Review Course «Musculoskeletal Oncology» October 6, 2011 UNIKLINIK BALGRIST

Pathological Diagnosis of Course Oncology» Soft TissueReview and Bone Tumors 2011 incl. Molecular Diagnostics6,

PD Dr. med. «Musculoskeletal Beata Bode BALGRIST Institute of Surgical Pathology October University Hospital, Zurich

Review Course „Musculoskeletal Oncology“UNIKLINIK 6th of October 2011 14.15 -14.40 WHY PATHOLOGY? Patient with s/o muculo-skeletal neoplasia

Course Oncology» What Reviewexactly is the problem? 6, 2011 «MusculoskeletalMultidisciplinaryOctober team BALGRIST of physicians

42 y, M

Tenosynovial UNIKLINIK Epitheloid giant cell tumor sarcoma 37 y, M 41y; F 37y, F 89y, F B11.36712 B10.50724 B11.7716

Course Oncology» Review Ziehl-Neelsen stain RCC 2011CD20 Acid fast bacillia (Mycobacterias) 6, «MusculoskeletalOctober BALGRIST UNIKLINIK

Osteomyelitis Metastasis Aggressive lymphoma Primary Diagnostics

• Type of tumor – Benign • Non-neoplastic • Neoplastic Course – Malignant Oncology» • MetastasisReview – Origin 2011 • Primary tumor 6,Malignancy grade Estimation of the expected clinical course according – Malignancy grade to histological and cytologial criteria - Probability of metastases BALGRIST- Survival • «MusculoskeletalEntity October EXCLUSIVELY (!) ON UNTREATED PRIMARY TUMOR

• TherapyUNIKLINIK (Hormon receptors; CD20, Her2; EGFR, KRAS, CD117, etc………) • Prognosis (Translocations type?) • Influence of therapy – chemotherapy (osteosarcoma, Ewing sarcoma) – radiotherapy (soft tissue sarcomas) Course Oncology» • ResectionReview margins 2011 – Extremity sparing surgery6, «MusculoskeletalOctober BALGRIST • Local recurrences • MetastasesUNIKLINIK Course- Leiomyosarcomas Oncology»- Synovial sarcomas Review 2011 6, - DSCRT - SFT «MusculoskeletalOctober BALGRIST

UNIKLINIK - Angiosarcomas Open (surgical) biopsy Needle biopsy

Excisional biopsy Core biopsy Fine needle biopsy (max 3-5 cm mass) NeedleCourse diameter Needle diateter Incisional biopsy >1mm (18G) <1mm (24G) (>5 cm) Oncology» HistologyReviewHistology Cytology 6, 2011 «MusculoskeletalOctober BALGRIST Seroma

UNIKLINIKTumor

CELL BLOCK Course Oncology» Review 6, 2011 «MusculoskeletalOctober BALGRIST UNIKLINIK OBLIGATORY DATA Submission Form Biopsy • Primary diagnostics

– Age, gender – Topography (printouts of Rtx, CT or MRI scans) – Dynamics of the tumor growth Course – Known accompanying diseases (esp. malignantOncology» tumors!) – Any other relevantReview data (prior trauma? prior surgery? ect…) • Resection specimen 6, 2011 – Prior (neo-adjuvant) therapy (radiation,BALGRIST drugs / therap. substances) –«Musculoskeletal Top. orientientationOctober (thread mark, correlation with CT / MRI)

– Relation / infiltration / distance to any critical, clinically relevant sites (resectionUNIKLINIK margins, periosteum, ect) TELL YOUR PATHOLOGIST

EVERYTHING (or almost) YOU KNOW ABOUT THE PATIENT (in the interest of theCourse patient and yourself) Oncology» Review Pathology is not about measuring6, 2011 concentrations Pathology is an interpretation / consultation «MusculoskeletalPathologyOctober is a very dynamic BALGRIST discipline PathologistsUNIKLINIK ARE PHYSICIANS and want to help the patient (and you managing the patient) Patient case

• 79 y, F Course • Tumor, upper arm, severalOncology» cm in diameter Review 2011 • PathInst 1: Consult in Zurich6, «MusculoskeletalOctober BALGRIST UNIKLINIK PI 1

PI 2 Course Oncology» Review 6, 2011 «MusculoskeletalOctober BALGRIST PI 3 UNIKLINIK WHY?

Surgeon: OncologistsCourse told me to do so...... Oncology» Review 2011 What about the resection6, margins? «MusculoskeletalOctober BALGRIST Surgeon: I resected it with clear margins ….. UNIKLINIK PI 1

PI 2 Course Oncology» Review 6, 2011 «MusculoskeletalOctober BALGRIST PI 3 3rd report -> dedifferentiated liposarcoma, grade 3 UNIKLINIK • NEVER split the biopsy or resection sample sending only small fractions to different pathology labs (malpractice!!) – Tumor heterogeneity and variable experience of the histopathologist may lead to discrepant diagnoses – and it is not the primary fault of the pathologists – it serves YOU right (pity on the patient)Course – Problems in evaluating resection margins (if Oncology» applicable) Review • If you are not happy with the diagnosis (if 2011 you think it is not correct), let the sample6, be send to other pathologists (any number «Musculoskeletal you wish) of your choice (usualBALGRIST practice among pathologists)October

• Work with a pathologist you know and trust – and communicateUNIKLINIK with him Sarcomas – epidemiology

USA 2007 (Gralow; JCO; 2008) - 1 444 920 new diagnosed malignancies - 9 220 soft tissue sarcomas (0.6%) - 2 370 bone sarcomas Course(0.2%) - 213 380 lung carcinomas Oncology» - 180 510 breast carcinomas - 153 760 colon Reviewcarcinomas - 100 000 lymphome/leukaemia 6, 2011 Incidence of soft tissue sarcomas: ca 25-30 «Musculoskeletal new cases pro 1 000October 000 / year: BALGRIST Switzerland: ca 175-200 Germany: 2000 - 2500

Incidence of bone sarcoma: ca 8 new cases pro 1UNIKLINIK 000 000 / year: Schweiz ca 55-65, including ca 15 osteosarcomas Germany: 600-700 WHO 2002 Classification Soft tissue and Bone Tumors Course Clinical presentation Oncology» HistopathologyReview 2011 Immunhistochemistry 6,

«MusculoskeletalMolecular geneticsOctober BALGRIST UNIKLINIK Schwannoma Leiomyosarcoma

Heterogenity

Osteosarcoma CourseMyx. liposarcoma Myx. chondrosarcoma Oncology» Review 6, 2011 BALGRIST Conv. chondrosarcoma «MusculoskeletalOctober Biph. Synovial sarcoma Ewing sarcoma UNIKLINIK Nomenclature

Morphological similarity to mature tissue types

• lipomatous lipoma, liposarcoma Course • leiomyomatous Oncology»leiomyoma, Leiomyosarcoma • fibroblasticReview fibromatosis 6, 2011 • endothelial hemangioma, angiosarcoma BALGRIST «Musculoskeletal• etc …. October NOT theUNIKLINIK „cell of origin“ - eg. rhabdomyosarcoma - eg. synovial sarcoma IMMUNHISTOCHEMISTRY line of differentiation

- myogenic differentiation - Actin, calponin, - Desmin caldesmone Course - Myogenin, MyoD1 Oncology» - neurogenic differentiation (S100, NSE) - endothelial differentiationReview (CD31, FVIII) 6, 2011 - epithelial markers (cytokeratins, EMA) - lymphatic «Musculoskeletal markersOctober (CD45, CD20, BALGRISTCD3, CD68, CD30…..) - melanocytic markers (S100, HMB45)

- CD34 (DFSP,UNIKLINIK Kaposi sarcoma, spindel cell lipom, endothel) - CD99 (Ewing sa, synovial sa, SFT, mes. chondro sarcoma) Line of differentiation uncertain NOT similar to any body tissue

- Ewing sarcoma / PNET

- Myxomas - Epitheloid sarcoma - Alveolar soft part sarcoma Course - Clear cell sarcoma Oncology» Review - Ossifying fibromyxoid tumor (OFMT) 2011 - Desmoplastic small round cell tumor (DSCRT)6, - Pleomorphic hyalinizing angiectatic tumor (PHAT) - Myxo-inflammatory fibroblastic sarcoma (MIFS) - Tumor «Musculoskeletal with perivascularOctober epitheloid differentiation BALGRIST (PECom) - Phosphaturic mesenchymalUNIKLINIK tumor (oncogenic osteomalacia) - …………. CYTOGENETICS & MOLECULAR BIOLOGY

Genetic event precursor (stem) cell

- Translocation (synovial sarcoma, DFSP,. .) - Amplification (atypical lipomatousCourse tumor) Oncology» - Point mutationReview (GIST) - Deletion (epitheloid sarcoma) 6, 2011 - etc… Specific:«Musculoskeletal eg. SYT-SSXOctober -> synovial sarcoma BALGRIST Exceptionally the same translocation in different tumor types

EWS-AFT1UNIKLINIK or EWS-CREB1 in - clear cell sarcoma (malignant melanoma of soft tissue) - angiomatoid fibrous histiocytoma CREB3L2 Low grade fibromyxoid sarcoma

CHOP Myxoid liposarcoma

ERG Myeloid leukemia FUS FEV Course FLI1 Ewing sarcoma Oncology» ReviewETV1 2011 E1AF 6, EWS «MusculoskeletalOctoberWT1 Desmoplastic BALGRISTsmall round cell tumor Angiomatoid fibrous Clear cell sarcoma ATF1 ATF1 histiocytoma

CREB1 Clear cell sarcoma CREB1 Angiomatoid fibrous UNIKLINIK histiocytoma TEC Extraskelettal myxoid chondrosarcoma Course Oncology» Review 6, 2011 «MusculoskeletalOctober BALGRIST UNIKLINIK Frequency of soft tissue sarcoma types

Ca: 1960 – 1980 - Malignant fibrous histiocytoma (MFH) - Liposarcoma - Fibrosarcoma Course - Leiomyosarcoma Oncology» Review Immunhistochemistry 6, 2011Molecular genetics 1990 - 2000 BALGRIST «Musculoskeletal- LiposarcomaOctober - Myxofibrosarcoma - Leiomyosarcoma - PleomorphicUNIKLINIK undifferentiated sarcoma - 97 (63%) other specific sarcoma types - 20 non mesenchymal (NHL, Ca, melanoma) - 42 non classified - 21 small or Coursenecrotc biopsies - 20 pleomorphic sarcomaOncology» NOS Review 6, 2011

- 8 lipogenic (4 pleo, 3 dediff, 1 combined) «MusculoskeletalOctober- 19 myogenic (11 LMS, 1BALGRIST rhabdo, 4 NOS) - 8 myxofibrosarcoma - 1 MPNST - 1 extraskel osteosarcoma UNIKLINIK- 1 mesenchymoma (dediff lipo?) - 1 sarcoma resembling prolif fasciitis

- 7 pleomorphic sarkoma NOS Problem entitity (1963, Stout) Malignant Fibrous Histiocytoma (MFH)

1. Myxoid Myxofibrosarcoma, …..

2. Pleomorphic-storiform Course Dedifferentiated liposarcoma, …... Oncology»Ampl mdm2 Review 3. Giant cell 2011 Giant cell containing leiomyosarcoma,6, . SMA 4. Inflammatoric BALGRIST Dedifferentiated«MusculoskeletalOctober liposarcoma, …..

Ampl mdm2 5. Angiomatoid Specific, UNIKLINIKgenetically def. entity Split EWS; t(12;22) Liposarcoma

Low grade (G1) High grade (G3) 1. Well differentiated (G1) Dedifferentiated (G2-3) Ring or giant chromosomes 12q Course Amplicon mdm2/cdk4 Oncology» Review 2. Myxoid (G1) 2011 Round cell (G2-3) 6, Translocation t (12;16) «MusculoskeletalOctober BALGRIST 3. Pleomorphic (G3) Komplex karyotypeUNIKLINIK Two groups of sarcoma with simple karyotypes and with komplex karyotypes WITH typical translocations WITHOUT typical translocations Course – Synovial sarcoma – LeiomyosarcomaOncology» – Ewing sarcomaReview / PNET – Myxofibrosarcoma – Myxoid liposarcoma – Osteosarcoma2011 – …. 6,– … «MusculoskeletalOctober BALGRIST

Histology + Immunhistochemistry Histology +/- Immunhistochemistry + Molecular geneticsUNIKLINIK (FISH+PCR) Course Oncology» Review 6, 2011 «MusculoskeletalOctober BALGRIST UNIKLINIK 80 y old woman

1989 – Tumor of the lung – diagnosis: Atypical carcinoidCourse Oncology» Review 2001 2011 – Locally advanced, radiologically6, malignant humerus tumor – Diagnosis: «Musculoskeletal SmallOctober cell osteosarcoma BALGRIST

2003 UNIKLINIK – Local recurrence upper arm Primary Humeral tumor metastasis FISH SYT C+ C- M

actin t(X;18)Course Oncology» Review 6, 2011 «MusculoskeletalOctober BALGRIST UNIKLINIK Course 28y F Oncology» Review Cytokeratin6, 2011 (AE1/AE3) «MusculoskeletalOctober BALGRIST UNIKLINIK FISH SYT Course Oncology» Review 6, 2011 «MusculoskeletalOctober BALGRIST UNIKLINIK t(X;18) RT-PCR / Sequencing

Fusion transcript

Course Oncology» Review 2011 SYT 6, SSX1, -2, -4 «MusculoskeletalOctoberSYT-Primer BALGRIST SSX-Primer 8 9 10 5 6 UNIKLINIK Biphasic synovial sarcoma Course Oncology» Review 6, 2011 «MusculoskeletalOctober BALGRIST UNIKLINIK Metastasis: most frequent malignant tumor of the bone (especially in adults)

Bone is following lung and liver the 3rd most common targetCourse organ of metastases Oncology» Review 2011 Primary tumors: 6, - Breast «Musculoskeletal- Lung October BALGRIST - Prostate ca 95% of the cases - Kidney - ThyroidUNIKLINIK Metastasis as a first manifestation of a tumor

Solitary metastasis: DD primary bone tumor

Two or more different primaryCourse tumors Oncology»

(mostlyReview with immunhistochemistry and/or mogecular studies) Biopsy 2011 • helpful in the search of the6, primry tumor • analysis of the predictive markers (ER, PR, Her2, EGFR,….) «MusculoskeletalOctober BALGRIST TTF1 – adenocarcinoma of the lung PSA –prostate cancer Thyreoglobulin (thyroid cancer) Estrogen receptor (breast cancer) UNIKLINIK Primary Bone Tumors WHO 2002

Accordingto thetypeof theextracellular matrix

- Osteogenic tumors -Osteoid osteoma Course-Osteoblastoma -OsteosarcomaOncology» - ChondrogenicReview tumors -Osteochondroma -(En-)Chondroma2011 -Chondroblastoma6, -Chondromyxoid fibroma «MusculoskeletalOctober-Chondrosarcomaa BALGRIST - Fibrous / fibro-histiocytic tumors

- Desmoplastic fibroma UNIKLINIK- Fibrosarcoma - Benign fibrous histiocytoma - Malignant fibrous histiocytoma - Ewing sarcoma / PNET (Peripheral NeuroEctodermal Tumor)

- Giant cell tumor of bone Course - Tumors/Lesions of unclear origin / differentiationOncology» - Simple bone cystReview - Aneurysmatic bone cyst typical2011 translocation (USP6 17p13) - Fibrous dysplasia 6,Akt. mutation GNAS gene - Langerhans cell histiocytosis «MusculoskeletalOctober BALGRIST - Metastases - HematopoieticUNIKLINIK tumors (plasmozytoma, lymphoma) - Notochordal tumors (chordoma) - Soft tissue tumores (angiosarcoma, leiomyosarcoma, …..) Frequency of the primary malignanr bone tumors

- Osteoblastic - Osteosarcoma (35%) - Chondroblastic - Fibroblastic - Small cell - Teleangiectatic - Parosteal Course - Periosteal

Oncology»- Conventional - Chondrosarcoma (25%) - Dedifferentiated Review - Mesenchymal 2011 - Myxoid 6, - Clear cell BALGRIST - Ewing «Musculoskeletal sarcomaOctober (16%) UNIKLINIK - Chordoma (8%) - MFH (malignant fibrous histiocytoma) (5%) Small, blue and round cell tumors

Ewing sarcoma / PNET

Neuroblastoma Rhabdomyosarcoma Course Small cell osteosarcoma Oncology» Mesenchymal chondrosarcomaReview Round cell liposarcoma 2011 Poorly differentiated synovial sarcoma6, Desmoplastic small and round cell tumor (DSRCT) «MusculoskeletalOctober BALGRIST Lymphoma / leukemia Small cell carcinoma ImmunhistochemistryUNIKLINIK + Molecular genetics • Influence of the therapy – Chemotherapy (osteosarcoma, Ewing sarcoma) – Radiotherapy (soft tissue sarcomas) Course Oncology» • ResectionReview margins 2011 – Extremity sparing resections6, «MusculoskeletalOctober BALGRIST • Local recurrences • MetastasesUNIKLINIK High grade osteoblastic osteosarcoma

Course Oncology» Review Neo-adjuvant chemotherapy2011 Completely devitalised tumor tissue 6, Vital tumor tissue «MusculoskeletalOctober BALGRIST UNIKLINIK

B2008.37414 B2008.32899 Course Oncology» Review 6, 2011 «MusculoskeletalOctober BALGRIST UNIKLINIK Prior to therapy

Course Oncology» Review Following neo-adjuvant therapy 6, 2011 «MusculoskeletalOctober BALGRIST UNIKLINIK Resection margins

Course Oncology» Review 6, 2011 «MusculoskeletalOctober BALGRIST UNIKLINIK Course Oncology» Review 6, 2011 «MusculoskeletalOctober BALGRIST UNIKLINIK Pathology of Soft tissue and Bone Tumors Summary

• Understanding of the pathogenesis • Developement of new concepts for diagnostics and treatment

• Diagnostics – Despite the progress in radiologicalCourse methods, histopathology remains gold standard in diagnosis of musculoskeletal tumorsOncology» – Differential diagnosisReview is based on clinical presentation; H&E, immunhistochemistry and advanced ancillary2011 studies (FISH, RT-PCR) – Minimally invasive histopathological diagnostics6, is only possible if adequate clinical and radiological correlation is available (multidisciplinary centers «Musculoskeletalwith a sufficient caseOctober load) BALGRIST • Therapy – Precise histopathologic diagnosis is crucial for the planning of the therapy and postoperativeUNIKLINIK management – Extend of the surgery – (Neo-) adjuvant chemotherapy Course Oncology» Review 6, 2011 «MusculoskeletalOctober BALGRIST UNIKLINIK