Giant cell lesions of bone

Includes all the reactive, benign and malignant lesions of bone with gaint cells in HPE

1. GIANT CELL LESIONS OF THE BONE PRESENTER - Dr Shreya Prabhu MODERATOR- Dr Shwetha J 1

2. Normal anatomy Adult bones are classified according to their shape- long, flat and short bones Long bones are divided into three regions:- diaphysis, metaphysis and epiphysis. 2

3. Compact bone contains vascular channels which are divided into two types on the basis of their orientation and their relation to lamellar structure of surrounding bone: Haversian canal Volkmann canal 3

4. Histology of bone Cells in bone:- Osteoblasts Osteoclasts Osteocytes 4

5. 5 osteocyte

6. A giant cell is a cell that is larger in dimension than the cells that are routinely encountered in histology. These cells are involved in many physiologic and pathological processes . A multinucleated giant cell (MGCs) is formed by the union of several distinct cells. They are usually of monocyte-macrophage lineage 6 GIANT CELL

7. In chronic inflammation when macrophages fail to deal with particles that has to be removed; fuse together and form multinucleated giant cells. Thus , their role in elimination of foreign substances, damaged tissue , pathogens is essential for host survival . These cells sequester persistent pathogens and prevent further spread of infection . They were first reported in tuberculous granulomas by Rokitansky and Langhans 7

8. These types of cells differ markedly in their Association with disease states Location and prevalence in various tissues or organs Stimuli that induce the formation Subsequent function of these cells The size of giant cells varies greatly, but is usually between 40 μm and 120 μ m. 8

9. NORMAL OCCURING REACTIVE NEOPLASTIC Megakaryocytes Foreign body giant cells RS cell Trophoblasts Langhan’s giant cells GC of GCT Osteoclasts Ascoff’s giant cells Touton giant cells 9

10. Macrophage derived Epidermal cell derived Melanocyte derived Others Foreign body giant cells Tzanck giant cells Starburst giant cells Floret‑like multi‑nucleated giant cells (FMGCs) Touton giant cells Multinucleated epidermal giant cells Giant cells in melanocytic nevus. Langhans ’ giant cells Balloon cells Giant nevus cells. 10

11. Osteoclasts are bone-resorbing cells that play a pivotal role in bone homeostasis and remodeling. Osteoclast precursors are derived from bone marrow as early mononuclear macrophages, which circulate in blood, and bind to the surface of bone. Osteoclast formation is driven mainly by two cytokines, Receptor Activator of Nuclear Factor Kappa β Ligand (RANKL) and macrophage - colony stimulating factor (M-CSF ). 11 OSTEOCLASTS

12. In addition a wide variety of factors like systemic hormones and growth factors influence the formation and function of osteoclasts. They usually contain 10 to 20 nuclei per cell and are found on bone surfaces on the endosteal surfaces within the haversian system on the periosteal surface beneath the periosteum 12

13. Giant cell lesions of bone 13

14. 14 REACTIVE BENIGN MALIGNANT Brown tumor GC Tumor Osteosarcoma GC reparative granuloma Aneurysmal Bone Cyst Clear cell chondrosarcoma Pseudomalignant myositis ossificans Chondroblastoma Metastatic Carcinoma Tubercular osteomyelitis Chondromyxoid Fibroma Non ossifying Fibroma Langerhans Cell Histiocytosis Benign fibrous histiocytoma of bone

15. Reactive GC lesions 15

16. A benign, reactive, intraosseous proliferation characterized by aggregates of giant cells in a fibrovascular stroma M ay occur in normal bone or in pre-existing lesions, such as brown tumor Site- Craniofacial, small bones of hands and feet Pain and swelling • Usually treated with simple curettage 16 GIANT CELL REPARATIVE GRANULOMA

17. 17

18. 18 Gross specimen shows a large red-brown lesion, friable, gritty

19. 19 appearance of a lesion that contains several multinucleated giant cells in a fibrogenic stroma and osteoid

20. 20 a .Clusters of spindle admixed with multinucleated giant cells. b Scattered osteoblast-like cells are seen among the spindle cells and multinucleated giant cells (arrow)

21. D/D: Brown tumor GCT ABC Non ossifying fibroma Ossifying fibroma 21

22. Reactive, often self-healing lesion, characterized by heterotopic ossification. In adolescents and young adults, typically after trauma Radiologically , mature lesions have a very characteristic zonal ossification pattern with a shell of calcifications at the periphery of a well demarcated mass 22 PSEUDOMALIGNANT MYOSITIS OSSIFICANS

23. Histologically- The central part is made up of fibrovascular tissue exhibiting reactive myofibroblasts , ganglion-cell-like large cells with prominent nucleoli, reactive osteoblasts and multinucleated osteoclast-like cells 23

24. The cytological features of PMO are Osteoblast-like cells Proliferating myofibroblasts Osteoclast-like multinucleated giant cells Small calcifications Differential diagnosis- Osteosarcoma I mportant diagnostic sign- The zonal ossification pattern 24

25. 25 a) A mixture of reactive osteoblasts and myofibroblasts b) Reactive osteoblasts c) A multinucleated osteoclast-like giant cell and reactive osteoblasts

26. Bone tumor composed of non neoplastic reactive tissue that occurs in setting of primary, secondary, or tertiary hyperparathyroidism Causes- Adenoma Chief cell hyperplasia PTH receptor on OB activates RANKL RANKL binds to RANK on OC OC activation 26 BROWN TUMOR OF HYPERPARATHYROIDISM

27. 3rd and 4th decades of life Females May be solitary or multiple SITE- pelvis, ribs, clavicles, and extremities( dia - or metaphyseal ) Painful mass 27

28. Biochemically- Hypercalcemia Hypophosphatemia Hypercalciuria Lowering of renal phosphate threshold Elevated PTH Elevated VIT D Enhanced excretion of nephrogenous cAMP Elevated serum ALP 28

29. Expansile , well circumscribed, lytic, and thin with subtle osteopenia 29

30. 30 Severe osteopenia with resorption of tufts Subperiosteal resorption of the proximal and middle phalanges A lytic lesion in the 5th proximal phalanx Lateral view of the skull shows significant osteoporosis producing a salt and pepper appearance of the cortices

31. Well-circumscribed, reddish-brown hemorrhagic mass with lobular architecture Thins and expands cortex Large , blood-filled cysts may develop ( osteitis fibrosa cystica ) Peripheral shell of reactive bone may be present 31

32. Lobules of plump fibroblasts, extravasated red blood cells, hemosiderin-laden macrophages, and osteoclast-type giant cells that cluster in areas of hemorrhage ○ Lobules separated by septa composed of reactive fibrous tissue and trabeculae of woven bone • Adjacent bone show evidence of hyperparathyroidism ○ Dissecting osteitis with osteoclasts resorbing centers of bony trabeculae -rail road tracks ○ Cortical cutting cones composed of osteoclasts expanding haversian systems 32

33. 33

34. 34

35. 35

36. 36 Dispersed or clustered spindle cells, and variable amounts of osteoclast-like giant cells and haemosiderin -laden macrophages

37. D/D- CGCG GCT Solid ABC Metastatic carcinoma 37

38. Benign GC lesions 38

39. A benign but locally aggressive neoplasm composed of uniformly distributed osteoclast-like giant cells ( osteoclastoma ) 20 % of benign bone tumors Driver mutation in H3F3A histone gene Develops in skeletally mature individuals during 3rd-5th Most common in female 39 GIANT CELL TUMOR

40. Pathogenesis Neoplastic cells express high levels of RANKL , which promotes the proliferation of osteoclast precursors and their differentiation into mature osteoclast via RANK expressed by these cells. Feedback between osteoclast and osteoblast that normally regulates this process during bone remodelling is absent Results is localised but highly destructive resorption of bone matrix by reactive osteoclast. 40

41. LOCATION 75% 41

42. MOST COMMON SITES DIST. FEMUR PROX. TIBIA DIST. RADIUS 42

43. RADIOLOGY Eccentric lytic / cystic lesion of a long bone No evidence of periosteal lifting No sclerotic rim 43

44. Highly variable gross appearance, can range from predominantly hemorrhagic to soft and fleshy Typically , sharp margin between the tumor and surrounding bone Surrounding bone is typically expanded with a thinned cortex 44 gross

45. 45

46. 46 Feature that might suggest malignant behavior but have no prognostic significance-intravascular invasion

47. 47 Necrosis spindle cell–rich areas

48. 48

49. 49

50. IMMUNOHISTOCHEMISTRY- Giant cells have immunoprofile similar to macrophages Osteoclast-type giant cells stain for RANK Many of stromal mononuclear tumor cells stain for RANKL, indicating that they may have osteoblastic phenotype Mononuclear tumor cells show nuclear staining for p63 50

51. Malignancy in gCT GCT- regarded as low grade malignancies due to its tendency to recur and occasional capacity to metastasize High-grade sarcoma is seen developing at the site of a previously treated GCT PRIMARY MALIGNANT GCT- Tumor that contains foci of GCT and pleomorphic sarcoma at first diagnosis (dedifferentiated GCT) SECONDARY MALIGNANT GCT- Initial tumor has appearance of classic GCT and sarcomatous transformation occurs after local recurrence/ following RT 51

52. A diagnosis of a lesion other than giant cell tumor should be favored if: The patient is a child The lesion is located in the metaphysis or diaphysis of a long bone rather than the epiphysis The lesion is multiple The lesion is located in the vertebrae, jaw (except for patients with paget disease), or bones of the hands or feet 52

53. D/D- Giant cell–reparative granuloma Brown tumor of hyperparathyroidism Aneurysmal bone cyst, especially solid variant Osteosarcoma with giant cells Metaphyseal fibrous defect 53

54. Destructive , expansile benign neoplasm of bone characterized by multiloculated , blood-filled cystic spaces Cytogenetic and molecular studies document presence of t(16;17 ) 54 ANEURYSMAL BONE CYST

55. Clinical Features Commonly seen in 2nd and 3rd decade of life Commonly affects females SITE- Metaphysis of long bones of upper and lower extremities Posterior elements of vertebra Small bones of hands and feet Craniofacial skeleton 55

56. Presentation Pain Swelling Limitation of range of motion Palpable mass Heralding event may be pathological fracture Tumors in spine can cause nerve compression and neurologic symptoms 56

57. 57

58. 58

59. 59

60. 60 1) Low-power appearance it contains several twisted septa of varying sizes. 2) Loose slender spindle cell proliferation within the cyst wall is accompanied b y multinucleated giant cells

61. 61 A ) Osteoid peripherally and within the fibrous septae . B ) The bone is often densely calcified , so-called blue bone.

62. 62 Clusters of osteoclast-like multinucleated giant cells with loose spindly stroma to cellular stroma . The cell block shows fragments of bland-appearing fibroconnective tissue with fibroblasts, myofibroblasts ; histiocytes , and giant cells without endothelium

63. IMMUNOHISTOCHEMISTRY- • There are no specific immunohistochemical findings in ABC; p63 can stain some tumor cells • Spindle fibroblast-like cells may express smooth muscle actin • Osteoclasts stain with CD68 GENETIC TESTING- • FISH using break-apart probe for USP6 can detect rearrangement 63

64. D/D: GCT Solitary bone cyst Hemangioma Telangiectatic OS CGCG 64

65. Extremely common, present in 30% to 50% of children older than 2 years Arise eccentrically in the metaphysis of the distal femur and proximal tibia Half are bilateral or multiple Often small, that grow to 5 or 6 cm in size are classified as Nonossifying fibromas 65 FIBROUS CORTICAL DEFECT AND NONOSSIFYING FIBROMA

66. 66 Both fibrous cortical defect and nonossifying fibroma produce sharply demarcated radiolucencies , surrounded by a thin rim of sclerosis

67. The solid red-brown tumor has resulted in expansion of the bone and thinning of the cortex. 67

68. 68 They consist of gray to yellow-brown cellular lesions containing fibroblasts and macrophages. The cytologically bland fibroblasts are frequently arranged in a storiform (pinwheel) pattern, and the macrophages may take the form of clustered cells with foamy cytoplasm or multinucleated giant cells Hemosiderin is commonly present

69. 69

70. D/D- GCT Solid ABC 70

71. G roup of conditions designated as Langerhans cell histiocytosis ( histiocytosis X, eosinophilic granuloma) is an infiltration by a cell of the accessory immune system known as Langerhans cell, accompanied by a variable admixture of eosinophils , giant cells, neutrophils, foamy cells, and areas of fibrosis S ite Skull>femur>pelvis>ribs Young adults 71 LANGERHANS CELL HISTIOCYTOSIS

72. LCH OF BONE- Solitary bone involvement (Most common) Multiple bone involvement (with or without skin involvement ) Multiple organ involvement (Hand– Schüller –Christian, Letterer- Siwe disease) 72

73. 73

74. 74

75. 75

76. 76 Histiocytes with abundant cytoplasm and rounded or ovoid nuclei mixed with neutrophilic and eosinophilic leucocytes. Lobulated or ‘coffee-bean’ nuclei

77. 77

78. 78

79. Main differential diagnosis Granulomatous inflammation Osteomyelitis Hodgkin lymphoma Osseous manifestations of Rosai-Dorfman disease Survival in unifocal disease is greater than 95%; with two organs involved, survival is 75% and decreases with increasing number of affected sites involvement (bone, liver, spleen, and others). Absence of bone lesions in multiorgan involvement is a poor prognostic sign 79

80. Benign primary bone neoplasia Female>male, 3 rd -4 th decade SITE -the spine and long bones, in a non- metaphyseal location Asymptomatic/ local pain Excellent prognosis, curettage/ simple excision 80 BENIGN FIBROUS HISTIOCYTOMA OF BONE

81. well-delimited medullar lesion. • The tumor tissue is firm , elastic, tan to whitish with yellowish areas . shows a mixture of spindle cells disposed in a predominant storiform fashion, a variable amount of osteoclast-type giant cells, foamy macrophages, hemosiderin, and chronic inflammatory infi ltrate 81

82. 82

83. 83

84. D/D- Non ossifying fibroma GCT Malignant fibrous histiocytoma 84

85. Benign neoplasm, rare (<1%) Skeletally immature individuals, 10-25 years Arises in the epiphyseal end of long bones before the epiphyseal cartilage has disappeared Distal end of the femur Proximal end of the humerus Proximal end of the tibia 85 CHONDROBLASTOMA

86. Intramedullary, well-defined tumor with sclerotic margins, radiolucent with internal calcifications 86

87. Gray-pink, well circumscribed firm tissue with gritty calcifications and hemorrhage, <5 cm, sharply marginated from surrounding bone 87

88. 88

89. 89

90. 90 Chicken wire calcification

91. 91 Fragments of chondroid matrix Double cell population

92. S 100 protein, vimentin 92 IHC

93. D/D- Giant cell tumor Primary aneurysmal bone cyst Chondromyxoid fibroma Clear cell chondrosarcoma 93

94. Rare benign tumor Long bones Young adults- 2 nd to 3 rd decade of life 94 CHONDROMYXOID FIBROMA

95. 95

96. 96

97. 97

98. 98

99. Coarse calcifications 99

100. 100 a) Clustered spindly or stellate cells in a myxoid background. b) The spindly and stellate cells exhibit moderate anisokaryosis c) Chondroblast like cells in the myxoid background show moderate pleomorphism

101. IHC S100- cartilaginous areas and sometimes myxoid regions SOX9 Negative for keratin 101

102. D/D- Chondroblastoma Enchondroma Low-grade chondrosarcoma Chondromyxoid fibroma-like osteosarcoma Fibromyxoma Osteochondromyxoma 102

103. 103

104. Malignant GC lesions 104

105. Malignant tumor in which the cancerous cells produce osteoid matrix or mineralized bone Most common primary malignant tumor of bone Occurs in all age groups, but has bimodal age group Male>female 105 OSTEOSARCOMA

106. Site - Metaphyseal region of the long bones:- Lower end of femur Upper end of tibia Upper end of humerus 106

107. PREDISPOSING FACTORS- Paget disease Radiation exposure Chemotheraphy Preexisting benign bone lesions Foreign bodies Genetic predisposition 107

108. Several subtypes Site of origin (intramedullary, intracortical , or surface) Histologic grade (low, high) Primary (underlying bone is unremarkable) or secondary to preexisting disorders (benign tumors, Paget disease, bone infarcts , previous radiation) Histologic features ( osteoblastic , chondroblastic , fibroblastic, telangiectatic , small cell, and giant cell) The most common subtype arises in the metaphysis of long bones and is primary, intramedullary, osteoblastic , and high grade 108

109. 109

110. 110

111. Histologic grading • In general, cellularity and cytologic atypia (enlargement, irregular nuclear contours, hyperchromasia ) of the tumor cells are the most important criteria for grading osteosarcoma • By definition, conventional, intramedullary osteosarcomas are considered high grade (grade 3 of 3, see later) • Grade 1 • Parosteal osteosarcoma • Low-grade central osteosarcoma • Grade 2 • Periosteal osteosarcoma • Grade 3 • Conventional osteosarcoma • Secondary osteosarcoma • High-grade surface osteosarcoma • Small cell osteosarcoma 111

112. Infiltrative, large, intramedullary lesion Can be pure osteoblastic , pure osteolytic , or mixed lytic and blastic Cortical destruction and soft tissue tumor extension are common Codman triangle (i.e., periosteal elevation) is seen due to tumor growth Sunburst configuration is tumor growth occurring in a radial fashion 112

113. Distal femoral osteosarcoma with prominent bone formation extending into the soft tissues. The periosteum , which has been lifted, has laid down a proximal triangular shell of reactive bone known as a Codman triangle (arrow ) . Soft tissue component has cloud like appearance 113

114. Gigantic mass in the proximal humerus distorting the shoulder region. The overlying skin is attenuated, and large veins that feed and drain the tumor are visible 114

115. Often large (>5 cm), fleshy or hard tumor, centered within the metaphysis Crosses the cortex with an associated soft tissue component Depending on predominant stromal component, can be gray-tan and granular ( osteoblastic osteosarcoma) or translucent bluish ( chondroblastic osteosarcoma) or a firm off-white mass (fibroblastic osteosarcoma) 115 gross

116. microscopy Admixture of 2 elements in varying proportions- High grade sarcoma with epithelioid , plasmacytoid , fusiform, ovoid, small round cells, Clear cells, mono- or multinucleated giant cells, spindle cells Bone produced by tumor cells Many osteosarcomas contain benign giant cells that have the appearance of osteoclasts 116

117. The giant cells may have the confi guration of those in classic giant cell tumors, and the mononuclear cells may show only subtle cytologic atypia If one encounters a tumor that has all the features of a giant cell tumor but occurs in an unusual location, such as in the metaphysis of a growing child, serious consideration should be given to osteosarcoma 117

118. 118

119. 119

120. Cytology- Variable cellularity Tumour cells-pleomorphic spindle, rounded, ovoid, polygonal and often large, osteoblast like Multinucleated tumour giant cells. Strands of osteoid matrix between tumour cells in clusters. Atypical mitosis Benign osteoclast-like giant cells are numerous in giant-cell-rich osteosarcoma. Occasional necrosis and calcifications 120

121. 121

122. 122

123. ihc Exhibit strong alkaline phosphatase activity Immunoprofile is nonspecific SATB2- nuclear transcriptor factor- stains OB- sensitive not specific May be positive for keratin and EMA Cartilagenous area S100 positive 123

124. 124 Strong positive cytoplasmic staining for ALP Expression of (B) osteonectin and (C) osteocalcin in tumor cells

125. D/D- • Dedifferentiated chondrosarcoma • Fibrosarcoma • Ewing sarcoma • Osteoblastoma • Undifferentiated pleomorphic sarcoma (so-called malignant fibrous histiocytoma ) 125

126. Chondrosarcoma Malignant tumor of chondroid differentiation 2 nd most common, axial skeleton Divided into 2 major categories on the basis of microscopic criteria :- Conventional chondrosarcoma Chondrosarcoma variant- Clear cell chondrosarcoma Myxoid chondrosarcoma Dedifferentiated chondrosarcoma Mesenchymal chondrosarcoma 126

127. 127 CENTRAL CHONDROSARCOMA PERIPHERAL CHONDROSARCOMA JUXTACORTICAL CHONDROSARCOMA Location Medullary cavity of flat or long bones De novo or from cartilaginous cap Of a pre-existing osteochondroma Shaft or long bones Radiography Osteolytic lesion with splotchy calcification Ill defined margins Fusiform thickening of the shaft Perforation of the cortex Presents as large tumors with a heavily calcified centre surrounded by a lesser denser periphery with splotchy calcification Cartilaginous lobular pattern with areas of spotty calcification and endochondral ossification CONVENTIONAL

128. 128

129. Clear cell chondrosarcoma A low-grade, cartilage-producing cells with characteristic large, clear cytoplasm Rarest variant Younger patients SITE - epiphysis of proximal femur , proximal humerus , and distal femur • Tender mass Pulmonary metastases En bloc resection typically curative 129

130. Epiphyseal (unique among chondrosarcomas ) Osteolytic or sclerotic Often circumscribed or marginated , suggesting a benign lesion such as chondroblastoma Larger tumors may have soft tissue extension and cortical destruction 130

131. Gross- Large bulky tumors Pale blue matrix, softer than normal hyaline cartilage Abundant gritty calcifications Cysts may be present Larger tumors may be destructive with extensive soft tissue component 131 This femoral head-CC-CSA-extends to the subchondral bone plate.The well circumscribed, oval tumor is heterogeneous with gray glistening,white,and hemorrhagic areas

132. 132

133. Small cartilaginous fragments in a background of myxoid matrix. Large tumour cells have well demarcated, abundant vacuolated cytoplasm and hyperchromatic nuclei with central nucleoli. Occasional osteoclast-like giant cells 133

134. IMMUNOHISTOCHEMISTRY • Cells express S100 protein and collagen II ELECTRON MICROSCOPY • Ultrastructurally , neoplastic cells contain abundant intracytoplasmic glycogen GENETICS • Lacks IDH1 and IDH2 mutations 134

135. D/D- Chondroblastic osteosarcoma Conventional chondrosarcoma Chondroblastoma (radiographic ) Metastatic clear renal cell carcinoma 135

136. More common than primary bone tumors Most common primary sites are lung, breast, prostate, kidney, and thyroid Commonly involved bones include skull, spine, ribs, pelvis, humerus , and femur Pain, pathologic fractures 136 METASTATIC TUMORS

137. radiography Lesions may be entirely sclerotic or lytic or mixture of sclerotic and lytic Typically lytic metastases : Renal cell carcinoma and thyroid carcinoma Typically sclerotic metastases : Prostate, breast, and neuroendocrine carcinomas PET/CT is very sensitive for detection of bone metastasis 137

138. 138

139. 139