EPIDEMIOLOGY z are rare tumors compared to other AND SOFT malignancies: 8,700 new sarcomas in 2001, with TISSUE TUMORS 4,400 deaths. z The incidence of sarcomas is around 3-4/100,000. z Slight male predominance (with some subtypes more common in women). z Majority of soft tissue tumors affect older adults, but important sub-groups occur predominantly or exclusively in children. z Incidence of benign soft tissue tumors not known, but Fabrizio Remotti MD probably outnumber malignant tumors 100:1.

BONE AND SOFT TISSUE SOFT TISSUE TUMORS TUMORS z Traditionally bone and soft tissue tumors have been treated separately. z This separation will be maintained in the following presentation. z Soft tissue sarcomas will be treated first and the sarcomas of bone will follow. Nowhere in the picture…..

DEFINITION Histological z Soft tissue pathology deals with tumors of the classification connective tissues. of soft tissue z The concept of soft tissue is understood broadly to tumors include non-osseous tumors of extremities, trunk wall, retroperitoneum and mediastinum, and head & neck. z Excluded (with a few exceptions) are organ specific tumors.

1 Histological ETIOLOGY classification of soft tissue tumors tumors z Oncogenic viruses introduce new genomic material in the cell, which encode for oncogenic proteins that disrupt the regulation of cellular proliferation. z Two DNA viruses have been linked to soft tissue sarcomas: – Human herpes virus 8 (HHV8) linked to Kaposi’s – Epstein-Barr virus (EBV) linked to subtypes of leiomyosarcoma

z In both instances the connection between viral infection and sarcoma is more common in immunosuppressed hosts.

ETIOLOGY ETIOLOGY

z The etiology of soft tissue sarcomas is

poorly understood, and what is known apply z Herbicides (“agent orange”) and only to a small fraction of the group. peripheral soft tissue sarcomas z Retained metal objects z The known etiologic agents are ionizing (shrapnel, surgical devices) and radiation, oncogenic viruses, and chemicals. AS and MFH z Vinyl chloride, inorganic z These agents are able to cause genetic arsenic, Thorotrast, anabolic alterations that can lead to tumorigenesis. steroids linked to AS and MFH.

ETIOLOGY ETIOLOGY z Host factors may also z Radiation induced sarcomas play a role in the develop in 1% of patients who development of soft have undergone therapeutic tissue sarcomas. irradiation. – Immunosuppression, besides Kaposi’s z The interval between irradiation sarcoma, may be and diagnosis of sarcoma varies associated with between 5 and 10 years. sarcomas. – Lymphedema, z The majority of radiation- congenital or acquired induced sarcomas are high grade (post-mastectomy) is a and poorly differentiated (MFH, rare cause of FS, OS, and AS). extremity-based AS. AS in lymphedema

2 SOFT TISSUE TUMORS CLASSIFICATION z All tumors are derived from stem cells that are programmed to differentiate into various mature cell types. z Some of the stem cells probably belong to local, organ-specific pools, as underscored by the fact that many tumors resemble tissues present in the region z Other involved stem cells may be bone marrow derived.

Vascular leiomyosarcoma

CONGENITAL SYNDROMES ASSOCIATED WITH BONE AND SOFT TISSUE TUMORS Disorder Inheritance Locus Gene Tumor

Albright hereditary AD 20q13 GNAS1 Soft tissue calcifications and CLASSIFICATION Bannayan -Riley- Ruvalcaba AD 10q23 PTEN Lipomas, hemangiomas syndrome z However, some tumors Beckwith- Wiedemann syndrome Sp/AD 11p15 Complex Embryonal RMS, myxomas, fibromas, hamartomas have no resemblance to Bloom syndrome AR 15q26 BLM normal tissue in the region Carney complex AD 17q23-24 PRKAR1AK Myxomas and pigmented schwannomas (metaplastic foci within a (Familial myxoma syndrome) 2p16 Familial AD 7q33 - tumor, or tumors of Costello syndrome Sporadic - - Rhabdomyosarcomas different histogenesis from Cowden disease AD 10q23 PTEN Lipomas, Hemangiomas the normal cells of the (Multiple hamartoma syndrome) region) Diaphyseal medullary stenosis AD 9p21-22 - MFH Familial adenomatous polyposis AD 5q21 APC Craniofacial osteomas, desmoid tumors z Some sarcomas have no Familial expansile AD 18q21 TNFRSF11A normal cell counterparts,

Familial infiltrative fibromatosis AD 5q21 APC Desmoid tumors probably reflecting an Langer- Giedion syndrome Sporadic 8q24 EXT1 , unique genetic makeup. Li-Fraumeni syndrome AD 17p13 TP53 Osteosarcomas, RMS, other sarcomas Alveolar soft part sarcoma 22q11 CHEK2 Familial multiple lipomas AD - - Lipomas Symmetrical lipomatosis Sporadic - - Lipomas, lipomatosis of head and neck

Uterine leiomyosarcoma CONGENITAL SYNDROMES ASSOCIATED WITH BONE AND SOFT TISSUE TUMORS

Disorder Inheritance Locus Gene Tumor CLASSIFICATION Sporadic - - , CS, hemangiomas, AS Mazabraud syndrome Sporadic 20q13 GNAS1 Fibrous dysplasia, OS, IM myxomas McCune –Albright syndrome Sporadic 20q13 GNAS1 Fibrous dysplasia, osteosarcomas

Multiple osteochondromas, AD 8q24 EXT1 Osteochondromas, chondrosarcomas z Purpose of classification is to link non- syndromic 11p11-12 EXT2 similar tumors in order to understand Myofibromatosis AR - - Myofibromas their behavior, determine the most Neurofibromatosis type 1 AD 17q11 NF1 Neurofibromas, MPNST appropriate treatment, and investigate their biology. Neurofibromatosis type 2 AD 22q12 NF2 Schwannomas z Soft tissue tumors are classified Sporadic 3p21-22 PTHR1 Enchondromas, chondrosarcomas according to the cell type they Paget disease of bone, familial AD 18q21 Osteosarcomas resemble. 5q31 5q35

Proteus syndrome Sporadic - - Lipomas Retinoblastoma AD 13q14 RB1 Osteosarcomas, soft tissue sarcomas Rhabdoid predisposition syndrome AD 22q11 SMARCB1 Malignant rhabdoid tumors

Rothmund- Thompson syndrome AR 8q24 RECQL4 Osteosarcomas Rubinstein- Taybi syndrome AD 16p13 CREBBP Rhabdomyosarcomas Venous malf. With glomus cells AD 1p21-22 - Glomus tumors Embryonal rhabdomyosarcoma Werner syndrome AR 8p11-12 WRN Bone and soft tissue sarcomas

3 SOFT TISSUE TUMORS CLASSIFICATION z Fibrous/myofibroblastic Fibroma-benign tumors

z Refinements are coming from cytogenetics, molecular, and gene expression studies. Desmoid-borderline

z The majority arise from -or show -malignant differentiation toward- mesenchymal cells, but some show other differentiation (neuroectodermal, histiocytic). z A small subset is of unknown histogenesis.

SOFT TISSUE TUMORS Lipoma-benign CLASSIFICATION z Lipomatous tumors

z Tumors are also classified according their biologic potential. Liposarcoma-malignant z A three-tiered system is used: – 1. Benign – 2. Borderline (intermediate malignant) – 3. Malignant.

SOFT TISSUE TUMORS SOFT TISSUE TUMORS z Smooth muscle tumors

MAJOR TYPES OF SOFT TISSUE TUMORS Cell type Malignant tumor (Myo)fibroblast Fibroma, myxoma Fibrosarcoma, MFH Leiomyoma Lipoma Liposarcoma Smooth muscle cell Leiomyoma Leiomyosarcoma Skeletal muscle cell Rhabdomyoma Rhabdomyosarcoma Endothelial cell Hemangioma Angiosarcoma Schwann cell Schwannoma, neurofibroma MPNST cell Leiomyosarcoma, low grade Interstitial cell GIST GIST Histiocyte JXG, GCTTS, RDD True histiocytic sarcoma Unknown No benign counterparts ES, SS, ES, ASPS Leiomyosarcoma, high grade

4 IMMUNOHISTOCHEMISTRY GRADING z Immunohistochemistry is the most practical way z Grading is an element of any current staging to evaluate the presence of certain protein and system. carbohydrate epitopes on tissue sections. z Evaluation of cell- or tumor-type specific or cell- z Correct grading requires correct histologic cycle related markers may have diagnostic typing of the sarcoma, as demonstrated by significance. the inclusion of the histologic type as a z Very few markers are specific for one tumor type. grading variable. z No cell-cycle marker is able to separate benign and malignant tumors.

IMMUNOHISTOCHEMISTRY z Myofibroblastic tumors: SMA, HHF35 GRADING z Smooth muscle tumors: desmin, SMA, HHF35 z Skeletal muscle tumors: desmin, myogenin, Myo- z Grading applies best to excision specimen D1, myoglobin because biopsies may be non-representative of the correct grade. z Nerve sheath tumors: S-100 protein, CD34, EMA z Preoperative treatments, such as radiation, z Fatty tumors: S-100 protein , or embolization, can make grading z Synovial sarcoma: CK, EMA, S-100 inapplicable. z Epithelioid sarcoma: CK, CD34 z Weak points of grading: z Carcinomas: CK, EMA – Subjective elements (number of mitoses, percent of z : S-100, HMB45, tyrosinase, Melan A necrosis, tumor differentiation) – Frequent vs. rare tumors Cam 5.2- synovial sarcoma

GRADING GRADING SYSTEM SOFT TISSUE SARCOMAS (FFCC) GRADING Score (1-3) TUMOR DIFFERENTIATION well diff 1 z Grading is an arbitrary estimate of the degree of defined histogenetic types 2 malignancy of a (basically an attempt to poorly diff & undef histogenesis 3 determine the biological potential of a tumor). MITOTIC COUNT 0-9/10HPF 1 z The purpose of grading is to provide guidance for 10-19/HPF 2 >20 HPF 3 prognostic prediction and treatment (mainly to TUMOR NECROSIS determine the need for adjuvant therapy). none 0 <50% 1 z Other independent variables evaluated with >50% 2 grading are tumor size and depth, margins of HISTOLOGIC GRADE Sum of scores resection, and clinical situation. 1 2 or 3 2 4 or 5 3 6, 7 or 8

5 GRADING GRADING DIFFERENTIATION SCORE 1 Well differentiated sarcoma (fibro-, lipo-, leiomyo-, chondro-) Differentiation score 3 Well differentiated MPNST (neurofibroma with malignant transformation) DIFFERENTIATION SCORE 2 Conventional fibrosarcoma, leiomyosarcoma, angiosarcoma Conventional MPNST Myxoid sarcomas (MFH, liposarcoma, chondrosarcoma) Storiform-pleomorphic MFH DIFFERENTIATION SCORE 3 Sarcomas of undefined histog. (ASPS, SS,ES,CCS, undiff. Sarc.,malig. rhabdoid tumor) Pleomorphic sarcomas (lipo-, leio-) Round cell and pleomorphic liposarcoma Rhabdomyosarcoma (except botryoid and spindle cell) Poorly differentiated angiosarcoma Triton tumor, epithelioid MPNST Extraskeletal mesenchymal CS, and osteosarcoma Giant-cell and inflammatory MFH Ewing sarcoma

GRADING STAGING Differentiation score 1 z The stage is an estimate of the extent or dissemination of a tumor (and in the current systems includes tumor grade). z Staging is important for planning of treatment and prognostication. z Clinical data and imaging studies are part of staging process z (Visceral sarcomas excluded)

Fibrosarcoma

GRADING STAGING (G-TNM) STAGE GRADE PRIMARY TUMOR LYMPH NODES ABSENT/PRE Differentiation score 2 I - IV LOW OR HIGH T1 (<5 CM) OR T2 (>5 CM) NEG/POS SENT

IA LOW T1a or T1b NEGATIVE ABSENT IB LOW T2a or T2b NEGATIVE ABSENT

IIA HIGH T1a or T1b NEGATIVE ABSENT IIB HIGH T2a NEGATIVE ABSENT

III HIGH T2b NEGATIVE ABSENT

IV ANY ANY POSITIVE ABSENT

POSITIVE OR ANY ANY NEGATIVE PRESENT

“a” superficial tumors of trunk and extremities (above fascia) “b” deep tumors of trunk and extremities or intra-abdominal, intra-thoracic or retro-peritoneal MFH

6 PARAMETERS TO BE INCLUDED IN STAGING OF SARCOMAS REPORT OF A SARCOMA

z FINAL REPORT z ADDENDUM REPORT(S) – 1. Tumor site, type of – 1. Immunohistochemistry 5-yr survival excision – 2. Electron microscopy – 2. Depth of the tumor – 3. Cytogenetics Stage % – 3. Tumor type and I 86 variant II 72 – 4. Grade (if possible) III 52 – 5. Tumor size IV 10-20 – 6. Status of margins & L.N. – 7. Percent of necrosis – NEJM 2005; 353: 701-711 8. Vascular invasion, if present

SOFT TISSUE SARCOMAS- IMAGING STUDIES z The ultimate goal is: COMPREHENSIVE ANALYSIS – 1. Detecting lesions Liposarcoma z Gross examination z Frozen tissue procurement – 2. Giving a specific diagnosis or a z Evaluation of inked z Formalin fixation reasonable differential diagnosis margins z Cytogenetics – 3. Staging the lesion z Gross description and z (E.M.) tumor measurements z Photograph z Sampling of tumor and margins z Frozen sections for diagnostic or triaging purposes MFH

SOFT TISSUE SARCOMAS IMAGING STUDIES MARGINS DESCRIPTION INTERPRETATION z CT and particularly MRI allow detection INTRALESIONAL The surgical plane of dissection passes through tumor and and staging by delineating anatomical tissue. extent in virtually all cases. MARGINAL The surgical plane of dissection passes through the pseudocapsule, without microscopic evidence of z A relatively specific diagnosis can be given tumor. in approximately 25-50% of cases, WIDE The surgical plane of dissection passes outside the reactive zone and through normal tissue. according to the type.

RADICAL The surgical margins are all wide and include the entire anatomical compartment(s) involved by the tumor. CONTAMINATED A margin obtained by the surgical re-excision of the wound previously found to be microscopically intra- lesional in the same operative procedure. 65 W, FS thigh (MRI)

7 GENETICS OF SOFT TISSUE TUMORS

z Numerous cancer-specific genetic alterations have been described. z Some of them (such as translocations, numerical changes, large deletions and gene amplifications) are seen at the cytogenetic level. z Subtle changes (such as single base pair substitutions, small deletions) require molecular genetic detection.

GENETICS OF SOFT TISSUE TUMORS GENE FUSIONS IN SARCOMAS z Many chromosomal FISH-F: Ewing translocations and other genetic rearrangements lead z These translocations: to formation of oncogenic 1. represent fundamental genetic steps in gene fusions or overexpression of normal the development of these cancers genes. 2. are useful markers for the diagnosis z Many of these changes may be used for diagnosis or 3. may constitute new therapeutic targets confirmation of diagnosis.

FISH-BA: Ewing t(11;22)(q24;q12)

GENE FUSIONS IN SARCOMAS GENE FUSIONS IN SARCOMAS z Nonrandom translocations were described first in hematopoietic malignancies. z Investigation of these translocation may: z Identified in many types of sarcomas. 1. clarify the molecular etiology of these z Also identified in benign soft tissue tumors. cancers z Each translocation results in a specific gene fusion. 2. help in identifying new markers for z Each gene fusion is present in most cases of a diagnosis and monitoring specific sarcoma category, and is not present in 3. lead to new therapeutic strategies any other sarcoma type. against tumor-specific markers. z These genetic events demonstrate consistency and specificity.

8 GENE FUSIONS IN SARCOMAS BONE TUMORS 1. These translocations disrupt genes located at the chromosomal breakpoints and juxtapose portions of these genes to create two reciprocal chimeric genes. 2. The breaks are confined to one or a few introns within the coding region of each gene. FISH with dual color 3. The chimeric genes are transcribed break-apart probe to generate chimeric transcripts. cocktail flanking the 4. The chimeric transcripts are EWS breakpoint region translated into chimeric proteins. at 22q12

BONE TUMORS GENE FUSIONS IN SARCOMAS • The majority of tumors involving bone are secondary (or metastatic): z The novel protein products have significantly - secondary (metastases) (95%) altered functional properties. - primary (5%) z In many cases, one or both involved genes are transcription factors, and the chimeric product is a novel transcription factor.

MELANOMA TO PROXIMAL HUMERUS BREAST CANCER TO HIP

SOFT TISSUE TUMORS METASTATIC BONE TUMORS SUMMARY

z Carcinomas are the z Tumors of . most common z Rare (sarcomas: 3-4 cases per 100,000). metastatic tumors to z Etiology unclear, with a few exceptions. bone. Mammary carcinoma z Classified according to tissue they resemble. z Other may z Biologically: benign, borderline or malignant. also metastasize to bone (sarcomas, z Grading and staging crucial elements to be added ). to diagnosis. z Some of the lesions have specific translocations.

Uterine leiomyosarcoma

9 Secondary Tumors of Bone BONE TUMORS

•The carcinomas most frequently involved HIGH RISK Ollier and Maffucci syndrome z The majority of bone with bone metastasis originate from: Familial Retinoblastoma syndrome sarcomas arise de Rothmund-Thompson syndrome • Lung novo. MODERATE RISK Multiple enchondromas Polyostotic Paget disease • Breast z Some, however, Radiation osteitis • Prostate develop in association LOW RISK Fibrous dysplasia • G.I with recognizable Bone infarct precursors. Chronic osteomyelitis • Kidney Metallic and polyethylene implants • Thyroid Giant cell tumor and

Cartilage tumors Chondroma WHO WHO Periosteal chondroma CLASSIFICATION Multiple chondromatosis BONE TUMORS OF BONE TUMORS Chondroblastoma Chondrosarcoma Central Peripheral z Primary bone tumors are rare. Dedifferentiated Mesenchymal z Sarcomas account for 0.2% of all neoplasms Clear cell Osteogenic tumors Osteoid (SEER Cancer Statistics Review, 1973- Osteoblastoma Osteosarcoma Conventional 1996). Telangiectatic Small cell z Soft tissue sarcomas are 10 times more Low grade central Secondary common than primary bone sarcomas. Parosteal Periosteal High grade surface Fibrogenic tumors Desmoplastic fibroma Fibrosarcoma Fibrohistiocytic tumors Desmoplastic fibroma Fibrosarcoma

WHO Ewing/PNET Ewing sarcoma

CLASSIFICATION Hematopoietic tumors Plasma cell myeloma OF BONE Malignant lymphoma BONE TUMORS TUMORS Giant cell tumor Giant cell tumor Malignant giant cell tumor Notochordal tumors Chordoma Vascular tumors Hemangioma z In North America and Europe, the incidence rate Angiosarcoma for bone in males is approximately 0.8 new cases Smooth muscle tumors Leiomyoma Leiomyosarcoma per 100,000 people a year. Lipogenic tumors Lipoma Liposarcoma z Osteosarcoma is the most common primary Neural tumors Schwannoma malignant tumor of bone (35%), followed by Miscellaneous tumors Metastatic malignancy chondrosarcoma (25%) and Ewing sarcoma Miscellaneous lesions Aneurysmal bone cyst (16%). Simple cyst Fibrous dysplasia z Chordomas and MFH represent 8 and 5% of the Langerhans cell histiocytosis the tumors in the group respectively. Erdheim -Chester disease Chest wall hamartoma Joint lesions Synovial chondromatosis

10 BONE TUMORS BONE TUMORS z Conventional radiographs are •Bone sarcomas as a group have a bimodal distribution. still important in the diagnosis of •The first peak is in the second decade. bone tumors. •The second peak occurs in patients older than sixty. z Many tumors are site-specific. z Many tumors have a 80 characteristic radiographic 70 60 OS appearance. 50 CS 1. Ewing sarcoma, lymphoma, myeloma 2. Osteofibrous dysplasia, adamantinoma 40 ES 3. 30 CH 4. Fibrous dysplasia 20 5. Chondromyxoid fibroma MFH 6. Non-ossifying fibroma 10 7. Bone cyst, osteoblastoma 0 8. Osteochondroma 9. Osteosarcoma 10. Enchondroma, chondrosarcoma 11. Giant-cell tumor 0 to 4 12. Chondroblastoma 10 to14 20 to24 30 to34 40 to44 50 to54 60 to64 70 to74 80 to85

BONE TUMORS BONE TUMORS

z The clinical presentation of bone tumors is at the beginning non-specific, with pain and swelling presenting first. z Later, limitation of movement and pathological fracture and general symptoms may occur. z A long time may elapse until the tumor is diagnosed.

Some fancy words from the world of shadows

BONE TUMORS BONE BONE TUMORS Geographic with TUMORS sharp margins and flocculent CONVENTIONAL X-RAY calcifications z The imaging (Enchondroma) z The diagnosis is characteristics of some based on imaging BENIGN SUSPICIOUS FOR MALIGNANCY lesions are diagnostic. and histological QUESTIONABLE RESULTS z Even if not clear to the criteria. TREATMENT radiologist, the images CT STAGING may help somebody CT X-RAY else down the MRI diagnostic chain (e.g. Sclerotic margin and BIOPSY lytic MRI BIOPSY the pathologist) (Chondroblastoma)

TREATMENT

11 BONE TUMORS BONE TUMORS z Geographic with ill defined margins: z The tumor need to be graded (grading is usually malignant (in an important element of the staging and this case a primary determines if the tumor is stage I or II). chondrosarcoma) z The TNM system follows a 2 tier grading system: low- and high-grade.

Previous biopsy site

BONE TUMORS BONE TUMORS z Moth-eaten and Primary tumor (T) TX Primary tumor cannot be assessed permeated are bad z The staging of T0 No evidence of primary tumor news (unless it’s bone T1 Tumor less or equal to 8 cm in greatest dimension sarcomas T2 Tumor equal or more than 8 cm in greatest dimension infection) T3 Discontinuous tumors in the primary bone site follows the Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed TNM system. NO No regional lymph node metastasis N1 Regional lymph node metastasis Distant metastases (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis: M1a: lung Previous biopsy site M1b: other sites

AJCC Cancer Staging Manual, 6th Edition, Springer, New York

BONE TUMORS BONE TUMORS

Stage IA T1 N0, NX M0 Low grade z Periosteal reactions (such Stage IB T2 N0, NX M0 Low grade as spiculated, Codman’s angle, onion skin) are Stage IIA T1 N0, NX M0 High grade witnesses of cortical Stage IIB T2 N0, NX M0 High grade destruction and soft tissue Stage III T3 N0, NX M0 Any grade extension ( usually bad Stage IVA Any T N0, NX M1a Any grade news, unless infective) Stage IVB Any T N1 Any M Any grade Any T Any N M1b Any grade

AJCC Cancer Staging Manual, 6th Edition, Springer, New York

12 BONE TUMORS OSTEOID OSTEOMA

z On plain x-rays the lesion is z Stage I: low grade intra-compartmental (risk characterized by dense cortical sclerosis surrounding a of metastasis <25%) radiolucent nidus. z CT scan best type of imaging z Stage II: high-grade extra-compartmental study. (risk of metastasis >25%) Nidus z Stage III: any grade, discontinuous tumor in the primary bone site z Stage IV: any grade, metastatic

BONE-FORMING TUMORS OSTEOID OSTEOMA Osteogenic tumors Osteoid osteoma z Small, cortically based lesion, Osteoblastoma red and gritty, surrounded by sclerotic bone. Osteosarcoma Conventional z The lesion is composed of a meshwork of osteoid Telangiectatic trabeculae lined by plump . Small cell

Low grade central

Secondary

Parosteal

Periosteal

High grade surface

OSTEOID OSTEOMA OSTEOID OSTEOMA

z Benign bone forming tumor. z Near diploid karyotype. z Small size, limited growth potential and disproportionate z Two cases with involvement of 22q13 and pain. z Most common in long , loss of distal part of 17q. but every bone may be affected. z Excellent prognosis following local z It may be painful on physical examination excision (nidus has to be removed z It may be associated with completely). redness of skin and swelling. z Lesions close to a joint may be associated with joint effusion.

13 OSTEOSARCOMA OSTEOSARCOMA • Conventional: - Osteoblastic (50%) • Malignant primary neoplasm of bone that - Chondroblastic (<25%) produces osteoid (osteoid directly produced - Fibroblastic (<1-2 %) • Telangiectatic (<4%) by the tumor cells). • Small cell (1.5%) • Intra-medullary origin (conventional type). • Low grade central (<1%) • Parosteal (4%) • Rare subtypes. • Periosteal (<2%) • High-grade surface (<<1%) • Most common, non-hematopoietic tumor of • Secondary (20% of OS in patients older bone (incidence 4-5 per million). than 40)

OSTEOSARCOMA OSTEOSARCOMA z Largely a disease of the young (60% <25 years) z 30 % >40 years. z Anaplastic, pleomorphic z In older people rule out tumor. predisposing conditions z Production of osteoid. (e.g. Paget’s disease of z Cartilage and fibrous bone, radiation) tissue may also be produced. z Long bones of appendicular skeleton are favored z 91% , 9%

OSTEOSARCOMA OSTEOSARCOMA

Central Surface z IHC not useful. -Low Grade z Complex clonal chromosomal aberrations (including numerical -Low Grade and structural alterations). - High Grade - High Grade z Recurrent involvement of 1p11, 13, 1q11-12, 1q21-22, 11p14-15, 14p11-13, 15p11-13, 17p, 19q13. z Imbalances of +1, -6q, -9, -10, -13 (retinoblastoma gene on chromosome 13) and -17. z Gains in 3q26, 4q12-13, 5p13-14, 7q31-32, 8q21-23, 12q14-15 (MDM2 and PRIM1), and 17p11-12 (Li-Fraumeni syndrome). z Over-expression of MET and FOS in >50% of OS, and MYC in <15%.

14 OSTEOSARCOMA ENCHONDROMA z Untreated is fatal (aggressive local growth and rapid hematogenous systemic metastasis).

z When treated with surgery alone, survival is limited. z Swelling of small bones of z Age, gender, location, size, stage and laboratory tests traditional hands and feet, thinning of prognostic factors. cortex and pathological fractures. z The most reliable indicator of survival is the response to z Asymptomatic in long bones. preoperative chemotherapy (good prognosis >90% tumor z Well marginated lesions on necrosis). imaging; lytic or mineralized. z In good responders survival in 80-90% of cases is nor unusual. z Usually in metaphysis, less common in diaphysis, rare in z Bad responders, without change in chemotherapy, die in 80-90% . of cases (but with change of regimen long-term survival can be z Hypocellular, avascular with greatly improved). abundant .

CARTILAGE-FORMING TUMORS CHONDROSARCOMA (PRIMARY)

z Malignant neoplasm with pure Cartilage tumors Osteochondroma hyaline cartilage differentiation.

Chondroma Enchondroma z Primary or conventional chondrosarcoma (90% of CS) Periosteal chondroma arises centrally in a previously normal bone. Multiple chondromatosis z Third most common primary Chondroblastoma malignancy of bone after myeloma and osteosarcoma. Chondromyxoid fibroma z Tumor of adulthood (majority of Chondrosarcoma Central patients >50 years). z Genetics: Peripheral – Near diploid or pseudo-diploid karyotypes. Dedifferentiated – Simple numerical changes (-X, -Y, Mesenchymal +5). – Rearrangements of 1p13-p22. Clear cell

ENCHONDROMA CHONDROSARCOMA (PRIMARY)

z Benign hyaline cartilage neoplasm of medullary bone. z Most commonly involved sites are: the pelvis, proximal femur and z Usually single. humerus, distal femur and ribs. z Common (10-25% of all benign bone tumors), but incidence is z Rare in the fingers (1%). probably significantly higher. z Extremely rare in spine and craniofacial bones. z Wide age distribution (5-80 years) with most patients z Local swelling and pain. between 2nd and 4th decade. z Metaphysis. z Most common in hands, z Expansion of bone, thickening of followed by long tubular bones. the cortex with possible cortical Rare in flat bones. erosion or destruction. z Exceedingly rare in craniofacial bones.

15 CHONDROSARCOMA (PRIMARY) z Cut surfaces translucent, blue-gray to white (cartilage), lobular, solid to myxoid areas, cortical erosion and soft tissue extension possible. z Lobules of cartilage separated by fibrous septa. z Host lamellar entrapment. z Three grades: – 1. Moderately cellular, oftentimes indistinguishable from enchondroma. – 2. More cellular and atypical with more myxoid matrix. – 3. More cellular,atypical and myxoid than grade 2 lesions. Mitoses are easily detected.

CHONDROSARCOMA (PRIMARY)

z The histological grade is the most important predictor of local recurrence and metastasis. z 89% of patients with grade 1 lesions are alive at 5 years. z Only 53% of patients with grade 2 and 3 lesions are alive at 5 years. z 10% of recurrent tumors show increase in grade or dedifferentiate. z Treatment is surgical (chemo and radiation resistant tumors).

Summary of bone sarcomas

z Tumors of connective tissue. z Very rare (bone sarcomas: 1/10 of soft tissue sarcomas). z Etiology unclear, with a few exceptions. z Classified according to tissue they resemble. z Biologically: benign, borderline or malignant. z Grading and staging crucial elements to be added to diagnosis. z No recurrent diagnostic translocation (unless a soft tissue equivalent exists, e.g. Ewing sarcoma).

16