Giant cells in dermatology.

What was known?

Giant cells are multinucleated, inflammatory and large size cells. These are basically formed by fusion of other cells.

Introduction

Giant cells are formed by fusion of various cells such as macrophage, epithelioid cells, monocytes, etc., These are multi-nucleated,[1] large in size, and most of the times present at the site of chronic inflammation and other granulomatous conditions.[1] In dermatology, giant cells are pathologically important and have diagnostic value although specific functions are unknown.

General Structure

Phenotype of multi-nucleated 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.[1] The size of giant cells varies greatly, but is usually between 40 µm and 120 µm.[2] In chronic inflammation when the macrophages fail to deal with particle to be removed, they fuse together and form multi-nucleated giant cells.[3] These cells contain 15-30 nuclei which are arranged in different patterns in different type of giant cells. Other cells which can also form giant cells are keratinocytes, melanocytes, etc.

Types of Giant Cells

Following types of giant cells are commonly seen in dermatology.

Macrophage derived

Langhans’ giant cells

Foreign body giant cells (FBGCs)

Touton giant cells: Xanthelasmatic giant cells.

Epidermal cell derived

Tzanck giant cells

Multi-nucleated epidermal giant cells.

Melanocyte derived

Starburst giant cells

Giant cells in melanocytic nevus.

Balloon cells

Giant nevus cells.

Other giant cells

Floret-like multi-nucleated giant cells (FMGCs).

Macrophage Derived

Formation of giant cells: Fusion of macrophages

In tubercular granuloma, pro-inflammatory glycolipids induce the fusion of macrophages into multi-nucleated giant cells (Langhans’ cells) and this process occurs through a toll-like receptor 2-dependent, A Disintegrin and Metalloproteinase domain 9, and β1 integrin-mediated pathway.[4] In foreign body giant cell formation, the β1 and β2 integrin receptors and IL-4 are important mediators.[5] In vitro cell culture studies using human monocytes/macrophages and lymphocytes demonstrated that pro-inflammatory cytokines such as IL-β, TNF-α, IL-6, IL-8, and MIP-1β were upregulated.[6]

Langhans’ Giant Cells

It should not be confused with Langerhans cell which is a dendritic cell and works as antigen presenting cells. Langhans’ giant cells have horse shoe-shaped nuclei arrangement at one pole of cell [Figures 1 and 4b]. It contains more than 15 nuclei, whereas low virulence mycobacterium species such as M. avium and M. smegmatis have low number of nuclei per cell. These are formed by fusion of epithelioid cells. They are not phagocytic but secrete interleukins and help in inflammation.[7] These giant cells are seen in granulomatous conditions especially in tuberculosis. Interactions with cluster Differentiation 40 and its ligand (CD40L) as well as interefron gamma are essential for the formation of Langhans’ giant cells. The expression of Dendritic cell-specific transmembrane protein, a known fusion-related molecule in monocytes, is upregulated during Langhans’ giant cell formation, and knock-down of DC-STAMP expression inhibits Langhans’ giant cell formation.[8] These cells are seen in following conditions:[78]

Figure 1

Langhans’ giant cell: Nuclei arranged at one pole

Figure 4

Diagrammatic representation of macrophage-derived giant cells (a) Nuclei randomly scattered in cytoplasm (b) Nuclei arranged at one pole (c) Central ring of nuclei

Tubercular granuloma

Leprosy (TT Type mainly)

Late Syphilis

Deep fungal infection

Sarcoidosis

Leishmaniasis

Crohn's disease.

Foreign body giant cells

Foreign body giant cells (FBGCs) are larger than Langhans’ giant cells with nuclei randomly scattered throughout their cytoplasm [Figures 2 and 4a]. It results from the body's attempt to remove or wall off impregnated foreign material.[7] FBGCs are also seen in tissues where the size of foreign particulate is too large to permit macrophage phagocytosis. FBGC is formed from the fusion of macrophages and is observed as a result of the response induced by biomaterials and other foreign bodies.[9] As a result of their large size and surface characteristics, these substances elicit a prolonged series of reactions, a process known as the foreign body response (FBR). Recent studies show that macrophage fusion, giant cell formation, and the foreign body response require matrix metalloproteinase 9(MMP-9).[11]

Figure 2

Foreign body giant cell: Nuclei scattered throughout cytoplasm

FBGCs most commonly are observed in foreign body granuloma formed in response to various exogenous or endogenous materials. Exogenous particles are starch, talc, tattoo material, cactus bristles, wood splinters, suture material, retained epicardial pacing wires, bioplastique, dermalive, artecoll microimplants, injected mineral oil, injected hyaluronic acid, pencil lead, bovine collagen, etc., Endogenous are calcium deposits, urates, oxalate, keratin, and hair. These giant cells are also seen in Borderline tuberculoid type of leprosy.[910]

Touton Giant Cell

It is discovered by Karl Touton.[12] These are also called as xanthelasmatic giant cell, whose characteristic appearance is determined merely by the presence of demonstrable lipid in the cytoplasm [Figure 4c]. It is proposed that Touton cells develop when the stimulus to cell fusion is accompanied by a factor stimulating lipid uptake. This factor is missing in the development of the other two giant cells.[12] Touton giant cells have a central ring of nuclei while the peripheral cytoplasm is clear due to accumulated lipid.[7] These cells are formed by fusion of lipid containing macrophages. These cells react positively to lysozyme, alpha 1-anti-trypsin, and alpha 1-anti-chymotrypsin, indicating their histiocytic origin.[13] These cells are seen in[7]

Fat necrosis

Xanthoma

Xanthogranulomas

Dermatofibroma.

Epidermal Cell Derived

Tzanck giant cells

These are multi-nucleated giant cell with molding of the nuclei as they are crowded together [Figure 3]. There is peripheral margin of the chromatin and a ground-glass appearance of the nuclei. The cell may also have a bizarre or atypical shape.[14] Viruses cause abnormal cell division in epidermal cells, and this creates multi-nucleated giant cells. These are epidermal cells that are much larger than the normal epidermal cells.[15] It is named after Arnault Tzanck, a French dermatologist. These cells are seen in:[1415]

Figure 3

Tzanck giant cells: In herpes zoster

Herpes simplex

Varicella and herpes zoster

Cytomegalovirus.

Multi-nucleated Epidermal Giant Cells

The occurrence of multi-nucleated epidermal giant cells (MEGCs) with more than three clumping nuclei has been considered an episodic and exceptional phenomenon in inflammatory skin diseases. These are giant cells formed by epidermal cells in response to various types of inflammation.[17] These giant cells are seen in[1617]

Chronic eczema or prurigo

Lichen amyloidosis

Dermatitis herpetiformis

Erythema multiforme

Pustular psoriasis

Lichen planus

Lupus erythematosus.

Melanocyte Derived

Starburst giant cells

Starburst giant cells are multi-nucleated melanocytes with a stellate appearance due to its prominent dendritic processes. These are useful indicator for the diagnosis of lentigo maligna from photo-damaged skin. The diagnosis of lentigo maligna is also more likely as the number of nuclei in Starburst giant cells increases.[18]

Giant Cells in Melanocytic Nevus

Balloon cells

Balloon cells may be multi-nucleated and larger than ordinary nevus cells. Their nuclei are small, round, finely granular, or vacuolated often with few small melanin granules. Electron microscopic examination reveals that in balloon cells, numerous large vacuoles are formed by enlargement and coalescence of degenerating melanosomes. These cells are present in:[19]

Balloon cell nevus

Balloon cell melanoma.

Giant nevus cells

These cells are multi-nucleated and bizarre in shape.[19] The cells resembled Touton giant cells in one case. Presence of this cell is one of the minor diagnostic criteria of Spitz nevus.[20] These are also seen in melanoma but nuclei are more pleomorphic, while in Spitz nevus, nuclei are regular and similar in size.[19]

Other Giant Cells

Floret-like multi-nucleated giant cells (FMGCs)

These cells have scanty cytoplasm and peripherally arranged nuclei in the intervening stroma. These are positive with vimentin and CD-34 and negative with S-100 and CD-68. The FMGCs may be mesenchymal or fibroblastic in origin. FMGCs have been described in:[21]

Gynaecomastia

Neurofibroma in NF-1

Giant cell angiofibroma

Pleomorphic lipoma.

What is new?

Multinucleated giant cells are larger in size and contain 15-30 nucleoli. These nucleoli arranged in different pattern in different giant cells. These are formed by fusion of macrophages, melanocytes, kerationocytes etc., Most of the time these are present at the site of inflammation. Langhans’ giant cell, foreign body giant cells and touton giant cells are the main giant cells. Starburst, epidermal, Floret-like multinucleated giant cells are other examples seen in various dermatological conditions.