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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 30  |  Issue : 3  |  Page : 297-301

Classifying giant cell lesions: A review


Department of Oral Medicine and Radiology, D.J College of Dental Sciences and Research, Modinagar, Uttar Pradesh, India

Date of Submission16-May-2018
Date of Acceptance02-Jul-2018
Date of Web Publication18-Oct-2018

Correspondence Address:
Dr. Sambuddha Chakrabarty
D.J College of Dental Sciences and Research, Modinagar, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jiaomr.jiaomr_81_18

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   Abstract 


Multinucleated giant cells are often encountered in oral lesions. Traditional classifications have placed a little importance on the type or histogenesis of multinucleated giant cells in grouping these lesions. The classification of giant cell lesions of the maxillofacial skeleton is the one that remains controversial. Classifying giant cell lesions of the jaw as granulomatous based solely on its location seems inappropriate. Giant cells lesions were classified based on the etiopathogenesis, origin, etiology, type, radiographic appearance and pathology of giant cells present. The rationale for this classification was based on the recent research findings regarding the histogenesis of giant cells. Multinucleated giant cells are morphologically characterized by the presence of multiple nuclei dispersed in cytoplasm. Multinucleated cells are commonly encountered in oral and maxillofacial lesions. An epidemiological study by Mohajerani et al. has reported that 6.36% of the oral biopsies received in their laboratory were multinucleated giant cells containing lesions. Classifying oral lesions with giant cells has always been problematic. However, accurate identification and categorization of these lesions based on nature, distribution and origin of giant cells is necessary. Correlation of histopathological features in relation to giant cells is required. The aim of this article is to review both the earlier and recent classification of giant cell lesions in order which would enable pathologists and oral physicians to ascertain the behavior and diagnosis of such lesions.

Keywords: Giant cells, histogenesis, multinucleated, oral cavity, oral biopsies


How to cite this article:
Ranjan V, Chakrabarty S, Arora P, Rastogi T. Classifying giant cell lesions: A review. J Indian Acad Oral Med Radiol 2018;30:297-301

How to cite this URL:
Ranjan V, Chakrabarty S, Arora P, Rastogi T. Classifying giant cell lesions: A review. J Indian Acad Oral Med Radiol [serial online] 2018 [cited 2019 Dec 14];30:297-301. Available from: http://www.jiaomr.in/text.asp?2018/30/3/297/243667




   Introduction Top


Multinucleated giant cells are morphologically characterized by the presence of multiple nuclei dispersed in cytoplasm. Multinucleated cells are commonly encountered in oral and maxillofacial lesions. An epidemiological study by Mohajerani et al. has reported that 6.36% of the oral biopsies received in their laboratory were multinucleated giant cells containing lesions. Classifying oral lesions with giant cells has always been problematic.[1] Traditionally, giant cell lesions of oral cavity has been classified with little importance based on the type or histogenesis of multinucleated giant cells present in the lesions.[2] Giant cells are of many different types and occur under different conditions and assume different configurations. They are formed by fusion of macrophages and are common in granulomatous inflammation, especially in infections such as tuberculosis, syphilis and those produced by fungi. Reaction to exogenous substances such as keratin, fat and cholesterol crystals are also commonly the cause of the development of giant cells. The origin of giant cells has not been established. One theory suggested that giant cell may originate from the proliferating giant cells associated with the resorption of deciduous tooth roots. Another theory suggested their origin from endothelial cells of capillaries or from the mitotic and amitotic division of monocyte nuclei in the absence of cellular division. The most accepted theory is that giant cells arise from the fusion of non-replicating monocytes. The size of giant cells varies greatly, but is usually between 40 μm and 120 μm. Giant cells have phagocytic and pinocytic activity. They secrete interferon, pyrogen, complement components, lysozyme, acid hydrolases, neutral proteases, cytotoxic factors and so on. They may process antigens too. In giant cells all centrioles are found in one area of the cells, cytofilaments radiating away from the centriole towards their respective nuclei. These collection of filaments may occasionally be accentuated and become visible at light microscopic level as so called “asteroid bodies.”[3] The phenotype of multinucleated giant cells varies depending on the local environment and the chemical and physical (size) nature of the agent to which the macrophage-derived giant cells (MGCs) and their monocyte/macrophage precursors are responding.[4]

Various classification described in the literature are as follows [Table 1]:
Table 1: Classification of giant cell lesions based on the following

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   Formation of Giant Cells Top


Mononuclear phagocytes fuse only in specific microenvironments, that is, bone surface for osteoclasts and chronic inflammatory sites for giant cells. It is clear that in order to fuse these cells must reach a “critical density” (cell ± cell contact) and are therefore dependent on the activity of local factors, either growth factors such as macrophage colony stimulating factor (M-CSF) or chemotactic factors. The cytokine interferon gamma is a strong inducer of osteoclast-like cell differentiation in vivo suggesting that it may regulate the production of local factors. Most recently, osteoprotegerin and osteoprotegerin ligand have been shown to inhibit and stimulate, respectively, osteoclast-like cell differentiation in spleen cell and bone marrow cultures.[16]

MGC formation is mediated by interacting cell surface proteins present on the fusing macrophages.[17] Dendritic cell-specific transmembrane protein (DC-STAMP) has been identified as being required for the fusion of both osteoclasts and foreign body giant cells (FBGCs). Osteoclasts derived from the DC-STAMP knock-out mice were mononuclear, exhibited bone-resorbing activity, expressed osteoclast markers and cytoskeletal structure, but did not demonstrate cell fusion. Retroviral introduction of DC-STAMP in osteoclast precursors re-established osteoclast multinucleation. Histological evaluation of Ivalon® (crosslinked polyvinyl alcohol) in DC-STAMP knock-out mice demonstrated abrogation of multinucleated FBGC formation. In vitro experiments using interleukin (IL)-3 and IL-4 treatment of macrophages from DC-STAMP knock-out mice demonstrated no FBGC formation. These studies clearly identify a common molecule necessary for the multinucleation, that is, cell fusion, of both osteoclasts and FBGCs. Vignery (2005) discussed the significance of identifying the ligand for DC-STAMP and determining if it is a surface protein expressed by macrophages or a soluble protein released by macrophages in a constitutive or regulated manner. Identification of a ligand for DC-STAMP has significant importance in developing therapeutic modalities related to osteoclasts, FBGCs and macrophage interactions with tumor cells.[3]

Osteoclast precursor cells respond to the osteoclast differentiation factor Receptor Activator of Nuclear Factor Kappa β Ligand (RANKL), which induces the expression of DC-STAMP. The DC-STAMP – expressing osteoclast becomes the master fusing cell, which can fuse with a DC-STAMP – negative follower cell. The ligand for DC-STAMP may be membrane bound or soluble; a soluble ligand might be released by either of the fusion partners. DC-STAMP ligation may trigger fusion of the two cells directly or may trigger the expression of as yet unknown membrane-bound molecules ('X') that mediate fusion. A similar scenario may occur during the formation of giant cells in which macrophages respond to IL-4 by inducing the expression of DC-STAMP, which then facilitates fusion. MGC formation within a granuloma is induced by the local microenvironment comprised of cytokines and signals derived from bacteria, parasites or other foreign materials. Macrophages have to aggregate a process which might be regulated by chemotactic factors.

Osteoclast formation is driven mainly by two cytokines: RANKL and M-CSF. In addition a wide variety of factors like systemic hormones and growth factors influence the formation and function of osteoclasts. The osteoclastic giant cells show positivity to cathepsin K, alkaline phosphatase, RANKL, osteoprotegerin and cluster of differentiation 68 (CD68). The calcitonin receptor is found to be a more specific marker of differentiation for osteoclasts from other giant cells derived from monocyte/macrophage cell lineage.[18]


   Classification of Giant Cell Lesions Top


1. Based on etiopathogenesis

Chattopadhyay, 1995[5]

  1. Where giant cells are present in the concerned background and are pathognomic:


    1. Hodgkin's syndrome
    2. Peripheral giant cell granuloma
    3. Giant cell fibroma


  2. Where giant cells are characteristic, but not pathognomic:-


    1. Tuberculosis
    2. Herpes simplex virus infection
    3. Measles
    4. Xanthoma


  3. Diseases associated with the presence of giant cells:


    1. Orofacial granulomatosis
    2. Fungal infection foreign body reactions
    3. Neoplasms
    4. Syphilis
    5. Leprosy
    6. Fibrous dysplasia
    7. Cherubism
    8. Paget's disease of the bone
    9. Aneurysmal bone cyst
    10. Ossifying fibroma
    11. Wegener's granulamatosis
    12. Actinomycoses
    13. Chronic diffuse sclerosing osteomyelitis
    14. Odontogenic giant cell fibromatoses
    15. Heerfordt's syndrome.


II. Chatterjee, et al. (2015)[4]

According to Paul Auclair et al. entities in which giant cells are the predominant histologic finding and form the basis of their recognition:

  • Central giant cell granuloma
  • Giant cell tumor of bone
  • Aneurismal bone cyst
  • Cherubism
  • Brown tumor of hyperparathyroidism.


Lesions containing giant cells

Infectious diseases:

Bacterial:

  • Tuberculosis
  • Leprosy
  • Syphilis
  • Actinomycosis
  • Cat scratch disease


Viral:

  • Herpes
  • Measles


Mycotic:

  • Histoplasmosis
  • Blastomycosis.


III. Varghese and Prakash, 2011[6]

  1. Microbial lesions: Tuberculosis, leprosy, actinomycosis, sarcoidosis
  2. Tumor and tumor-like lesions: Central giant cell granuloma, peripheral giant cell granuloma, giant cell fibroma, giant cell tumor, osteosarcoma, rhabdomyosarcoma, Hodgkin'slymphoma
  3. Cystic lesions: Traumatic bone cyst, aneurysmal bone cyst
  4. Metabolic lesions: Hyperparathyroidism
  5. Osteodystrophic lesions: Noonan-like multiple giant cell lesion syndrome
  6. Miscellaneous lesions: Cherubism, Paget's disease, fibrous dysplasia.


2. Based on origin (Gupta, et al., 2014)[7]

  1. Macrophage derived:


    1. Langhans giant cells
    2. FBGCs
    3. Touton giant cells: Xanthelasmatic giant cells


  2. Epidermal cell derived:


    1. Tzanck giant cells
    2. Multinucleated epidermal giant cells


  3. Melanocyte derived:


    1. Starburst giant cells
    2. Giant cells in melanocytic nevus


    1. Balloon cells
    2. Giant nevus cells


  4. Other giant cells:


    1. Floret-like multinucleated giant cells.


3. Based on origin and etiology (Chattopadhyay, 1995)[5]

  1. Damaged striated muscle fiber:


    1. Regenerating sarcolemmal cells in damaged voluntary muscle
    2. Aschoff giant cells in heart muscle (fused myocardial macrophages)


  2. Fused fibroblasts:


  3. Giant cell fibroma

  4. Osteoclast:


  5. Paget's disease

  6. Tumor giant cells:


    1. Reed–Sternberg cells in Hodgkins lymphoma
    2. Giant cells in central giant cell granuloma, poorly differentiated astrocytoma
    3. Giant cells in other tumors, for example, malignant fibrous histiocytoma


  7. Viral infections:


    1. Epithelial giant cells as in HSV infection
    2. Connective tissue cells as in measles (Warthin–Finkeldey cells)


  8. Fused macrophages:


    1. Due to reaction to foreign bodies (exogenous or endogenous materials) for example, FBGC with scattered nuclei
    2. Due to reaction to organisms as in tuberculosis (langhans giant cell) and fungal infections
    3. Touton giant cells of xanthoma.


4. Based on functional characteristics (Sankari, et al., 2014)[8]

  1. Physiologic giant cells:


    1. Osteoclast
    2. Odontoclast
    3. Megakaryocytes
    4. Syncytiotrophoblast
    5. Skeletal muscle fibers


  2. Pathologic giant cells:


    1. FBGC
    2. Langhans giant cells found in TB
    3. Touton giant cells, seen in histocytosis Y
    4. Aschoff giant cell, seen in rheumatic carditis
    5. Dorothy reed giant cell, seen in Hodgkin's disease
    6. Giant cells found in malignancy
    7. Giant cells found in viral infection


  3. Fused fibroblasts:


  4. Giant cell fibroma

  5. Osteoclast:


  6. Paget's disease

  7. Tumor giant cells:


    1. Reed–Sternberg cells in Hodgkins lymphoma
    2. Giant cells in central giant cell granuloma, poorly differentiated astrocytoma
    3. Giant cells in other tumors, for example, malignant fibrous histiocytoma


  8. Viral infections:


    1. Epithelial giant cells as in HSV infection
    2. Connective tissue cells as in measles (Warthin–Finkeldey cells)


  9. Fused macrophages:


    1. Due to reaction to foreign bodies (exogenous or endogenous materials) for example, FBGC with scattered nuclei
    2. Due to reaction to organisms as in tuberculosis (langhans giant cell) and fungal infections
    3. Touton giant cells of xanthoma.


5. Based on the type of giant cells present (Mathew, et al. 2016)[9]

  1. Epithelial-derived viral-induced multinucleated giant cell containing lesions


    1. Tzank giant cells – herpes simplex
    2. Tzank giant cells – herpes zoster


  2. Monocyte/MGCs containing lesions


    1. Inflammatory granuloma-associated giant cells
    2. Langhans giant cell containing pathologies
    3. Infections – tuberculosis, leprosy, late syphilis, deep fungal infections
    4. Unknown antigenic stimuli – sarcoidosis and orofacial granulomatosis
    5. FBGC containing lesions
    6. Foreign body granuloma
    7. Osteoclastic giant cell containing lesions
    8. Lesions with osteoclastic giant cells being the primary pathologic cells – Paget's disease


  3. Lesions with reactive osteoclastic giant cells formed secondarily by the activation of lesional stromal cells


    1. Peripheral and central giant cell granulomas, cherubism and aneurysmal bone cyst
    2. Fibrous dysplasia, brown tumor of hyperparathyroidism


    • Touton giant cells


      • Xanthoma, xanthogranuloma, fibroushistiocytoma.


    • Tumor giant cells


      • Tumors where giant cells are pathognomonic
      • Giant cell fibroma, Hodgkin's lymphoma
      • Other anaplastic malignancies.


6. Classification based on arrangement, composition of organelles and function

  1. Haythorn, et al., 1929[10]:


    1. Langhans' giant cells
    2. FBGC
    3. Osteoclasts
    4. Megakaryocytes
    5. Muscle giant cells
    6. Giant cells of nervous tissue
    7. True tumor giant cells


  2. Quinn MT and Schepetkin IA 2009[11]:


    1. FBGCs
    2. Langhans giant cells
    3. Touton giant cells
    4. Osteoclast-like cells
    5. Osteoclasts.


7. Based on radiographic appearance (Enneking and Campanacci, 2016)[12]

Grade – I tumor has a well-marginated border of a thin rim of mature bone, and the cortex is intact or slightly thinned but not deformed.

Grade – II tumor has relatively well-defined margins but no radiopaque rim; the combined cortex and rim of reactive bone is rather thin and moderately expanded but still present. Grade-II lesions with a fracture are graded separately.

Grade – III designates a tumor with fuzzy borders, suggesting a rapid and possibly permeative growth; the tumor bulges into the soft tissues, but the soft-tissue mass does not follow the contour of the bone and is not limited by an apparent shell of reactive bone.

8. Based on pathology involved

I. Lucas (1976)[13]

  1. Intrabony lesions


    1. Giant cell tumor of bone
    2. Giant cell granuloma
    3. Focal giant cell lesion or “Brown tumor of hyperparathyroidism”


  2. Soft tissue lesions


    1. Peripheral giant cell granuloma
    2. Giant cell fibroma.


II. Cotran, Kumar and Robbins 1994[14]

  1. Giant cells in inflammation:


    1. Foreign body giant cells
    2. Langhan's giant cells
    3. Touton giant cells
    4. Aschoff giant cells


  2. Giant cells in tumor:


    1. Tumor giant cells
    2. Reed–Sternberg cells
    3. Giant cell tumor of bone.
s

III. Rosenberg, et al., 2001[15]

  1. Giant cell lesions of bone


    1. Reactive:


      • Brown tumor
      • Hemophiliac pseudo tumor
      • Intraosseous haemorrhage


    2. Benign:


      • Giant cell granuloma


        • Non-ossifying fibroma
        • Giant cell tumor
        • Aneurysmal bone cyst
        • Chondroblastoma
        • Chondromyxoid fibroma
        • Langerhans cell histiocytosis
        • Pigmented villonodular synovitis


    3. Malignant:


      • Osteosarcoma
      • Clear cell chondrosarcoma
      • Metastatic carcinoma


  2. Mucosal lesions with giant cells


    1. Peripheral giant cell granuloma
    2. Giant cell fibroma
    3. Oral granulomatosis


      • Specific: Fungal, bacterial, viral infection
      • Non-specific: Sarcoidosis, Wegener's granulomatosis


    Xanthogranuloma

    1. Hodgkins lymphoma
    2. Temporal arteritis.



   Conclusion Top


Giant cells are large cells that often contain more than one nucleus and appear as a merger of several distinct cells. They are derived from multiple lineages, but are usually of monocyte or macrophage origin. These cells can be seen either in physiologic or in pathologic conditions. Osteoclasts in the bones, trophoblasts in placenta, megakaryocytes in the bone marrow are the physiologically present multinucleated giant cells. However, in common pathological states such as chronic inflammation when macrophages fail to deal with particles that has to be removed; they fuse together and form multinucleated giant cells. Thus, their role in elimination of foreign substances, damaged tissue and pathogens is essential for host survival. Multinucleated giant cells can be classified into several morphological variants depending on the arrangement and composition of their organelles, as well as their functional characteristics. These variants include FBGC, Langhans giant cells, Touton giant cells, osteoclasts and osteoclast-like cells. Since most of the giant cell variants are derived from monocyte/macrophage precursors, their morphological and functional heterogeneity seems to be determined by the specific tissue location and local factors present in the milieu where cell fusion occurs. The giant cell lesions of oral cavity have been classified on the basis of etio-pathogenesis, the presence of which at times being pathognomic like in Hodgkin's disease, peripheral giant cell granuloma and giant cell fibroma. Also, there are conditions like tuberculosis, herpes simplex virus infection, measeles and xanthomas where giant cells are characteristic but not pathognomic. Diseases like orofacial granulomatosis, fungal infections, fibrous dysplasia cherubism, Paget's disease of bone are also associated with the presence of giant cells.

Clinically, Chattopadhyay, et al. (1995) classifies giant cell lesion according to origin is the most accepted and followed classification. Pathologically, Rosenberg, et al. (2001) is the most accepted and followed classification.

Multinucleated giant cells are commonly encountered in various lesions of oral cavity. These giant cell containing lesions have overlapping histopathological features which need to be differentiated from each other. Accurate identification and categorization of these lesions based on nature, distribution and origin of giant cells is necessary. Hence, characterization of giant cells in any giant cell lesion is essential to assist the clinician and researchers for precise diagnosis and management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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