GIANT CELL LESIONS.pptx

Giant cell lesions are a group of lesions that typically display multinucleate giant cells as one of the characteristic histopathological features which are significant and aids in diagnosis.

1. GIANT CELL LESIONS BY DR SUNITA PATHAK

2. CONTENTS INTRODUCTION GIANT CELLS FORMATION TYPES OF GIANT CELLS INTRODUCTION GIANT CELL LESIONS CONCLUSION REFERENCES

3. INTRODUCTION 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. May be mononucleated or multinucleated which can be explained by the mechanism of their formation . Easily recognized under light microscopy and hence provide a vital clue in arriving to a diagnosis. Essential to know the histogenesis of these unique cells, as the presence of giant cell can have a major implication on the disease process.

4. A multinucleated giant cell (MGCs) is a mass formed by the union of several distinct cells . Usually of monocyte or macrophage lineage. Physiologically present multinucleated giant cells. - Osteoclasts in the bones, - Trophoblasts in placenta , - Megakaryocytes in the bone marrow.

5. In chronic inflammation when macrophages fail to deal with particles that has to be removed; fuse together and form multinucleated giant cells. Their role in elimination of foreign substances, damaged tissue, and pathogens is essential for host survival. These cells are able to sequester irremovable materials or persistent pathogens and prevent further spread of infection.

6. Monocyte /macrophages are phagocytic leukocytes that play a multitude of functional roles in the body and represent key players in both innate and acquired immune systems. Fusion of macrophages can result in the formation of osteoclasts or a variety of different MGCs. Giant cells showing variations in their morphology and functional patterns are observed in various oral lesions . Hence it is important to know the pathogenesis of these lesions with regards to the role played by the giant cells in them.

7. FORMATION Multinucleated giant cells were first reported in tuberculous granulomas by Rokitansky and Langhans , over a century ago. Cells of monocyte /macrophage lineage are capable of fusion to form MGCs . These types of cells differ markedly in their association with disease states, location & prevalence in various tissues or organs ; stimuli that induce the formation of the respective MGCs, and subsequent function of these cells.

8. Giant cells are found in- Granulomas associated with the immune response to tuberculosis , leprosy, syphilis, Various fungal and parasitic infections Non-immune responses - Toxic agents such as silica, beryllium , and asbestos; - Non-toxic agents such as carbon particles, plastic beads , and iron particles.

9. Since a variety of agents produce granulomas , it is thought that the giant cells are produced by different mechanisms . The two theories that were considered are: 1. Amitotic division of monocyte nuclei in the absence of cellular division. 2. Fusion of non replicating monocytes .

10. Auto-radiographic studies have revealed that giant cells indeed form due to fusion , which has been supported by other authors also. Cell fusion results from an alteration of cell surface which allows close membrane approximation, followed by establishment of continuity between the apposed lipid bilayers .

11. The process of fusion can occur due to a variety of mechanisms. Firstly, an immune mediated phenomenon has been proposed for the formation of giant cell. Here large amount of lymphokines are produced that causes fusion of macrophages to form multinucleated giant cells. Macrophage MGCs are commonly found in areas containing poorly removable foreign material which are antigenic (microorganisms ). Even when the foreign material itself has no antigenicity ( Eg : Glass ) it is possible that the inflammatory process itself produces antigen which is responsible for macrophage fusion.

12. Secondly, it was also proposed that fusion occurs between " young“ macrophages and "older" cells, the latter having existed for some time in the granulomatous environment acquiring chromosomal abnormalities and changes on macrophage surface. Recognition of altered and abnormal cell surface by young macrophages is the stimulus for cell fusion. Third mechanism proposed , suggested that when two or more macrophages try to ingest the same particle , there is simultaneous attempted phagocytosis resulting in the fusion of endosomal margins to form multinucleated giant cells.

13. The role of viruses in fusion of many cell types throughout the body, including macrophages has been explained . Fusion may be achieved by large doses of inactivated virus or by much smaller doses of infective virus. With inactivated virus there appears to be a direct interaction between the viral envelope and cell surface . Attachment of viral envelope leads to the reduction in cell coat thickness and fusion with the cell membrane .

14. Cell fusion results if the virus is in contact with more than one cell . Antigens from the viral envelope become incorporated into the polykaryon membrane, resulting in the fusion between the two cells by forming a "bridge ". Live virus penetrates a cell and leads to fusion following the appearance of virally coded proteins on the cell surface . The infected cell thus has a surface modified by viral proteins which leads to fusion with adjacent uninfected cells. Fusion extends in a plaque to form an expanding syncytium .

15. TYPES OF GIANT CELLS Multinucleated giant cells can be classified into several morphological variants Depending on the arrangement and composition of their organelles. Functional characteristics. Osteoclasts , odontoclasts , skeletal muscle fibers , syncytotrophoblasts and megakaryocytes are the physiologically present multinucleated giant cells . Few of these also have a role to play in various pathological processes.

16. GIANT CELLS NORMAL TISSUES

17. OSTEOCLASTS Named by Kolliker 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). Factors like systemic hormones and growth factors influence the formation and function of osteoclasts .

18. Morphologically, osteoclasts are similar to foreign body giant cells, although they have considerably fewer nuclei. 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 .

19. The osteoclastic giant cells show positivity to cathepsin K, alkaline phosphatase , RANKL, osteoprotegerin & Cluster of Differentiation 68 (CD68). Calcitonin receptor is found to be a more specific marker of differentiation for osteoclasts from other giant cells derived from monocyte / macrophage cell lineage.

20. SYNCYTIOTROPHOBLASTS IN PLACENTA Trophoblasts  (from Greek  trephein : to feed , and  blastos : germinator ). Cells form the outer layer of a blastocyst , which provide nutrients to the embryo and develop into a large part of the placenta. They are formed during the first stage of pregnancy  and are the first cells to differentiate from the fertilized egg.

21. Trophoblasts are specialized cells of the placenta that play an important role in embryo implantation and interaction with the maternal uterus. The core of placental villi contain mesenchymal cells and placental blood vessels that are directly connected to the fetal circulation via the umbilical cord. This core is surrounded by two layers of trophoblast ; a single layer of mononuclear cytotrophoblast that fuse together to form the overlying multinucleated syncytiotrophoblast layer that covers the entire surface of the placenta.

22. Cytotrophoblast - inner layer single celled, inner layer of the trophoblast . Syncytiotrophoblast - outer thick layer that lacks cell boundaries and grows into the endometrial stroma . It secretes  hCG   in order to maintain progesterone secretion and sustain a pregnancy. It is in direct contact with the maternal blood that reaches the placental surface, and thus facilitates the exchange of nutrients, wastes and gases between the maternal and fetal systems.

23. MEGAKARYOCYTES Megakaryocyte  ( mega +  karyo  +  cyte "large-nucleus cell ") is a large bone marrow cell with a lobulated nucleus. Responsible for the production of blood  thrombocytes  (platelets), which are necessary for normal blood clotting. Normally account for 1 out of 10,000 bone marrow cells but can increase in number nearly 10-fold during the course of certain diseases.

24. Megakaryocytes are 10 to 15 times larger than a typical red blood cell, averaging 50-100 μm in diameter. During its maturation, it grows in size and replicates its DNA without  cytokinesis  in a process called  endomitosis . As a result, the nucleus of the megakaryocyte can become very large and lobulated , which, under a light microscope, can give the false impression that there are several nuclei. In some cases, the nucleus may contain up 32 copies of the normal complement of DNA in a human cell.

25. Megakaryocytes are derived from  hematopoietic stem cell precursor cells in the bone marrow. Produced primarily by the liver, kidney, spleen, and bone marrow. These  multipotent  stem cells live in the marrow sinusoids and are capable of producing all types of blood cells depending on the signals they receive. The primary signal for megakaryocyte production is thrombopoietin  or TPO. Other molecular signals for megakaryocyte differentiation include GM-CSF, IL-3,IL-6, IL-11, chemokines  (SDF-1, FGF-4) and erythropoietin. 

26. The megakaryocyte develops through the following lineage: Pluripotential hemopoietic stem cell or hemocytoblast ->  megakaryoblast  ->  promegakaryocyte  -> megakaryocyte . The cell eventually reaches megakaryocyte stage and loses its ability to divide. Still able to replicate its DNA and continue development, becoming polypoid .  The cytoplasm continues to expand and the DNA complement can increase up to 64N in human. Once the cell has completed differentiation and become a mature megakaryocyte , it begins the process of producing platelets.

27. GIANT CELLS INFLAMMATION

28. TOUTON GIANT CELLS Characterized by multiple nuclei that cluster together in the cell and are surrounded by foamy cytoplasm. These cells were originally known as xanthelasmatic giant cells and are formed by fusion of macrophage derived foam cells.

29. Touton giant cells are another type of multinucleated giant cells derived from macrophages and contain lipid. They are found in xanthoma , xanthogranuloma and fat necrosis. Nuclei are arranged in a wreath like pattern . Its peripheral cytoplasm has a foamy or vacuolated appearance due to lipid and nuclei surrounds central area of eosinophilic cytoplasm.

30. Frequently found in lesions containing cholesterol and lipid deposits, and are associated with various pathologic processes, such as xanthomas and xanthogranulomas . Touton types of giant cells are appreciated in cases of fibrous histiocytoma . The lipid droplets in the cytoplasm of these cells can be demonstrated in frozen section by special stains. Lysozyme , α1 antitrypsin, CD68 & factor XIIIa can be used as a marker for differentiation of these multinucleated giant cells.

31. LANGHANS GIANT CELLS Characterized by the presence of few nuclei (< 20) arranged peripherally, within the giant cell. Commonly found in immune granulomas and granulomatous inflammations in the presence of indigestible particles of organisms, eg : the tubercle bacillus.

32. In Langhans giant cell the nuclei are disposed to the periphery of the cell in the form of a horse shoe. These are conspicuous in lesions of Tuberculosis.

33. Presence of MGCs in the tuberculous granuloma was first described by Langhans in 1868. Interferon gamma (IF-γ) plays a central role in inducing Langhans ’ giant cell formation. These cells show positivity to CD68. It has also been seen that larger the size and more the number of nuclei in MGCs, the virulence of disease increases.

34. Lay et al have shown that High virulence mycobacterium , i.e., Mycobacterium tuberculosis , induces large MGCs with more than 15 nuclei per cell. Low virulence mycobacterium species, Mycobacterium avium and Mycobacterium smegmatis , have low number of nuclei per cell , less than seven . High-virulence mycobacterium species resulted in granulomas where the MGCs phagocytic activity was absent. Low-virulence species produced MGCs where phagocytic activity was present.

35. FOREIGN BODY GIANT CELLS Foreign body giant cells (FBGCs) are generated by macrophage fusion and serve the same purpose as osteoclasts : degradation/ resorption of the underlying substrate .

36. . Foreign-body giant cells are frequently seen around exogenous foreign material like catgut, silk, talc, silica and plastic sponges. They are also present around endogenous debris as sequestra , keratin, cholesterol crystals and uric acid crystals (in gout). Nuclei are scattered haphazardly throughout the cytoplasm and some are present centrally and in close clusters.

37. Unlike osteoclasts , which adhere to bone, FBGCs adhere to markedly different synthetic surfaces that display distinct differences in hydrophilic/hydrophobic character as well as chemical and physical properties. Contain many nuclei (up to 100 - 200) that are arranged in a diffuse manner throughout the cytoplasm. Observed at the tissue-material interface of medical devices implanted in soft and hard tissue and remain at the implant-tissue interface for lifetime, of the device in vivo.

38. ASCHOFF NODULES/BODY Aschoff bodies  are nodules found in the  hearts of individuals with rheumatic fever . Result from inflammation in the heart muscle and are characteristic of rheumatic heart disease. These nodules were discovered independently by  Ludwig Aschoff  and Paul Rudolf Geipel , and for this reason they are occasionally called  Aschoff-Geipel bodies .

39. Spherpoidal  or fusiform distinct tiny structures, 1-2mm in size, occurring in the interstitium of the heart. Fully developed Aschoff bodies are granulomatous  structures consisting of  fibrinoid  change, lymphocytic infiltration, occasional plasma cells, and characteristically abnormal macrophages surrounding necrotic centres. Some of these macrophages may fuse to form multinucleated giant cells

40. They are pathognomic foci of fibrinoid necrosis found in many sites, most often the myocardium. Initially they are surrounded by lymphocytes, macrophages, and a few plasma cells, but they are slowly replaced by a fibrous scar. They are especially found in the vicinity of small blood vessels in the myocardium and endocardium and occasionally in the pericardium.

41. GIANT CELLS TUMOUR

42. TUMOR GIANT CELLS Many epithelial and mesenchymal neoplasms contain tumor giant cells. Nuclei of these giant cells are pleomorphic , often diploid, shows abnormal mitosis and resemble those of mononuclear tumor population. Tumor cells are known to possess an abnormal surface and are predisposed to fusion in different ways. Release extracellular enzymes which may reduce the surface coat thickness and cause close approximation of lipid bilayers leading to fusion . Some tumors have been found to be associated with passenger viruses, which are known to cause cell fusion.

43. Anaplastic cancer giant cells

44. Classic Reed-Sternberg cell Large, binucleate or bilobed , with the two halves often appearing as “mirror-image” of each other. Nucleus: may be multiple or multilobate , contains large, inclusion-like, owl-eyed nucleoli, generally surrounded by a clear halo , that are about the size of a small lymphocyte . Cytoplasm: abundant amphophilic .

45. For the diagnosis of Hodgkin’s lymphoma the presence of Reed Sternberg cells must be established . This cell of lymphocytic origin is characterized by its large size and bilobed nucleus ; each containing a large amphophilic or eosinophilic nucleolus . The nuclear chromatin pattern is vesicular and condensed at the periphery. Reed Sternberg cells may be lacunar , polyploid or pleomorphic . Reed–Sternberg cells are  CD30 and CD15 positive , usually negative for CD20 and CD45.

46. GIANT CELL LESIONS OF ORAL CAVITY Giant cell lesions of oral cavity can be cystic , neoplastic, microbial, etc. For proper diagnosis and management of giant cell lesions, it is necessary to know about the pathogenesis of disease and the nature of giant cells . Giant cell lesions of oral cavity have been classified based on the etiopathogenesis as described by Chattopadhyay A ( 1995) and Varghese et al.

47. Classification 1 . Microbial lesions a. Tuberculosis b. Leprosy c. Actinomycosis d. Sarcoidiosis 2. Tumor and tumor like lesion a. Central giant cell granuloma b. Peripheral giant cell granuloma c. Giant cell fibroma d. Osteosarcoma e. Rhabdomyosarcoma f. Hodgkins lymphoma 3. Cystic lesion a. Traumatic bone cyst b. Aneurysmal bone cyst 4. Metabolic lesion a. Hyperparathyroidism 5. Osteodystrophic lesion a. Noonan-like multiple giant cell lesion syndrome 6. Miscellaneous lesion a. Cherubism b. Paget’s disease c. Fibrous dysplasia Varghese I, Prakash A. Giant cell lesion of oral cavity. OMPJ 2011;2:976-1225.

48. Classification of giant cell lesions of oral cavity based on the pathogenesis. Lesions where giant cells in the concerned background are pathognomic Hodgkins lymphoma Peripheral/central giant cell granuloma Giant cell fibroma Lesions where giant cells are characteristic but not pathognomic Tuberculosis Herpes Simplex Virus infection Measles Xanthoma Lesions associated with presence of giant cell Orofacial granulomatosis , fungal infection, foreign body reaction, neoplasm, syphilis, leprosy, fibrous dysplasia, cherubism , ossifying fibroma , aneurysmal bone cyst, paget’s disease of bone, wegners granulomatosis actinomycosis , odontogenic giant cell fibromatosis Chattopadhyay A. Giant cells and giant cell lesions of the oral cavity. Journal of Indian Dental Association. 1995;66 (11):326-327.

49. MICROBIAL LESIONS

50. Oral Tuberculosis Tuberculosis (TB) is a specific infectious granulomatous disease caused by Mycobacterium tuberculosis. Tuberculous lesions of oral cavity may be primary or secondary to pulmonary tuberculosis. Primary tuberculosis occurs in previously unexposed people and mostly involves the lungs. Secondary tuberculosis occurs from a reactivation of organism in a previously infected person, typically associated with compromised host defenses .

51. TB Invades/Infects the Lung TB: Airborne Transmission

52. Tongue is the commonest site for oral tuberculous lesions, they may also occur on gingiva , floor of mouth, palate, lips and buccal mucosa. Typical oral lesions consist of a stellate ulcer with undermined edges and a granulating floor. The characteristic histopathologic appearance is due to cell-mediated hypersensitivity reaction.

53. Formation of granuloma exhibiting foci of caseous necrosis surrounded by epitheloid cells, lymphocytes , and occasional multinucleated giant cells are seen. Langhans ’ giant cells are seen, the presence of which is not diagnostic but indicative of tuberculosis .

54. Typical tuberculous granuloma showing an area of central necrosis surrounded by multiple Langhans -type giant cells, epithelioid cells, and lymphocytes. In Langhans giant cell the nuclei are disposed to the periphery of the cell in the form of a horse shoe. These are conspicuous in lesions of Tuberculosis.

55. Diagnosis of tuberculosis is confirmed by the presence of acid fast bacilli in the specimen or culture of sputum. The acid-fast bacteria mycobacteria appear bright red following Ziehl-Neelsen staining.

56. Acid-Fast ( Kinyoun ) Stain of Mycobacterium NOTE : cord growth (serpentine arrangement) of virulent strains

57. Eight Week Growth of Mycobacterium tuberculosis on Lowenstein-Jensen Agar

58. Mycobacterium Tuberculosis Stained with Fluorescent Dye

59. Pneumonia Granuloma formation with fibrosis Caseous necrosis Tissue becomes dry & amorphous (resembling cheese) Mixture of protein & fat (assimilated very slowly) Calcification Ca ++ salts deposited Cavity formation Center liquefies & empties into bronchi Typical Progression of Pulmonary Tuberculosis

60. Chest X-Ray of Patient with Active Pulmonary Tuberculosis Postero -anterior chest radiograph showing bilateral upper lobe consolidation and cavitation , consistent with pulmonary tuberculosis.

61. Oral leprosy Leprosy is a chronic multi-systemic disease caused by acid fast, rod shaped bacilli Mycobacterium leprae . It is mainly a Granulomatous disease affecting: peripheral nerves and mucosa of the upper-respiratory tract. C linico -pathological presentation is determined by the complex interaction between the invading organism and immune status of the individual.

62. The transmission of leprosy is thought to occur through the respiratory tract. Infected individuals discharge bacilli through their nose and a healthy individual breaths them in. Nasal/oral Droplets Dermal Inoculations

63. Hard palate is the most frequent site of oral involvement, followed by soft palate, labial maxillary gingiva , tongue, lips, and buccal mucosa. Spectrum of oral lesions may vary from papules, nodules and ulcers showing bacillary positivity. Involvement of lip may result into cheilitis granulomatosa . Gingival hyperplasia with loosening of teeth has also been reported.

64. Signs of leprosy Pale or slightly reddish patch Definite loss of sensation in the patch Signs of damage to nerves definite loss of sensation in hands/feet weakness of muscles of hands/feet/face visible deformity of hands/feet/face Diagnosis is clinical, by finding signs of leprosy and supported with the use of acid-fast bacilli smear or skin biopsy

65. Symptoms & Diagnosis: (2) Skin Smear Tests Ziehl Neelsen Carbol Fuchsin Stain (ZNCF)

66. The typical granulomatous nodule shows collections of epitheloid histiocytes and lymphocytes in a fibrous stroma . Langhans ’ type giant cells are variably present. First line drugs are rifampicin , dapsone , and clofazimine and Second line drugs are ofloxacin and minocycline . (6-24 months)

67. Oral actinomycosis Actinomycosis is a chronic suppurative soft-tissue infection caused by Actinomyces israelii , which are filamentous , gram-positive, non acid-fast, anaerobic to microaerophilic bacteria that live as commensal organisms in the oral cavity , respiratory and digestive tracts. Clinical manifestations of actinomycosis occur in three areas : - Cervicofacial (50 %), - Abdominal-pelvic (23%), - Thoracic (17%).

68. Suppurative reaction of the infection may discharge large yellowish flecks that represent colonies of bacteria called sulphur granules. Cervicofacial actinomycosis affects the areas of prior trauma, due to soft tissue injury, periodontal pocket, non vital tooth, extraction socket or infected tonsil.

69. HISTOPATHOLOGY Central abscess formation with colonies of microorganisms floating in a sea of polymorphonuclear leukocytes is observed. Often associated with multinucleated giant cells and macrophages particularly around the periphery of the lesion .

70. Actinomycosis. This single, complete loculus is from an early case of actinomycosis . The colony of actinomyces with its paler staining periphery (a 'sulphur' granule) is in the centre; around it is a dense collection of inflammatory cells, surrounded in turn by proliferating fibrous tissue.

71. The diagnosis is usually made by fine-needle aspiration biopsy followed by observing actinomycosis colonies or sulfur granules in microscopic examination.

72. Oral Sarcoidosis Sarcoidosis , in Greek meaning “ flesh like condition” is a systemic non caseating granulomatous disease of unknown etiology . Genetic, infectious and environmental factors have been postulated as possible cause. Most common presentation consists of pulmonary infiltration and hilar lymphadenopathy ; dermal and ocular lesions. When the parotid glands are affected , 4-6% of cases present as parotitis and Heerfordt syndrome.

73. . Histopathology of sarcoidosis will show non caseating granulomas , the center of which usually contains epitheloid macrophages surrounded by a rim of lymphocytes. Langhans type giant cells resulting from the fusion of epitheloid mononuclear cells, occasionally containing many inclusion bodies such as Schaumann bodies or stellate asteroid bodies are observed. Non- caseating granuloma of sarcoidosis (giant cell indicated). 

74. Corticosteoids have remained as the mainstay in treatment of sarcoidosis although with a chance of around 70% relapse within a two years period.

75. Asteroid bodies (ABs): ABs are striking cytoplasmic inclusions in giant cells of granulomas of many types including those of sarcoidosis , tuberculosis, leprosy, fungal infections, schistosomiasis , and lipoid and foreign body types. Vary in size from 5 to 30 µm and have up to 30 rays forming a star-like, spider, or umbrella pattern. The surrounding cytoplasm is vacuolated . Pathophysiologic changes that produce the ABs are unknown. Ultrastructural findings:  The fibrillar material of the spokes radiates from a granular center . The vacuoles between the spokes contain lamellated , lipoidal , myelin figures that may be related to the formation of Schaumann bodies. 

76. Two multinucleated giant cells shown here has an asteroid body with surrounding vacuoles in the cytoplasm. The basophilic body in the giant cell to the left may be an early, small Schaumann body. As with Schaumann bodies, the ABs are found in the non-necrotizing granulomas and not in necrotic areas.

77. TUMOUR AND TUMOUR LIKE LESION

78. Central giant cell granuloma Classified by the World Health Organization in 2005 as a rarely aggressive idiopathic benign intraosseous lesion that occurs almost exclusively in the jaws. Most lesions are asymptomatic. Minority of cases present with pain, paraesthesia , or perforation of cortical plate resulting in ulceration of mucosal surface .

79. Radiology shows a well demarcated and in places corticated radiolucency . Lesions may be large and often displace the adjacent teeth

80. HISTOPATHOLOGY CGCG shows hemosiderin laden macrophages and extravasated erythrocytes along with small inconspicuous capillaries. Multinucleated giant cells are present throughout the connective tissue stroma , and may be seen in patches or evenly distributed around areas of haemorrhage . The giant cells contain up to 30 nuclei. Foci of osteoid may be present, particularly around the peripheral margins of lesion.

81. Accumulations of multinucleated giant cells embedded in a cellular stroma composed predominantly of plump mononuclear cells. These are primarily osteoblasts and mononuclear osteoclast precursors. The lesion is vascular with areas of red cell extravasation .

82. Peripheral giant cell granuloma PGCG is one of the most frequent giant cell lesion of the jaws and originates from the periosteum or periodontal membrane. It is not a true neoplasm but rather a benign hyperplastic reactive lesion occurring in response to local irritation such as tooth extraction , poor dental restorations, illfitting dentures , plaque, calculus, food impaction and chronic trauma.

83. HISTOPATHOLOGY Fibroblasts are the basic element of peripheral giant cell granulomas . Other features include a nonencapsulated highly cellular mass with abundant giant cells, inflammation, interstitial hemorrhage , hemosiderin deposits , mature bone or osteoid .

84. Scattered among the plump, young fibroblasts are numerous multinucleated giant cells with abundant eosinophilic cytoplasm which appear to be non-functional in the usual sense of phagocytosis and bone resorption .

85. Management of this gingival lesion is surgical excision and elimination of any local contributing factors.

86. Giant cell tumor of bone Benign bone tumors arising from bone marrow , which account for about 5% of all biopsied primary bone tumors . The head and neck region constitute approximately 2% of all GCTs , with the majority occurring in sphenoid , ethmoid , or temporal bones. Radiologically , it is usually lytic and expansile without prominent peripheral sclerosis and periosteal reaction.

87. Osteoclastoma Soap bubble appearance Expanding lytic lesion surrounded by a thin rim of bone It may have a soap-bubble appearance

88. HISTOPATHOLOGY The histopathology of GCTs is characterized by frank and marked haemorrhage, numerous giant cells and stromal cells. The haemorrhage gives rise to the characteristic grossly lytic picture. The giant cells are considered reactive while stromal cells are considered “true” neoplastic cells.

89. The giant cells are thought to be originating from circulating monocytes which then transform into osteoclasts . Treatment includes simple or aggressive curettage. Tumor resection and reconstruction with prosthesis or a large segment allograft has a low rate of local recurrence.

90. Difference between Giant cell granuloma and Giant cell tumour CENTRAL GIANT CELL GRANULOMA GIANT CELL TUMOUR Reactive lesion Neoplastic lesion Generally occur in younger subjects Hemorrhagic background Absence of hemorrhage Presence of plump bland fibroblasts & presence of large areas of fibrosis, Absence of fibroblasts Haemosiderin Fewer giant cells . Diffuse sheets of large giant cells and polygonal mononuclear cells seen Giant cells with smaller number of nuclei Giant cells with larger number of nuclei Giant cells are less uniformly distributed Uniformly scattered Deposition of osteoid is occasionally observed Lacking Higher proliferative activity Less

91. CENTRAL GIANT CELL GRANULOMA GIANT CELL TUMOUR young patients Older patients predilection for females Males anterior part of the mandible articular end of tubular bones unilocular or a multilocular radiolucent lesion entirely lytic and expansile lesion in the epiphysis, usually without peripheral bone sclerosis or periosteal reaction Histologically , the tumor consists of a moderately vascularized network of stromal cells and multinucleated giant cells meagerly interspersed with collagenous fibrils. The stromal cells are mononuclear and in general resemble young connective tissue cells. They are spindle shaped or ovoid in varying Proportions. The histopathology of GCTs is characterized by frank and marked haemorrhage, numerous giant cells and stromal cells. The haemorrhage gives rise to the characteristic grossly lytic picture. The giant cells are considered reactive while stromal cells are considered “true” neoplastic cells.

92. Both diseases showed similar cellular phenotype in respect of Vimentin , S100 protein, CD68 and CD34. There is increased immunoreactivity of GCT to Ki-67, P53 and αSMA .

93. Giant cell fibroma GCF is a relatively rare fibrous hyperplastic lesion that is considered to occur due to chronic irritation . Characterized by functional changes in the fibroblastic cells. Occurs as an asymptomatic sessile or pedunculated nodule, usually less than 1 cm in size affecting mandibular gingiva twice as common as maxillary.

94. HISTOPATHOLOGY GCF are characterized by a diffuse, somewhat immature , rather avascular collagenic stroma with small bipolar and slightly stellate fibroblasts scattered throughout in moderate numbers. Occasional fibroblasts will be quite large and angular, and may have more than one nucleus.

95. GCF is characterized by the presence of numerous large stellate and multinucleated giant cells in a loose collagenous stroma . The giant fibroblasts are negative for CD68 but show positivity for vimentin .

96. Giant cell angiofibroma GCA is a distinctive benign, mesenchymal tumor commonly encountered in the orbit. Occur in submandibular region , parascapular area, posterior mediastinum and in the oral cavity. Presents as a slow growing nodule or mass with normal overlying mucosa.

97. HISTOPATHOLOGY GCA is characterized by a richly vascularized , patternless spindle-cell proliferation containing pseudovascular spaces . Multinucleated giant cells (often of floret type) and cells with large, rounded nuclei are present both in the cellular areas and also lining the pseudovascular spaces.

98. The stroma is variably collagenized or sometimes myxoid . Immunohistochemically , the spindle and giant cells are positive for both vimentin and CD34.

99. OSTEOSARCOMA Most common primary malignant tumor of bone Clinically: Males> females Most occur in teenagers (age 10-25 years) Localized pain and swelling Osteosarcoma is an aggressive malignant neoplasm arising from primitive transformed cells of mesenchymal origin that exhibit osteoblastic differentiation and produce malignant osteoid .

100. Classic X-ray findings: Codman's triangle ( periosteal elevation) Sunburst pattern Bone destruction Pathology: Often involves the metaphysis of long bones Usually around the knee (distal femur and proximal tibia) Large firm white tan mass with necrosis and haemorrhage

101. Codman triangle is a term used to describe the triangular area of new subperiosteal bone that is created when a lesion, often a tumour , raises the periosteum away from the bone. Sun-burst" appearance on X-ray examination due to the tumor spicules of calcified bone radiating in right angles

102. Codman's triangle Osteosarcoma

103. Codman triangle 104

104. Osteosarcoma

105. Osteosarcoma

106. HISTOPATHOLOGY Osteosarcoma is formed of Spindle shaped cells showing malignant criteria in form of pleomorphism , hyperchromasia , abnormal mitosis, giant cells .

107. Osteoid Deposition In between spindle cells there is malignant osteoid .

108. RHABDOMYOSARCOMA Embryonal Rhabdomyosarcoma  : Usually occurs in children  (before the age of 10 years). Common sites include head and neck region, genitourinary tract and retroperitoneum .

109. HISTOPATHOLOGY Alternating cellular and myxoid areas. Classical form is composed of undifferentiated round or spindle cells together with a few scattered eosinophilic rhabdomyoblasts . Some elongated rhabdomyoblasts show angulation of muscle fibres (broken straw sign). Multivacuolated or spider web cells may be present. Cytoplasmic cross striations are noted in about 20-30% cases. Intracellular glycogen is more prominent in well-differentiated forms.

110. Immunohistochemistry plays an important role in establishing the diagnosis.  Desmin and muscle actin are positive. MyoD1 and myogenin (myf4) are also useful markers. Variants:    Botryoid      Spindle cell     Anaplastic

111. Hodgkin’s lymphoma Malignant lymphoproliferative disorder which affects primarily lymph nodes with secondary extranodal spread. Presents as cervical lymphadenopathy and rarely involves extranodal sites. Palate, tonsil , floor of mouth, buccal alveolar mucosa , buccal vestibule, and mandibular bone , with no one site accounting for a predominance of cases. Commonly described clinical presentations are ulcerations and swellings.

112. HODGKIN LYMPHOMA—LYMPH NODE. A binucleate Reed-Sternberg cell with large, inclusion-like nucleoli and abundant cytoplasm is surrounded by lymphocytes, macrophages, and an eosinophil . HODGKIN LYMPHOMA, NODULAR SCLEROSIS TYPE—LYMPH NODE. A distinctive " lacunar cell" with a multilobed nucleus containing many small nucleoli is seen lying within a clear space created by retraction of its cytoplasm. It is surrounded by lymphocytes.

113. Treatment includes cytotoxic drugs, immunotherapy and radiotherapy. High dose chemotherapy and autologous stem cell transplantation has also become an established mode of treatment. The prognosis of the disease can be related to the number of giant cells. Lymphocyte depletion type of Hodgkin’s lymphoma which has the most abundant Reed Sternberg cells shows the least favorable prognosis.

114. CYSTIC LESIONS

115. Traumatic Bone Cyst Pseudocyst (lacks an epithelial lining) Uncommon lesion , comprises of 1 % of all jaw cysts. Etiology is unknown. Trauma hemorrhage theory most accepted. Hemorrhage occurring within the medullary spaces of bone leads to clot formation which breaks down and leaves an empty cavity within the bone. Steady expansion of the lesion occurs , secondary to altered or obstructed lymphatic or venous drainage. This expansion cease when the cyst like lesion reaches the cortical layer of bone and expansion is not a common finding in solitary bone cyst.

116. Other theories of origin: Cystic degeneration of primary bone tumours . Result of faulty calcium metabolism such as that induced by parathyroid disease. Ischemic necrosis of fatty marrow. End result of low grade chronic infection. Result of osteoclasis , resulting from a disturbed circulation caused by trauma creating an unequal balance of osteoclasis and repair of bone.

117. CLINICAL FEATURES Occurs in young persons Second decade of life, mean age- 18 yrs. No definite sex predilection, but males more common than females. Mandible > Maxilla Posterior> Anterior Swelling Rarely pain Bony cavity may be empty May contain sero-sanguinous fluid, shreds of necrotic blood clot, fragments of necrotic blood clot, fragments of fibrous connective tissue.

118. RADIOGRAPHIC FEATURES Well-defined (corticated) radiolucency . Variable size- few cm to several cm involving body and ramus of mandible Cavity may have a lobulated or scalloped appearance extending between the roots of the teeth. Seldom displacement of teeth. Vital teeth

119. Traumatic bone cyst usually lies above the mandibular canal. Asymptomatic traumatic bone cysts may be detected on panoramic radiography.

120. HISTOLOGIC FEATURES Thin connective tissue membrane lining the cavity. No such membrane may be demonstrable. Extensive osteophytic reaction on the outer surface of cortical plate. May be presence of few red blood cells, blood pigments, or giant cells adhering to the surface.

121. TREATMENT Clinically, surgeons report an empty cavity at entrance in about two thirds of the cases. Blood clot is also present occasionally. The bony cavity is scraped to generate bleeding , which is considered the treatment of choice for this condition. Other methods of treatment include, packing the curetted cavity with autogenous blood, autogenous bone and hydroxyapetite . Exploration surgery usually leads to healing. Recurrence are rare.

122. Aneurysmal bone cyst Nonneoplastic benign bony lesions with multilocular appearance. When present in the jaw, these manifest as a swelling which develops rapidly. Pain is often reported; paraesthesia , compressibility, and crepitus are rare. According to Hillerup and Hjorting -Hansen , an intra- medullary haematoma secondary to trauma, may be the causative factor for the development of ABC.

123. ANEURYSMAL BONE CYST Bone is expanded and appears cystic. Honey comb or soap bubble appearance and is eccentrically ballooned. Cortical bone may be destroyed and periosteal reaction may be evident.

124. HISTOPATHOLOGY Numerous cavernous , sinusoidal spaces filled with blood are surrounded by loose, fibrous connective tissue . Connective tissue septa contain small capillaries, multinucleated giant cells, inflammatory cells , extravasated erythrocytes, and hemosiderin . Multinucleated, osteoclast -like giant cells often aggregate adjacent to the sinusoidal spaces.

125. Various treatment options include percutaneous sclerotherapy , diagnostic and therapeutic embolization , curettage, block resection and reconstruction, radiotherapy and systemic calcitonin therapy. Self healing cases have also been reported on long term follow up.

126. METABOLIC LESION

127. HYPERPARATHYROIDISM Endocrine abnormality in which there is an excess of circulating parathyroid hormone (PTH). The PTH mobilizes calcium from the skeleton and decreases renal tubular reabsorption of phosphate. Primary hyperparathyroidism is caused by a benign tumor or hyperplasia of the parathyroid gland , producing an excess quantity of PTH hormone. In primary hyperparathyroidism, the serum calcium is elevated beyond its normal 9-11 mg % range by resorption of calcium from bones and decreased renal excretion of calcium. The serum phosphorus level is decreased.

128. Secondary hyperparathyroidism is the result of certain types of kidney diseases that cause hypocalcemia , thereby stimulating the parathyroid glands to secrete excess PTH in an attempt to elevate the serum calcium level. The serum calcium is normal to decreased and serum phosphorus is increased.

129. Stones, bones, abdominal groans and psychiatric moans (renal stones, peptic ulcers, pancreatitis, confusion, lethargy, weakness)

130. Hyperparathyroidism is a common cause of generalized rarefaction of the jaws. The skeleton undergoes generalized osteoporosis and is seen on a radiograph as having a ground glass appearance with loss of trabecular bone pattern. In a small percentage of patients there is loss of lamina dura around all the teeth. The lost lamina dura returns after successful treatment of the disorder.

131. Late in the disease, a small number of cases develop central giant cell lesions known as "brown tumors .“ These "brown tumors " appear radiographically as ill-defined radiolucencies . Panoramic radiography showing a multilocular radiolucency of the right mandible.

132. There is a tendency for the patients to develop renal stones. The serum alkaline phosphatase level is elevated. Increase in serum alkaline phosphatase level occurs in systemic and bone diseases whenever there is significant bone resorption or turnover. Note: "Brown tumors " are histologically identical with the central giant cell granuloma of the jaws. For this reason, hyperparathyroidism should always be ruled out in a patient with a giant cell lesion of the jaws .

133. OSTEODYSTROPHIC LESION

134. Noonan-like/multiple giant cell lesion syndrome (NL/ MGCLS) Clinical similarities with Noonan’s syndrome and cherubism . It is unclear whether it is a distinct entity or a variant of Noonan’s syndrome or cherubism . Inheritance - Autosomal dominant or sporadic. Head/neck- Giant cell lesions in bone/soft tissue, Hypertelorism , Prominent, posterior ears, Short webbed neck, Ptosis , downward palpebral fissures, Epicanthic folds, High arched palate, Enlarged submandibular lymph nodes, Bitemporal narrowing. Growth - short stature. Cardiovascular- pulmonary stenosis and aortic regurgitaton .

135. Dermatological - Cafe´ au lait spots, Involuted haemangioma Neurological - Developmental delay Hematological - Clinically non-significant increase in PT/PTT

136. MISCELLANEOUS LESION

137. PAGET'S DISEASE ( Osteitis deformans ) Disease of unknown etiology . Incidence increases in older individuals, especially those over the age of 40 years. Pain in a bone may be mistaken for arthritis. Initial lesion is one of destruction by resorption ; later an excessive amount of bone is deposited in a haphazard fashion with a diminution of vascularity of the lesion. New bone is of poor quality and may result in increased bone fragility and a tendency to fracture. Pathologic fracture is one of the most common complications of Paget's disease.

138. Neurologic symptoms in Paget's disease develop gradually and consist of bone pain, severe headache, deafness, loss of sight, dizziness, facial paralysis, mental disturbance and weakness. Disease may be monostotic or polyostotic . When polyostotic , the bones most prominently affected are those of the axial skeleton which include the skull, vertebral column, extremities and maxilla. Progressive enlargement of the skull, bowing deformity of long bones and dorsal kyphosis (spinal curvature). The patient develops a waddling gait.

139. Jaws are involved in only 20% of cases; the maxilla is more frequently affected than the mandible (3:1 ratio). In some instances, both jaws are involved. Ultimately the alveolar ridge widens, with a relative flattening of the palatal vault. Enlargement of the maxilla and/or the mandible results in migration, spacing of the teeth and malocclusion. Dentures may have to be remade periodically to accommodate the increase in jaw size.

140. An important diagnostic feature of Paget's disease is that the serum alkaline phosphatase level is increased to extreme limits although serum calcium and phosphate levels are normal. The disease often proceeds with exacerbations and remissions. During remissions the value of alkaline phosphatase is usually normal.

141. HISTOPATHOLOGY Varies remarkably, depending upon the stage of the disease encountered. Initial osteolytic phase- disordered areas of resorption by an increased no of large osteoclasts . Osteoblastic phase- haphazard laying of new bone matrix and formation of woven bone without regards to the pattern of stress.

142. HISTOPATHOLOGY Repeated episodes of bone removal and formation results in the appearance of many small irregularly shaped bone fragments that appear to be joined in a Jigsaw or mosaic pattern, with deeply staining hematoxyphilic reversal lines. Histologic hallmark of Pagets disease.

143. As the disease progresses, the osteoblastic phase predominates and excessive abnormal bone formation occurs. Pagetic bone is coarse and fibrous. Marrow spaces are filled with loose highly vascularized connective tissue. Normal trabecular pattern is distorted with a mosaic pattern of irregular cement lines joining areas of lamellar bone. No tendency to form Haversian systems and the bones are very hard and dense. Eventually burned out phase predominates and new bone is disordered, poorly mineralized and lacks structural integrity. Proliferation of bone and hypercementosis sometimes results in obliteration of the periodontal ligament.

144. On a radiograph, in the early stages, the density of bone is decreased. As the disease progresses, osteoblastic activity is more than osteoclastic activity; so that apposition exceeds resorption of bone. The osteoblastic areas appear as patchy radiopacities and give the characteristic "cotton-wool" appearance similar to that of florid osseous dysplasia (chronic diffuse sclerosing osteomyelitis ).

145. The lamina dura around the teeth in the involved regions may be absent. The teeth may be hypercementosed only after the bony changes in the jaw are manifested. The most serious complication of Paget's disease is osteogenic sarcoma and occurs in 10% of the patients. On extraction of teeth in an affected part of bone, the wound healing is disturbed and may result in suppurative osteomyelitis . There is no specific treatment for Paget's disease.

146. CHERUBISM Also known as Hereditary fibrous dysplasia of the jaws, Familial intraosseous swellings of the jaws, Familial multilocular cystic disease of the jaws. Hereditary condition that produces firm, painless swellings that occur bilaterally in the jaws, especially over the mandibular angles. Autosomal dominant disease is usually detected between the ages of 2 and 7 years.

147. Mandible is more frequently affected and produces full, round lower face similar to those of cherubs portrayed in Renaissance religious paintings. Often the eyes are upturned to reveal the white sclera beneath. Where the maxilla is involved, the skin of the cheeks appears to be stretched. Photograph of a 7 year old boy with cherubism showing bilateral swelling at the mandibular angles.

148. On a radiograph of the mandible, the expansion of the buccal and lingual cortical plates is seen on occlusal and postero -anterior views. The mandibular body and rami are frequently involved. Enlargement of the maxilla is at the expense of the maxillary sinuses. The lesion consists of multiple cyst-like radiolucencies which are located bilaterally in the jaws.

149. These bilateral multilocular radiolucencies are a characteristic feature of cherubism . Teeth may be unerupted and displaced and some of them appear to be floating in the cyst-like spaces. The lesions are typically multilocular giving a characteristic ‘‘soap bubble’’ appearance , and ‘free floating teeth’.

150. HISTOPATHOLOGY The giant cells and areas of haemorrhage are similar to those seen in giant cell granuloma . In cherubism the stroma tends to be composed of fibrous connective tissue with fibroblasts arranged in sheets with a slight storiform or fascicular pattern.

151. In some areas osteoclasts are not conspicuous and blood vessels are prominent , and in some cases may be surrounded by a cuff of hyalinized collagen.

152. This benign, self-limited disorder tends to regress after puberty , thus eliminating the need for surgical intervention. Treatment, if necessary, consists of recontouring the bone for cosmetic reasons after the lesions have stabilized in size.

153. FIBROUS DYSPLASIA A benign fibro-osseous lesion characterized by replacement of bone with abnormal fibrous connective tissue interspersed with varying amounts of calcification. The cause is unknown. One theory is it may be due to abnormal mesenchymal cell function. Types of Fibrous Dysplasia - Monostotic fibrous dysplasia - Polyostotic fibrous dysplasia

154. Monostotic Fibrous Dysplasia Characterized by involvement of a single bone The maxilla is more frequently involved than the mandible. Most commonly diagnosed in children and young adults with no sex predilection. Clinical examination reveals a painless swelling or bulging of the buccal plate.

155. Polyostotic Fibrous Dysplasia Characterized by involvement of more than one bone. Typically occurs in children with a female predilection When long bones are involved, they may exhibit bowing and an associated dull aching pain. Patients may have skin lesions appearing as light-brown macules called café au lait spots . Association of fibrous dysplasia and intramuscular myxoma is a rare disease known as Mazabrauds syndrome . Association remains unclear but greater risk of sarcomatous transformation in FD with Mazabrauds syndrome has been reported.

156. Polyostotic Fibrous Dysplasia There are several types Craniofacial fibrous dysplasia Involves the maxilla with extension into the sinuses and adjacent zygoma , sphenoid, and occipital bones. Jaffe type Involves multiple bones along with café au lait macules on the skin Albright syndrome Characterized by endocrine abnormalities , precocious puberty in females, stunting or deformity of skeletal growth in both sexes as a result of premature closing of the epiphyseal plates, café au lait spots.

157. Café au lait spots Pigmented macules or café-au- lait spots are related to increased amounts of melanin pigmentation in the basal layers of the epidermis. Arranged in a linear or segmental pattern near the midline of the body. Usually over the lower lumbar spine, sacrum, buttock, upper back, neck and shoulders. May occur on the lips and oral mucosa. May occur at birth, and occasionally precede the development of skeletal and endocrinal abnormalities.

158. Clinical and radiographic features A painless enlargement of affected bone or bones Typically, a painless, progressive, unilateral enlargement of the mandible or maxilla. The classic radiographic appearance is a diffuse radiopacity looking like “ground glass .” Radiographic changes blend into the surrounding normal bone.

159. HISTOPATHOLOGY Classic appearance of dense fibrous stroma of low to moderate cellularity surrounding irregularly shaped bony trabeculae . This pattern has been described as resembling “Chinese characters.” No osteoblastic rimming of trabeculae is seen. Treatment: Surgical recontouring of bone for cosmetic reasons

160. CONCLUSIONS Multinucleated giant cells are commonly encountered in various lesions of oral cavity. They may be characteristic for the lesion or exist just as a reactive process , related to the elimination of microbes or foreign materials. Nonetheless , they provide a vital clue to the diagnosis . Although, various theories have been put forward to explain the genesis of the multinucleated giant cells, the exact mechanism still remains enigmatic and interesting. So a definite criterion to identify individual giant cells in any giant cell lesions however is required to assist the clinician and researchers for proper diagnosis and management .

161. REFERENCES Shafer, Hine, Levy. Shafer’sTextbook of Oral pathology, 6 th Edition; Elsevier: 2009. Regezzi JA, Sciubba JJ, Jordan RC. Oral Pathology Clinical Pathologic correlations, 5th Edition; Saunders. Neville, Damm , Allen, Bouquot . Oral and Maxillofacial Pathology, 3rd Edition; Saunders: 2009. Varghese I, Prakash A. Giant cell lesion of oral cavity. OMPJ 2011;2:976-1225. Chattopadhyay A. Giant cells and giant cell lesions of the oral cavity. Journal of Indian Dental Association. 1995;66 (11):326-327. J S Lee, M Tartaglia , B D Gelb, K Fridrich , S Sachs, C A Stratakis , M Muenke , P G Robey,M T Collins, A Slavotinek Phenotypic and genotypic characterisation of Noonan-like/ multiple giant cell lesion syndrome. J Med Genet 2005;42:e11

162. REFERENCES MK Gupta , SG Naidu, VJ Maheshwari Giant Cell Lesion of the Jaw: A Case Report in a Child People’s Journal of Scientific Research Vol. 4(1), Jan. 2011, 63-67. Adrienne M. Flanagan, Paul M. Speight. Giant Cell Lesions of the Craniofacial Bones. Head and Neck Pathol (2014) 8:445–453. William G. Brodbeck and James M. Anderson. GIANT CELL FORMATION AND FUNCTION . Curr Opin Hematol . 2009 January ; 16(1): 53–57. Gabriela de Morais Gouvêa Lima, Janete Dias Almeida, Luiz Antonio Guimarães Cabral. Cherubism : Clinicoradiographic Features and Treatment. J Oral Maxillofac Res 2010 (Apr-Jun);1(2):e2 D. P. Von Arx and A. Husain. Oral tuberculosis. BRITISH DENTAL JOURNAL VOLUME 190 NO. 8 APRIL 28 2001 420-422.

163. Thank you