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Bone updates.ip
- 1. Updates in Bone Tumors Ipsita Panda Prof. Nandita Kakkar
- 2. Outline Changes in WHO 2020 Bone tumours Molecular Classification Ancillary Techniques in diagnosis of Bone tumours
- 4. • Chondroblastoma is no longer in the intermediate (rarely metastasizing) tumor category. • Reported rate of metastases is <1%, and consequently chondroblastoma is better classified as a benign tumor. Chondrogenic Tumors
- 5. • 95% of chondroblastomas harbour a p.K36M mutation in either H3F3A (chromosome 1) or H3F3B (chromosome 17) • H3F3B mutations (K36M) were exclusively found in 95% of chondroblastoma • Both the H3F3A gene and the H3F3B gene encode for the replication-independent histone H3.3
- 8. Chondrogenic Tumors • Reclassified as a benign neoplasm • Recurrent fusions of the GRM1 gene • The prognosis is excellent, even for recurrent tumours. Recurrence has been reported in approximately 9-15% of cases treated locally
- 9. Chondrogenic Tumors • High Incidence of Local Recurrence • Disease recurs in 15-20% of patients, with higher rates reported for tenosynovial cases • Malignant trans occurring in 5-10%
- 10. • 57% of benign cases rearrangement involving FN1 and/or ACVR2A as detected by FISH.
- 11. Chondrogenic Tumors • Usage of the term Atypical Cartilaginous tumor (ACT) • In the long bones, behave in a locally aggressive manner and do not metastasize • cartilaginous tumors in the appendicular skeletons (long and short tubular bones) : ACT • “CS1” reserved for axial skeleton, including the pelvis, scapula, and skull base (flat bones), reflecting the poorer clinical outcome
- 12. Secondary Chondrosarcoma IDH1 (R132C; R132H) or IDH2 (R172S) Malignant transformation 2% 0.2% to 25% CDKN2A (p16INK4a)
- 14. Secondary peripheral ACT/CS1s show a thick ( > 2 cm), lobulated cartilaginous cap (mean cap thickness: 3.9 cm)
- 15. • Characterized by aneuploidy and complex karyotypes • RB1 pathway is affected in 86% of high-grade chondrosarcomas. • TP53 is mutated in 20% to 49% • Hedge- hog signaling, mTOR signaling, Src and Akt pathways, and metabolic pathways. • Mutations in the COL2A1 gene are present in ~45% of central chondrosarcomas • CDKN2A (p16INK4a) copy number variation occurs in about 75% of high- grade central chondrosarcomas but not in enchondromas Central chondrosarcoma Gr 2,3
- 17. Mesenchymal Chondrosarcoma • Widespread anatomical distribution that include bone, soft tissue, and intracranial sites. • highly specific recurrent gene fusion between HEY1 and NCOA2 in almost >90%. • Tumor cells can be positive for S100 protein, CD99, and SOX9 an in-frame fusion HEY1 exon 4 to NCOA2 exon 13
- 18. 10% to 15% of central chondrosarcomas t(1;5)
- 21. • Recurrent translocations in FOS (87%) and FOSB (3%) found in osteoblastoma and osteoid osteoma
- 22. Prognosis is good, but recurrences in as many as 23% of the cases
- 23. Cases of osteosarcoma showing different patterns of c- FOS expression Epithelioid osteoblastoma • The presence of epithelioid osteoblasts does not consistently predict an aggressive clinical course • some osteo blastomas > 4 cm with locally destructive features and repeated recurrences may lack epithelioid cytomorphology.
- 25. • Originates within the intramedullary cavity • consists of fibroblastic tumour cells with low-grade nuclear atypia and well-formed neoplastic bony trabeculae. • LGCOS has a good prognosis when widely resected, with a metastatic rate of < 5% and 5-year and 10-year overall survival rates of 90% and > 80%.
- 26. • Parosteal osteoarcomas are low-grade malignant bone-forming neoplasm that arises on the cortical surface of bone. • cartilage cap in some parosteal osteosarcomas is mildly hypercellular and the chondrocytes show mild atypia and lack the perpendicular columnar arrangement seen in osteochon dromas.
- 27. • Combination of these two markers thus shows 100% sensitivity and 97.5% specificity for the diagnosis of low- grade osteosarcoma.
- 29. Diffuse nuclear expression of CDK4 • Extremely rare, locally aggressive bone tumor composed of bland spindle cells set in abundant collagen, with histology reminiscent of desmoid-type fibromatosis. • Desmoplastic fibroma of bone presenting a CTNNB1 mutation nuclear β-catenin immunostaining. STRN-NTRK3 gene fusion was reported in one case of primary fibrosarcoma of the radius. LGCOS
- 30. • Aneurysmal bone cyst (ABC) (previously classified as an intermediate locally aggressive tumor in the category of tumors of undefined neoplastic nature) is reclassified as benign tumor in the category of osteoclastic giant cell-rich tumors. • Fibrohistiocytic tumors and Giant cell lesion of the small bones: removed in the 2020 WHO classification. • Non-ossifying fibroma is now included in the category of osteoclastic giant cell-rich tumors. • Use of the term “benign fibrous histiocytoma (BFH)” is no longer recommended. • Denosumab-treated giant cell tumor (GCT) is newly described as a distinctive variant of GCT
- 31. • Aneurysmal bone cyst (ABC), USP6 rearrangements are restricted to the neoplastic spindle cells ubiquitin-specific protease 6 (USP6), also known as Tre-2, is located on chromosome
- 33. • 95% of GCTs harbor pathogenic H3.3A (H3F3A) mutations, about 90% of which are H3.3 p.Gly34Trp (G34W) • H3.3A (H3F3A) mutation is absent in a subset of malignant GCTs.
- 34. • Malignant GCTs account for 1-10% of all GCTs • May develop de novo or secondary (eg, after radiation therapy of primary GCT) • areas of giant cell loss and increased stromal cellularity. • Focal areas of marked pleomorphism, nuclear hyperchromasia • Abundant mitotic activity (>10/10HPF)
- 35. • Denosumab, a RANKL inhibitor, treat GCT • Leads to a marked alteration in the histologic appearance : giant cell depletion and new bone deposition
- 36. • The pattern of bone deposition: not the lace-like pattern • Lesser degree of cytologic atypia • Contained few mitotic figures (< 1 to 4/10 HPF) • Permeation of preexisting bone was not
- 37. • PDC is crucial as a new distinct subtype of chordoma. • represents a molecularly distinct entity with aggressive behavior. • deletions involving SMARCB1 in most cases. • heterozygous co- deletion of the EWSR1 locus, which lies in close proximity.
- 38. Primary Vascular tumors of Bone and D/D Epithelioid Hemangioma Epithelioid Hemangioendothelioma Epithelioid Angiosarcoma Epithelioid Osteoblastoma Epithelioid Chordoma Epithelioid Osteosarcoma Metastasis • Extremely rare and accounting for ~1 to 2% of all bone tumours • Tend to exhibit a distinctive epithelioid morphology
- 39. Epithelioid Hemangioma • FOS B IHC in nearly half of cases • Characteristic recurrent fusions in FOS or FOSB, involving as many as half cases
- 40. Epithelioid Hemangioendothelioma (EHE) EHE With WWTR1-CAMTA1 • > 90% of cases harbor translocation t(1;3)(p36;q23-25) • Malignant vascular neoplasm composed of epithelioid endothelial cells in a distinctive myxohyaline stroma.
- 41. EHE With YAP1-TFE3 • Novel YAP1-TFE3 fusion in a small subset • younger patients and shows distinctive histology • Composed of large epithelioid cells with voluminous pale cytoplasm • Often nested growth pattern with a focally vasoformative architecture
- 43. • Requirement of DNA or RNA from lesions for molecular analysis. • DNA and RNA isolated from formalin- fixed, paraffin-embedded bone tumors are often degraded due to decalcification. • Non-availability of frozen tumor tissue • Chelating agents: EDTA is the gentlest and takes up calcium ions, suitable for decalcification. Molecular Techniques in diagnosis of Bone Tumors
- 44. • Limited acid decalcification in 5% formic acid can preserve DNA sufficient for FISH • High number of non-tumour cells • cutting artefacts and unusual patterns, such as the loss of one of the split signals • Detection of translocations utilizing both split-apart and fusion probes • Amplification detection, for example in parosteal osteosarcoma FISH
- 46. Break apart Probe Fusion Probe
- 47. • NGS using different platforms allows for high-throughput sequencing with the production of an enormous amount of data • Although whole-genome and whole-exome sequencing as well as whole-transcriptome sequencing are widely used as research tools • Targeted enrichment strategies :specific pathogenic somatic hotspot mutations • Detection of specific pathogenic somatic hotspot mutations • primers includes different exons of 26 genes, all relevant in bone and soft tissue tumor diagnostics Next Gen Sequencing
- 48. Molecular Classification of Bone tumours • Translocations, mutations, or amplifications. • Nonspecific multiple molecular alterations
- 50. EWSR1-ETS fusion protein Aberrant transcription factor up-regulation of PDGFC, CCDN1, MYC angiogenesis (VEGF) replicative immortality (up- regulation of hTERT), invasion, metastasis (matrix metalloproteinases) Promoter swapping Aneurysmal Bone cyst CDH1:USP6 over- expression of USP6 due to juxtaposition to the highly active promoter. Induces matrix metalloproteinase production via activation of NF-kB, leading to osteolysis, inflammation, and a high degree of vascularization
Editor's Notes
- Histologically, chondroblas- toma has a characteristic heterogeneous appear- ance comprising sheets of discohesive neoplastic mononuclear cells with small grooved nuclei,2,3 ariable numbers of osteoclast-like giant cells: the latter can dominate or can be scant. Islands of eosinophilic chondroid (chondroid–osseous) matrix are also present, whereas hyaline cartilage is uncommon. Pericellular ‘chicken wire’ calcification,
- Recurrent fusions of the GRM1 gene have been implicated in the pathogenesis of chondromyxoid fibroma; upregu- lation of the glutamate metabotropic receptor 1 (GRM1) bland-appearing spindle- and stellate-shaped cells. The cells tend to become more condensed near the periphery of the lobules and are often cuffed by areas of bland round or spindle-shaped cells with osteoclast-type giant cells and prominent hemangio- pericytoma-like staghorn vessels Chondromyxoid fibroma is a benign lobulated cartilaginous neoplasm with a zonal architecture composed of chondroid, myxoid, and myofibroblastic areas lytic metaphyseal eccentric appearsnee on convex tional radiograph with sharp margins; lobulated lesion with zonal architecture
- 60-70% of cases affecting the knee. Multiple hyaline cartilaginous nodules involving the joint space, subsynovial tissue, or tenosynovium
- In the 2013 WHO classi- fication, the terminology “ACT” was introduced as a synonym for CS1 and classified as intermediate (locally aggressive) to reflect the clinical behavior of well-differentiated/low-grade lesions.4 The argument was that such lesions, especially in the long bones, behave in a locally aggressive manner and do not metastasize; therefore, they should not be classified as having full malignant potential.
- primary and secondary types are characterized by mutations in the isocitrate dehydrogenase isoforms IDH1 and IDH2, which have been detected in approximately 50% to 60% of primary and secondary central chondrosarcomas. Chondrosarcoma (CHS) is a rare malignant tumor that produces cartilage matrix. The estimated overall incidence of CHSs is 1 in 200,000 per year [1], and it is the third most frequent malignant bone tumor after multiple myeloma and osteosarcoma. Multiple hereditary exostosis
- Cellularity in central ACT/CS1 is low, but slightly higher than in enchondroma. Binucleation is frequently observed matrix is predominantly hyaline, sometimes with more mucoid or myxoid changes. usually permeate and entrap the preexisting lamellar bone trabeculae.
- accounts for 2% to 4% of all chondrosarcomas and mainly affects adolescents and young adults, with a wide age range high-grade, malignant, biphasic, primitive mesenchymal tumor with a well-differentiated, organized hyaline cartilage componen Intraosseous lesions mainly involve the jaw, ribs, ilium, vertebrae, and lower extremities.
- high-grade, non- cartilaginous sarcoma common sites of involvement are the femur (46%), pelvis (28%), humerus (11%), and scapula (5%). Patients with dedifferentiated chon- drosarcoma have a dismal prognosis, most often because of widespread lung metastases
- telangiectatic osteosarcoma, and small cell osteosarcoma are included in the section of osteosarcoma NOS. Clear cell and chondroblastoma-like osteosarcoma subtypes were classified as histologic subtypes of osteosarcoma in the 2013 WHO classification but were deleted in the 2020 classification.
- Osteoid osteoma and osteoblastoma are common bone- forming tumors and typically present during the second decade of life. They have no malignant potential, but osteoblastoma can behave locally aggressive [1, 2]. Both le- sions are more or less histologically indistinguishable, and distinction is predominantly based on size (diameter below or above 2 cm, respectively) [3]. In addition, osteoid osteomas are usually located in the long bones and present with noctur- nal pain relieved by nonsteroidal anti-inflammatory drugs (NSAIDs), while osteoblastomas have a preference for the posterior column of the spine. The most essential feature in osteoid osteoma is the radiographic presence of a central lu- cent area (nidus), which is surrounded by dense sclerotic bone tissue. In the nidus, regular trabeculae of woven bone are present. These trabeculae are lined by active osteoblasts with vascularized stroma in between. In osteoblastoma, the distri- bution of woven bone can be slightly less organized, as com- pared to the nidus of an osteoid osteoma.
- They have no malignant potential, In some instances it may be difficult, and occasionally impossible to differentiate osteoblastoma from the so-called osteoblastoma-like osteosarcoma.7,8 The controversial con- cept of the histologically labelled “aggressive osteoblastoma” also plays a role in the differential diagnosis of unusual cases. Aggressive osteoblastoma was initially defined as an osteo- blastoma with a distinct epithelioid morphology and therefore also referred to as epithelioid osteoblastomas.9 However, not all epithelioid osteoblastomas are clinically aggressive. Fur- thermore, some nonepithelioid osteoblastomas, usually larger than 4 cm, are associated with bone destruction and locally aggressive behavior which adds to the controversy around the term “aggressive” osteoblastoma.10 To compound the diag- nostic challenge, rare cases of osteoblastomas transforming into osteosarcomas have been reported
- Epithelioid osteoblastoma and osteoblastoma-like osteosarcoma. H&E staining of an epithelioid osteoblastoma shows maturation with presence of trabeculae of woven bone, while the central area shows less osteoid deposition a and b. Numerous large, plump osteoblasts with abundant eosinophilic cytoplasm are scattered throughout the specimen. Atypia can be frequently encountered, with osteoblasts harboring hyperchromatic and irregular enlarged nuclei, which may resemble osteosarcoma c. FOS immunohistochemistry showing diffuse and strong nuclear staining in all osteoblasts. Osteoclasts-like giant cells are negative (arrow) d. Osteoblastoma-like osteosarcoma with extensive soft tissue involvement (H&E) e. Tumor cells show an epithelioid aspect with enlarged nuclei with a prominent nucleolus. Note the trabeculae of neoplastic woven bone, mimicking osteoblastoma f and g. FOS immunohistochemistry is negative h. Scale bar, 100 μm a and e. Scale bar, 50 μm b–d and f–h revealed mul- tiple copies of the FOS locus reflecting the polyploid/ aneuploidy nature of most osteosarcomas The diagnosis of so-called aggressive osteoblastomas morpho- logically characterized by the presence of large, epithelioid osteoblasts is controversial and not recommended using the term of “aggressive osteoblastoma” as the presence of epi- thelioid osteoblasts does not predict an aggressive clinical course in osteoblastoma.
- Low-grade central osteosarcoma (LGCOS) is a low-grade malignant bone-forming neoplasm that originates within the intramedullary cavity and consists of fibroblastic tumour cells with low-grade nuclear atypia and well-formed neoplastic bony trabeculae. Parosteal osteosarcoma is a low-grade malignant bone-forming neoplasm that arises on the cortical surface of bone. Parosteal osteosarcoma and low-grade central osteosarcoma are two types of low-grade osteosarcoma that show similar clinical behaviors, histological features, and genetic background (ie, amplified sequences of 12q13–15, including MDM2 and CDK4).
- Low-grade malignant bone-forming neoplasm Permeation of host bone is invariably it， Present. Cortical destruction with soft tissue infiltration may also
- Most tumors previously considered giant cell lesion of the small bones (primarily located in the hands and feet) represent a true solid variant of ABC “giant cell reparative granuloma (GCRG)” should be limited to lesions from gnathic location
- ABC is a benign neoplasm of bone containing multi- loculated blood-filled cystic spaces.113 It occurs in all age groups but is most common in children and adolescents. It usually arises in the metaphysis of long bones, especially the femur, tibia, and humerus, and the posterior elements of vertebral bodies. CT and magnetic resonance imaging findings show characteristic fluid- fluid levels. USP6 gene at chromosome band 17p13.2 are found in neoplastic spindle cells in 70% of ABCs but not in other tumors containing ABC-like changes
- GCT of bone is a locally aggressive and rarely metasta- sizing neoplasm composed of neoplastic mononuclear stromal cells admixed with macrophages and osteoclast-like giant cells Malignant GCTs account for <10% of all GCTs.
- Early lesions: highly cellular, combination of cellularity, atypia, and haphazard bone deposition caused the lesion to resemble high-grade osteosarcoma. Prolonged therapy showed decreased cellularity and abundant new bone, deposited as broad, rounded cords or long, curvilinear arrays.
- Histologically, PDC is composed of cohesive sheets or nests of poorly differentiated epithelioid cells, often with a focal rhabdoid morphology Mitotic activity is increased,
- that is associated with a broad variety of diagnostically challenging tumor entities, each with diverse clinical courses
- The diagnostic cytologic finding is that of plump epithelioid endothelial cells with round nuclei, small nucleoli, and abundant eosinophilic cytoplasm containing occasional vacuoles
- Classic variant includes cords and nests of epithelioid cells with eosinophilic cytoplasm and occasional intracytoplasmic vacuoles in a characteristic myxohyaline stroma
- decalcification is essential for adequate histologic evaluation of bone tissue,
- NGS-based studies resulting in the unraveling of the molecular landscape of diverse bone tumors. the possibility of sample exhaus- tion associated with the limited amount of assays per slide, and the dependency of probe availability.
- As a conceptual framework, molecu- lar alterations of bone tumors can be divided into two categories: simple or complex karyotype. Simple karyotypes include recurrent trans- locations, such as those predominantly seen in round cell tumors pecific translocations, mutations, or amplifications. be achieved gradually during tumor progression (eg, multistep progression model Combined binary ratio labelingeFISH illustrates a complex chaotic karyotype, with numerous regions of amplification and deletions, combined with many translocations.