BONE Normal anatomy Adult bones Classification according to shape: 1. Long (such as femur) 2. Flat (such as pelvis) 3.

Short (such as bones of hand and feet) Long bones (and some short bones such as metacarpal bones) three regions: 1. Diaphysis- shaft 2. Epiphysis- both ends of the bone 3. Metaphysis- junction of the diaphysis and epiphysis Epiphyseal plate (epiphyseal disk, physis) where endochondral ossification takes place- a process by which longitudinal, regularly spaced columns of vascularized cartilage are replaced by bone. Bone has reached its adult length- this process ends, and the epiphysis closes by becoming totally ossified. Most common site of occurrence of most primary bone tumors Classification according to embryologic development: 1. Membranous (such as the skull) - if formed de novo from primitive connective tissue 2. Endochondral (such as long bones) - if their formation is preceded by a cartilaginous anlage Mature bones are seen formed by: 1. Outer compact layer (cortex, cortical bone, compact bone) Vascular channels: i. longitudinal (haversian canals) ii. transverse/oblique (Volkmann canals) Except for the region of the articular cartilage: the cortex Surrounded by the periosteum which consists of an outer fibrous layer and an inner cellular (cambium) layer of osteoprogenitor cells (fibroblasts and osteoblasts). Contains nerve filaments that carry proprioceptive and sensory impulses. Sharpey fibers or perforating fibers - Coarse bundles of collagenous fibers penetrating the outer compact layer from the outer layer of the periosteum

2. Central spongy region (spongiosa, medulla, cancellous bone) Blood supply of bone: 1. Metaphysis - mainly supplied by end arteries that enter from the diaphysis and terminate at the level of the epiphyseal plate. The metabolic exchange of calcium and phosphorus occurs

2. Epiphyses - from a network of widely anastomosing vessels 3. Diaphyseal cortex - vessels that enter through Volkmann canals and communicate with the haversian system Osteoblasts bone-producing cells derived from marrow-residing mesenchymal cells Plump appearance and often exhibit a perinuclear halo resulting from a prominent Golgi zone that gives them a resemblance to plasma cells High cytoplasmic content of alkaline phosphatase. Regarded as a specialized (sophisticated) form of fibroblast Osteocytes - Once these are incorporated into the bone matrix and housed in lacunae Osteoclasts Multinucleated giant cells involved in bone resorption and bone remodelling Often are found in shallow concavities in the surface of bone called Howship lacunae Arise from mononuclear monocytemacrophage precursors. Contain abundant tartrate-resistant acid phosphatase, respond to osteotropic hormones, and contract under the influence of calcitonin. Express osteoclast-specific antigens (detected by monoclonal antibodies 13c2 and 23c6) and various matrix metalloproteinases; Unreactive for T-cell antigens, most myeloid antigens, and mature macrophage antigens. Ultrastructure: a ruffled edge is present in the area of the cell membrane that is in the process of bone resorption. Osteoid Unmineralized organic precursor matrix of bone. Composed of a mixture of collagen (mainly type I), acid mucopolysaccharides, and noncollagen protein: osteopontin, osteocalcin, and bone morphogenetic protein - is play a critical role in initiating the process that begins with cartilage resorption and ends with bone formation Bone is formed through mineralization of the organic matrix of the osteoid. In woven bone (fiber bone) o haphazard arrangement of collagen fibers within the matrix, which is best appreciated with reticulum stains or under polarized light.

o Formation of woven bone is the key criterion for the diagnosis of fibrous dysplasia, but it also appears in any condition associated with accelerated bone turnover, such as the callus of a healing fracture or osteitis fibrosa cystica. Normal skeletal growth results from a balance between the processes of bone matrix synthesis and resorption, these activities being regulated by systemic and local factors: 1. Transforming growth factor (TGF)- activity - important for bone matrix production. 2. Vitamin D and parathyroid hormone (PTH) 3. Molecules thought to regulate the growth plate thickness and bone length through their action on chondrocytes during endochondral ossification: Fibroblast growth factor receptor-3 PTH-related protein Tartrate-resistant acid phosphatase 4. Proteins act as negative regulators of bone cell function: Osteoclasts eosteoprotegerin Osteoblasts - osteocalcin, bone sialoprotein, and 5-lipoxygenase Bone necrosis Lacunar cells are absent, and the margins of the bone are ragged. The presence of osteoclasts on these margins indicates that the necrotic bone is already being reabsorbed. Bone production Presence of well-stained small spicules of bone with cells in their lacunae and a prominent row of osteoblasts along their margins. Bone resorption (destruction) Presence of numerous osteoclasts in the bone margins and in Howship lacunae. It can involve necrotic bone, as indicated above, or viable bone, as in osteitis fibrosa cystica. Metabolic bone diseases 1. Osteoporosis Decreased mass of normally mineralized bone. Quantitative microradiographic studies : Increase in the amount of resorption, bone formation levels being generally normal. Osteoporosis occurs frequently after menopause : estrogen deficiency Fluoride consumption : important prevention 2. Osteomalacia (comparable to rickets in a young person in whom the epiphyses are not yet closed)

 Accumulation of unmineralized bone matrix resulting from a diminished rate of mineralization. Secondary to congenital and acquired metabolic abnormalities that result in sufficient decrease in serum calcium, phosphorus, or both to impair mineralization of the skeleton and epiphyseal growth As a complication of bone and soft tissue neoplasms Fractures Breaks in the continuity of bone, usually with severance of periosteum, blood vessels, and sometimes muscles. Following a fracture, a hematoma forms between the two severed ends of bone. Organization of this hematoma begins with the ingrowth of young capillaries. After about 3 days, the devitalized bone fragments begin to be reabsorbed. Intramembranous bone growth makes its appearance from the inner layer of the periosteum, both proximal and distal to the fracture site. The newly formed trabeculae begin to calcify as the cartilage is replaced by bone. This process on each side of the fracture meets at the fracture site to form the primary callus. This is later reabsorbed and replaced by the secondary callus, which is made up of mature lamellar bone. The new bone is laid down predominantly along lines of stress. Osteomyelitis Bacterial osteomyelitis o 7090% of the cases are due to coagulase-positive staphylococci. o Other organisms involved are Klebsiella, Aerobacter, Proteus, Pseudomonas, Streptococcus, pneumococcus, gonococcus, meningococcus, Brucella, and Salmonella. Garre osteomyelitis, sclerosing osteomyelitis, or periostitis ossificans: o A variant of osteomyelitis characterized by very extensive regenerative bone changes , particularly common in the jawbone Microscopically: Admixture of inflammatory cells (including neutrophils, lymphocytes, and plasma cells), fibrosis, bone necrosis, and new bone formation. Plasma cell osteomyelitis : When the plasma cell population is particularly prominent. Xanthogranulomatous osteomyelitis :When foamy macrophages are abundant. Chronic osteomyelitis may be accompanied by prominent periosteal bone proliferation. Tuberculous osteomyelitis o Hematogenous infection is usually seen in young adults or children o Most often infected are the vertebrae, pelvis, knee, ankle, elbow, and wrist. o Areas usually involved are the metaphysis, epiphysis, and synovium.

 Fungal infections of bone: o blastomycosis, actinomycosis, histoplasmosis, and coccidioidomycosis. o Actinomycosis is particularly common following osteoradionecrosis. Tertiary syphilis o may involve the bone and cause both osseous destruction and production, often in association with conspicuous periosteal bone proliferation .The necrotic, well-defined defects are mainly cortical and periosteal, and are surrounded by sclerotic bone. Bone necrosis Infarct Radiographically: Resorption of the dead bone results in areas of decreased density, whereas new bone formation growing in apposition to dead trabeculae (creeping apposition) leads to an increase in bone density. The process of reossification is often irregular, and the combination of incomplete resorption of dead bone and focal deposition of new bone results in a mottled and irregular radiographic appearance . Aseptic (avascular) bone necrosis OsgoodSchlatter disease - for necrosis of the tibial tuberosity. LeggCalvPerthes disease - for necrosis of the upper femoral epiphysis. Pathogenetic mechanism : interruption of the blood supply induced in most cases by a mechanical disruption, such as fracture or dislocation. Microscopically: osteoclastic activity on one side of the dead trabeculae and osteoblastic activity on the other. Osteochondritis dissecans Results from a small area of necrosis involving the articular cartilage and subchondral bone that totally or partially separates from the adjacent structures. It occurs most frequently on the lateral aspect of the medial femoral condyle, near the intercondylar notch (Fig. 24.9). Microscopically: a portion of articular cartilage is always present, often exhibiting secondary calcification.

Radiation necrosis Radiation changes resulting in serious complications have been reported in the jaw, ribs, pelvis, spine, humerus, and several other bones. Microscopically: consist of necrotic bone, fibrosis of the bone marrow, and neovascularization. Paget disease About 90% of the patients are over 55 years of age. The most common sites are the lumbosacral spine, pelvis, and skull. It may also occur in the femur, tibia, clavicle, radius, ulna, fibula, and jaws, but is extremely rare in the ribs. Basic abnormality of Paget disease is a focal acceleration of bone turnover. The initial lesion is osteoclastic and therefore lytic (osteoporosis circumscripta). Abnormal hyperplasia soon follows, as evidenced by the deposition of primitive coarsefibered bone in discontinuous trabeculae, which in turn is replaced by thick trabeculae with a disjointed lamellar pattern The disorganization in the structure of the lamellar bone leads to the formation of cement lines. Two important complications of Paget disease: o fractures o development of bone tumors. Bone sarcoma in Paget disease (so-called Paget sarcoma): low o Osteosarcoma is the most common type (about 80% of all cases) Osteopetrosis AKA: AlbersSchnberg disease;marble-bone disease defect in bone remodeling secondary to malfunction or, less commonly, failure of development of osteoclasts. Cause: encoding molecules involved in acidification machinery (e.g., proton pump vacuolar ATPase, chloride channel and carbonic anhydrase II) and those affecting osteoclast differentiation which result in the osteoclast-poor form of the disease (e.g., IKBKG, RANK, RANKL). Microscopically: persistence in the marrow cavity of unresorbed osteocartilaginous matrix. Tumors Benign bone lesions that predispose the patient to the development of skeletal malignancies: o Paget disease, chondromatosis, osteochondromatosis, fibrous dysplasia, osteofibrous dysplasia, and osteogenesis imperfecta.

Bone-forming tumors Osteoma Almost exclusively in the flat bones of the skull and face, where it has been divided into central and peripheral (periosteal) It may protrude inside a paranasal sinus (particularly the frontal and ethmoid) and block the normal drainage from these sinuses. Microscopically: composed of dense, mature, predominantly lamellar bone. Osteoid osteoma Benign bone neoplasm (between 10 and 30 years of age) Intense pain is the most prominent symptom; o this is often sharply localized and unaccompanied by clinical or laboratory evidence of infection. o characteristically more intense at night, relieved by nonsteroidal antiinflammatory drugs such as aspirin, and eliminated by excision of the lesion Occurs most frequently in the femur, tibia, humerus, bones of the hands and feet, vertebrae, and fibula. Radiographically: the typical finding is a radiolucent central nidus that is seldom larger than 1.5 cm and that may or may not contain a dense center. Osteoblastoma (benign osteoblastoma, giant osteoid osteoma) Tumor closely related to osteoid osteoma. Distinguished by larger size of the nidus, the absence or inconspicuousness of a surrounding area of reactive bone formation, and the lack of intense pain. The majority of the cases are located in the spine or major bones of the lower extremity Osteomalacia can be seen as a complication. Osteosarcoma Most frequent primary malignant bone tumor, exclusive of hematopoietic malignancy. Bet. 10 and 25 years of age Another: peak age incidence occurs after 40, in association with other disorders. Predisposing factors: 1 2 3 4 5 6 7 Paget disease Radiation exposure Chemotherapy Preexisting benign bone lesions: fibrous dysplasia, osteochondromatosis, chondromatosis, and osteogenesis imperfecta Foreign bodies: arising at the site of a total hip replacement or at sites of other orthopedic implants. Trauma Genetic predisposition: Patients with Li-Fraumeni syndrome (usually caused by germline mutation of the TP53 gene), hereditary retinoblastoma (caused by germline mutation of the

RB1 gene), RothmundThomson syndrome, Werner syndrome, and familial Paget disease have an increased risk of developing osteosarcoma. Location: Most osteosarcomas arising de novo are located in the metaphyseal area of the long bones, particularly the lower end of the femur, the upper end of the tibia, and the upper end of the humerus. Gross appearance and spread From its usual origin in the metaphysis of a long bone, the tumor may: 1 2 3 Spread along the marrow cavity Invade the adjacent cortex. Elevate or perforate the periosteum Radiographic sign: Codman triangle - The two long sides of this triangle are formed by the elevated periosteum and the underlying bone; the space within them is mainly occupied by reactive new bone, arranged perpendicular to the bone surface. Extend into the soft tissues Extend into the epiphysis Extend into the joint space Form satellite nodules independent from the main tumor mass proximal to the primary lesion, either in the same bone or transarticularly - called skip metastases Metastasize through the bloodstream to distant site: Four main sites of metastases were lung (98%), other bones (37%), pleura (33%), and heart (20%).

4 5 6 7 8

Histochemical: exhibit strong alkaline phosphatase activity Electron microscopic features: osteoblastic or fibroblastic- feature of diagnostic value Ultrastructurally: cells resemble normal osteoblasts in their abundance of dilated cisternae of granular endoplasmic reticulum and sparse mitochondria CARTILAGE FORMING TUMORS I. CHONDROMA is a common benign cartilaginous tumor that occurs most frequently in the small bones of the hands and feet, particularly the proximal phalanges. Microscopically: chondromas are composed of mature lobules of hyaline cartilage Foci of myxoid degeneration, calcification, and endochondral ossification are common. Juxtacortical chondroma tends to be more cellular than its medullary counterpart and may contain occasional plump or double nuclei.

Ollier disease- refers to multiple enchondromas having a predominantly unilateral distribution Ollier disease is also associated with ovarian sex cord-stromal tumors Maffucci syndrome- the association of multiple enchondromas with soft tissue hemangiomas (including spindle cell hemangioendotheliomas) In both conditions, there is a significant risk of malignant transformation, usually in the form of chondrosarcoma,sometimes developing in multiple bones Chondromas are usually asymptomatic but may cause bone deformity, pain and fracture Enchondromastumors within the bone that begin in the spongiosa of the diaphysis from which they expand and thin the cortex. Juxtacortical (periosteal) chondromas are much less common than enchondromas; Origin: periosteal region of a long bone or a small bone of the hand or foot They characteristically erode and induce sclerosis of the contiguous cortex Cartilaginous and vascular hamartoma (mesenchymoma) A peculiar chest wall lesion of infancy which is benign and cartilaginous Exhibit endochondral ossification mixed with spindle areas with an aneurysmal bone cyst-like appearance II. OSTEOCHONDROMA AND RELATED LESIONS Osteochondroma is the most frequent benign bone tumor usually asymptomatic, but it may lead to deformity or interfere with the function of adjacent structures such as tendons and blood vessels may also undergo spontaneous regression The most common locations are metaphyses of the lower femur, upper tibia, upper humerus, and pelvis. The radiographic appearance is very characteristic; one of the most typical features is the fact that the lesions, when located in metaphyses of long bones, grow out in a direction opposite to the adjacent joint.

Average age at onset : app. 10 years ( before the patient is 20 years old. ) Average greatest diameter : app. 4 cm ( others may reach sizes of 10 cm or more.) Smaller tumors sessile; larger-pedunculated. Morphologically:

 Mushroom-shaped protrusions, covered by perichondrium which overlies a cap of hyaline cartilage. This cap is usually lobulated and usuallu undergoes enchondral osssification The bulk of the lesion is made up of mature bone trabeculae located beneath the cartilaginous cap and containing normal bone marrow. .

Osteochondromatosis (multiple cartilaginous exostoses, Ehrenfried hereditary deforming chondrodysplasia, diaphyseal aclasis ) caused by germline mutation in the EXT1 (at 8q24) or EXT2 (at 11p11p12) gene upregulation of PTHrP and BCL2 expression Associated with the progression of osteochondroma to chondrosarcoma

Bizarre parosteal osteochondromatous proliferation (Nora lesion), may occur in the bones of the hands and feetand occasionally in long bones radiographically distinctive but can simulate chondrosarcoma microscopically because of the presence of enlarged, bizarre, and binucleated chondrocytes Subungual exostosis (Dupuytren exostosis) is usually located on the great toe It is thought to represent a different entity from osteochondromas but is also composed of a proliferating cartilaginous cap that merges into mature trabecular bone at its base. Dysplasia epiphysealis hemimelica (Trevor disease) a rare developmental disorder of childhood asymmetric enlargement of the epiphyseal cartilage of long bones, is yet another condition that can mimic osteochondroma. III. CHONDROBLASTOMA More common in males under 20 years of age, and it can be quite painful. Uncommon and benign It usually arises in the epiphyseal end of long bones before the epiphyseal cartilage has disappeared, particularly in the distal end of the femur, proximal end of the humerus, and proximal end of the tibia A distinctive microscopic change is the presence of small zones of focal calcification. These zones range from a network of thin lines (chicken wire) to obvious deposits surrounded by giant cells. By electron microscopy

often have a prominent fibrous lamina lying against the inner aspect of the nuclear membrane, resulting in the membrane thickening

Cytoplasmic glycogen abundant + Proteoglycans and calcium in the extracellular matrix. Diagnosis : Fine needle aspiration which in a typical case will consist of neoplastic chondroblasts, multinucleated osteoclast-like giant cells, and chondroid matrix fragments. Curetting with bone grafting: preferred treatment

IV. CHONDROMYXOID FIBROMA AND RELATED TUMORS Chondromyxoid fibroma It usually occurs in a long bone of a young adult, but it has also been reported in the small bones of the hands and feet, pelvis, ribs, vertebrae, and skull base Grossly: it is solid and yellowish white or tan, replaces bone, and thins the cortex. Microscopically: comprises hypocellular lobules with a myxochondroid appearance, separated by intersecting bands of highly cellular tissue composed of fibroblast-like spindle cells and osteoclasts Calcification may occur, particularly in the juxtacortical variant Immunohistochemical reactivity for S-100 protein is the rule The basic cartilaginous nature of this tumor has been demonstrated through its immunoreactivity for Sox9 (an essential regulator of chondrogenesis) and further supported by the presence of type II collagen. In contrast to chondroblastoma, it is consistently negative for keratin. Treatment : en bloc excision is recommended whenever possible Soft tissue extension or implantation may occur, but distant metastases have not been reported. Fibromyxoma is microscopically similar to chondromyxoid fibroma but lacks cartilaginous areas and tends to occur in older individuals. Myxoma of long bones characterized by an expansile radiographic appearance, distal location, benign behavior, and microscopic appearance similar to soft tissue myxoma.

V. CHONDROSARCOMA a malignant tumor of cartilage-forming tissues divided into two major categories on the basis of microscopic criteria: a. conventional chondrosarcoma Majority are between 30 and 60 years of age. In children - uncommon tends more often to be located in the extremities than its adult counterpart b. chondrosarcoma variants. Types of Chondrosarcomas according to location a. Central chondrosarcomas Located in the medullary cavity, usually of a flat or long bone Radiographic appearance present a rather characteristic picture of an osteolytic lesion with splotchy calcification Ill-defined margins, fusiform thickening of the shaft, and perforation of the cortex are three important diagnostic signs. The pelvic bones, ribs (usually at the costochondral junction), and shoulder girdle are the most common locations. Chondrosarcoma can also involve the bones of the skull Osteochondromatosis is particularly prone to this complication, as already indicated. The signs of malignancy in an osteochondroma include increased growth during adolescence diameter over 8 cm cartilaginous cap that is irregular and thicker than 3 cm. Radiographically: present as large tumors, with a heavily calcified center surrounded by a lesser denser periphery with splotchy calcification Malignant change should be suspected radiographically in an osteochondroma if the cartilage cap has irregular margins or if there are lucent zones within the lesion.

C. Juxtacortical (periosteal) chondrosarcoma involves the shaft of a long bone (most often the femur) and is characterized by a cartilaginous lobular pattern with areas of spotty calcification and endochondral ossification. In well-differentiated chondrosarcoma, the nuclei are plump and hyperchromatic; there may be two or more nuclei per cell and two or more cells per lacuna have emphasized permeation of the bone marrow with trapping of host lamellar bone on all sides in welldifferentiated chondrosarcoma as an important sign in the differential diagnosis with chondroma. Large tumors of the long bones or ribs or those that begin to grow rapidly over adolescence and reach a size of 8 cm or more are almost invariably malignant. Chondrosarcoma is distinguished from osteosarcoma by the lack of direct osteoid or bone formation by the tumor cells. Histochemically, well-differentiated chondrosarcomas have a staining reaction similar to that of adult cartilage, whereas poorly differentiated tumors resemble fetal cartilage Ultrastructurally, the cells of well-differentiated tumors show cytoplasmic accumulation of glycogen, lipid droplets, and dilated cisternae of granular endoplasmic reticulum. Immunohistochemically (+) reactivity for S-100 protein, estrogen receptors, and Sox9, the latter being an essential regulator of chondrogenesis

BCL2 is positive (50%), whereas it is negative in 95% of osteochondromas. Chondrosarcomas also show positivity for MCM6 (minichromosome maintenance protein) and CXCR4, the degree of staining being related in both instances to the tumor grade.

The surprising claim has been made that ezrin (a cytoskeletal linker protein) is consistently absent in chondrosarcoma while often present in osteosarcoma, including the chondroblastic subtype of this tumor. Management Complete excision

common denominator of the 3 types being the production of a cartilaginous matrix and the lack of direct bone formation by the tumor cells.

Chondrosarcoma variants 1. Clear cell chondrosarcoma characterized by tumor cells with an abundant clear or ground glass cytoplasm and sharply defined borders, often interspersed with small trabeculae of woven bone. exhibits immunoreactivity for S-100 protein and collagens types II and X (but not I).

Most patients are older than those affected by chondroblastoma. Radiographically, the lesion is usually entirely lytic, slightly expansile, and sharply marginated.

Most of the cases have involved the proximal end of the femur or humerus, and the behavior has generally been that of a low-grade malignancy, with some outstanding exceptions 2. Myxoid chondrosarcoma (chordoid sarcoma) occur in bone but is much more common in the soft tissues It is morphologically reminiscent of chordoma because of the rows of cuboidal cells separated by a myxoid background. Reactive for for S-100 protein and vimentin but, in contrast to chordoma, is negative for keratin. 3. Dedifferentiated chondrosarcoma refers to the presence of a poorly differentiated sarcomatous component at the periphery of an otherwise typical low-grade chondrosarcoma. acquire immunohistochemical positivity for a1-antichymotrypsin, actin, desmin, myoglobin, myogenin, and exceptionally even keratin. At the molecular level, the process of anaplastic transformation is accompanied by overexpression of TP53 and HRAS mutation.

Mesenchymal chondrosarcoma a specific variant of chondrosarcoma characterized microscopically by a dimorphic pattern in which areas of well-differentiated cartilage alternate with undifferentiated stroma pleomorphism and mitotic activity are inconspicuous. Immunohistochemically, the small cell component is positive for vimentin, CD99, and Leu7 but not for S-100 protein There is also nuclear immunoreactivity for Sox9 (a master regulator of chondrogenesis), osteocalcin, desmin and myogenin

Most patients are females in the second or third decade of life. The bones most commonly affected are the jaw, pelvis, femur, ribs, and spine. A high percentage of these neoplasms involve extraosseous structures, such as the orbit, paraspinal region, meninges, or soft tissues of the extremities.The prognosis is generally poor, although there is great variability in the clinical course.

Granular cell chondrosarcoma tumor of the humerus which combined in a biphasic fashion the typical features of a well-differentiated chondrosarcoma with those of an equally typical granular cell tumor. Interestingly, the latter component metastasized to the lung.

GIANT CELL TUMOR usually seen in patients over 20 years of age. It is more common in women than in men The classic location is the epiphysis of a long bone, from which it may spread into the metaphyseal area, break through the cortex, invade intermuscular septa, or even cross a joint space. The sites most commonly affected (in order of frequency) lower end of the femur the upper end of the tibia lower end of the radius Multicentricity has been reported, particularly in young patients and in the small bones of hands and feet Radiographically: entirely lytic, expansile lesion in the epiphysis, usually without peripheral bone sclerosis or periosteal reaction

Microscopically, the two main components of giant cell tumor a. stromal cells neoplastic; the only proliferating component a. giant cells- non- neoplastic elements but rather the result of fusion of circulating monocytes that have been recruited into the lesion. Treatment should be surgical whenever technically feasible. It consists of curettage with bone grafting or en bloc excision with replacement with allograft or artificial material, depending on the location. The natural history of giant cell tumor is that of a low-grade malignancy.

Malignant giant cell tumor a lesion that retains the clinical, topographic, and general microscopic features of giant cell tumor but that exhibits clearcut evidence of malignancy in the mononuclear stromal component (equivalent to a grade III giant cell tumor. )

MARROW TUMORS 1. Ewing Sarcoma/Primitive Neuroectodermal Tumor (PNET) Characterized by the presence of the gene fusion, resulting from the 11;22 chromosomal translocation Clinical Features o Occurs between ages of 5 and 20 years o occurs most often in long bones and in bones of the pelvis, rib, vertebrae, mandible, and clavicle o arises in the medullary canal of the shaft from which it permeates the cortex and invades the soft tissues o tumor arose in the medullary canal and that it diffusely permeated the marrow spaces to extend outside the bone without destroying a significant amount of bone trabeculae o radiographic changes cortical thickening and widening of the medullary canal reactive periosteal bone may be deposited in layers parallel to the cortex (onionskin appearance) or at right angles to it (sun-ray appearance) Microscopic Features o solid sheets of cells divided into irregular masses by fibrous strands o cell outlines are indistinct, resulting in a syncytial appearance o nuclei are round, with frequent indentations, small nucleoli, brisk mitotic activity o tumor cells may arrange themselves around the vessels in a pseudorosette fashion o Some tumors are composed of larger and more pleomorphic cells exhibiting conspicuous nucleoli (so-called large cell or atypical variant) while other tumors display an organoid pattern characterized by bicellular strands of tissue separated by a filmy vascular stroma, referred to as the filigree pattern Histochemical, Electron Microscopic, and Immunohistochemical Features o contain large amounts of cytoplasmic glycogen o positivity for vimentin,and reactivity for low-molecular-weight keratin and other epithelial markers Spread and Metastases o metastatic spread of ES/PNET is to the lungs and pleura, other bones (particularly the skull), central nervous system, and (rarely) regional lymph nodes o 25% of the patients - multiple bone and/or visceral lesions at the time of presentation Treatment o combination of high-dose irradiation and multidrug chemotherapy - 5-year disease-free survival = 75%

o Radiographic evidence of effective treatment: reconstitution of the cortical pattern, periostitis, and regression of the extraosseous soft tissue mass if one was present o recurrence : any localized lysis at the primary site Prognostic Factors 1. Osseous versus extraosseous location 2. Soft tissue extension 3. Metastases 4. Surgical margins 5. Therapy-induced necrosis 6. Microscopic features 7. Neural differentiation 8. Type of gene fusion transcript 9. TP53 10. MYC 11. INK4A 12. DNA content

2. Malignant Lymphoma and Related Lesions A. Large B-cell Lymphoma most common type of primary bone lymphoma in adults with 60% of the cases occurring in patients over the age of 30 years no sex predilection and most cases are solitary involve the diaphysis or metaphysis of a long bone or the vertebrae, producing patchy cortical and medullary destruction tumor is pinkish gray and granular, frequently extends into the soft tissues and invades the muscle Large B-cell Lymphoma Ewing Sarcoma Larger and prominent nucleoli Well defined cytoplasmic outlines Fine nucleoli Indistinct cytoplasmic outlines

B.

Reticulin fibers occur between individual mainly restricted to perivascular areas cells and groups of cells 5-year survival rate = 95% stage of the disease - single most important prognostic determinator work up: skeletal survey and bone marrow examination treatment - combination of radiation therapy and chemotherapy Hodgkin Lymphoma 15% = radiographically detectable bone lesions 60% = multifocal involvement most frequent sites: vertebrae, pelvis, ribs, sternum, and femur present initially as a bone mass, with or without associated involvement of the adjacent soft tissues

C. Burkitt lymphoma - presents with massive jawbone involvement. It can also result in tumor masses in the long bones and pelvis. VASCULAR TUMORS 1. Hemangiomas most common locations: skull, vertebrae, and jawbones When a lesion involves the flat bones (particularly the skull) - sunburst trabeculation occurs because of elevation of the periosteum Grossly:currant jelly appearance Microscopically: thick-walled lattice-like pattern of endothelial-lined cavernous spaces filled with blood mainly seen in children 2. Massive osteolysis(Gorham disease) results in reabsorption of a whole bone or several bones and the filling of the residual spaces by a heavily vascularized fibrous tissue

3. Hemangiopericytoma - Is a primary bone lesion, most commonly in the pelvis 4. Epithelioid Hemangioendothelioma most common and distinctive member of the family of epithelioid (histiocytoid) vascular neoplasms microscopically: presence of epithelial- or histiocyte-like endothelial cells with abundant acidophilic and often vacuolated cytoplasm, large vesicular nucleus, modest atypia, scanty mitotic activity, inconspicuous or absent anastomosing channels, recent and old hemorrhage, inflammatory component rich in eosinophils 5. Angiosarcoma(malignant hemangioendothelioma, hemangioendothelial sarcoma) Characterized by atypia of the tumor cells, formation of solid areas alternating with others with anastomosing vascular channels, and foci of necrosis and hemorrhage Distant metastases are common - lungs OTHER MESENCHYMAL TUMORS Fibrous and Related Tumors 1. Infantile Myofibromatosis present as a solitary lesion in bone occur in patients 2 years old or younger involve almost always the craniofacial bones 2. Fibrosarcoma arises in the metaphyseal area of the long bones 50% = distal segment of the femur or proximal portion of the tibia Radiographically: soap-bubble appearance Treatment: Wide local excision and amputation 3. Malignant Fibrous Histiocytoma located in long bones or the jaw 30% = arise in bone infarcts (often secondary to sickle cell disease), around foreign bodies, following irradiation, in Paget disease, or as expression of dedifferentiation or anaplastic transformation in chondrosarcoma, chordoma, or giant cell tumor mean age at the time of presentation = 40 years CHORDOMA AND OTHER NOTOCHORDAL LESIONS 1. Giant Notochordal Hamartoma (Benign Notochordal Cell Tumor) usually solitary but sometimes multifocal nuclei are round and bland, there are cytoplasmic hyaline globules, and there is no myxoid matrix or necrosis benign but regarded as precursors of chordomas 2. Chordoma more frequent in the 5th and 6thdecades but occurs in all ages and in both sexes grow slowly with the duration of the symptoms before diagnosis usually being over 5 years

50% arise in the sacrococcygeal area - more common in the fifth and sixth decades of life 35% arise in the spheno-occipital area, and the remainder along the cervicothoraco-lumbar (mobile) spine - occur in children and adolescents retroperitoneal space - often involved by direct extension Grossly: gelatinous and soft and contains areas of hemorrhage Microscopically o grows in cell cords and lobules separated by an extensive amount of mucoid intercellular tissue and by fibrous septa o Mitotic figures - scanty or absent Ultrastructurally: contain mitochondrialendoplasmic reticulum complexes and parallel bundles of crisscrossing microtubules within the granular endoplasmic reticulum characterized by repeated episodes of local recurrence which may develop 10 years or longer after the initial therapy Distant metastases - most common sites: skin and bone Treatment: surgical excision, radiation therapy, or both modalities Adverse prognostic factors are represented by large tumor size, positive surgical margins, tumor necrosis, and high proliferative activity 3. Chondroid Chordoma occurs most often in the spheno-occipital region overall prognosis is better than that of conventional chordoma Adamantinoma of Long Bones involves the tibia located in the shaft or in the metaphyseal area of the bone Radiographically: single or multiple lytic areas in the cortex or medulla, surrounded by marked sclerosis Grossly: poorly defined and may extend into the overlying soft tissues Microscopically: consists of solid nests of basaloid cells with palisading at the periphery and sometimes a stellate configuration in the center Immunohistochemically: it lacks immunoreactivity for keratins 8 and 18 low-grade malignant tumor characterized by a tendency for local recurrence and the occasional development of lymph node and distant metastases, particularly to lung Treatment: En bloc excision and amputation Peripheral Nerve Tumors 1. Schwannoma strong predilection for the mandible Schwannomas of the sacrum - present as retrorectal masses and they may simulate a malignant tumor on radiographic grounds (particularly chordoma) and present great technical difficulties for their surgical removal 2. Recklinghausen disease - results in several types of skeletal abnormalities (such as scoliosis, bowing, pseudoarthrosis, and other disorders of growth) and may be

accompanied by malignant bone tumors such as fibrosarcoma or malignant fibrous histiocytoma Xanthoma presents in patients over the age of 20 years and has a male:female ratio of 2:1 almost always solitary most frequent sites: flat bones (pelvis, ribs, skull) Radiographically: well-defined, expansile lytic lesion, often with a sclerotic margin Microscopically: admixture of foamy cells, multinucleated giant cells, cholesterol clefts, and fibrosis METASTATIC TUMORS most frequent malignant neoplasms of bone >80% of all bone metastases - originate in the breast, lung, prostate, thyroid, or kidney 70% - affect the axial skeleton (cranium, ribs, spine, sacrum) 30% - involve the appendicular skeleton (long bones) or both compartments Metastases - preferentially situated in the red bone marrow usually osteolytic but may be osteoblastic or mixed o Tumors with a tendency to produce pure osteoblastic metastases prostatic carcinoma, carcinoid tumor, and other neuroendocrine neoplasms, and less commonly breast carcinoma mechanism : production of bone growth factors by the tumor cells, such as transforming growth factor (TGF)-, fibroblast growth factor, and bone morphogenetic proteins Thyroid carcinoma - metastasizes to the bones of the shoulder girdle, skull, ribs, and sternum Carcinoma of the kidney - involve the skull, sternum, flat bones of the pelvis, femur, and scapula Any tumor metastatic to bone, if extensive enough, may lead to hypercalcemia and elevation of serum acid phosphatase. Treatment o Goals: relief of pain and to prevent fracture of weight-bearing bones o Localized radiation therapy - partial or complete relief of pain in over 80% of the cases. o Internal fixation and radiation therapy - provide the best results when a pathologic fracture supervenes o Estrogen therapy and/or orchiectomy - patients with disseminated metastases from carcinoma of the prostate o Hormonal therapy with estrogens or tamoxifen, or ovarian ablation - metastatic breast cancer

Tumorlike lesions Solitary (Unicameral) Bone Cyst long bones- upper portion of the shaft of the humerus and femur short bones- calcaneus males, <20 years of age Most are centered in the metaphysis and their natural evolution is to migrate away from the epiphyseal line. The cortex is thinned, but periosteal bone proliferation does not take place except in areas of fracture. Affected bones often fracture- proximal portion of the cystic area Microscopically: o well-vascularized connective tissue o hemosiderin (often within macrophages) o cholesterol clefts Aneurysmal Bone Cyst 10-20 years of age more common in females vertebrae and flat bones X-ray: eccentric expansion of the bone, with erosion and destruction of the cortex and a small peripheral area of periosteal new bone formation Grossly: spongy hemorrhagic mass covered by a thin shell of reactive bone Microscopically: o large spaces filled with blood o no endothelial lining but are rather delimited by cells with the morphologic, ultrastructural, and immunohistochemical features of fibroblasts, myofibroblasts, and histiocytes o deposition of a degenerated calcifying fibromyxoid tissue Other names: giant cell reaction, (extragnathic) giant cell reparative granuloma, giant cell-containing fibrous lesion, and solid variant of aneurysmal bone cyst

Ganglion Cysts intraosseous location, always close to a joint space surrounded by a zone of condensed bone, multiloculated, and has a gelatinous content and a wall of attenuated fibrous tissue ankle (tibia)- most commonly affected Subpubic Cartilaginous Cyst fibrocartilaginous mass with extensive degenerative cystic changes observed in the proximity of the symphysis pubis Metaphyseal Fibrous Defect (Nonossifying Fibroma) adolescents

long tubular bones (upper or lower tibia or the lower femur) When loose and associated with an intramedullary component=>nonossifying or nonosteogenic fibromas Grossly: granular and brown or dark red Microscopically: o cellular masses of fibrous tissue, often arranged in a storiform pattern o Scattered osteoclasts and collections of foamy and hemosiderin-laden macrophages o bizarre nuclear features Clinically, there are few or no symptoms except pain

Fibrous Dysplasia two form o monostotic older children and young adults rib, femur, and tibia o polyostotic unilateral distribution associated with endocrine dysfunction, precocious puberty in female individuals, and areas of cutaneous hyperpigmentation (McCuneAlbright syndrome) caused by activating mutations in the GNAS1 gene X-ray: o Rib- fusiform, expanded mass with thinning of the cortex o Tibia- a lobulated, sharply delimited lesion of the shaft Fibrous dysplasia protuberans- lesion protrudes far beyond the normal bone contour Grossly o gritty consistency; grayish white o cortical bone often is thinned and expanded Microscopically o fishhook configuration, interspersed with fibrous tissue of variable cellularity o coarsefiber (woven) bone does not transform into lamellar bone- represents a maturation defect so that the process of bone formation is arrested at an early stage resembling membranous ossification. Ultrastructurally, the immature woven bone trabeculae are lined by abnormal osteoblasts with a fibroblast-like appearance. Immunohistochemically: expressperiostin, a marker of intramembranous ossification

Osteofibrous Dysplasia (Fibro-Osseous Dysplasia, Ossifying Fibroma; Campanacci Lesion) distinguished from fibrous dysplasia by: o microscopically: osteoblastic rimming of the bone trabeculae and presence of lamellar bone o radiographically by its cortical rather than medullary location

o greater tendency to recur tibia and fibula eccentrically located Immunohistochemically: keratin, neurofibromin, S-100 protein, and Leu7 no activating mutations of GNAS1

Myositis Ossificans reactive condition that is sometimes mistaken microscopically for osteosarcoma.[ history of trauma in half of the patients flexor muscles of the upper arm (especially the brachialis anticus), the quadriceps femoris, the adductor muscles of the thigh, the gluteal muscles, and the soft tissues of the hand X-ray: periosteal reaction and faint soft tissue calcification within 36 weeks of the injury; replaced by mature heterotopic bone by 1012 weeks Microscopically o highly cellular stroma associated with new bone and, less commonly, cartilage formation. o The most important diagnostic feature is provided by the maturation pattern (zonal phenomenon)characterized by central cellular area intermediate zone of osteoid formation peripheral shell of highly organized bone Ultrastructurally, cells with features of myofibroblasts are prominent DDx: o extraosseous and juxtacortical osteosarcoma o extraosseous osteosarcoma- greater cytologicatypia, and the zonal phenomenon does not occur Langerhans Cell Histiocytosis histiocytosis X, eosinophilic granuloma infiltration by Langerhans cell admixture of eosinophils, giant cells, neutrophils, foamy cells, and areas of fibrosis Langerhans cells o Nuclei- lobulated or indented, sometimes with a longitudinal groove o Cytoplasm- acidophilic Langerhans or Birbeck granule- intracytoplasmic organelle three major categories (based on type and extent of the organ involvement) 1. Solitary bone involvement o most common o Young adults o Any bone can be involved, with the possible exception of the hands and feet o X-ray: osteolytic lesion often in the metaphyseal area of long bones, sometimes associated with periosteal bone proliferation.

2. Multiple bone involvement (with or without skin involvement) o the bony infiltration may result in proptosis, diabetes insipidus, chronic otitis media o The eponym of HandSchllerChristian disease has been applied to this variety. o characterized by a prolonged clinical course, often marked by alternating episodes of regressions and recrudescences 3. Multiple organ involvement (bone, liver, spleen, and others). o Following the skeletal system, the skin and the lungs are the two most common sites affected

DDx: osteomyelitis, osseous manifestations of RosaiDorfman disease

Other Histiocytic Lesions RosaiDorfman disease (sinus histiocytosis with massive lymphadenopathy) involve the skeletal system either as a manifestation of multisystem disease or as a mass limited to this site secondary xanthomatous changes and fibrosis are common ErdheimChester disease lipid-storinghistiocytosis of non-Langerhans cell type which may be restricted to the bones or involve multiple organ systems, including lung and central nervous system. The foamy histiocytes that accumulate are CD68+ and CD1aJOINTS AND RELATED STRUCTURES Non-Neoplastic Diseases Ganglia (Ganglion Cysts) Individuals overusing the wrist and fingers (pianists, computer operators) are prone to this condition. develop by myxoid degeneration and cystic softening of the connective tissue of the joint capsule or tendon sheath 2 most common locations: o dorsal carpal area of the hand o volar surface of the wrist, superficial and medial to the radial artery not lined by synovia and do not communicate with the joint cavity, two features distinguishing them from Baker cysts Baker Cyst occurs in the popliteal space from herniation of the synovial membrane through the posterior part of the capsule or from escape of joint fluid through normal anatomic connections of the knee joint with the semimembranous bursa

lined by true synovium result from any joint disease leading to increased intra-articular pressure, such as degenerative joint disease, neuropathic arthropathy, and rheumatoid arthritis

Carpal Tunnel Syndrome Carpal Tunnel- space between the flexor retinaculum or transverse carpal ligament and the carpal bones The medial nerve courses through this tunnel and its compression in this location by a variety of causes produces the symptoms of carpal tunnel syndrome Arthritis Degenerative Joint Disease (Osteoarthrosis) pathologic changes are related directly to age earliest change is an even degeneration of the hyaline cartilage of the articular surfacethinning of cartilage and compensatory overgrowth of the apposite joint surface Once the articular cartilage disappears, the two bony surfaces are brought into contact, with progressive thickening of the trabeculae (eburnation) increased activity of the perichondrium at the periphery of the joint with formation of Heberden nodes The synovial membrane may remain normal or undergo thickening, with formation of papillary metaplastic masses of cartilage, bone, or adipose tissue. Detachment of these masses gives rise to intra-articular loose bodies known as rice bodies. Chondromalacia Patellae softening, fibrillation, fissuring, and erosion of the articular cartilage of the patella Rheumatoid arthritis immune-complex disease manifests as chronic polyarticular arthritis mostly seen in women during 2nd and 3rddecades of life Mostly involve: joints of the feet and hands Others : elbows, knees, wrists, ankles, hips, spine, and temporomandibular articulations mediators of the inflammatory reaction: Lysosomes and interleukins unknown etiology but viral participation has long been suspected on the basis of epidemiologic, morphologic, and immunohistologic findings autoimmune: human leukocyte antigen (HLA) linkage and the autoantibody production earliest morphologic changes: o hyperemia in the synovial membrane followed by proliferation of the synovial lining cells and infiltration by plasma cells and lymphocytes o Lymphoid follicles often present. o small synovial blood vessels lined by plump endothelial cells, and fibrin deposits close to the synovial lining or within the stroma. o Nonspecific:

presence of synovial giant cells in patients with active , seropositive disease bone and cartilage fragments within the actual synovial membrane in patients with advance disease Result from erosive destructive process of the articular surface Distinguished by their position and clear demarcation from metaplastic cartilage and bone Also seen in synovial membranes of osteoarthritis, osteochondritis dissecans, chondromalacia patellae, and particularly in neuropathic joints need to be distinguished from multinucleated plasma cells, foreign body cells, and Touton giant cells that can also occur in joints with rheumatoid arthritis. o second phase: granulation tissue grows into the subchondral marrow of the bone. Osteoporosis spontaneous fractures of long bones (particularly the femoral neck) and the pelvis Prominent pannus formed over the articular cartilage

o granulation tissue and pannus attack the cartilagefibrous ankylosiseventually bony ankylosis. o Increased articular pressure may lead to: bursting of the joint capsule acute joint rupture bone cysts (rheumatoid geodes): similar w/ those seen in degenerative joint disease difference: contain granulation tissue instead of fluid or myxoid material herniation of the capsule into the soft tissues most common extra-articular manifestations: o Tenosynovitis o rheumatoid nodules 20% of the patients often in tendons and tendon sheaths and periarticular subcutaneous tissue but also in the heart and large vessels, lung and pleura, kidney, meninges, and synovial membrane itself Microscopically: composed of a necrotic center impregnated with fibrin, surrounded by a predominantly histiocytic inflammatory reaction, often arranged in a palisading fashion NOT specific to RA Amyloidosis: significant complication

Infectious arthritis Bacterial, fungal, and parasitic infections hematogenous spread or by contiguous extension from a neighboring osteomyelitis

Gout and pseudogout 25% of chronic joint disease (gout) metatarsophalangeal joints are first to be involved Calcification and ossification of tophi urate deposits progressively destroy the cartilage cause osteolytic, irregular destruction of subchondral bone extend out and cause destruction of the ligaments subcutaneous deposits that erode through the skin. Fixation in alcohol: important for the preservation of sodium urate monohydrate deposits; appear as needle-shaped, doubly refractile crystals deGalantha stain: even w/o fixation, appearance of tophi is usually diagnostic Histiocytes and foreign body giant cells predominate in the infiltrate. chondrocalcinosis o pseudogout, calcium pyrophosphate dihydrate crystal deposition disease o symptoms result from diffuse deposition of calcium pyrophosphate crystals in the articular cartilage o involve the temporomandibular joint

Intervertebral disk prolapse mechanical overload-induced degeneration of the disk mediated through the mitochondrial apoptotic pathway indicators of degeneration related to prolapse: o fibrillation o clustering of chondrocytes o granular change o neovascularization occurring at the edges of the fibrocartilaginous fragments (Weidner and Rice)

Other articular and periarticular diseases Hemophilia o accumulation of hemosiderin-laden macrophages in the synovium. o In contrast to pigmented villonodular synovitis (PVNS): few if any foamy macrophages or spindle cells o morphologic feature: degenerative rather than an inflammatory process Scleroderma (progressive systemic sclerosis) o accompanied by arthralgia or arthritis o microscopic changes in the synovial membrane are superficial deposition of fibrin, mild mononuclear infiltrate, minimal hyperplasia of synovial lining cells, proliferation of collagen fibers, and focal obliteration of small vessels Lupus erythematosus o microscopic changes in the synovium indistinguishable from rheumatoid arthritis. o more intense surface fibrin deposition and a lesser degree of proliferation of synovial cells.

Amyloid o deposit in the synovium, articular cartilage, menisci, periarticular tissue, and intervertebral disk in old age o Heavier amounts in primary amyloidosis or multiple myeloma SAPHO o unknown etiology; synovitis in combination with acne, pustulosis, hyperostosis, and osteitis

Tumors and tumorlike conditions Tenosynovial giant cell tumor TSGCT, nodular tenosynovitis, fibrous histiocytoma of tendon sheath, xanthogranuloma, benign synovioma W>M men, appearing in young and middle-aged persons between the wrist and fingertips and between the ankle and toe tips proximal than distal on both the hands and feet; most frequently on flexor surfaces single mass usually measuring 13 cm in diameter; well-defined capsule, somewhat lobulated, from whitish gray to yellowish brown Microscopically: closely packed medium-sized polyhedral cells with a variable admixture of giant cells containing fat and hemosiderin nearly always benign; erode contiguous bone by pressure; if incompletely removed, recur locally differential diagnosis: epithelioid sarcoma o include presence of granuloma-like formations, necrosis, invasiveness, epithelioid features, and keratin immunoreactivity

Pigmented villonodular synovitis and bursitis closely related to TSGCT; occur in young adults. usual site: knee joint ; may involve: ankle, hip, shoulder, or even the elbow join Usually only one articulation is affected focal or diffuse; appearance depends on the content of hemosiderin pigment. cellular component similar to that of TSGCT o additions: papillary projections made up of foamy cells and hemosiderincontaining phagocytes o Large clefts and pseudoglandular or alveolar spaces lined by synovial cells o expression of both histiocytic and synoviocyte-associated markers (clusterin) production of metalloproteinases such as collagenase and stromelysin: result in bone cyst formation and late cartilage and bone loss Treatment: excision o recur locally because complete removal is often impossible

Synovial osteochondromatosis and chondrosarcoma characterized by the formation of osteocartilaginous bodies in the synovial membrane

monoarticular, affecting the knee or hip and communicating bursae aggravated by infection and trauma. tenosynovial or extra-articular chondromatosis o seen in the soft tissue adjacent to but not communicating with the joint o unknown etiology usually are partially calcified disease follow this sequence: 1 active intrasynovial disease with no loose bodies, 2 intrasynovial proliferation and free loose bodies, and 3 multiple free osteochondral bodies with no demonstrable intrasynovial disease diagnosis: cartilaginous or osteocartilaginous bodies attached to the synovial membrane in addition to those free in the joint spaces. can occur in degenerative joint disease, neuropathic arthropathy, and osteochondritis dissecans secondary synovial chondrometaplasia chondrocytes of primary synovial osteochondromatosis show some degree of atypia and even binucleated formsnot necessarily indicate malignancy. Synovial chondrosarcoma o rare o resembles synovial chondromatosis radiographically and grossly o distinction: based on the presence in the chondrosarcoma of obvious cytologic features of malignancy in the chondrocytes

Other tumors and tumorlike conditions Most represent direct extension from neoplasms initially located in the adjacent bones. Synovial hemangioma o only primary tumor of the joints o young adults; male predominance; knee: most common site, followed by the elbow and finger. o confined to the intra-articular synovium, sometimes ina bursa adjacent to a joint o cavernous hemangioma: most common microscopic pattern;followed by: lobular capillary hemangioma, arteriovenous hemangioma, and venous hemangioma