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Similar to Round cell tumours
Round cell tumours
- 1. BY – Dr.KANWALPREET KAUR MODERATOR-Dr. KARUNA GUPTA
- 2. Heterogeneous group ofneoplasms are characterised by the sheets of poorly differentiated cells: • Small (similar to lymphocyte in size) • Round (round nuclei and scanty cytoplasm) • Blue (blue staining due to high nuclear/cytoplasmic ratios
- 3. • Ewings sarcoma/Primitiveneuroectodermal tumour(ES/PNET • Hematopoietic malignancies • Plasma cell neoplasms • Small cell osteosarcoma • Mesenchymal chondrosarcoma • Poorly differentiated small cell synovial sarcoma • Rhabdomyosarcoma(embryonal and alveolar subtypes)
- 4. • Histological gradingof bone sarcomas is an attempt to predict the biological behaviour of a malignant tumour • Criteria used— 1. Cellularity i.e., the relative amount of cells compared to matrix 2.Nuclear features of the tumour cells • Tumours which are monomorphic, such as small cell malignancies (Ewing sarcoma, malignant lymphoma and myeloma), do not lend themselves to histological grading. • Mesenchymal chondrosarcomas and dedifferentiated chondrosarcomas are always high grade
- 5. • Round cellsarcomas that show varying degrees of neuroectodermal differentiation Ewing’s sarcoma - limited neural differentiation PNET - more neural features • AGE- 5-20 years (commonly) • infancy or adulthood rarely • SEX PREDILITION- males:females=1.4:1
- 7.
- 8. • Generally arisesin medullary cavity of shaft from which it permeates cortex and invades soft tissue • Rarely, periosteal • Soft, tan-white, areas of haemorrhage and necrosis
- 9. 1. Classic orconventional (typical) Ewing sarcoma 2. Primitive neuroectodermal tumor(PNET) 3. Atypical Ewing sarcoma • Same immunohistochemical and molecular features, differing only in the extent of neural differentiation. • Each subtype is considered a high-grade tumor.
- 10. sheets of uniform populationof cells; round nuclei ; finely granular chromatin; indistinct cell borders; necrosis common; mitotic activity usually not prominent
- 11.
- 12. 3. ATYPICAL-most difficultgroup to recognize • Great degree of cytologic variability and/or unusual growth patterns e.g. large nuclei with irregular nuclear membranes and prominent nucleoli; abundant eosinophilic cytoplasm imparting a rhabdoid appearance.
- 13. The cells ofES/PNET usually contain large amounts of cytoplasmic glycogen, as demonstrated by a PAS stain with diastase control
- 14. Non reactive forchromogranin, glial fibrillary protein, desmin, muscle specific actin, myogenin and CD45. Keratin is positive in 20% to 30% of cases, usually with a focal distribution.
- 15. CD 99 reactivityFLI-1 Protein expression
- 16. • CD99- strong,diffuse membranous staining pattern • 84-100% sensitive. If a tumor is negative for CD99, it is highly unlikely to be Ewing sarcoma • NOT A SPECIFIC MARKER • Can be seen in RMS, glial tumours, neuroendocrine tumours, lymphoblastic lymphoma, WT, clear cell sarcoma of kidney, teratoma, synovial sarcoma, osteosarcoma and mesenchymal chondrosarcoma • CD99 is important for distinction between Ewings sarcoma/PNET and metastatic neuroblastoma
- 17. • FLI1- Onlynuclear staining is considered positive NOT SPECIFIC MARKER But also positive in lymphoblastic lymphoma, myeloid neoplasms, DSRCT, Malignant melanoma, merkel cell carcinoma,synovial sarcoma, and some vascular neoplasms.
- 18. • Reciprocal translocationt(11;22)(q24;q12) • Fusion of EWSR1 gene(encodes for RNA binding protein) at 22q12 with FLI1 gene(member of ETS family of transcription factors) • The t(21;22)(q12;q12) translocation involves the gene ERG, which is located on chromosome 21 • t(7;22)(p22;q12) translocation involves a gene known as ETV1 at 7p22. • Recently a translocation involving chromosomes 4 and 9 with CIC and DUX4 gene has been identified
- 19. • Rearrangements ofEWSR1 with non–ETS-family genes—including NFATC2,POU5F1, SMARCA5, ZSG, and SP3—are also rarely identified
- 20. • FISH forEWSR1 genomic rearrangements is highly sensitive (>95%) but nonspecific because other tumours may show rearrangement of this locus. • RT-PCR for EWSR1 fusion genes - highly sensitive (>95%) and specific (100%).
- 21. • Primary Lymphoma-Originates in bone with no evidence of extraskeletal disease or disseminated bone marrow involvement. Rare • Secondary skeletal involvement by a primary extraosseous lymphoma is much more common than primary bone lymphoma • AGE-usually affects 40-60 years • Lymphoma however can involve children; though it is much less common than Ewing sarcoma in this age group • SITE- meta-diaphyses of long bones (femur, humerus, and tibia) and axial skeleton (pelvis and vertebrae)
- 22. Extensive involment withpermeative destructive process. Shaft is usually involved Radiographs appear as if there are multiple small holes with intervening normal bone Lesion shows mixture of lysis and sclerosis Periosteal new bone formation is unusual Bone scan- positive Positive bone scan or lesion on MRI + normal radiograhs = suggest malignant lymphoma
- 24. ->Under low power,lesion is visible between normal bony trabeculae and in marrow fat ->Nodular growth pattern- distinctly uncommon ->Fine fibrosis may be evident ->Most lymphomas show polymorphic infiltrate ->Nuclei are not uniform in shape and size This lack of uniformity is helpful in distinguishing lymphoma from Ewings sarcoma of bone
- 25. • B-cell lymphomas,most commonly diffuse large B-cell lymphoma • T-cell lymphomas of bone-Anaplastic large cell lymphoma • Lymphoblastic lymphoma • Non-Hodgkin B-cell lymphomas, including follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma, and small lymphocytic lymphoma • Hodgkin lymphoma- late stages • Myeloid sarcoma (granulocytic sarcoma)
- 26. TUMOUR MARKERS B-cell lymphomasCD45, pan B-cell markers (CD19, CD20, CD79a,PAX-5) Negative for CD3, CD5 Anaplastic large cell lymphoma CD30 ,CD3, CD4, Lymphoblastic lymphoma terminal deoxynucleotidyl transferase. CD10, CD43, CD99, FLI-1, CD45 - weakly positive or negative Hodgkin’s lymphoma CD30, PAX-5, CD15. Myeloid sarcoma (granulocytic sarcoma) Positive- myeloperoxidase, lysozyme, and CD43,CD45 Negative for CD20 and CD3 Most of lymphomas except lymphoblastic lymphoma are negative for CD99
- 27. • Lymphoblastic lymphomamay be positive for CD99 and negative for CD45, an immunoprofile that overlaps with that of Ewing sarcoma • TdT, CD34,CD43,CD10, CD79a and genetic rearrangement studies- distinguish lymphoblastic lymphoma from EWS/PNET
- 28. • Specific studieson primary lymphomas of bone are lacking.
- 29. • malignant proliferationof monoclonal plasma cells • can present as a solitary lesions (solitary plasmacytoma) or more commonly as part of widespread disease (multiple myeloma) • AGE-50-70years • rare below 40 years • SITE-: vertebrae, ribs, skull, pelvis, femur, clavicle and scapula
- 30. Multiple punched outlesions Purely lytic Rarely associated with sclerosis Purely lytic lesion; Well defined margins
- 31. • Usually hasa soft red-brown appearance. • However, some myelomas show the fish-flesh appearance typical of malignant lymphoma.
- 32. WELL DIFFERNTIATED MYELOMAPOORLY DIFFERNTIATED MYELOMA
- 33. • HISTOLOGICAL DIFFERENTIALDIAGNOSIS INCLUDES: • 1.Lymphoma • 2.malignant carcinoma • 3.occasionally chronic osteomyelitis • Immunohistochemitry plays an important role here
- 34. • Myeloma cellspositive- CD38 CD138 Multiple myeloma oncogene 1 (MUM-1) • Characteristically express monotypic cytoplasmic Ig and lacks surface Ig • The monotypic expression of kappa or lambda immunoglobulin by the tumour cells establishes the diagnosis of malignancy
- 35. • Myeloma cellsnegative CD19,CD20,CD27,CD22 Normal plasma cells CD 27+ , CD 19+ • Myeloma cells frequently express the natural killer antigen CD56/58 which is not expressed in reactive plasma cells
- 36. • Myeloma cellsweakly positive or negative for CD45,CD20 most B-cell lymphomas strong staining for both markers. • Both myeloma and carcinoma are positive for EMA Keratin markers are more reliable in ruling out carcinoma • Myeloma cells positive for CD138 Multiple myeloma oncogene 1 (MUM-1) Some carcinomas occasionally express CD138 MUM-1 is helpful in making distinction
- 37. • Aggressive cartilaginousneoplasm • AGE-20-60 year • BONES COMMONLY AFFECTED- jaw bones • ribs • vertebrae • pelvis • USUAL LOCATION WITHIN LONG BONE- diaphysis (cortex or medulla)
- 38. Hemangiopericytomatous patternmalignant cartilaginousnodule ; hypercellular region of small cells
- 39. • Vimentin • S-100protein staining- limited to chondroblastic islands. lacking in small cell component • CD57 • CD99- limited to small cell component • Nuclear immunoreactivity – Sox9 and osteocalcin • Focal reactivity for actin,desmin,myogenin,NSE MOLECULAR GENETICS • HEY1–NCOA2 gene fusion • complex cytogenetic alterations, including identical Robertsonian translocation t(13;21)(q10;q10)
- 40. • Hematopoietic stainswill rule out lymphoma • Both mesenchymal chondrosarcoma and Ewings sarcoma/PNET share immunoreactivity for CD99 FLI-1-positive in 75% cases of Ewings sarcoma Sox9- sensitive and specific marker for mesenchymal chondrosarcoma
- 41. • Osteosarcoma isthe most common nonhematopoietic primary malignant bone tumor. • But small cell osteosarcoma ( histological variant) is an extremely uncommon tumor with a poor prognosis • AGE- 10-25 years ; rare in preschool children • another peak age incidence- after 40 • SEX- M:F=3:2 • SITE- metaphyseal area of long bones • lower end of femur • upper end of tibia • upper end of humerus
- 42. • Small cellosteosarcoma is a rare histological variant • MICROSCOPY- Small size and uniformity of tumour cells and diffuse pattern of growth is seen – simulating appearance of Ewing sarcoma/PNET and malignant lymphoma • Some cases- these cells are spindle rather than round • Focal production of osteoid – distinguishing feature • Areas of cartilage production can be seen • Difficult to distinguish small cell osteosarcoma from ewings sarcoma/PNET when osteoid is not present
- 43. • IMMUNOHISTOCHEMISTRY- • Nospecific immunophenotype for osteosarcoma • Immunohistochemically heterogenous • Positive for vimentin, • desmin, • smooth muscle actin, cytokeratin epithelial membrane antigen, S-100 type I collagen, type II collagen, type IV collagen proteins associated with bone metabolism like- osteonectin,osteocalcin, osteopontin. CD 99
- 44. • Hematopoietic immunostainswill distinguish lymphoma from small cell osteosarcoma • Small cell osteosarcoma can be immunoreactive with CD99, so it is not a useful stain in ruling out Ewing sarcoma FLI-1 is a better marker most Ewing sarcomas are positive but small cell osteosarcomas are negative.
- 45. • The stromalcomponent of small cell osteosarcoma may resemble mesenchymal chondrosarcoma. both can show reactivity to CD99 - Careful attention paid to the type of matrix production— osteoid in osteosarcoma and cartilage in mesenchymal chondrosarcoma is the best way to make the distinction
- 46. • Small cellvariant of poorly differentiated synovial sarcoma is easily misdiagnosed for other small round cell tumours • IMMUNOCHEMISTRY- positive for keratin 7,13 and 19 EMA, vimentin , CD99 • MOLECULAR GENETICS- t(x;18)(p11.2;q11.2) fusion of SS18( chr 18) with SSX1 (chr X)
- 47. • Only twocategories show small round cell picture on histology: 1.Embryonal rhabdomyosarcoma 2.Alveolar rhabdomyosarcoma
- 48. EMBRYONAL RHABDOMYOSARCOMA • Arisesfrom unsegmented and undifferientiated mesoderm • SITE- head and neck region- orbit, nasopharynx, middle ear retroperitoneum bile ducts urogenital tract • AGE- 3-12 years • GROSS- poorly circumscribed, white, soft ALVEOLAR RHABDOMYOSARCOMA • AGE- 10- 25 years • SITE- Extremities- forearm,arms, perirectal, perineal regions Most common sites of metastatic involvement bone marrow, lungs, soft tissues, lymph nodes
- 49.
- 50. Spindle shaped cells;Nuclei oval; cytoplasmscanty & eosinophilic
- 51. Small round cells Connectivetissue septa
- 52.
- 53.
- 54. ALVEOLAR RHABDOMYOSARCOMA: • t(2;13)(q35;q14)with PAX3/FOXO1A fusion • t(1;13)(p36;q14) with PAX7/FOXO1A fusion (FOXO1A was previously known as FKHR) Detected in paraffin embedded tissue with FISH technique EMBRYONAL RHABDOMYOSARCOMA • No distinctive genetic alterations • Loss of heterozygosity at 11p15.5 • Gain of chromosomes 2,8,13
- 56.
Editor's Notes
- #4 These tumors can have overlapping clinical and radiographic features; therefore a final diagnosis is based on careful histologic review in combination with strategic use of immunohistochemical stains and, at times, molecular studies
- #8 Ewing sarcoma of femur. Frontal radiograph and lateral radiographs of the femur demonstrate mottled, osteolytic lesion (blue circle) with poorly marginated edges in the diaphysis of the bone. There is sunburst periosteal reaction (red circle) and lamellated periosteal reaction (white arrows).
- #9 soft gray-white mass extending into soft tissue.
- #15 PAS stain in Ewing sarcoma/PNET showing large amounts of cytoplasmic glycogen. The material was entirely removed by diastase digestion.
- #18 CD99 reactivity in Ewing sarcoma/primitive neuroectodermal tumor typically shows a strong membranous staining pattern. FLI1 protein expression with nuclear reactivity is found in Ewing sarcoma/primitive neuroectodermal tumor but can also be observed in other small round blue cell tumors, particularly lymphoblastic lymphoma
- #26 Clinical features- pain;pathological fractures; systemic features like fever weight loss
- #27 Lymphoma forms an ill-defined, lytic, and destructive lesion in the proximal humeral metaphysis. Plain radiography may be negative even when marrow is extensively involved.
- #28 gray-white (fish-flesh) tumor has permeated through the cortex into surrounding soft tissue.
- #29 Primary bone lymphoma demonstrating cytologic variability with irregular nuclear outlines and fine fibrosis weaving among the tumor cells.
- #39 PAGE 1883 FLETCHER. The spectrum of cytologic features in plasma cell myeloma ranges from those that closely resemble normal plasma cells to those that bear little resemblance. However, in almost all tumors, the plasma cell nature of the neoplasm is apparent, at least focally. Welldifferentiated myeloma is easily recognized by plasma cells with eccentric nuclei, “clock-face” chromatin, and amphophilic perinuclear Golgi apparatus (Fig. 25-2). Poorly differentiated myeloma, however, is a more challenging diagnosis because the tumor cells often display significant cytologic atypia and pleomorphism . This can cause diagnostic problems because of overlapping features with lymphoma, carcinoma, and at times sarcoma.
- #46 fig 1.Mesenchymal chondrosarcoma shows a malignant cartilaginous nodule merging with a hypercellular region of small cells. Fig 2. Hemangiopericytomatous pattern of growth within a mesenchymal chondrosarcoma illustrates round to oval small cells surrounding staghorn-like vascular spaces. Fletcher pg 1899
- #47 NCOA2 is a member of the p160 nuclear hormone receptor transcriptional coactivator family that facilitates chromatin remodeling and transcription of nuclear receptor target genes. HEY1 seems to participate in the regulation of bone morphogenic protein (BMP)9-induced osteoblastic-lineage differentiation of mesenchymal stem cells
- #57 A signiacant numbr consists only of densly apposed undifferntiated small cells.
- #58 Morphological image varies widely depending on degree of differtiation,cellularity, pattern of growth.
- #59 Small round cells separated into nests by connective tissue septa. Cases in which alveolar pattern is poorly developed reffered as solid variant most difficult to diagnose
- #60 MSA= muscle specific actin. Myo D1 not well demonstrated in formalin fixed paraffin sections;lesser diagnostic utility.
- #61 Extent of staining helps in subclassification. Alveolar type shows extensive labelling in nearly all neoplastic cells. E-rms SHOWS MORE HETEROGENOUS reactivity.
- #62 PAX3 –FOXO1A : more aggressive course. FOXO1A was previously known as FKHR gene. PAX3 codes for a developmentally regulated transcription factor involved in muscle development 21 and FKHR is a member of the fork head family of transcription factors. 22 The PAX3-FKHR fusion protein has been shown to be a more potent transcriptional activator than PAX3 protein alone