Bone Tumors



Bone Tumors


Judith V.M.G. Bovée

Carlos E. de Andrea



Neoplasms and tumorlike lesions of bone are not often encountered in daily clinical practice. Although certain bone lesions are common, they are often symptomless and indolent and do not come to clinical attention. Therefore, their true incidence is unknown. Bone sarcomas are rare and account for only 0.2% of neoplasms. Incidence rates of bone sarcomas are age-related; the first peak occurs during the second decade of life, in which age group osteosarcoma and Ewing sarcoma are most frequent, and the second peak occurs in patients older than 60 years of age, when chondrosarcoma is the most frequently encountered bone sarcoma (1). In addition, bone sarcomas have a particular spatial distribution in the long bones (Table 8.1). Most bone sarcomas present around the knee (up to 56% younger than the age of 20 years), followed by the pelvis. Most patients experience pain and/or swelling; therefore, symptoms are not very specific.

Ideally, all patients with suspected bone tumors should be discussed in multidisciplinary team meetings, including the radiologist and pathologist involved in the diagnosis and the (orthopedic) surgeon and oncologist involved in treatment (2,3). Radiographic imaging is of utmost importance in diagnosing bone tumors, and very often, a reliable histologic diagnosis cannot be made without adequate radiographic information and correlation, emphasizing the importance of multidisciplinary team meetings to establish a final diagnosis (4). The site of the lesion is important as some bone tumors preferentially affect specific areas of the skeleton. Information about the location within the bone is also crucial because some lesions occur predominantly in the metaphysis, whereas others affect specifically the epiphysis or diaphysis (Table 8.1). Moreover, lesions can originate centrally (e.g., enchondroma), eccentrically (e.g., aneurysmal bone cyst), cortically (e.g., osteoid osteoma), or juxtacortically. Multifocality is observed for enchondromas, osteochondromas, fibrous dysplasia, vascular tumors, Langerhans cell histiocytosis, multiple myeloma, and metastases. The formation of matrix (calcification), the destructive pattern, the appearance of tumor margins, cortical damage, and presence or absence of periosteal reaction or soft tissue extension are crucial for interpretation and for narrowing the differential diagnosis (5). One should always start with a conventional radiograph in two planes, which can be followed by magnetic resonance imaging (MRI) or computed tomography (CT) to further define the extent of the lesion. Imaging should always be performed before biopsy.








TABLE 8.1 Common Spatial Distribution of Bone Tumors in Long Bones








































Benign/Intermediate


Malignant


Epiphysis


Chondroblastoma


Clear cell chondrosarcoma


Giant cell tumor


Metaphysis


Osteoblastoma


Osteosarcoma


Osteochondroma


Chondrosarcoma (including periosteal)


Nonossifying fibroma


Osteoid osteoma


Chondromyxoid fibroma


Giant cell tumor


Aneurysmal bone cyst


Diaphysis


Enchondroma


Ewing sarcoma


Fibrous dysplasia


Chondrosarcoma


Adamantinoma


Although most bone sarcomas arise de novo, they can also develop within other conditions, such as Paget disease of bone, or in preexisting benign lesions such as enchondromas and osteochondromas. Also, bone sarcomas occur within hereditary syndromes such as Li-Fraumeni (osteosarcoma) (Table 8.2).


CLASSIFICATION OF BONE TUMORS

The classification of bone tumors is based on the differentiation of the tumor cells and the extracellular matrix that is being deposited. Main categories include chondrogenic tumors (depositing cartilaginous matrix), osteogenic tumors (depositing osteoid), and osteoclastic giant cell-rich tumors. In addition, fibrogenic, fibrohistiocytic, hematopoietic, notochordal, vascular, myogenic, and lipogenic tumors are distinguished based on their line of differentiation. In addition, there are tumors of undefined neoplastic nature (including, e.g., fibrous dysplasia or aneurysmal bone cyst) and miscellaneous tumors (including Ewing sarcoma, adamantinoma, and undifferentiated pleomorphic sarcoma of bone). Immunohistochemistry plays a limited role in diagnosing bone tumors, whereas molecular diagnostics can be helpful in a subset of tumors (Table 8.3).

The fourth edition of the WHO Classification of Tumours of Soft Tissue and Bone (1) set out to classify bone tumors in four categories, similar to their soft tissue counterparts: benign, intermediate locally aggressive, intermediate rarely metastasizing, and malignant. Benign tumors have a limited capacity for local recurrence, and if they do, recurrence will be nondestructive. Intermediate locally aggressive bone tumors such as atypical cartilaginous tumor (previously called chondrosarcoma grade 1) often recur locally and display an infiltrative locally destructive growth pattern, although they do not have an evident potential to metastasize. They require wide excision or application of a local adjuvant (e.g., phenol or cryotherapy) for local control. Intermediate rarely metastasizing bone tumors, such as giant cell tumors of bone, bear, in addition to their locally aggressive behavior, a very small risk (<2%) of distant (lung) metastases. Such behavior cannot be predicted on histologic
grounds. Malignant bone sarcomas carry a significant risk of distant metastases, ranging from 20% to 100% depending on the histotype and grade.








TABLE 8.2 Tumor Syndromes in Which Bone Tumors Are Frequently Encountered




























































Syndrome


Gene


Inheritance


Bone Tumors Encountered


Enchondromatosis (Ollier disease, Maffucci syndrome)


IDH1, IDH2


Mosaicism


Enchondromas, secondary central chondrosarcoma


Li-Fraumeni syndrome


TP53


AD


Osteosarcoma


Cherubism


SH3BP2


AD


Spindled giant cell containing tumors of the jaw


McCune-Albright syndrome and Mazabraud syndrome


GNAS


Mosaicism


Fibrous dysplasia


Multiple osteochondromas


EXT1, EXT2


AD


Osteochondroma, secondary peripheral chondrosarcoma


Retinoblastoma syndrome


RB1


AD


Osteosarcoma


Rothmund-Thomson syndrome


RECQL4


AR


Osteosarcoma


Werner syndrome


WRN


AR


Osteosarcoma


Diaphyseal medullary stenosis with undifferentiated pleomorphic sarcoma


MTAP


AD


Undifferentiated pleomorphic sarcoma


Infantile myofibromatosis


PDGFRB, NOTCH3


AD


Myofibromas


AD, autosomal dominant; AR, autosomal recessive; Mosaicism, nonhereditary, mutation is distributed as somatic mosaicism.



METHODS OF BIOPSY

After complete radiologic workup, the biopsy should be performed by the surgeon who will also perform the final surgery (2,6). The location and the technique used for the biopsy will severely affect decisions on the final surgery as the biopsy tract should be considered contaminated in the case of a sarcoma and should be removed. Unwanted contamination of unaffected tissue may therefore require radical resection or amputation, although previously, limb salvage surgery may have been an option. Prior imaging studies should be used to determine the most optimal biopsy tract and to identify the most representative part of the tumor to sample. The choice for open biopsy or core needle biopsy is dependent on the experience and preference of the surgeon and the pathologist as well as the location of the tumor. Core needle biopsy can be performed with ultrasound or CT guidance to sample the most appropriate areas. In experienced hands, core needle biopsy results in an adequate diagnosis in 80% to 90% of patients (7,8).

Frozen sections are recommended to determine whether the biopsy is adequate and representative. Moreover, frozen sections will enable the immediate request of special techniques without the loss of time due to calcification. If an infectious disease is suspected based on the frozen section, one may ask for tissue to be sent for bacterial cultures. If the frozen tissue is not representative, a second biopsy can be taken within the same procedure. The frozen tissue is also valuable for molecular diagnostics, for instance, in cases of Ewing sarcoma.


SPECIMEN HANDLING

Tissue specimens should be sufficiently formalin-fixed and adequately decalcified before embedding in paraffin. Decalcification should be used to dissolve the calcium hydroxyapatite crystals and to keep them out of the tissue, which is usually performed with an acidic solution. Various methods may be used, each with advantages and disadvantages. Proper decalcification should not compromise immunoreactivity. These paraffin sections constitute the cornerstone of histopathologic diagnosis. In the case of curettage, adequate and extensive sampling is required, e.g., to exclude dedifferentiation in chondrosarcoma, to identify an underlying primary lesion in aneurysmal bone cyst, or to identify characteristic areas of giant cell tumor within extensive reactive changes. For handling resection specimens, first, adequate orientation and identification of possibly contaminated areas or compromised resection margins are required. Correlation with preoperative radiographs may be helpful. If they are not available, one could consider preparing a specimen radiograph for orientation purposes and to visualize the relationship of the tumor to resection margins. Then, slices can be cut using a band saw, the tumor can be documented, and macroscopic images should be made. The slice with the largest tumor diameter can be divided in parts and, as such, fully submitted for microscopy (9), which is important, for example, to evaluate response to neoadjuvant treatment or to identify areas with higher histologic grade or dedifferentiation. Alternatively, one could submit one section per centimeter of maximum dimension (10). Extra sections should be obtained of the tumor in relation to vital structures (synovium, vessels, nerves, margins). A small portion of tissue should be snap frozen whenever possible, for molecular assays.


GRADING OF BONE SARCOMAS

Bone tumors vary considerably in their clinical and biologic behavior. Histologic grading is an attempt to predict the behavior of a malignant tumor based on histologic features (1). There is no widely accepted grading scheme for bone sarcomas. The 2010 College of American Pathologists (CAP) Bone Tumor Protocol advocates a pragmatic approach based mainly on histologic type or subtype (Table 8.4) (1,10). Conventional osteosarcoma and most osteosarcoma subtypes are classified as high-grade tumors with the exception of low-grade intramedullary (central) osteosarcoma and parosteal osteosarcoma (both low grade) and periosteal osteosarcoma (intermediate-grade). Grading has not proven useful in predicting the behavior of conventional giant cell tumor of bone, but malignancy in giant cell tumor is considered high grade. Certain chondrosarcoma
histologic subtypes are considered high grade (mesenchymal and dedifferentiated chondrosarcoma) or low grade (clear cell chondrosarcoma).








TABLE 8.3 Specific Genetic Changes in Bone Tumors That Can Be Used in Diagnosis

































































































































Tumour


Chromosomal Alteration


Genes Involved


Specific Translocations


Ewing sarcoma


t(11;22)(q24;q12)


EWSR1-FLI1


t(21;22)(q22;q12)


EWSR1-ERG


t(7;22)(p22;q12)


EWSR1-ETV1


t(17;22)(q12;q12)


EWSR1-ETV4


t(2;22)(q33;q12)


EWSR1-FEV


t(16;21)(p11;q22)


FUS-ERG


t(2;16)(q35;p11)


FUS-FEV


Ewing sarcoma-like tumors without ETS involvement


t(6;22)(p21;q12)


EWSR1-POU5F1


inv(22)(q12)


EWSR1-ZSG (ZNF278)


t(4;22)(q31;q12)


EWSR1-SMARCA5


t(2;22)(q31;q12)


EWSR1-SP3


t(1;22)(p36.1;q12)


EWSR1-ZNF278


t(20;22)(q13;q12)a


EWSR1-NFATC2


t(4;19)(q35;q13)


CIC-DUX4


Aneurysmal bone cyst


t(16;17)(q22;p13)


CDH11-USP6 (TRE2)


t(1;17)(p34.1-34.3;p13)


TRAP150-USP6


t(3;17)(q21;p13)


ZNF9-USP6


t(9;17)(q22;p13)


OMD-USP6


t(17;17)(q12;p13)


COL1A1-USP6


Mesenchymal chondrosarcoma


NA


HEY1-NCOA2


t(1;5)(q42;q32)


IRF2BP2-CDX1


Myoepithelial tumor of bone


t(6;22)(p21;q12)


EWSR1-POU5F1


t(19;22)(q13;q12)


EWSR1-ZNF444


t(1;22)(q23;q12)


EWSR1-PBX1


Epithelioid hemangioendothelioma


t(1;3)(p36;q25)


WWTR1-CAMTA1


NA


YAP1-TFE3


Bizarre parosteal osteochondromatous proliferation (Nora lesion)


t(1;17)(q32;q21)


RDC1?


Subungual exostosis


t(X;6)(q24-q26; q15-21)


COL12A1-COL4A5


Specific Amplifications/Gains


Chordoma


6q27


T (brachyury)


Low-grade (parosteal and intramedullary) osteosarcoma


12q14-15 (ring/marker chromosome)


CDK4, MDM2, HMGA2, GLI, SAS


Specific Gene Mutations


Fibrous dysplasia



GNAS


Enchondroma, central and periosteal chondrosarcoma



IDH1, IDH2


Osteochondroma



EXT1, EXT2


a Complex ring chromosome with amplification of the translocated segments.


Modified from Szuhai K, Cleton-Jansen AM, Hogendoorn PCW, et al. Molecular pathology and its diagnostic use in bone tumors. Cancer Genet 2012;205:193-204.









TABLE 8.4 Bone Sarcoma Grading

















Grade I


Low-grade intramedullary osteosarcoma


Parosteal osteosarcoma


Osteofibrous dysplasia-like adamantinoma


Clear cell chondrosarcoma


Grade II


Periosteal osteosarcoma


Classic adamantinoma


Chordoma


Grade III


Osteosarcoma (conventional, telangiectatic, small cell, secondary, high-grade surface)


Undifferentiated high-grade pleomorphic sarcoma


Ewing sarcoma


Dedifferentiated chondrosarcoma


Mesenchymal chondrosarcoma


Dedifferentiated chordoma


Malignancy in giant cell tumor of bone


Angiosarcoma


Variable


Conventional chondrosarcoma (grades 1-3 according to Evans)


Leiomyosarcoma of bone (grades 1-3 according to FNCLCC)


Modified from Rubin BP, Antonescu CR, Gannon FH, et al. Protocol for the examination of specimens from patients with tumors of bone. Arch Pathol Lab Med 2010;134:e1-e7.


Conventional chondrosarcoma and sarcomas of soft tissue type are the two exceptions to this rule. In conventional chondrosarcoma, the grading system as proposed by Evans et al. (11) is now universally accepted (1). Under this system, conventional chondrosarcoma is divided into three grades based on cellularity, cytologic atypia, and mitotic figures (see the following discussion). Soft tissue tumor-type sarcomas such as leiomyosarcoma of bone can be graded according to the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system, as is commonly used for soft tissue sarcomas.


STAGING OF BONE SARCOMAS

Although staging systems have been described for both benign and malignant bone tumors, they are more useful in the management of malignant bone tumors. Bone sarcomas are staged using either the Musculoskeletal Tumor Society (MSTS) system, first described by Enneking et al. (12), or the American Joint Committee on Cancer (AJCC) system. The MSTS and AJCC system have many features in common.

The MSTS staging system also includes benign tumors (Table 8.5). The sarcomas are classified as stage I, II, or III based on their histologic features (stage I: low grade, stage II: high grade) or metastatic spread to regional lymph nodes or distant sites (e.g., the lung) (stage III). For staging purposes, grade 1 is considered low grade (G1), whereas grade 2 and grade 3 are considered high grade (G2) (10). In addition, tumors are also classified on the basis of whether they are confined to the bone (intracompartmental; type A) or whether they extend outside the bone (extracompartmental; type B).

The AJCC recommends four histologic grades based on differentiation, which cannot be readily applied to bone tumors as
discussed earlier. Therefore, a grade 1 or 2 tumor in the AJCC system is equivalent to a stage I tumor in the MSTS system; grade 3 or 4 is equivalent to MSTS stage II. In addition, the TNM staging system includes histologic subtype, size, continuity, and grade as well as local and distant spread to estimate the prognosis of the patient (Table 8.6). Lymph node metastases are, however, rare in bone sarcomas.








TABLE 8.5 Musculoskeletal Tumor Society Staging System for Bone Tumors



























Benign Tumors (G0)


Stage 1—Inactive, latent (G0)


Stage 2—Active (G0)


Stage 3—Aggressive (G0)


Malignant Tumors


Stage I—Low grade (G1)


Stage II— High grade (G2)


Stage III—Low- or high-grade tumors with metastases


Subdivisions


A—Intracompartmental


B—Extracompartmental


Originally described by Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop 1980;153:106-120.



CHONDROGENIC TUMORS


Osteochondroma

Osteochondroma is a benign cartilage-capped bony projection arising on the external surface of bone containing a marrow cavity that is contiguous with that of the underlying bone (1). The base of osteochondroma can be broad (sessile) or small (pedunculated) (Fig. 8.1). The lesion is entirely surrounded by periosteum. Osteochondromas are the most frequent cartilaginous lesions, most often found on the femur (21%), humerus (17%), and tibia (11%) (13). Osteochondromas develop and increase in size during the first decade of life and stop growing when growth plates close during puberty. The majority of osteochondromas are asymptomatic. Sporadic (solitary) osteochondromas are six times more common than those occurring within the hereditary multiple osteochondroma syndrome (previously called hereditary multiple exostoses) (Fig. 8.2). Multiple osteochondromas is an autosomal dominant condition caused by mutations in EXT1 or EXT2 (14). Radiologically, the osteochondroma is characterized by its typical localization at the transition of the metaphysis to the diaphysis, projected away from the joint, the contiguity of the cortex of the underlying bone with the cortex of the osteochondroma stalk, and the presence of spongiosa within the stalk (Figs. 8.1 and 8.3). Histologically, three layers are seen: perichondrium, cartilage, and bone (Fig. 8.4). The organization of chondrocytes in columns, as is normally observed in the growth plate, can usually also be recognized in the cartilaginous layer of osteochondroma (Fig. 8.5). Endochondral ossification is seen at the cartilage-bone interface. Cellularity is variable, depending on the age of the patient. Binucleated cells, calcification, necrosis, nodularity, and cystic changes can be seen (Fig. 8.6). Malignant transformation to secondary peripheral chondrosarcoma occurs in 1% to 5%. There are no accepted histologic criteria to distinguish osteochondroma from low-grade secondary peripheral chondrosarcoma (4); the imaging studies and gross macroscopic documentation of the thickness of the cartilaginous cap are extremely important, as a cartilage cap exceeding 1.5 to 2 cm in adults is suggestive of malignancy (1,4).








TABLE 8.6 TNM Staging System for Bone Tumors






























































































































T—Primary tumor


TX


Primary tumor cannot be assessed


T0


No evidence of primary tumor


T1


Tumor 8 cm or less in greatest dimension


T2


Tumor more than 8 cm in greatest dimension


T3


Discontinuous tumors in the primary bone site


N—Regional lymph nodes


NX


Regional lymph nodes cannot be assessed


N0


No regional lymph node metastasis


N1


Regional lymph node metastasis


M—Distant metastasis


M0


No distant metastasis


M1


Distant metastasis


M1a


Lung


M1b


Other distant sites


G—Histologic grade


GX


Grade cannot be assessed


G1


Well differentiated (low grade)


G2


Moderately differentiated (low grade)


G3


Poorly differentiated (high grade)


G4


Undifferentiated (high grade)a


Stage grouping


Stage


Tumor (T)


Node (N)


Metastasis (M)


Grade (G)


Stage IA


T1


N0


M0


G1, 2 low grade, GX


Stage IB


T2


N0


M0


G1, 2 low grade, GX


T3


N0


M0


G1, 2 low grade, GX


Stage IIA


T1


N0


M0


G3, 4 high grade


Stage IIB


T2


N0


M0


G3, 4 high grade


Stage III


T3


N0


M0


G3, 4 high grade


Stage IVA


Any T


N0


M1a


Any G


Stage IVB


Any T


N1


Any M


Any G


Any T


Any N


M1b


Any G


a Ewing sarcoma is classified as high grade.


From Bone. In Edge SE, Byrd DR, Carducci MA, et al, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer 2010, with permission.



Enchondroma

Enchondroma is a benign hyaline cartilage neoplasm of medullary bone. Most tumors are solitary; however, they occasionally involve more than one bone or site in a single bone (1). Enchondromas are relatively common and have a wide age range. Enchondromas are located in the long bones, and 50% of all cases are located in the bones of the hands and feet (15). Chondrosarcomas are only rarely seen at this location (16). The size of an enchondroma is usually less than 3 cm. Radiologically,
the presence of matrix mineralization in the form of “popcorn” calcifications is most typical. The edge of the lesion is most often lobular and sharply circumscribed. Histologically, enchondroma consists of lobular, relatively cell-poor hyaline cartilage, often demarcated by a zone of reactive bone formation (encasement) (Fig. 8.7). The chondrocytes have nuclei with condensed chromatin and are evenly dispersed. Binucleated cells are infrequent and mitoses are absent. Occasionally, degenerative features such as ischemic necrosis or calcifications are found (Fig. 8.8). The distinction between an enchondroma and atypical cartilaginous tumor/chondrosarcoma grade 1 can be difficult radiologically (Fig. 8.9) (17). Moreover, this distinction is also difficult on histology (18), causing high interob-server variability (19,20). Mucomyxoid matrix degeneration and entrapment of preexisting host bone are most predictive
of atypical cartilaginous tumor/chondrosarcoma grade 1 (Fig. 8.10) (20). Immunohistochemistry or molecular diagnostics cannot help in this differential diagnosis. Radiologic presentation, localization, and age should also be taken into account. For instance, in the phalanges, the matrix of enchondromas can contain more myxoid features, and the lesion may be more cellular. At this location, the main characteristics of malignancy are the presence of mitoses, cortical breakthrough, and soft tissue involvement (16). Malignant transformation of enchondromas is thought to be extremely rare (<1%) (13). Multiple enchondromas are seen in the context of nonhereditary Ollier disease (multiple enchondromas with a unilateral predominance) (Fig. 8.11) and Maffucci syndrome (multiple enchondromas combined with [spindle cell] hemangiomas) (21) caused by somatic mosaic mutations in the IDH1 or IDH2 gene (22,23). In these conditions, the risk of malignant
transformation is increased to 18% to 46%, depending on the extent and localization of the lesions (24).






FIGURE 8.1 Gross specimen of an osteochondroma. The lesion is sessile formed by a stalk of medullary bone covered by a smooth, pale, blue-gray cartilage cap that has a thickness of less than 1 cm.






FIGURE 8.2 Multiple osteochondromas. Multiple bony lesions around the knee, projecting away from the joint.






FIGURE 8.3 Osteochondroma of the femur. Note that the medullary cavity of the lesion is continuous with the medullary cavity of the bone.






FIGURE 8.4 Osteochondroma. The tumor consists of three layers: perichondrium, cartilage, and bone.






FIGURE 8.5 Osteochondroma. The cartilage cap in osteochondroma usually displays a growth plate-like columnar arrangement of chondrocytes. Endochondral ossification is present at the cartilagebone interface.






FIGURE 8.6 Osteochondroma. The cartilage cap contains small chondrocytes as well as hypertrophic cartilage cells. Trabecular bone is seen at the base of the cartilage cap.






FIGURE 8.7 Enchondroma. The lesion consists of lobular, relatively cell-poor hyaline cartilage, often demarcated by a zone of reactive bone formation (encasement) indicating slow growth.






FIGURE 8.8 Enchondroma. The cells have nuclei with condensed chromatin and are irregularly dispersed. Binucleated cells are infrequent and mitoses are absent. Occasionally, necrosis and irregular calcifications are observed.






FIGURE 8.9 Atypical cartilaginous tumor/chondrosarcoma grade 1 of the distal femur. (A) The lesion is eccentric with sharp sclerotic margin and areas of calcification. (B) Erosion of the cortex can be seen (endosteal scalloping). The distinction between enchon-droma and atypical cartilaginous tumor/chondrosarcoma grade 1 is very difficult at radiography.






FIGURE 8.10 Chondrosarcoma. Entrapment of preexisting host bone by the cartilaginous neoplasm indicating invasive growth.


Periosteal Chondroma

Periosteal chondroma is a rare, benign hyaline cartilage neoplasm of bone surface that arises from the periosteum and is often located on the fingers or proximal humerus (1). On radiographic imaging, a small (<5 cm), sharply demarcated tumor is seen on the surface of bone, with erosion of the exterior cortex, whereas marrow invasion is absent. In contrast to enchondroma, the mixture of low and highly cellular areas, the presence of binucleated cells, hyperchromasia of the nuclei, myxoid change of the matrix, and nuclear pleomorphism are histologically tolerated, whereas these features would lead to a diagnosis of chondrosarcoma if the tumor were located outside the periosteal area (25,26). The distinction between a periosteal chondroma and a periosteal chondrosarcoma is mainly based on the presence of cortical destruction in the case of a periosteal chondrosarcoma. Furthermore, periosteal chondrosarcomas are usually more than 5 cm in size (27). Approximately 70% of periosteal chondromas harbor mutations in IDH1 (28).


Osteochondromyxoma

Osteochondromyxoma is an extremely rare, benign, sometimes locally aggressive chondroid and osteoid matrix-producing tumor with extensive myxoid change, occurring in approximately 1% of patients with Carney complex (29). Carney complex is an autosomal dominant condition with multiple neoplasms characterized by cardiac, endocrine, cutaneous, and neural myxomatous tumors as well as a variety of pigmented lesions of the skin and mucosae.






FIGURE 8.11 Ollier disease. Conventional radiograph of the hand demonstrating multiple enchondromas affecting multiple bones.


Subungual Exostosis and Bizarre Parosteal Osteochondromatous Proliferation of Bone (Nora Lesion)

Bizarre parosteal osteochondromatous proliferation (BPOP) is an osteochondromatous proliferation involving the surface of the small bones of the hands and feet (30,31). There is a wide age range with no sex predilection. In contrast to osteochon-droma, the lesion is not contiguous with the underlying cortex and medulla. Histologically, bone and spindle cells are seen, with hypercellular cartilage with enlarged chondrocytes and irregular bone-cartilage interfaces (Fig. 8.12). A characteristic, strikingly blue color can be found, even after decalcification (“blue bone”). There is marked proliferative activity. In contrast to chondrosarcoma, the cartilaginous matrix is typically fibrillary. The maturation to trabecular bone with spindle cells in the intertrabecular spaces that is often present may lead to confusion with parosteal osteosarcoma (30), although in contrast to parosteal osteosarcoma, BPOP never shows atypia of the fibrocytes (31). The lesion has a pronounced tendency to recur (about 55%), whereas metastases have not been reported. A recurrent chromosomal translocation t(1;17) has been found (32).

Subungual exostosis is a benign osteochondromatous proliferation involving the distal phalanx (1). The histology resembles BPOP, although the classic blue bone is lacking, and the lesion is more organized with a gradual maturation from peripheral spindle cell proliferation, to hyaline cartilage, to trabecular bone. Subungual exostosis, as the name implies,
is typically located at the distal phalanx, whereas BPOP is not located at that site. In contrast to osteochondroma, which is extremely rare on the digits, the cartilaginous matrix is highly fibrillary. Subungual exostosis is characterized by a recurrent chromosomal translocation t(X;6), rearranging the COL12A1 and COL4A5 genes in chromosome bands 6q13-14 and Xq22 (33), upregulating expression of the IRS4 gene (34).






FIGURE 8.12 Bizarre parosteal osteochondromatous proliferation of bone. The lesion is composed of a proliferation of cartilage, which matures into bone, and bone-forming cells in a fibroblastic stroma. Bluish calcification is seen.


Synovial Chondromatosis

Synovial chondromatosis is a rare benign neoplasm presenting as multiple hyaline cartilage nodules in the subsynovial tissue (1). There is a male predominance, with an average age of 41 years (35). The condition is monoarticular, with the knee most often affected (35). At radiography, the presence of opaque bodies and/or stippled calcification is found (35). At macroscopy, multiple gray-white nodules are seen. Histologically, cartilaginous nodules are seen surrounded by a thin layer of synovium. Characteristically, the chondrocytes in the nodules cluster together in nests (Fig. 8.13) (35). The cartilage is hypercellular with plump hyperchromatic nuclei, with numerous binucleate cells (35). Inflammation and ossification can be found. Malignant transformation to chondrosarcoma is extremely rare and is suggested by the presence of atypical chondrocytes not arranged in nests, mitoses, crowding and spindling of nuclei at the periphery of lobules, myxoid change, necrosis, and, most importantly, permeation of bone trabeculae (35).


Chondromyxoid Fibroma

Chondromyxoid fibroma is a very rare benign cartilaginous neoplasm composed of lobules of spindle-shaped or stellate cells with abundant myxoid or chondroid intercellular material (1). The lesions can affect any bone. Patients are adolescents or young adults, predominantly males. Radiologically, the lesion presents as an eccentric, oval, radiolucent lesion in the metaphysis (Fig. 8.14) (36). Histologically, the periphery of the lobules are most cellular, containing spindle-shaped or round cells, mixed with a varying number of multinucleated giant cells (Fig. 8.15). In the center of the lobules, more stellate cells are found lying in a mucomyxoid matrix. Nuclear enlargement and hyperchromasia can be seen, sometimes causing confusion with high-grade central chondrosarcoma. Mitoses are unusual but can be seen. High-grade chondrosarcoma, however, has a different clinical and radiologic presentation, and the architecture is different. Moreover, expression of CD166, cyclin D1, and p16 would favor chondromyxoid fibroma (37). The cells in
chondromyxoid fibroma express S100, and the cells at the periphery of the lobules are myofibroblastic, expressing MSA and SMA. Chromosome 6 aberrations are frequent (38). These variable rearrangements were all shown to target the GRM1 gene, as they all result in upregulation of GRM1 (39). High GRM1 expression was shown to be specific for chondromyxoid fibroma, suggesting that aberrant glutamate signalling is involved in its histogenesis (39).






FIGURE 8.13 Synovial chondromatosis. Nodules of cartilage are surrounded by a thin layer of synovium. Chondrocytes are clustered together in nests.






FIGURE 8.14 Chondromyxoid fibroma of the iliac wing. The lesion is seen as an eccentric (arrow), well-circumscribed lytic defect, with a “soap-bubble” appearance.






FIGURE 8.15 Chondromyxoid fibroma. Lobules of myxoid or chondroid matrix with numerous spindle-shaped or stellate cells (left) are seen, with increased cellularity at the edge of the lobules (right) where cells are more rounded and admixed with multinucleated osteoclastic giant cells.


Chondroblastoma

Chondroblastoma is a rare benign, chondroid-producing neoplasm composed of chondroblast-like cells usually arising in the epiphyses of skeletally immature patients. The lesion has a slight predominance in males. In general, its behavior is benign and the lesion is treated by curettage, although very rare (˜ 1%) metastases have been described after biopsy or curettage (intermediate, rarely metastasizing category according to WHO 2013) category (1). At radiography, chondroblastoma presents as an eccentric radiolucent lesion, with a sharp sclerotic margin and areas of calcification, characteristically located in the epiphysis of the long bones (Fig. 8.16). Histologically, the tumor is highly cellular with relatively uniform, immature, rounded, or polygonal chondroblast-like cells with sharp cell borders, intermingled with multinucleated osteoclast-like giant cells, which are arranged individually or in clusters (Fig. 8.17). There is a variable deposition of extracellular matrix, both cartilaginous and osteoid, and small areas of cartilage matrix with focal net-shaped (“chicken wire”) calcification (Fig. 8.18). Occasionally, (nonatypical) mitoses are found. In about 15% of cases, the formation of a secondary aneurysmal bone cyst is observed (40). The cells express S100 and may express keratins. Distinction from giant cell tumor can sometimes be challenging (Table 8.8); the morphology of the mononuclear cells and the extracellular matrix are helpful distinguishing features.
Immunohistochemistry is not particularly helpful in this distinction, although recently, the expression of DOG1 by clusters of cells in chondroblastoma has been reported (41). Very recently, a consistent mutation in H3F3B (p.Lys36Met), which is one of the two genes for histone H3.3, was found in chondroblastoma (42). Interestingly, giant cell tumor of bone harbors alterations in H3F3A, the other gene for histone H3.3 (42).






FIGURE 8.16 Chondroblastoma of the proximal humerus. (A) The lesion is typically located at the epiphysis, is well circumscribed, and has a sclerotic rim. (B) Extension of the chondroblastoma across the physis and reactive edema visible on MRI.






FIGURE 8.17 Chondroblastoma. Immature, rounded or polygonal chondroblast-like cells with sharp cell borders embedded in a chondroid-like matrix and admixed with multinucleated osteoclast-like giant cells.






FIGURE 8.18 Chondroblastoma. Lacy, “chicken wire” calcification occurs within the matrix (right).


Conventional Chondrosarcoma

Chondrosarcoma is a locally aggressive to malignant cartilaginous matrix-producing neoplasm. The term chondrosarcoma is used to describe a heterogeneous group of lesions with diverse morphologic features and clinical behavior (Table 8.7) (1). Chondrosarcoma is mainly seen in adults in the third to sixth decade of life, with equal gender distribution. They usually arise in the thoracic, pelvic, and long bones. Surgery is the mainstay of treatment as chondrosarcomas are highly resistant to chemotherapy and radiotherapy (43).

Primary central chondrosarcoma arises centrally in previously normal bone as opposed to secondary chondrosarcoma arising in a preexisting benign cartilaginous tumor. Primary central chondrosarcomas account for about 75% of all chondrosarcomas, and the majority is well differentiated. Central chondrosarcoma can be found in almost all parts of the skeleton arising from endochondral ossification. Radiologically, it can be difficult to distinguish enchondroma from chondrosarcoma (Fig. 8.9) (17). In chondrosarcomas of higher grade, the edge of the lesion is no longer lobular and sharply demarcated, and cortical destruction and soft tissue extension can be seen. At macroscopy, a typical translucent, lobular, blue-gray or white cut surface is seen (Fig. 8.19). Primary central chondrosarcoma is divided into three histologic grades, as described in the following section.

Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 are found in 38% to 70% of respectively primary central chondrosarcomas (23,28). Hot spot mutations are exclusively found at the IDH1 R132 and the IDH2 R172 positions, of which the R132C mutation is most common in chondrosarcoma. Mutation analysis can be helpful for instance in the distinction between high-grade chondrosarcoma and chondroblastic osteosarcoma (28,44). Mutations in IDH are early events because
they occur in enchondromas and therefore do not distinguish between enchondroma and chondrosarcoma (23,28). The (epi)genetic events causing malignant transformation of enchondroma to chondrosarcoma are so far unknown, although upon progression, chondrosarcomas become aneuploid and karyotypes become complex with increasing histologic grade, with aberrations in the p53 and Rb pathways.








TABLE 8.7 Clinicopathologic Features of the Different Types of Chondrosarcoma
























































































Conventional Central Chondrosarcoma


Conventional Peripheral Chondrosarcoma


Periosteal Chondrosarcoma


Dedifferentiated Chondrosarcoma


Mesenchymal Chondrosarcoma


Clear Cell Chondrosarcoma


% of all chondro-sarcomas


˜75


˜10


<1


˜10


<2


<2


Precursor lesion


Enchondroma (up to 40%?)


Osteochondroma (100%)


None


Conventional chondro-sarcoma


None


None


Occurrence within syndrome


Enchondromatosis (Ollier disease)


Multiple osteochondromas (MO)


None


Rarely in MO or enchondromatosis


None


None


Age


>50 years


Younger than central chondro-sarcoma


Peak in fourth decade


Median age 59 yr


Any age (peak in second to third decade)


Any age (peak in third to fifth decade)


Preferential location


Pelvis, proximal femur, proximal humerus, distal femur, ribs


Pelvis, shoulder girdle bones


Distal femur and humerus


Femur and pelvis


65%-86% skeleton (jawbones, ribs, ilium, vertebrae)


Epiphysis of humeral or femoral head


14%-43% extraosseous (meninges)


Histologic grading


Evans et al. (11)


Evans et al. (11)


Prognosis usually good despite worrisome histology


High grade


High grade


Low grade


Survival


ACT/grade 1: 83%, grade 2: 64%, grade 3: 29% at 10 yr


ACT/grade 1: 83%, grade 2: 64%, grade 3: 29% at 10 yr



24% at 5 yr


28% at 10 yr


89% at 10 yr


Sensitivity to chemotherapy


None


None


None


Uncertain


Possibly, if high percentage of round cells


None


Sensitivity to radiotherapy


Low


Low


Low


Low


Possibly high


Low


Adapted from Gelderblom H, Hogendoorn PCW, Dijkstra SD, et al. The clinical approach towards chondrosarcoma. Oncologist 2008;13: 320-329.







FIGURE 8.19 Gross specimen of chondrosarcoma. The tumor occupies much of the medulla and has the pearly white and lobular appearance of cartilage. Note the endosteal scalloping.

Secondary central chondrosarcoma is a chondrosarcoma arising in a preexisting enchondroma. Although the risk of malignant transformation in solitary enchondroma is estimated to be very low (<1%), patients with Ollier disease and Maffucci syndrome have a markedly increased risk of developing secondary chondrosarcomas (18% to 46%) (24). IDH mutations are found in 86% of secondary central chondrosarcomas. Radiologic, macroscopic, and histologic features are identical to primary central chondrosarcoma.

Secondary peripheral chondrosarcoma arises in a preexisting osteochondroma. A minority of chondrosarcomas (up to 15% in referral centers) develop through malignant transformation within the cartilage cap of a preexisting osteochondroma (Fig. 8.20) (13,45). Secondary peripheral chondrosarcoma is mainly found in the ilium (19%), scapula (15%), tibia (12%), femur (11%), pubic bone (10%), and ribs (10%). The radiologic and gross macroscopic documentation of the thickness of the cartilaginous cap is extremely important in the distinction of osteochondroma and secondary peripheral chondrosarcoma, as a cartilage cap exceeding 1.5 to 2 cm in adults is suggestive of malignancy (1,4). Histologically, central and peripheral chondrosarcomas are similar and three grades are applied, which correlate with outcome, as described in the following section.

Although for osteochondroma formation inactivation of the EXT1 or EXT2 genes is required, most secondary peripheral chondrosarcomas arising in osteochondroma are EXT wild-type, indicating that EXT is not important for malignant transformation and that the nonmutated cells in osteochondroma are more vulnerable for as yet unknown (epi)genetic changes promoting them to become malignant (46).


Histologic Grading of Conventional Chondrosarcoma.

Both conventional central and peripheral chondrosarcomas are histologically classified in three grades using the criteria of Evans et al. (1,11). Histologic grade is thus far the best predictor of clinical behavior. What was previously called central chondrosarcoma grade 1 has now been renamed atypical cartilaginous tumor (1), and the histology shows an abundance of predominantly hyaline cartilaginous matrix in which chondrocytes with small, condensed nuclei are seen. Atypical cartilaginous tumor/chondrosarcoma grade 1 (ACT/CS1) is distinguished from enchondroma by its higher cellularity, irregular distribution of the cells, and the occurrence of binucleated cells. An important criterion is the growth pattern, in which the presence of entrapment (of preexisting lamellar bone) (Fig. 8.10) (18,20) and the absence of encasement (Fig. 8.7) favor ACT/CS1 over enchondroma (18). Also, the presence of more than 20% mucomyxoid change of the matrix is an important argument for the diagnosis of ACT/CS1 (20). For the distinction between osteochondroma and secondary peripheral chondrosarcoma, no reliable histologic criteria could be identified, indicating the diagnosis can only be made in a multidisciplinary team setting, taking the thickness of the cartilaginous cap into account (Fig. 8.20) (4). In grade 2 chondrosarcomas, the cellularity and nuclear atypia are increased, and mitoses, although scarce, can be seen. The matrix becomes more mucomyxoid (Fig. 8.21). In grade 3 chondrosarcomas, the cellularity is high, with nuclear atypia, and mitoses are even more easily identified (Fig. 8.22). At the periphery of the lobules, spindle cell change may occur (11). The 10-year survival of grade 1, 2, and 3 tumors is 83%, 64%, and 23%, respectively (11). ACT/CS1 has a relatively high chance of recurrence in case of incomplete resection but only rarely metastasizes, whereas 10% of grade 2 tumors and 71% of grade 3 tumors metastasize (10,47). However, in approximately 13% of recurrent chondrosarcomas, progression to a higher grade of malignancy is observed (11,48). Because considerable heterogeneity may occur in chondrosarcoma, it is important to
select several areas to be submitted for histology. The tumor needs to be graded based on those areas demonstrating the highest grade. Also, histologic grading has been shown to be subject to interobserver variability (19,20). An absolute correlation between histology and biologic behavior is lacking. This is especially true for the chondrosarcomas of the phalanges, in which the histology can be highly malignant but the behavior indolent. Grading of phalangeal chondrosarcomas therefore does not seem useful (16).






FIGURE 8.20 Secondary peripheral chondrosarcoma. Lobules of tumor cartilage separated by fibrous tissue are seen invading soft tissue.






FIGURE 8.21 Grade 2 chondrosarcoma. The cellularity is increased and myxoid change of the matrix can be seen (right).


Periosteal Chondrosarcoma

Periosteal chondrosarcoma is a malignant hyaline cartilage tumor, which occurs on the surface of bone and originates from the periosteum (1). The tumor is extremely rare (<1% of chondrosarcomas) and is mainly found in the metaphysis of the femur or humerus in young adults, preferentially in males, with the highest incidence in the fourth decade of life. Radiologically, the tumor presents as a large lobular mass (often >5.5 cm) located on the cortex, with irregular borders (Fig. 8.23) (49). The histology is very similar to conventional chondrosarcoma, displaying well-differentiated lobular cartilage with extensive areas of secondary calcifications and endochondral ossification. Osteoid or bone directly formed by the tumor cells is absent. Bone marrow invasion is rare. The demarcation with the soft tissue is indistinct, occasionally with infiltrative growth into the soft tissues. Erosion and invasion of the underlying cortex is usually seen and distinguishes periosteal chondrosarcoma from periosteal chondroma (Fig. 8.24) (26). Moreover, periosteal chondrosarcoma often has a larger tumor diameter (>5 cm) (27). Periosteal chondrosarcomas also need to be distinguished from secondary peripheral chondrosarcomas, in which the medulla of the underlying bone is contiguous with that of the stalk of the lesion, whereas in periosteal chondrosarcoma, the underlying cortex can usually still be recognized. In the differential diagnosis, periosteal (chondroblastic) osteosarcoma should also be considered. Periosteal osteosarcoma, which is often of the chondroblastic subtype, has a much worse prognosis (26,50).
Within periosteal osteosarcomas, by definition, direct deposition of osteoid by tumor cells is seen. Moreover, the cartilaginous areas in periosteal osteosarcoma display considerable nuclear pleomorphism, whereas this is usually limited in chondrosarcoma.






FIGURE 8.22 Grade 3 chondrosarcoma. The neoplasm contains highly cellular areas with spindle cell change.






FIGURE 8.23 Periosteal chondrosarcoma of the proximal humerus. A well-circumscribed cartilage mass on the bone surface producing erosion of the underlying cortex.






FIGURE 8.24 Periosteal chondrosarcoma. Low- and highly cellular areas, myxoid change of the matrix, and cortical invasion (right).


Dedifferentiated Chondrosarcoma

Dedifferentiated chondrosarcoma is a highly malignant variant of chondrosarcoma, characterized by the occurrence of two clearly defined components: a well-differentiated cartilaginous tumor, either an enchondroma, ACT/CS1, or grade 2 chondrosarcoma, juxtaposed to a high-grade noncartilaginous sarcoma. There is a histologically abrupt transition between the two components (Fig. 8.25) (1). Dedifferentiated chondrosarcoma comprises about 10% of all chondrosarcomas. Dedifferentiated chondrosarcomas are usually central, as dedifferentiated chondrosarcoma arising in osteochondroma is extremely rare (51). Patients are often older than 50 years, and males and females are equally affected. The lesion is most often located in the pelvic bones, proximal femur or humerus, distal femur, or the ribs. The prognosis is unfavorable, irrespective of treatment (52). The metastases typically only show the high-grade anaplastic component. The sharp transition between the two components is an important criterion in the distinction between grade 3 chondrosarcoma (in which the cells at the edge of the lobules show a gradual transition toward more cellular spindle-shaped cells) and dedifferentiated chondrosarcoma. The non-cartilaginous, anaplastic component can show characteristics of undifferentiated pleomorphic sarcoma, osteosarcoma, fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma, or angiosarcoma. The demonstration of the presence of a low-grade cartilaginous component is crucial for the distinction; however, on biopsy specimens, one of the components can be absent. Radiologic correlation is therefore crucial in the diagnosis. Radiology of the resection specimen can be of help, and extensive sampling for histologic examination is required. Macroscopically, the different components can often clearly be identified at the cut surface of the resection specimen. The rare genetic reports on dedifferentiated chondrosarcoma demonstrate that both components share identical genetic aberrations with additional genetic changes in the anaplastic component (53), indicating a common precursor cell with early diversion of the two components. Approximately 50% of dedifferentiated chondrosarcomas carry mutations in IDH1 or IDH2 in both components (23,28,54). The demonstration of an IDH mutation may confirm the diagnosis of dedifferentiated chondrosarcoma in case the biopsy specimen only shows the anaplastic component, whereas the radiology suggests the presence of a low-grade cartilaginous component as well.






FIGURE 8.25 Dedifferentiated chondrosarcoma. There is an abrupt transition between the conventional low-grade cartilaginous component (lower half) and the high-grade spindle cell sarcoma (upper half). Note the permeative growth pattern.


Mesenchymal Chondrosarcoma

Mesenchymal chondrosarcoma is a rare malignant neoplasm characterized by a biphasic pattern that is composed of poorly differentiated small round cells and islands of well-differentiated hyaline cartilage (1). Mesenchymal chondrosarcoma comprises about 2% of all chondrosarcomas. The tumor can be found at all ages, with a peak in the second and third decades, without a gender predilection (55). The majority (65% to 86%) of mesenchymal chondrosarcomas is located in the skeleton, especially in the lower extremities such as the femur; facial bones; and the pelvis (55). A minority of cases (14% to 34%) are of extraosseous origin, in which the meninges and lower extremities are most often affected (55). Mesenchymal chondrosarcomas are in general of high-grade malignancy, with a 10-year survival of less than 30% (56). In contrast to conventional chondrosarcoma, metastases to lymph nodes and other bones are common (56). Radiologically, a lytical and destructive lesion is seen, with spotlike calcifications, resembling a conventional chondrosarcoma (55). Histologically, mesenchymal chondrosarcoma is characterized by the presence of areas with usually well-differentiated cartilage mixed with highly vascular, cellular areas containing undifferentiated small spindle-shaped or round cells with scant cytoplasm, with a hemangiopericytoma-like vascular pattern (Fig. 8.26) (55). Mitoses can be observed. The cartilaginous areas are often relatively small, sharply demarcated, and cytologically benign or low grade (55). The
small cell component is positive for SOX9 and variably for CD99 and can show expression of desmin. The undifferentiated small cell areas may morphologically resemble Ewing sarcoma, and both tumors contain cytoplasmic glycogen (57). However, by definition, cartilage is absent in Ewing sarcoma. Furthermore, small cell osteosarcoma and dedifferentiated chondrosarcoma should also be considered in the differential diagnosis. Irregular fine trabecular deposition of osteoid, characteristic of small cell osteosarcoma, and a sharp demarcation between the two components, characteristic of dedifferentiated chondrosarcoma, are absent in mesenchymal chondrosarcoma (55). A recurrent HEY1-NCOA2 fusion has been identified in mesenchymal chondrosarcoma (58). When the cellular, undifferentiated component predominates, the tumors can be sensitive to chemotherapy and radiation (56).






FIGURE 8.26 Mesenchymal chondrosarcoma. The neoplasm is formed by areas with more or less differentiated cartilage mixed with vascular, cellular areas containing undifferentiated small spindleshaped or round cells with scant or no cytoplasm.


Clear Cell Chondrosarcoma

Clear cell chondrosarcoma is a rare, low-grade variant of chondrosarcoma with a predilection for the epiphyseal ends of long bones. It is characterized histologically by bland clear cells, resembling the hypertrophic cells in the growth plate, in addition to hyaline cartilage (1). The tumor comprises about 2% of all chondrosarcomas and is often found in adults, with a slight male predominance and a peak in the third and fourth decades (59). Similar to chondroblastoma, the proximal parts of the femur, humerus, or tibia are most often affected. Radiologically, the lesion is located in the epiphysis, can be lytic, and demonstrates expansile growth, often with a sharp border (Fig. 8.27) (59,60). Macroscopically, the tumor is distinguished by the absence of the typical glassy white-gray aspect of conventional chondrosarcoma but is red and granular, occasionally with cavities. Histologically, round cells are seen with large round nuclei with centrally located nucleoli and clear empty cytoplasm with sharp cell borders; the tumor cells are positive for S100 (Fig. 8.28) (59,61). Throughout the lesion, metaplastic woven bone is regularly deposited, and osteoclast-like giant cells are present. Mitoses are rare. Focally, a hyaline cartilaginous matrix or even areas of more conventional chondrosarcoma can be observed. Areas of cystic degeneration resembling aneurysmal bone cyst are often seen. Owing to its epiphyseal location, chondroblastoma is often raised in the differential diagnosis, although clear cells are rare or absent in chondroblastoma. Metastasis of (renal) clear cell carcinoma should be considered in the differential diagnosis, in which case immunohistochemistry for keratin and PAX8 may be helpful. IDH mutations are absent (23). Clear cell chondrosarcomas often recur after curettage or marginal excision, whereas metastases are rare.






FIGURE 8.27 Clear cell chondrosarcoma of the proximal humerus. The lesion is heavily mineralized, extends to the end of the bone, and appears well circumscribed.

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Sep 22, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Bone Tumors
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