BONE

JOINT SOFT TISSUE

BLOK 13 SISTEM MUSKULOSKELETAL

dr. Al Munawir FK Universitas Jember

Modeling/RE-modeling

CELLS of BONE
OSTEOPROGENITOR (STEM)(TGF) OSTEOBLASTS (surface of spicule), under
control of calcitonin to take blood calcium and put it into bone.

OSTEOCYTES (are osteoblasts which are now completely surrounded by bone)

OSTEOCLASTS (macrophage lineage),
under control of PTH to chew up the calcium of bone and put it into blood

 Type 1 (TYPE [B]ONE) collagen (90%)

Cell adhesion proteins, i.e. CAMs: Osteopontin, fibronectin, thrombospondin Calcium-binding proteins: Osteonectin, sialoprotein Proteins involved in mineralization: Osteocalcin Enzymes: Collagenase, Alk. Phos. Growth factors
IGF-1, TGF-, PDGF

Proteins (organic) of BONE

Cytokines
Prostaglandins, IL-1, IL-6, RANKL

Proteins Concentrated from Serum

2 microglobulin Albumin IGF, insulin-like growth factor TGF, transforming growth factor PDGF, platelet-derived growth factor IL, interleukin RANKL, RANK ligand

Minerals (IN-organic) of BONE

HYDROXY-APATITE

Ca5(PO4)3(OH) Ca10(PO4)6(OH)2

 Compact
Dense Cortical

ADJECTIVES of BONE

Spongy
Cancellous Membranous Endosteal Spicular

Woven vs. Lamellar

-BLASTS/-CLASTS

Ca++

PTH

Ca++ Calcitonin

1) MALFORMATIONS AND DISEASES CAUSED BY DEFECTS IN NUCLEAR PROTEINS AND TRANSCRIPTION FACTORS, polydactyly, syndactyly, absence of a bone 2) DISEASES CAUSED BY DEFECTS IN HORMONES AND SIGNAL TRANSDUCTION MECHANISMS, achondroplasia, thanatophoria 3) DISEASES ASSOCIATED WITH DEFECTS IN EXTRACELLULAR STRUCTURAL

BONE DISEASES

PROTEINS
Type 1 Collagen Diseases (Osteogenesis Imperfecta) Types 2, 10, and 11 Collagen Diseases 4) DISEASES ASSOCIATED WITH DEFECTS IN FOLDING AND DEGRADATION OF

MACROMOLECULES
Mucopolysaccharidoses 5) DISEASES ASSOCIATED WITH DEFECTS IN METABOLIC PATHWAYS (ENZYMES, ION CHANNELS, AND TRANSPORTERS) Osteopetrosis 6) DISEASES ASSOCIATED WITH DECREASED BONE MASS Osteoporosis 7) DISEASES CAUSED BY OSTEOCLAST DYSFUNCTION Paget Disease (Osteitis Deformans) 8) DISEASES ASSOCIATED WITH ABNORMAL MINERAL (Ca++) HOMEOSTASIS Ricketts and Osteomalacia Hyperparathyroidism Renal Osteodystrophy

1) MALFORMATIONS AND DISEASES CAUSED BY DEFECTS IN NUCLEAR PROTEINS AND

TRANSCRIPTION FACTORS
proteinDNAmRNA

Congenital absence of a, usually single, bone: phalanx, rib, clavicle Supernumerary digit (polydactyly) Syndactyly CRANIORACHISCHISIS

2) DISEASES CAUSED BY DEFECTS IN HORMONES AND

Achondroplasia, dwarf (non-lethal) Thanatophoria, dwarf (lethal, FGF-3 mutations)

SIGNAL TRANSDUCTION MECHANISMS

a point mutation (usually Arg for Gly375) in the gene that codes for FGF receptor 3 (FGFR3), which is located on the short arm of chromosome 4. In the normal growth plate, activation of FGFR3 inhibits cartilage proliferation, hence the term achondroplastic; A MUTATION causes FGFR3 to be constantly activated.

Achondroplastic dwarf

Thanatophoric dwarf, often lethal

Short arms and extra folds of skin

3) DISEASES ASSOCIATED WITH DEFECTS IN EXTRACELLULAR

STRUCTURAL PROTEINS
OSTEOGENESIS IMPERFECTA TYPES (Brittle bone disease, too LITTLE bone), BLUE sclerae Mutations in genes which code for the alpha-1 and alpha-2 chains of COLLAGEN 1 Mutations of COLLAGEN 2,10, 11 manifest themselves as CARTILAGE diseases, ranging from joint cartilage destruction to fatal sequelae

Osteogenesis Imperfecta

BLUE SCLERA

4) DISEASES ASSOCIATED WITH DEFECTS IN FOLDING AND

DEGRADATION OF MACROMOLECULES

(glycosaminoglycans)
MUCOPOLYSACCHARIDOSIS (one of MANY lysosome storage diseases) DECREASES in ENZYMES which degrade:
DERMATAN

AN KERATAN
HEPAR

Chiefly CARTILAGE disorders: short, chest wall, malformed bones

MUCOPOLYSACCHARIDOSES

5) DISEASES ASSOCIATED WITH DEFECTS IN METABOLIC PATHWAYS (ENZYMES, ION CHANNELS, AND TRANSPORTERS)
OSTEOPETROSIS, 4 types One common one has a CARBONIC
ANHYDRASE deficiency, i.e., acid DECREASED osteoclast resorption MARBLE bone, increased bone, brittle, sclerotic bone

OSTEOPETROSIS

6) DISEASES ASSOCIATED WITH

DECREASED BONE MASS

OSTEOPOROSIS
PEAK bone mass is early adulthood Normal decline, slow Osteoporosis is accelerated bone loss Factors:
AGE Physical activity Estrogen withdrawal (menopause) Nutrition (Ca++) Genetics

Categories of Generalized Osteoporosis

Primary Postmenopausal Senile Secondary Endocrine disorders Hyperparathyroidism Hypo-hyperthyroidism Hypogonadism

Idiopathic

Rheumatologic disease Drugs Anticoagulants Chemotherapy

Pituitary tumors
Diabetes, type 1 Addison disease Neoplasia Multiple myeloma Carcinomatosis

Corticosteroids
Anticonvulsants Alcohol

Miscellaneous
Osteogenesis imperfecta Immobilization

Gastrointestinal
Malnutrition, Malbs., Hepatic Insuf., Vit C,D

Pulmonary disease
Homocystinuria Anemia

OSTEOPOROSIS

7) DISEASES CAUSED BY

OSTEOCLAST DYSFUNCTION Paget Disease (Osteitis Deformans)

Matrix madness, Osteoblasts/-cytes gone wild THREE PHASES:
1) Increased osteoclast resorption 2) Increased hectic bone formation (osteoblasts) 3) Osteosclerosis

ELEVATED ALKALINE-PHOSPHATASE ELEVATED urine HYDROXYPROLINE

PAGETs DISEASE (of BONE)

85% MONOSTOTIC, WHOLE BONE

15% POLY-OSTOTIC (skull, pelvis) JIGSAW, NOT LAMINAR, BONE

CLINICAL:

PAIN!!!

(MICROFRACTURES)

PAGETs DISEASE

NON-Lamellar bone

8) DISEASES ASSOCIATED WITH

ABNORMAL MINERAL HOMEOSTASIS

Ricketts and Osteomalacia
VITAMIN D deficiency/dysfunction

Hyperparathyroidism, PRIMARY (PTH ADENOMA)

ENTIRE SKELETON OSTEITIS FIBROSIS CYSTICA (von Recklinghausens disease (of bone) BROWN* TUMOR

Hyperparathyroidism, SECONDARY (RENAL) (NOT AS SEVERE AS 1) Renal Osteodystrophy = ANY bone disorder due to chronic renal disease

PRIMARY HYPERPARATHYROIDISM

OSTEITIS FIBROSA CYSTICA

BROWN TUMOR

RENAL OSTEODYSTROPHY
PHOSPHATE RETENTION HYPOPHOSPHATEMIA HYPOCALCEMIA INCREASED PTH INCREASED OSTEOCLASTS METABOLIC ACIDOSIS release of HYDROXYAPATITES from matrix

FRACTURES

FRACTURES, adjectives
Complete, incomplete Closed, open (communicating) Communited (splintered, greenstick) Displaced (NON-aligned) PATHOGENIC, (non-traumatic, 2 to other disease, often metastases) STRESS fracture

FRACTURES
THREE PHASES

HEMATOMA, minutes days PDGF, TGF-, FGF SOFT CALLUS (PRO-CALLUS), ~1 week HARD CALLUS (BONY CALLUS), several weeks
COMPLICATIONS PSEUDARTHROSIS (non-union) INFECTION (especially OPEN [communicating] fractures)

FRACTURES

OSTEONECROSIS
Also called AVASCULAR necrosis Also called ASEPTIC necrosis CAUSE:

ISCHEMIA

Trauma Steroids Thrombus/Embolism Vessel injury, e.g., radiation INCREASED intra-osseous pressurevascular compression Venous hypertension too

OSTEONECROSIS
Disorders Associated with Osteonecrosis
Idiopathic Pregnancy

Trauma Corticosteroid administration

Infection Dysbarism Radiation therapy

Gaucher disease
Sickle cell and other anemias

Alcohol abuse
Chronic pancreatitis Tumors

Connective tissue disorders

Epiphyseal disorders

OSTEONECROSIS

OSTEONECROSIS

OSTEOMYELITIS
Pyogenic: Staph, E. coli, Pseudom, Kleb,
Salmonella

Hematogenous Contiguous, e.g., from a nearby joint Direct implantation

TB Syphilis

OSTEOMYELITIS
DX: X-ray, Bone scan

OSTEOMYELITIS
DX: Histology

OSTEOMYELITIS
COMPLICATIONS
Subperiosteal abscess Draining sinus Joint involvement

SEQUESTRUM (dead bone) vs. INVOLUCRUM (new bone)

OSTEOMYELITIS
Tuberculous
Usually blood borne TB of spine is known as POTTS disease

Syphilis
CONGENITAL TERTIARY, SABRE shins

POTTs DISEASE

SABER SHINS

Classification of Primary Tumors Involving Bones

Histologic Type
Hematopoietic (40%)

Benign
Myeloma

Malignant
Malignant lymphoma Chondrosarcoma Dedifferentiated chondrosarcoma Mesenchymal chondrosarcoma

Chondrogenic (22%)

Osteochondroma Chondroma Chondroblastoma Chondromyxoid fibroma

Osteogenic (19%)

Osteoid osteoma Osteoblastoma Giant cell tumor

Osteosarcoma

Unknown origin (10%)

tumor Giant cell tumor Adamantinoma Malignant fibrous histiocytoma

Histiocytic origin Fibrogenic

Fibrous histiocytoma

Metaphyseal fibrous defect (fibroma) Desmoplastic fibroma Fibrosarcoma Chordoma Hemangioendothelioma Hemangiopericytoma Liposarcoma

Notochordal Vascular

Hemangioma

Lipogenic Neurogenic

Lipoma Neurilemmoma

BONE TUMORS
BONE CARTILAGE FIBROUS MISC.
Ewings sarcoma Giant Cell Tumor METASTASES

BONE- BONE TUMORS

OSTEOMA OSTEOID OSTEOMA (nidus) OSTEOBLASTOMA OSTEOSARCOMA (OSTEOGENIC SARCOMA)

OSTEOMA
SOLITARY MIDDLE AGE FROM SUBPERIOSTEAL or ENDOSTEAL surfaces SKULL, FACE, most common Totally BENIGN To be distinguished from REACTIVE BONE, (can be difficult)

FRONTAL SINUS

Why am I not showing you HISTOLOGY?

OSTEOID OSTEOMA
At least 2 cm in diameter Teens, twenties, APPENDICULAR skeleton M>>F PAINFUL Has a

NIDUS

Responds to aspirin Induces a MARKED bony reaction

NIDUS

OSTEOBLASTOMA
AXIAL SKELETON, i.e., SPINE NO nidus NO bony reaction NOT relieved by aspirin

OSTEOSARCOMA (OSTEOGENIC SARCOMA)

LATE TEENS KNEES METAPHYSES PAINFUL!!!

TYPES of OSTEOSARCOMAS
The anatomic portion of the bone from which they arise (intramedullary, intracortical, or surface) Degree of differentiation Multicentricity (synchronous, metachronous[NOT synchronous]) Primary (pre-existing bone is unremarkable) or secondary (e.g., osteosarcoma associated with pre-existing disorders such as benign tumors, Paget disease, bone infarcts, previous irradiation) Histologic variants (osteoblastic, chondroblastic, fibroblastic, telangiectatic, small cell, and giant cell)

The most common subtype is osteosarcoma that arises in the metaphysis of long bones; is primary, solitary, intramedullary, and poorly differentiated; and produces a predominantly bony matrix

BONE- CARTILAGE TUMORS

OSTEOCHONDROMA (EXOSTOSIS) CHONDROMA CHONDROBLASTOMA CHONDROMYXOID FIBROMA CHONDROSARCOMA

OSTEOCHONDROMA (EXOSTOSIS)
Common, Cartilage AND Bone present Often MULTIPLE as a hereditary syndrome M>>>F PELVIS, SCAPULAE, RIBS

CHONDROMA
Chondroma vs. EN-chondroma PURE Hyaline Cartilage MULTIPLE enchondromas = Olliers dis. Maffucci Synd. if hemangiomas present

CHONDROBLASTOMA
RARE, in teenagers M>>F KNEES, usually Epiphyses MUCH LESS matrix than a chondroma

CHONDROMYXOID FIBROMA
RAREST of all TEENS, MALES MYXOID concept ATYPIA

CHONDROSARCOMA
ANATOMY
INTRAMEDULLARY JUXTACORTICAL

HISTOLOGY
CONVENTIONAL
HYALINE MYXOID

CLEAR DE-DIFFERENTIATED MESENCHYMAL

CHONDROSARCOMA

BONE- FIBROUS TUMORS

FIBROUS CORTICAL DEFECT/NONOSSIFYING FIBROMA FIBROUS DYSPLASIA FIBROSARCOMA/MALIGNANT FIBROUS HISTIOCYTOMA

FIBROUS CORTICAL DEFECT

COMMON, usually LESS THAN 1 CM CHILDREN >2 IF MORE THAN 5-6 CM, they are then called NONOSSIFYING FIBROMA

FIBROUS DYSPLASIA
BENIGN TUMOR THREE TYPES
SINGLE BONE (70%) POLY-OSTOTIC (27%) POLY-OSTOTIC (3%) with caf-au-lait and endocrine disorders, especially precocious puberty

1) CURVED thin spicules 2) LACK of osteoblastic rimming

FIBROSARCOMA/MFH
METAPHYSES of LONG BONES PELVIC FLAT BONES LYTIC FRACTURES OF COURSE, SARCOMATOUS METASTASIS

FIBROSARCOMA/MFH

MISC. TUMORS of BONE

EWING sarcoma/PNET (Primitive NeuroEctodermal Tumor) GIANT CELL TUMOR METASTASES

EWING/PNET
SAME TUMOR SMALL ROUND BLUE CELL TUMOR NEUROENDOCRINE CELL ORIGIN CHROMOSOME TRANSLOCATION 11&22 SECOND most COMMON bone malignancy in CHILDREN ARISE IN MEDULLARY CAVITY of BONE LOOK LIKE LYMPHOMA

GCT (Giant Cell Tumor), BONE

METASTASES
MALE: PROSTATE FEMALE: BREAST RENAL, THYROID also seek bone early also

LYTIC? BLASTIC?

SYNOVIAL JOINTS

 1) fibroblasts
Hyaluronin Lubricin

TWO KINDS of cells form the synovial intima

2) macrophages
The SUB-intima is loose CT or fat

 ARTHRITIS

JOINT DISEASES

DEGENERATIVE (OSTEOARTHRITIS) RHEUMATOID

JUVENILE RHEUMATOID NON-INFECTIOUS: Ankylosing Spond., Reactive, Psoriasis, IBD INFECTIOUS: Supp., TB, Lyme, Viral GOUT (URATE) PSEUDOGOUT (PYROPHOSPHATE)
Tumors (all are of synovium)
Ganglion (Synovial Cyst), non-neoplastic Giant Cell Tumor (Pigmented VilloNodular Synovitis[PVNS]), benign Synovial Sarcoma, malignant

DEGENERATIVE ARTHRITIS aka, OSTEOARTHRITIS

Etiology/Risk Factors: Age, Trauma, Genes Pathogenesis: Progressive EROSION of articular cartilage Morphology: X-Ray, eburnation, joint mice, osteophytes Clinical Expression: PAIN, Limitation of motion

HEBERDENS NODES DIP, NOT MP or PIP

RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder that may affect many tissues and organsskin, blood vessels, heart, lungs, and muscles but principally attacks the joints, producing a nonsuppurative proliferative and inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis of the joints.

 1) fibroblasts
Hyaluronin Lubricin

TWO KINDS of cells form the synovial intima

2) macrophages
The SUB-intima is loose CT or fat

RHEUMATOID ARTHRITIS
Etiology/Risk Factors: Autoimmune Pathogenesis: Progressive SYNOVITIS Morphology: Synovial lymphocytes, macrophages, plasma cells, neutrophils,

osteoclasts, pannus, hyperemia, rheumatoid nodules, vasculitis Clinical Expression: PAIN, Limitation of motion, malaise, fatigue, rheumatoid factor IgMIgG-Fc,

HANDSWRISTELBOWS

The rheumatoid nodule shows palisading fibroblasts

DIAGNOSIS
CLINICAL FEATURES (1% of population F>>M)
MORNING STIFFNESS, MEAN AGE 45 YRS ARTHRITIS in MORE THAN 3 JOINT AREAS TYPICAL hand findings, MP ULNAR deviation SYMMETRIC ARTHRITIS SERUM RHEUMATOID FACTOR TYPICAL X-RAY findings

JUVENILE Rheumatoid Arthritis

Begins BEFORE age 16, by definition Generally LARGER joints than RA Often POSITIVE ANA

SERONEGATIVE ARTHRITIDES
ANKYLOSING SPONDYLITIS (aka, rheumatoid spondylitis, or MarieStrumpell Disease [HLA-B27] (M>>F) REACTIVE ARTHRITIS (FOLLOWS GU or GI INFECTIONS)
REITER SYDROME (urethral & conjunctival inflammation too) [HLA-B27] Arthritis associated with IBD

PSORIATIC ARTHRITIS [HLA-B27]

Ankylosing Spondylitis

INFECTIOUS ARTHRITIS
From OSTEOMYELITIS USUALLY SUPPURATIVE

GC, staph, strep, H. flu, E. coli,

(Salmonella in sicklers) 4 cardinal signs, fever,

leukocytosis, ESR

INFECTIOUS ARTHRITIS
TB LYME Disease, i.e., Borrelia burgdorferi, from Ixodes ticks VIRAL
Parvovirus B19 Rubella Hepatitis C

GOUT
Endpoint of HYPERURICEMIA from ANY cause resulting in JOINT deposition of monosodium urate crystals (TOPHI)
ACUTE CHRONIC

10% of population has hyperuricemia (>7 mg/dl), but only 1/20 of these has gout

Classification of Gout
Clinical Category Metabolic Defect

Primary Gout (90% of cases)

Enzyme defects unknown (85%90% of primary gout) Overproduction of uric acid
Normal excretion (majority) Increased excretion (minority) Underexcretion of uric acid with normal production Known enzyme defectse.g., partial HGPRT deficiency (rare) Overproduction of uric acid

Secondary Gout (10% of cases)

Associated with increased nucleic acid turnovere.g., leukemias Chronic renal disease Inborn errors of metabolisme.g., complete HGPRT deficiency (LeschNyhan syndrome) Overproduction of uric acid with increased urinary excretion Reduced excretion of uric acid with normal production Overproduction of uric acid with increased urinary excretion

HGPRT, hypoxanthine guanine phosphoribosyl transferase.

HYPERURICEMIA GOUT
Age of the individual and duration of the
hyperuricemia are factors. Gout rarely appears before 20 to 30 years of hyperuricemia. M>>F Genetic predisposition is another factor. In addition to the well-defined X-linked abnormalities of HGPRT, primary gout follows multifactorial inheritance and runs in families. Heavy alcohol consumption predisposes to attacks of gouty arthritis. Obesity increases the risk of asymptomatic gout. Certain drugs (e.g., thiazides) predispose to the development of gout. Lead toxicity increases the tendency to develop gout

FEATURES
TOPHACEOUS ARTHRITIS GOUTY NEPHROPATHY

GOUTY NEPHROPATHY

GOUT
Associated with ATHEROSCLEROSIS Associated with HYPERTENSION

 Gout: Monosodium Urate Pseudo-GOUT: Calcium Pyrophosphate

Pseudo-GOUT

PSEUDOGOUT is also called CHONDROCALCINOSIS, or CPPD (Calcium Phosphate Deposition Disease) IDIOPATHIC, HEREDITARY, SECONDARY

Secondary joint damage,

hyperparathyroidism, hemochromatosis, hypomagnesemia, hypothyroidism, ochronosis, and diabetes

GOUT vs. PSEUDOGOUT

JOINT TUMORS
BENIGN
GANGLION (SYNOVIAL CYST) GIANT CELL TUMOR of TENDON SHEATH, aka PVNS, Pigmented VilloNodular Synovitis

MALIGNANT
SYNOVIAL SARCOMA

GANGLION

PVNS/GCT

Synovial Sarcoma

SOFT TISSUE TUMORS

FAT FIBROUS TISSUE FIBROHISTIOCYTIC SKELETAL MUSCLE SMOOTH MUSCLE VASCULAR PERIPHERAL NERVE UNCERTAIN: SYNOVIAL SARCOMA, ALVEOLAR
SOFT PART SARCOMA, EPITHELIOD SARCOMA

 MOSTLY UNKNOWN

CAUSES

RADIATION association CHEMICAL BURN association THERMAL BURN association TRAUMA association VIRUS association (HHV8 for Kaposi) GENETICS Parts of many SYNDROMES MANY TRANSLOCATIONS

Chromosomal and Genetic Abnormalities in Soft Tissue Sarcomas

Tumor Extraosseous Ewing sarcoma and primitive neuroectodermal tumor Cytogenetic Abnormality t(11:22)(q24;q12) Genetic Abnormality FLI-1-EWS fusion gene

t(21:22)(q22;q12)
t(7;22)(q22;q12) Liposarcomamyxoid and round cell type Synovial sarcoma Rhabdomyosarcomaalveolar type t(12:16)(q13;p11) t(x;18)(p11;q11) t(2;13)(q35;q14) t(1;13)(p36;q14) Extraskeletal myxoid chondrosarcoma t(9;22)(q22;q12)

ERG-EWS fusion gene

ETV1-EWS fusion gene CHOP/TLS fusion gene SYT-SSX fusion gene PAX3-FKHR fusion gene PAX7-FKHR fusion gene CHN-EWS fusion gene

Desmoplastic small round cell tumor

Clear cell sarcoma Dermatofibrosarcoma protuberans Alveolar soft part sarcoma Congenital fibrosarcoma

t(11;22)(p13;q12)
t(12;22)(q13;q12) t(17:22)(q22;q15) t(X;17)(p11.2;q25) t(12;15)(p13;q23)

EWS-WT1 fusion gene

EWS-ATF1 fusion gene COLA1-PDGFB fusion gene TFE3-ASPL fusion gene ETV6-NTRK3 fusion gene

SOFT TISSUE TUMORS

ALL SPINDLY Deep (desmoid) vs. Superficial (skin) Importance of counting MITOSES Importance of STAGING Importance of IMMUNOPEROXIDASE Importance of CONSULTATION

FAT
LIPOMA LIPOSARCOMA

NORMAL FAT

LIPOMA, encapsulated

LIPOSARCOMA, often retroperitoneal

FIBROUS TISSUE
NODULAR FASCIITIS (pseudosarcomatous) FIBROMATOSES (plantar, palmar, penile) FIBROSARCOMA

MYOSITIS OSSIFICANS
BENIGN FIBROUS TISSUE

PROLIFERATION PLUS OSSEOUS METAPLASIA

FIBROHISTIOCYTIC
FIBROUS HISTIOCYTOMA DERMATOFIBROSARCOMA PROTUBERANS MALIGNANT FIBROUS HISTIOCYTOMA

SKELETAL MUSCLE
RHABDOMYOMA RHABDOMYOSARCOMA

SMOOTH MUSCLE
LEIOMYOMA LEIOMYOSARCOMA

VASCULAR
HEMANGIOMA LYMPHANGIOMA HEMANGIOENDOTHELIOMA HEMANGIOPERICYTOMA ANGIOSARCOMA

PERIPHERAL NERVE
NEUROFIBROMA SCHWANNOMA GRANULAR CELL TUMOR MALIGNANT (SCHWANNOMA)

UNCERTAIN
SYNOVIAL SARCOMA ALVEOLAR SOFT PART SARCOMA EPITHELIOD SARCOMA