SC #06. Common Challenging Problems in Bone and Soft Tissue Pathology. Andrew L. Folpe, MD Mayo Clinic Rochester, MN

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1 SC #06 Common Challenging Problems in Bone and Soft Tissue Pathology Andrew L. Folpe, MD Mayo Clinic Rochester, MN Andrew E. Horvai, MD, PhD University of California, San Francisco San Francisco, CA

2 Short Course #06 Common Challenging Problems in Bone and Soft Tissue Pathology USCAP 2015 Common problems in bone and soft tissue pathology: Introduction to bone pathology. Andrew Horvai MD PhD Clinical Professor, Pathology UCSF, San Francisco, CA Disease of bone Approach to bone diagnosis Pathology Clinical Relative incidence 8 million thousands Imaging 1

3 Approach to bone diagnosis Pathology Imaging Clinical Fracture Non-ossifying fibroma Osteoporosis Pathology Clinical Imaging Metastatic carcinoma Myeloma, lymphoma Pleomorphic undifferentiated sarcoma Approach to bone diagnosis: Necessary information Clinical : Age Location Pain Underlying disease: hyperparathyroidism, IVDU Radiology: Definitions Histology Clinical: Age Age Benign Malignant <10 Unicameral bone cyst, Langerhans Skeletal dysplasias Acute osteomyelitis Non-ossifying fibroma, ABC, osteochondroma, osteoblastoma, chondroblastoma Enchondroma, Giant cell tumor >40 Osteoma Osteonecrosis Renal osteodystrophy Paget disease Ewing, Leukemia/Lymphoma Osteosarcoma Ewing Adamantinoma Chondrosarcoma Myeloma, Chondrosarcoma, Chordoma Clinical: Pain Pain: Growing lesion Pathologic fracture Local tissue reaction Osteoid osteoma: Night pain, relieved by aspirin or NSAIDs Grade 1 chondrosarcoma: Usually painful vs. enchondroma (painless, unless fracture). 2

4 Clinical: Location epiphysis Chondroblastoma Giant cell tumor Clear cell chondrosarcoma Radiology: Modalities Plain radiographs*: 2 views metaphysis Osteosarcoma Osteochondroma Aneurysmal bone cyst Non-ossifying fibroma CT: Axial location, permeative lesions diaphysis Fibrous dysplasia Osteoid osteoma Ewing sarcoma Adamantinoma Lymphoma MRI: Soft tissue, neurovascular, surgical planning Radiology: Patterns of growth Radiology: Opacity Opacity Border Periosteum Lytic B Sclerotic 3

5 Radiology: Border Radiology: Periosteum Marginated Circumscribed Permeative Solid Codman s triangle Spiculated Histology: what is normal? Lamellar Always abnormal: woven bone Lamellar Woven Marrow: fat and hematopoetic cells only Lacunae contain osteocytes Evenly spaced cement lines Remodeling <20% of surface Neoplasms Osteoblastoma Osteosarcoma Inflammatory Osteomyelitis Metabolic/Developmental Osteogenesis Imperfecta Osteopetrosis 4

6 Always abnormal: excess cement lines Paget disease Always* abnormal: Empty lacunae Empty lacunae Neoplasms Low grade osteosarcoma Inflammatory/Metabolic Paget disease Necrosis Inflammatory Bone infarct Radiation osteonecrosis Osteomyelitis (sequestrum) Artifact (overdecalcification) Interstitial lamellae Always abnormal: Marrow replaced Chondrosarcoma Always abnormal: Excess remodeling Hyperparathyroidism Neoplasms Chondrosarcoma Metastasis Hematolymphoid Inflammatory Osteomyelitis Metabolic/Developmental Fibrous dysplasia Xanthomatosis Inflammatory Paget disease Chronic osteomyelitis Metabolic/Developmental Hyperparathyroidism Renal osteodystrophy 5

7 Cartilage: what is normal Widely dispersed chondrocytes Small, dark chondrocyte nuclei Always abnormal: Cartilage High cellularity Large bizzare chondrocytes Myxoid matrix solid hyaline matrix USCAP 2015 Common problems in bone and soft tissue pathology: Cartilage tumors Outline Common intramedullary tumors Enchondroma Conventional chondrosarcoma ( atypical cartilage tumor ) Chondrosarcoma variants Dedifferentiated chondrosarcoma Mesenchymal chondrosarcoma Clear cell chondrosarcoma (Chondroblastoma to be discussed with giant cell rich lesions) Andrew Horvai MD PhD Clinical Professor, Pathology UCSF, San Francisco, CA Pitfalls and controversies Grading Malignant transformation from benign tumors Cartilage tumors of small bones of hands and feet 6

8 Principles: Definitions Unifying characteristics Collagen II Proteoglycan matrix 65% water Aggrecan most common Chondrotoin and Keratan sulfate side chains Principles: Radiology Ring-like calcifications Principles: Treatment Principles: Syndromes Enchondroma Observation Grade 1 chondrosarcoma, chondroblastoma Grade 2-3 chondrosarcoma Curettage and cement Wide local excision +/- chemo Dedifferentiated chondrosarcoma Wide local excision + chemotherapy Syndrome MOI* Locus Genes Associated conditions Ollier disease Sporadic 2q33, 15q26 IDH1, IDH2 Maffucci syndrome Sporadic Spindle cell hemangiomas (Glomangiomas Angiosarcomas Hepatobiliary) Malignant transformation 15-20% 20-30% Mesenchymal chondrosarcoma Wide local excision + chemotherapy Clear cell chondrosarcoma Wide local excision Multiple hereditary exostoses (osteochondromas) Autosomal dominant 8q24, 11p11 EXT1, EXT2 Deformities of forearm, knee, short stature 5-35% *MOI: Mode of inheritance 7

9 Ollier / Maffucci syndrome Malignant transformation of sporadic cartilage tumors Enchondroma: Case reports, <<1% Osteochondroma: 1 8% Synovial chondromatosis: <1% Ollier Case A 16 year old girl, incidentally discovered proximal tibia lesion No pain, no palpable mass. 8

10 Case A Case A Enchondroma Pitfalls: Enchondroma Necrosis Mucin in lacunae Clinical Radiology Histology Ddx Age: All Loc: Hands/feet, long tubular bones ~3% of adults Metaphysis Lytic, lobular Ring calcifications Intact cortex Lobular Peripheral ossification No permeation Low cellularity No atypia/mitoses Grade 1 Chondrosarcoma 9

11 Pitfalls: Enchondroma Binucleation Case B 57 year old man with painful hip for 2 months Needle biopsy performed of acetabular mass enchondroma chondrosarcoma 10

12 Case B Case B Conventional chondrosarcoma Grade 1 chondrosarcoma or enchondroma? Clinical Radiology Histology Ddx Age: 50+ Loc: pelvis, metadiaphysis long bones Large (> 5 cm) Cortical disruption Endosteal scalloping Soft tissue extension Permeates viable, lamellar bone Myxoid change Hypercellular Atypia open chromatin Mitoses Enchondroma Clear cell chondrosarcoma Chondroblastic osteosarcoma Histology Radiology Molecular Pathology 11

13 Enchondroma or Grade I chondrosarcoma: Histology Chondrosarcoma: Permeation Enchondroma: Multiple nodules of hyaline cartilage separated by normal marrow (and) plates of lamellar bone that conform to the irregular shapes of cartilage lobules. Kappa ~ 0.5 Two features >95% sensitivity and specificity Permeation = host bone entrapment > 20% myxoid matrix Eefting D et al. Am J Surg Pathol :50-57 Chondrosarcoma: Single confluent mass of cartilage trapping host lamellar bone or invasion into Haversian or Volkman systems. J. Mirra (1985) Pitfalls Small biopsy Curettage Endochondral ossification Mirra JM et al. Clin Ortho Rel Res : Permeation: host bone entrapment Permeation 12

14 Chondrosarcoma: permeation Permeation Permeation Enchondral ossification Chondrosarcoma: Myxoid change Enchondroma or Grade 1 chondrosarcoma: Radiology Most predictive Least predictive Pathologic fracture Axial skeleton Infiltrating margin Soft tissue mass Size > 5 cm Lobulated contour Periosteal reaction Cortical disruption or thickening Deep endosteal scalloping Murphey MD et al. Radiographics (5): Brien EW et al. Skeletal Rad 1997; 26(6) Giuffrida AY et al. J Bone Joint Surg Am :

15 Enchondroma or Grade I chondrosarcoma: Molecular Genetic and molecular features: Karyotype: (C.H.A.M.P. study) Enchondroma (n=14) and CHUMP (n=3): karyotypicallynormal Grade I chondrosarcoma: Numerical and structural aberrations (n=3). Comparative genomic hybridization: Enchondroma: 13q21; 19, 22q Chondrosarcoma: 2 11, 14, 15, 18, 21 Similar numbers of aberrations Exome sequencing: COL2A1, IDH1, IDH2, TP53 Chondrosarcoma: Histologic Grading Grade 1 Grade 2 PROGNOSTIC FACTORS IN CHONDROSARCOMA OF BONE A Clinicopathologic Analysis with Emphasis on Histologic Grading Histology HARRY L. EVANS, M.D.* ALBERTO G. AYALA, MD AND MARVIN M. ROMSDAHL, MD, PHD Cancer 40: , Hypercellular, uniform but hyperchromatic nuclei, nuclear detail not visible Diffusely hypercellular, nuclei paler with visible intranuclear detail 5 year survival year survival Tallini G et al. J Pathol, 2002; 196(2):194 Ozaki T et al. Anticancer Res 2004; 1721 Amary MF et al. J Pathol. 2011; 334. Szuhai, et al. Cancer Genet 2012; 193. Tarpey PS et al. Nat Genet 2013; 923. Grade 3 Sheets of cells, larger nuclei, mitotic activity > 2mf/10 hpf Grade 1 Chondrosarcoma Grade 2 Chondrosarcoma 14

16 Grade 2 Chondrosarcoma Grade 3 Chondrosarcoma Grade 3 Chondrosarcoma Pitfall: cartilage tumors of the hands and feet Enchondroma of hands and feet Clinical: Very common site (~30% of all enchondromas), painful, pathologic fracture common Radiographs: Cortical erosion common Histology: Hypercellular, myxoid change, nuclear hyperchromasia, permeation within medulla 15

17 Enchondroma of the phalanx Enchondroma of the phalanx Summary: chondrosarcoma of small bones of hands and feet Metacarpals, metatarsals, wrist and ankle: Soft tissue extension, Grade 3 cytology Behavior similar to chondrosarcoma grade 1 at other sites Phalanges: Soft tissue extension Metastatic rate is very low (<2%) Local resection is favored over amputation Dedifferentiated chondrosarcoma Ogose A et al. Cancer, (1):50 9 Ostrowski ML et al. Am J Surg Pathol, (6): Bovee JV et al.cancer, (9):

18 Dedifferentiated chondrosarcoma Dedifferentiated chondrosarcoma Dedifferentiated chondrosarcoma Dedifferentiated chondrosarcoma Clinical Radiology Histology Ddx Age: Adult >50 Loc: Pelvis>Femur> Humerus 5 year survival < 10% Metaphysis Bimorphic (especially on MRI) Abrupt transition: 1. Chondrosarcoma grade 1 2. osteosarcoma/ MFH / fibrosarcoma Chondroblastic osteosarcoma -Less abrupt transition -High grade cartilage component Mesenchymal chondrosarcoma -Young patients -Benign cartilage islands -Less abrupt transition 17

19 Dedifferentiated chondrosarcoma ~100% mortality Chondroblastic osteosarcoma ~30% mortality Mesenchymal chondrosarcoma Mesenchymal chondrosarcoma Mesenchymal chondrosarcoma 18

20 Mesenchymal chondrosarcoma Mesenchymal chondrosarcoma Clinical Radiology Histology Ddx Age: Loc: Jaw, rib, pelvis, soft tissue Multifocal 10yr survival 25% Variable course Lytic Ring calcifications Rarely circumscribed 1. Cartilage islands/perivascular 2. Small round blue cell tumor HPC-ish vessels common CD99, S100*, desmin Ewing sarcoma Dediff chondrosarc Small cell osteosarcoma Genetics: Inv(8q21.1;8q13.3) HEY1 NCOA2 Wang L, Genes Chromosomes Cancer 51:127. Clear cell chondrosarcoma Clear cell chondrosarcoma 19

21 Clear cell chondrosarcoma Clear cell chondrosarcoma Clinical Radiology Histology Ddx Age: M>F Loc: Proximal femur Skull, rib, spine Slow growing ~25% Metastasize ~15% mortality Epiphysis Circumscribed Early: lytic, septae Late: sclerotic Permeates Osteogenic No hyaline cartilage Clear cells, well defined membrane, macronucleoli Chondroblastic osteosarcoma Osteoblastoma Chondroblastoma (radiology Ddx) Take home messages Correlation of radiologic, clinical and histologic features are critical, especially in low grade cartilage lesions. Permeation is the most sensitive histologic criterion separating enchondroma from chondrosarcoma. Chondrosarcoma of small bones of the hands and feet should be diagnosed with caution. Chondrosarcomas, especially grade 1, are predominantly locally aggressive, but local disease can be fatal even in the absence of metastases Dermatofibrosarcoma Protuberans and Cutaneous Fibrous Histiocytoma Andrew L. Folpe, M.D. Professor of Laboratory Medicine and Pathology Mayo Clinic, Rochester, MN 20

22 Most common in young to middle aged adults Usually occurs in trunk and proximal extremities Initially presents as plaque, with progression to uni/multinodular mass Plaque stage may mimic sclerosing dermatitis Nodular DFSP may have only clinically subtle dermal involvement and present as subcutaneous mass 2011 MFMER slide-82 Histopathology Uniform storiform growth, sometimes with short fascicles Monotonous, slender spindled cells with lightly eosinophilic cytoplasm and dark nuclei Honeycomb pattern of infiltration around individual adipocytes Low mitotic rate Lacks epidermal hyperplasia, siderophages, foamy macrophages, multinucleated giant cells Almost always intensely CD34-positive; usually negative for S100 protein, actins, desmin 21

23 CD34 22

24 Important Variants Atrophic Presenting as a subcutaneous mass Myxoid With myoid nodules Pigmented (Bednar tumor) 23

25 Fibrosarcomatous Change Exact incidence difficult to determine (<5-16%) Often presents as new, rapidly growing nodule Should account for 5-10% of tumor, usually with abrupt transition from typical DFSP Fascicular growth pattern Increased mitotic activity Greater cytologic atypia Often diminished CD34 expression 2011 MFMER slide-96 24

26 CD34 Outcome Local recurrence Identical for DFSP and FS-DFSP (20-50%) Conventional wide (2-3cm) excision lowers recurrence rate to <20% Moh s surgery reduces LR rate to 2-7% Metastasis Very rare (<2%) in DFSP, almost always in recurrent tumors Higher metastatic risk in FS-DFSP (~15%) Unclear whether wide excision has any impact on metastatic risk 2011 MFMER slide-100 Excision Pathology Uniform fibrohistiocytic cells in a whorled pattern with collagen and fat entrapment Deep to the above proliferation Proliferation of atypical spindled cells with hyperchromasia Numerous mitoses Occasional herringbone pattern Deep margin involved 25

27 Genetics Liver Met Supernumerary ring chromosomes by conventional cytogenetics Subsequently found to contain occult t(17;22) (q22;q13.1) COL1A1/PDGF-β fusion gene, resulting in autocrine growth stimulation Identical fusion found in giant cell fibroblastoma PDGF-β Primary CD34 Targeted Therapy Giant Cell Fibroblastoma Now known to be juvenile variant of DFSP Histologic overlap with hybrids GCFB recurrent as DFSP and vice versa Almost always occurs in 1 st decade; very rare in adults Usually located in trunk and proximal extremities Myxoid to hyalinized stroma Monomorphic, spindled cells infiltrating fat Pseudovascular spaces lined by large, hyperchromatic multinucleated cells Frequent local recurrences; metastases and fibrosarcomatous change extremely rare 26

28 Differential Diagnosis Fibrous histiocytoma variants Diffuse neurofibroma Lipofibromatosis Fibrous hamartoma of infancy Cellular Fibrous Histiocytoma Proximal extremities, head and neck Lightly eosinophilic spindled cells, fascicular to storiform pattern Lacks siderophages, giant cells and foam cells Necrosis in 10%; mitotic figures frequent Limited involvement of subcutaneous fat Key is recognition of ordinary BFH 20-30% local recurrence rate Complete excision recommended 27

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30 Aneurysmal Fibrous Histiocytoma Darkly pigmented, often thought to be vascular or melanocytic tumor May be large at time of diagnosis Plump spindled cells in a fascicular to tight storiform pattern Hemorrhage with siderophages Key is identifying features of ordinary BFH Behavior similar to C-BFH Factor XIIIa CD34 29

31 Atypical Fibrous Histiocytoma Clinically similar to conventional BFH/ dermatofibroma Low power resemblance to ordinary BFH High power examination shows foci of markedly atypical, sometimes multinucleated cells, with mitotic figures (including atypical forms) Behavior similar to cellular BFH 30

32 Differential Diagnosis: AFX Usually much older patients Sun damaged skin Absence of areas of BFH IHC in the Diagnosis of BFH Multiple cell populations Factor XIIIA-positive dendrocytes CD34-positive interstitial cells S100 protein-positive Langerhans cells CD68-positive macrophages Actin-positive myofibroblasts May show a peripheral rim of reactive CD34-positive cells 31

33 Factor XIIIA CD34 CD68 S100 CD34 Metastasizing BFH Approximately 20 reported cases Most often associated with cellular FH, but reported with all subtypes May be related to repeated local recurrences No histologic features of primary tumors predictive of metastasis Cases reported as cystic fibrohistiocytic tumor of the lung represent metastatic BFH Prognosis generally favorable if metastases can be completely resected; rare deaths from disease 32

34 Lipofibromatosis Formerly known as infantile or juvenile fibromatosis Usually occurs in infants and young children Most common in distal extremities Poorly circumscribed, partially fatty-appearing, infiltrative Histopathology Admixture of adipose tissue and short fascicles of immature-appearing, bland, fibroblastic cells CD34-negative or very weakly positive Frequent local recurrences, no metastases 33

35 Diffuse Neurofibroma Children and young adults Usually occurs in head and neck Associated with NF1 in 10% Histopathology Bland, round cells, diffusely infiltrating dermal structures and fat Myxoid, finely fibrillary matrix Wagner-Meissner bodies S100 protein-positive, usually CD34-negative May recur locally, extremely low risk of malignant transformation Fibrous Hamartoma of Infancy Infants and very young children Much more common in males Axillary region, proximal extremities Triphasic, organoid appearance Mature fat Variably hyalinized, fibroblastic zones Nodules of primitive-appearing mesenchymal cells Often CD34-positive Benign with potential for local recurrence S100 34

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37 Overview Post-Irradiation Vascular Proliferations Radiation-associated vascular proliferations Selected benign mimics of angiosarcoma Andrew L. Folpe, MD Professor of Laboratory Medicine and Pathology Mayo Clinic, Rochester, MN Iatrogenic Angiosarcomas Secondary to chronic lymphedema (Stewart-Treves) Arteriovenous fistula-related Prosthetic material-associated Thorotrast-related Following breast-conserving surgery and irradiation AS arising in chronic lymphedema 36

38 Cahan Criteria For Radiation- Induced Sarcoma History of radiation to the tissue in which the sarcoma arises The latency period between radiation therapy and diagnosis is relatively long (usually >10 years) The second malignancy arises within the area of radiation treatment The new disease is pathologically distinct from the primary malignancy Post-irradiation Cutaneous Angiosarcomas of the Breast Prior to 1970 s: Radical and modified radical mastectomy Lymphedema-associated AS Late 1970 s- present time: Breastconserving surgery plus axillary LN dissection plus adjuvant breast irradiation 1981: Maddox and Evans (MDACC) reported first cutaneous post-irradiation breast angiosarcoma Incidence and Prevalence Approximately 300 reported cases Overall incidence estimated at % of patients receiving WLE+RT Approximately 10-fold RR Incidence appears to be increasing Report of 0.03% incidence in a single institution (Orange, CA) Clinical Features Almost always women Wide age range (median 60 years) Skin of breast or chest wall, much less commonly breast parenchyma Post-radiation interval may be very short (< 3 years) but typically > 5 years Violaceous or erythematous plaques, nodules, or areas of eccymoses Variable in size Frequently multicentric 37

39 Angiosarcoma Most are histologically high-grade Highly malignant-appearing cells Diffuse dermal infiltration by poorly formed vascular channels Endothelial mitotic activity and multilayering Occasional cases appear low-grade Vessels are relatively well-formed but infiltrative Subtle nuclear atypia and rare mitoses No study to date has convincingly shown histopathological grading to accurately stratify patients with angiosarcoma All should be regarded as clinically high-grade 38

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42 Outcome May be impossible to completely excise Over 70% will recur with surgery alone 84% of LR are < 1yr LR occur in >40% of patients treated with radical salvage surgery Metastases extremely uncommon at presentation (<1%); usually occur after multiple LR Nearly 50% ultimately metastasize to lungs, contralateral breast, skeleton Approximately 35% of patients dead of disease in less than 3 years MSKCC series: Median survival of post-rt breast AS (2.6 yrs) worse than for de novo AS (5.1 yrs) Radiation-Associated Cutaneous Vascular Proliferations Fibrosis with increased vascularity Benign lymphangiomatous papules Atypical vascular lesions Angiosarcoma Benign Lymphangiomatous Papules Also known as lymphatic-type atypical vascular lesions Solitary, well-circumscribed, superficial Dilated lymphangioma-like spaces lined by slightly enlarged, uniform endothelial cells Absent nuclear atypia, mitotic activity or endothelial multilayering BLAP 41

43 BLAP 42

44 Atypical Vascular Lesions Described by Fineberg and Rosen (1994); originally regarded as benign Solitary or multicentric Relatively circumscribed proliferation of small, irregular vascular spaces Endothelial cells may be hyperchromatic but lack significant nuclear atypia No endothelial stratification or mitotic activity Confined to dermis AVL AVL- Suspicious for AS 43

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46 AVL Clinical Behavior Multiple synchronous or metachronous lesions in 10-20% Local recurrences in 7-20% Progression to angiosarcoma in 0-6% Unclear significance True precursor lesions? Markers of patients at risk for angiosarcoma? Unrelated radiation-related vascular proliferations? Early angiosarcomas? Significant interobserver variability Must be completely excised to exclude AS; long-term follow-up with rebiopsy of new or recurrent lesions within radiation field 45

47 MYC in Post-Radiation Vascular Lesions of the Breast (Mentzel et al, Mod Pathol 2012; 25: 75-85) Oncogene located on 8q24 Stimulates angiogenesis, may promote invasion and metastasis High level MYC amplification, detectable by IHC and FISH, seen in all postradiation cutaneous AS Amplification absent in BLAP, AVL, and primary AS Suggests either that AVL are not AS precursors, or require secondary MYC amplification to progress to AS 46

48 BLAP: MYC negative AVL: MYC negative AS: MYC positive AS: MYC positive 47

49 Angiolipoma Benign Mimics of AS Diffuse dermal angioendotheliomatosis Angiolipoma Common in superficial soft tissues of extremities and in breast May be multiple and painful Well-circumscribed with variable amount of fat; little if any fat in cellular angiolipoma Fibrin microthrombi Absent endothelial atypia 48

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51 Diffuse Dermal Angioendotheliomatosis Typically limited to skin Reactive, secondary to underlying peripheral vascular disease, calciphylaxis, croglobulinemeia, others Exuberant dermal/subcutaneous capillary proliferation, often with infiltrative pattern Absent endothelial atypia Retained pericyte layer around vessels 50

52 CD31 51

53 Well-differentiated Adipocytic Neoplasms Andrew L. Folpe, M.D. Professor of Laboratory Medicine and Pathology Mayo Clinic, Rochester, MN Overview Approach to the diagnosis of atypical lipomatous neoplasms/ well differentiated liposarcomas (ALN/WDL) Differential diagnosis of ALN Dedifferentiated liposarcoma ALN/WDL Nomenclature Pre-1979: All cases diagnosed as WDL (any depth/location) Evans and Kempson: suggested term atypical lipoma for superficial or intramuscular tumors; WDL reserved for retroperitoneal tumors Weiss: proposed retention of WDL for intramuscular tumors Current WHO classification: considers atypical lipomatous neoplasms in any location to be mesenchymal tumors of intermediate (borderline) malignancy Personal recommendation: 1) Use ALN for superficial and intramuscular tumors in extremities; 2) Use WDL for inguinal, paratesticular and retroperitoneal tumors 52

54 ALN/WDL Large, fatty-appearing masses Irregular fibrous septae and mature fat containing enlarged hyperchromatic cells Lipoblasts usually rare or absent Hypercellular blood vessels containing intramural hyperchromatic cells 53

55 Low-grade Variants of ALN/WDL Spindle cell Myxoid Inflammatory Lipoleiomyosarcoma WDL with rhabdomyoblasts Spindle cell WDL Inflammatory WDL Lipoleiomyosarcoma 54

56 Genetics WDL with rhabdomyoblasts Giant ring and marker chromosomes Amplified sequences from 12q14-15, other parts of 12q, 1q Amplification of MDM2, CDK4, SAS and HMGIC Overexpression of MDM2 and CDK4 may be detected by IHC or FISH/CISH in ALN/WDL and in DL Clinical Behavior Tumor of intermediate malignancy (no metastatic capability) incomplete excision Local recurrence complete excision Cure Tumor progression (dedifferentiation) MDM2 CISH Metastasis 55

57 Differential Diagnosis Fat necrosis/ Lochkern cells Intramuscular lipoma Spindle cell and pleomorphic lipoma Exogenous lipid reaction Hibernoma Angiomyolipoma Massive localized lymphedema Myxoid liposarcoma Mixed-type liposarcoma Fat necrosis and Lochkern cells Fat necrosis May show irregular fibrous septae Adipocyte variability Histiocyte nuclei may be enlarged Lipid-laden histiocytes mimic lipoblasts Lochkern cells Enlarged adipocyte nucleus with intranuclear pseudovacuole, mimicking lipoblasts Usually in thick sections 56

58 Intramuscular Lipoma May be large and infiltrative Atrophic skeletal muscle cells mimic enlarged hyperchromatic cells of ALN Spindle Cell/ Pleomorphic Lipoma Now regarded as ends along the spectrum of a single entity Shoulder/neck region of older men Generally superficial to fascia Admixture of mature fat, myxoid stroma, bland spindled cells, wiry collagen Hyperchromatic, multinucleated cells, floret-like giant cells in PL 57

59 Exogenous Lipid Reaction Silicone and other exogenous materials Numerous pseudolipoblast-like vacuolated histiocytes Foreign body-type giant cells 58

60 Hibernoma Multivacuolated brown fat cells mimic lipoblasts Centrally placed, normochromatic nuclei Important to remember that hibernomatous differentiation may be seen in essentially any fatty tumor, in particular liposarcomas Angiomyolipoma Expansile, non-infiltrative, hemorrhagic masses Triphasic histology Abnormal thick walled vessels Spindled to epithelioid PEC Lipid distended PEC ( adipocytes ) Myomelanocytic immunophenotype Adipocyte -rich variant may mimic WDL Hyperchromatic cells Pseudolipoblasts WDL with brown fat 59

61 Massive localized lymphedema Massively obese patients, usually in the medial thigh Huge, edematous masses Epidermal thickening Expansion of fibrous septae and fibroblastic proliferation Lymphatic proliferation HMB45 60

62 From: Bae, D. K. et al. Arch Dermatol 2008;144:

63 Myxoid and Round Cell LPS Middle aged patients; most common pediatric LPS Most often occur in proximal extremities RCL is now considered a high-grade form of myxoid LPS Pure MLPS are relatively low-grade sarcomas; ~20% risk of distant metastasis even for lesions without round cell component >5% RCL component: high-grade sarcoma with >40% metastases Importance of careful sampling and strict criteria t(12;16) (q13; p11) (FUS-DDIT3): 95% t (12;22) (q13;q12) (EWS-DDIT3): 5% 62

64 Mixed WDL-MLPS Most often reported in the retroperitoneum Shows genetic features of ALN/WDL, but not MLPS MLPS does not occur in the retroperitoneum Represents myxoid ALN/WDL, not MT-LPS Dedifferentiated Liposarcoma Definition: The development of a (usually) highgrade, non-lipogenic sarcoma in the setting of a pre-existing ALN/WDL May be present at initial presentation or following multiple recurrences over many years Most common in retroperitoneal WDL > inguinal/paratesticular WDL >> deep soft tissue of extremities >>> superficial ALN Regarded as time-dependent, rather than sitedependent, phenomenon WDL with myxoid change 63

65 Pathologic Features Grossly visible, solid, non-lipogenic area +/necrosis, within larger fatty mass Usually consist of pleomorphic, undifferentiated sarcoma (MFH-like) Heterologous differentiation may be present May rarely appear histologically low-grade, resembling low-grade fibrosarcoma or fibromatosis Rare variant with meningothelial-like whorls and metaplastic bone High-grade DL Low-grade DL 64

66 Differential Diagnosis Cellular ALN/WDL Some ALN/WDL show increased cellularity and atypia, falling short of clear-cut DL DL should contain at least a 1cm focus of non-lipogenic sarcoma The significance of smaller areas of non-lipogenic sarcoma is uncertain Such cases should be very carefully sampled Non-lipogenic sarcoma infiltrating fat Clear-cut ALN/WDL must be present at least 1 cm away from areas of non-lipogenic sarcoma Pleomorphic liposarcoma Admixture of non-lipogenic sarcoma with pleomorphic lipoblasts DL with perineurial-like whorls 65

67 Sarcoma infiltrating fat Pleomorphic LPS Clinical Behavior DL should be considered high-grade sarcomas Local recurrences in 50%, metastases in 15-20%, 5-year disease-specific mortality of 30% Data suggesting that DL have a better prognosis than other pleomorphic sarcomas are preliminary, and use principally metastases as a clinical endpoint 66

68 That s a lot of giant cells USCAP 2014 Common problems in bone and soft tissue pathology: Giant cell rich lesions Giant cell tumor of bone (GCT) Aneurysmal bone cyst (ABC) Solid aneurysmal bone cyst / giant cell reparative granuloma / brown tumor Chondroblastoma Giant cell rich osteosarcoma Andrew Horvai MD PhD Clinical Professor, Pathology UCSF, San Francisco, CA A trimodal approach Clinical Radiology Pathology Age Location Clinical Number of lesions Co morbidities Fracture Hyperparathyroidism / renal failure 67

69 Clinical: Age at presentation Clinical: Treatment and prognosis GCT Chondroblastoma ABC GC rich osteosarcoma Recurrence 25% 6-20% <5% N/A Metastasis 2-4% Case reports None* >80% Malignancy <<1% primary Case reports None* 100% Treatment Curettage Denosumab (?) Curettage Curettage Neo-adjuvant chemo, resection Is it intraosseous? Location Compartment Opacity Border Periosteum Radiology Giant cell tumor Chondroblastoma ABC GC rich Osteosarcoma 68

70 Radiology Summary Pathology GCT Chondroblastoma ABC GC rich osteosarcoma Compartment Epiphysis Epiphysis Metaphysis Metaphysis Opacity Purely lytic Lytic + calcifications Purely lytic Lytic + sclerotic Border configuration Circumscribed Marginated, sclerotic rim Marginated, expansile Permeative Denosumab What does this have to do with pathology? Giant cells are not the neoplastic population Pay attention to other components Mononuclear cells Matrix Atypia, pleomorphism Squamous cell carcinoma Roux et al. Am J Clin Pathol 2002;117:

71 Case C: 43 year old woman, proximal fibula mass, undergoes curettage Case C: Giant cell tumor Giant cell tumor Giant cell tumor 70

72 Chondroblastoma Chondroblastoma: GC rich area Chondroblastoma: fibrochondroid matrix Chondroblastoma: chickenwire calcifications 71

73 Chondroblastoma: nuclear grooves Aneurysmal bone cyst Aneurysmal bone cyst: fibrous septae Aneurysmal bone cyst: cells, matrix 72

74 Aneurysmal bone cyst: blue bone Solid ABC Brown tumor = solid ABC Giant cell rich osteosarcoma 73

75 Giant cell rich osteosarcoma Giant cell rich osteosarcoma Giant cell rich osteosarcoma Pathology summary GCT Chondroblastoma Matrix Absent Fibrochondroid plaques + calcification Mononuclear cells Ovoid, uniform, nuclei similar to GC Ovoid, eccentric nuclei, grooves ABC Osteoid, Collagen Blue bone Hemosiderin Spindled, fibroblastic/ fibrohistiocytic GC rich osteosarcoma Osteoid Polygonal to spindled, hyperchromatic Mitosis Abundant Rare Variable Abundant, atypical Atypia Absent Absent Absent Marked Distribution of giant cells Uniform Heterogeneous Heterogeneous Heterogeneous 74

76 Ancillary tests Immunohistochemistry p63: sensitive for giant cell tumor, not specific RunX2, Sox9, Twist: New markers, may become useful Molecular/Genetic ABC: 17p13 (USP6) rearrangement Present in conventional and solid ABC Absent in giant cell reparative granuloma of jaw and brown tumor GCT: Histone H3F3A mutations at Gly34 Chondroblastoma: Histone H3F3B at Lys36 Pitfalls Frozen section, scant material Trimodal approach still applies Exclude osteosarcoma or other malignancy Giant cell rich lesion, no malignancy is acceptable if distinction cannot be made between GCT, ABC and chondroblastoma Treatment will be curettage with follow up Lee et al. Mod Pathol : Dickson et al. Mod Pathol : De la Roza. Archives Path Lab Med :776-9 Horvai et al. Mod Pathol : Panoutsakopoulos G et al. Genes Chrom Ca : Oliveira A et al. Oncogene : Behjati S et al. Nat Genet : Agaram NP et al. Hum pathol : Pitfalls: Giant cell tumor Exceptions to no matrix Cartilage: healing pathological fracture Bone: Capsule, residual cortex, secondary ABC change Malignancy in GCT Benign GCT Necrosis Abundant mitotic activity (>20 mf / 10 hpf) Intravascular invasion Lung metastases in 2 4% Metastases can spontaneously regress 75

77 Case D: 53 year old woman, distal radius bone mass Case D: Malignant giant cell tumor Malignant giant cell tumor Primary malignant GCT Typical GCT mixed with or adjacent to high grade sarcoma Transition gradual, or entire tumor malignant Atypical mitotic figures and atypia in mononuclear cells diagnostic Secondary 10+ year interval after initial diagnosis Radiotherapy Histological types: osteosarcoma, fibrosarcoma Pitfalls: Chondroblastoma Only ~30% of cases demonstrate all characteristic features Fibrochondroid matrix, chicken wire calcifications, nuclear grooves 76

78 Pitfalls: Chondroblastoma unusual sites Temporal bone Talus T2 fat sat Take home messages Pathologic diagnosis of giant cell rich lesions requires careful correlation with radiographic and clinical findings The benign lesions in this category (GCT, ABC, chondroblastoma) are treated similarly, so the most important consideration is to exclude malignancy, especially giant cell rich osteosarcoma RANK RANK L interaction likely mediate the accumulation of giant cells in these lesions, explain their morphologic similarity, and may be a therapeutic target 77