroid foci may be seen

Special Stains and Immunohistochemistry

• SATB2 immunohistochemistry may be useful

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

Clinical Features

• Also known as exostosis

• Most common benign tumor involving bone

• Male-to-female ratio is about 2:1

• Most occur in second and third decades, but can present at any age

• Majority occur in distal femur, proximal tibia, and humerus; pelvis is also a relatively common site

• Extremely rare in craniofacial bones, vertebrae, sacrum, and sternum

• Patients present with a longstanding mass that may be painful or asymptomatic

• Some lesions are asymptomatic and are identified incidentally on radiographs obtained for other reasons

• Pain may be secondary to impingement of a bursa, fracture, or infarction of the lesion

• May develop after radiation treatment (more than 1 year) for other malignant processes

• Hereditary form (autosomal dominant) is called osteochondromatosis or multiple hereditary exostosis (any bone may be involved except craniofacial bones)

• Other hereditary forms with multiple osteochondromas include Langer-Giedion syndrome and DEFECT-11 syndrome

• Fewer than 2% of osteochondromas undergo malignant transformation; clinical features suggestive of malignant transformation include pain, rapid growth, large tumor size (>6 cm), and location (axial skeleton)

Radiographic Findings

• Radiographs reveal a pedunculated metaphyseal mass projecting from the surface of a bone ( Figure 16.7A )

  

• Variable smooth or irregular surface and a variable base (narrow to wide); points toward the diaphysis and away from the nearest epiphysis

• Has appearance of mature bone and is continuous with the cortex of the uninvolved adjacent bone

• Surface cap represented by cartilage is not identified with routine radiographs unless calcified; MRI is necessary to evaluate the nonmineralized cartilaginous cap

Gross Pathology

• Pedunculated or broad-based mass containing a smooth, thin (<1 cm) cartilaginous cap

• In older patients, the cartilaginous cap may be attenuated or absent

• Central part of the mass is represented by normal-appearing medullary bone

Histopathology

• Outer surface is covered by a thin layer of periosteal fibrous tissue

• Cap is represented by hyaline cartilage that contains evenly distributed chondrocytes (see Figure 16.7B )

• Nuclei may exhibit atypia and pleomorphism

• Junction of the cap and bone mimics the epiphyseal plate and contains linear rows or columns of chondrocytes

  • Columns undergo endochondral ossification and form bony trabeculae

  • Medullary spaces between the trabeculae of bone contain adipose tissue and sometimes hematopoietic tissue

• Chondrocytic atypia must be evaluated with clinicoradiographic features to determine their significance

  • Nuclear enlargement, variation in nuclear shape, multinucleation, and formation of chondrocytic clusters that are irregularly shaped may cause some concern but can be found in osteochondromas

  • Chondrocytic atypia along with clinical features of malignancy (pain, rapidly enlarging tumor, size > 6 cm) and radiographic features of malignancy (irregular thickened cartilaginous cap > 2 cm, radiolucent areas of the cartilaginous cap, extension through periosteum into soft tissue, and bone destruction) are more ominous and concerning for a secondary chondrosarcoma

  • High mitotic activity is indicative of malignancy

Special Stains and Immunohistochemistry

• Noncontributory

Other Techniques for Diagnosis

• Chromosome rearrangement of 8q24.1 (EXT1) is found in patients with Langer-Giedion syndrome

• Deletions of chromosomal bands 11p11-12 (EXT2) is seen in patients with DEFECT-11 syndrome

• The EXT1 and EXT2 gene products add heparan sulfate to proteoglycans and may have tumor suppressor functions

Differential Diagnosis

Clinical Features

• Male-to-female ratio is about equal; affects all age groups (most occur in second to fifth decades)

• Occurs predominantly in the appendicular skeleton, with most occurring in bones of the hands and feet (hands more often affected than feet)

• Proximal humerus and femur and distal femur are also affected; rarely found in the pelvis, ribs, sternum, and vertebrae (no reported cases in craniofacial bones)

• In general, these tumors are asymptomatic and may be identified on routine radiographs or nuclear scans

• Phalangeal tumor may present as a mass

• Pain may be a presenting feature in association with a pathologic fracture or trauma to the tumor

Radiographic Features

• Well-defined, predominantly lucent diaphyseal intramedullary mass ( Figure 16.8A )

  

• Usually lobulated and sharply demarcated with variable mineralization, stippled, ringlike, or flocculent

• Cortical expansion and thinning may be seen, but the cortex should be intact; rare evidence of periosteal reaction

Gross Pathology

• Curettage produces fragments of blue-gray translucent, glistening chondroid tissue intermixed with fragments containing yellow foci representing calcification

• Resected specimens consist of a well-circumscribed medullary, confluent, lobulated, cartilaginous mass; periphery of the tumor may be irregular

Histopathology

• Composed of lobulated, mature, hyaline-like cartilage (see Figure 16.8B )

• Lobules may be separated by marrow hematopoietic tissue or endochondral bone

• Chondrocytic cellularity is low and usually evenly distributed

• Bland cytologic features with small, slightly hyperchromatic nuclei without pleomorphism; rare multinucleated forms may be present

• Nuclei with open chromatin patterns and mitoses are generally absent

• Cellularity may be higher in tumors of the hands and feet

• Calcifications and endochondral ossification may be present

• Myxoid areas should arouse suspicion of malignancy except in tumors of the hands and feet

Special Stains and Immunohistochemistry

• Mib-1 (Ki-67): in tumors involving bones other than the hands and feet in which malignancy is suspected clinically or radiologically, Mib-1 may be used to demonstrate proliferative activity

• Proliferative index is low in enchondroma

• Insulin-growth factor II mRNA binding protein (IMP3) is negative in enchondromas that helps to distinguish from chondrosarcomas (IMP3 is overexpressed in 36% of chondrosarcomas)

Other Techniques for Diagnosis

• Enchondromas may exhibit abnormalities of chromosomes 6 and 12

• Molecular studies have shown chromosomal rearrangements involving the HMGA2 gene localized to 12q15 in some patients with enchondromas

Differential Diagnosis

Clinical Features

• Male-to-female ratio is 2:1

• Most cases occur in second and third decades

• Proximal humerus, proximal femur, distal femur, and hand bones are most commonly affected

• Usually asymptomatic and often found incidentally on routine radiographs

• Occurs near tendon insertions and thus may cause functional abnormalities and discomfort related to movement

• May occasionally be palpable

Radiographic Features

• Typically a periosteal mass with variable mineralization

• May appear lytic or markedly calcified

• Erodes the outer cortex but does not extend into the medullary cavity

• Periosteal bone formation creating a peripheral buttress causing the tumor to be cup-shaped or crater-like

Gross Pathology

• Cortical, subperiosteal, gray-white lobulated chondroid mass with an outer thin layer of periosteum

• Does not extend into the medullary cavity

• Yellow calcifications may be present

Histopathology ( Figure 16.9 )

• Similar features to those of an enchondroma composed of hyaline cartilage

• May exhibit higher cellularity, increased nuclear atypia, and more multinucleated chondrocytes than enchondromas

• Myxoid change may be present

• Tumor may appear to extend or push into the medullary cavity, but there is a rim of lamellar bone at the junction of the tumor and medullary cavity

Special Stains and Immunohistochemistry

• Tumor cells express S-100 protein

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

Clinical Features

• Male-to-female ratio is 1.5:1

• Most cases occur in second decade; 95% occur between ages 5 and 25 years

• Predilection for epiphyses of bones

• Typically involves long bones in skeletally immature patients

• Common sites include distal femur, proximal tibia, and proximal humerus

• Other sites include acetabular area, iliac crest of pelvis, ribs, scapulae, spine, tarsal bones, base of skull, and temporal bone

• Usually presents with pain over months to years; may have muscle wasting, arthralgia of the adjacent joint, and joint effusion

• Rare (<1% of primary neoplasms involving bone)

Radiographic Findings

• Circumscribed, well-demarcated epiphyseal lytic mass with a rim of sclerotic bone

• Calcifications vary from focal stippling to coarse trabecular patterns

• Periosteal reaction is variable, but never to the degree seen in malignant neoplasms

Gross Pathology

• Curettage reveals friable and gritty red tissue with yellow foci of calcifications

• Resected specimens reveal a well-circumscribed, epiphyseal gray mass containing regional calcification, hemorrhage, and cystic changes

• Usually measure 3 to 6 cm in greatest dimension

• May have bluish-gray areas representing chondroid matrix

• Rim of sclerotic bone surrounds the tumor

Histopathology

• Composed of immature cells with features of fetal chondroblasts (stromal cells), multinucleated giant cells, and chondroid matrix ( Figure 16.10 )

  

• Stromal cells are round and have distinct cell membranes

  • Contain predominantly eosinophilic cytoplasm and a centrally placed round nucleus, which gives a fried-egg appearance to the cell

  • Nuclei contain grooves or clefts, and chromatin patterns are finely granular and evenly distributed

  • Infrequent mitotic figures without atypical forms are seen

  • Regional areas where cells do not have well-demarcated borders and form syncytia may be seen

  • Often have areas in which the cells contain larger atypical nuclei

• Multinucleated giant cells containing numerous nuclei (more than 20) are scattered throughout the tumor

• Variable amounts of chondroid matrix, which may contain stromal cells

• Calcification is an important histologic feature and has two patterns

  • Most common pattern is represented by linear calcifications surrounding stromal cells, imparting a chicken-wire appearance

  • Other pattern includes coarse calcifications of the chondroid matrix

• May also have areas of spindle-shaped cells, secondary aneurysmal cystic changes, myxoid changes, and cystic changes containing eosinophilic amorphous material

Special Stains and Immunohistochemistry

• H3F3 K36M mutant antibody is a sensitive and specific marker

• S-100 protein: stromal cells are positive

  • May be helpful to identify the scant numbers of stromal cells in tumors with prominent secondary aneurysmal cystic changes

Other Techniques for Diagnosis

• 95% of chondroblastomas harbor a p.K36M mutation in either H3F3A (chromosome 1) or H3F3B (chromosome 17), with the majority involving H3F3B

Differential Diagnosis

Clinical Features

• Extremely rare benign tumor

• Male-to-female ratio is 1.5:1

• Most cases occur in second and third decades, 80% before the age of 40 years

• Typically occur in the metaphyses of long bones in the lower extremity; most common sites are the distal femur and proximal tibia; may also involve the pelvis or small bones of the feet

• Patients usually present with a long-term history of pain

Radiographic Features

• Eccentric, expansile, lobulated metaphyseal mass that sometimes extends to the epiphysis

• Long axis of the tumor runs parallel to the long axis of the parent bone

• Well-demarcated, completely lytic mass with scalloped margins

• Calcifications on radiographs are rare

• Pelvic tumors have a multiloculated soap-bubble appearance

• Secondary aneurysmal bone cystic changes may be present

Gross Pathology

• Sharply circumscribed, lobulated, soft, gray-white tumor, usually 3 to 8 cm in greatest dimension

• Hemorrhagic and cystic areas may be present

• Myxoid areas may be seen, but are usually not prominent

Histopathology ( Figure 16.11 )

• At low magnification, the tumor has a lobulated appearance

  

• Lobulated areas are myxoid and composed of spindled or stellate cells

• The lobules are hypocellular centrally and hypercellular at the periphery

• In the hypercellular peripheral areas, the cells have features of chondroblasts

• In about 30% of cases, bizarre cells with pleomorphic hyperchromatic nuclei are present and may suggest malignancy; however, there is no mitotic activity

• Matrix of the lobules may have chondroid or myxoid characteristics

• Lobules are separated by fibrous tissue containing vessels, multinucleated giant cells, and occasionally osteoid

• Secondary aneurysmal bone cyst changes and foci of necrosis may be seen

• Rare to absent mitotic activity

• Solid cellular areas with features of chondroblastoma may be present

• Although not seen on radiographs, calcifications are extensive histologically and interfere with appreciation of a lobular architecture

• Longstanding tumors may show hyalinization

Special Stains and Immunohistochemistry

• S-100 protein is helpful in demonstrating the presence of chondroid differentiation

• Smooth muscle actin (SMA) and CD34 positivity can be seen in nonchondroid areas

Other Techniques for Diagnosis

• Recurrent anomalies of the long arm of chromosome 6 (6q25), in particular the pericentromeric inversion inv(6)p25q13), have been described

Differential Diagnosis

Clinical Features

• Male-to-female ratio is 1.5:1

• Usually seen in older adults; most patients are older than 50 years; rare in patients younger than 45 years

• Predilection for the trunk, with pelvis, ribs, proximal femur, and proximal humerus also affected

• Childhood tumors oftentimes involve the extremities

• Dull pain at rest that is often worse at night; symptom duration is typically several months to years

Radiographic Features

• Radiolucent mass with variable calcifications ranging from ring-shaped or punctate calcifications to markedly calcified lesions

• Cortex is thin with endosteal scalloping and erosion through the cortex

• Prominent cortical thickening, representing extension into haversian canals, may be seen

• Periosteal reaction is minimal or absent

Gross Pathology

• Nodular mass with blue-gray, glistening, translucent tissue resembling cartilage ( Figure 16.12A )

  

• Areas of yellow calcifications at the periphery

• May have foci of necrosis, hemorrhage, or myxoid degeneration

• Presence of fleshy tissue indicates a high-grade tumor

Histopathology

• Significant histologic variation; diagnosis of low-grade tumors requires clinical and radiographic features to correlate with histology

• Large amounts of chondroid matrix with variable cellularity; no tumor osteoid

• Chondrocytes within the matrix form clusters and are swollen as a result of cytoplasmic vacuolization

• Nuclei are mildly pleomorphic, and multinucleated forms are present in variable numbers

• Cells with chondroid differentiation containing nuclei with open chromatin patterns, nucleoli, and mitoses are indicative of malignancy

• The following are criteria for grading based on cellularity and cytology

  • Grade 1: cellularity is low, chondrocytes have small, dark nuclei, and multinucleated forms are rare; no mitotic activity, small foci of necrosis

  • Grade 2: cellularity is increased mainly at the periphery of lobules, myxoid change is present, chondrocytes have more abundant cytoplasm with mildly pleomorphic nuclei, and multinucleated forms are more common; mitoses are rare, foci of necrosis are present

  • Grade 3: cellularity is increased with sparse chondroid matrix; nuclei are large and pleomorphic and contain nucleoli; mitoses are present, and necrosis may be prominent

• Features suggestive of malignancy (hypercellularity, hyperchromasia, binucleated forms, and myxoid changes) may be seen in benign chondroid processes of the hands and feet; must have clinical and radiologic data before rendering diagnosis

Special Stains and Immunohistochemistry

• S-100 protein positive in grades 1 and 2 tumors; grade 3 tumors may be negative in poorly differentiated areas

• Insulin-growth factor II mRNA binding protein (IMP3) is overexpressed in 36% of chondrosarcomas

Other Techniques for Diagnosis

• DNA ploidy analysis may have prognostic significance

  • Grade 1 tumors are diploid

  • Grade 2 tumors may be diploid or aneuploid

  • Grade 3 tumors are aneuploid

  • Gains of the long arms of chromosomes 20 and 8 (20q+ and 8q+) are oftentimes seen

Differential Diagnosis