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Giant cell granulomas are enigmatic lesions of the oral cavity characterised by a peculiar combined proliferation of mononuclear and multinucleated giant cells in a mesenchymal stromal background. Central and peripheral giant cell granulomas may have similar pathogenesis and histology but differ in their location and biological behaviour. It is important to differentiate them from other giant cell lesions that can occur in the oral cavity, such as giant cell tumour of the bone, aneurysmal bone cyst, brown tumour of hyperparathyroidism, and giant cell lesions of Ramon syndrome, Noonan syndrome, neurofibromatosis and Jaffe-Campanacci syndrome. A recent insight into their molecular genetics and pathogenesis, with identification of KRAS , FGFR1 and TRPV4 mutations, allows for better diagnostic differentiation and opens the door to the use of pathway inhibitors in the treatment of recurrent or dysmorphic lesions. In this review, we provide an updated summary of the clinical and pathological features of oral cavity giant cell granulomas that help with their precise diagnosis and management., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Foreign body reaction is a tissue response against implanted materials. We described for the first time the eosinophilic peritonitis and foreign body giant cell reaction to dialysis catheter in a nonatopic child on continuous ambulatory peritoneal dialysis. We found tenderness, redness, and swelling without purulent discharge around the peritoneal catheter; increased eosinophil count in cloudy dialysis fluid; and blood and hyperechoic granulomatous formation appearance surrounding the peritoneal catheter on ultrasonography and foreign body giant cell reaction to dialysis catheter in pathologic examination of granulomatous lesionin in our patient. The peritoneal dialysis catheter was removed due to resistance to antibiotic and antihistamine treatments for suspected peritonitis and tunnel infection. Foreign body reaction and eosinophilic peritonitis with eosinophilic cloudy dialysis effluent can exist simultaneously. Foreign body reaction should be considered in the differential diagnosis of exit site and/or tunnel infection. Ultrasonography helps distinguish between foreign body reaction and exit-site or tunnel infection.

Background: The unpredictable behavior of giant cell lesions (GCLs) of the jaws parallels its controversial histogenesis. This study evaluated a possible association between the immunohistochemical expression of NF-ĸB, the inhibitory subunits IĸBα/IĸBβ, and clinicopathological variables with the behavior of central and peripheral GCLs of the jaws., Materials and Methods: Paraffin-embedded samples of GCLs of the jaws (n = 68) were prepared for histological/immunohistochemical assessment. Demographic and clinicopathological parameters were assessed to determine the behavior of the lesions. A staining-intensity-distribution (SID) score was used to assess the immunomarkers reactivity. The association between significant candidate immunohistochemical predictor variables regarding clinical behavior was analyzed individually and adjusted for confounding using a binary logistic regression model., Results: While univariate analysis revealed a positive association of NF-ĸB SID score, NF-ĸB nuclear expression, IĸBα SID score, and NF-ĸB to inhibitors average ratio with the aggressive status of GCLs, after bivariate logistic regression analysis, only NF-ĸB nuclear expression, IĸBα SID score, and NF-ĸB to inhibitors average ratio remained as robust predictors of aggressiveness. Confounding and interaction effects regarding clinicopathological candidate predictor variables were also noted., Conclusion: It looks that clinical behavior of GCLs of the jaws may be strong/independently linked to the increased nuclear expression of NF-ĸB, higher NF-ĸB to inhibitors average ratio, and decreased IĸBα SID score. Notwithstanding, there are simultaneously synergistic and opposing interactive effects with respect to age stratum, growth rate, multinucleated giant cells count, and mononuclear stromal cells density in the susceptible host that may increase the tissue destruction observed in aggressive GCLs., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Multinucleated giant cells (MNCs) form an integral part of numerous bone and soft tissue tumors, tumor-like lesions and are often associated with granulomas of immunological and nonimmunological origin. The presence of various types of giant cells depends on the lesions in which they are present which are difficult to be diagnosed under routine histological techniques. Immunohistochemistry can be used for a better diagnosis and understanding of the origin of various giant cells using various markers of immune response like human leukocyte antigen-DR (HLA-DR) and those expressed on monocytes and macrophages like CD 68 and leukocyte common antigen (LCA)., Materials and Methods: The study group consisted of 10 cases of giant cell tumor (GCT) of long bones, tuberculous granuloma, and giant cell granuloma to evaluate and analyze the expression pattern of LCA, CD 68, and HLA-DR in various giant cell lesions., Results: Strong expression of CD 68 was observed in 80% of the lesions, strong and moderate expression of CD 45 observed in 70% of the lesions among and within the groups. In contrast, HLA-DR demonstrated negative expression in 80% of cases except for tuberculous granuloma where all the 10 cases showed moderate to strong immunoreactivity., Conclusion: CD 68 and CD 45 expression was found in central giant cell granuloma, peripheral giant cell granuloma and GCT, suggesting the origin from mononuclear phagocyte system and considering their clinical behavior of osteoclast type. High expressivity of HLA-DR in tuberculous granulomas which is an essential factor for presentation of the microbial antigen to CD 4 helper cells thus reassuring the fact that they are up-regulated in response to infection.

Objectives: the expression of the osteoclastogenic cytokines TNF-α, IL-6 and IL-1β were immunohistochemically evaluated in peripheral (PGCG) and central (CGCG) giant cell granulomas of the jaws in order to determine differences between these two lesions and between the two distinct tumor cell populations (multinucleated giant cells, MGCs and stromal spindle-shaped cells)., Study Design: Paraffin-embedded tissue sections from 40 PGCG and 40 CGCG were immunohistochemically stained using antibodies against TNF-α, IL-6 and IL-1β. The percentage of positively stained cells and the staining intensity were assessed to provide a combined immunoreactivity score value., Results: TNF-α, IL-6 and IL-1β were expressed in all lesions. The CGCG compared to the PGCG showed significantly increased expression of TNF-α and IL-6 and decreased expression of IL-1β by the spindle-shaped cells and increased expression of IL-1β by the MGCs. The MGCs demonstrated in comparison to the stromal spindle-shaped cells significantly increased expression of all three cytokines in both PGCG and CGCG., Conclusions: The proinflammatory cytokines TNF-α, IL-6 and IL-1β seem to be involved in the growth process of PGCG and CGCG of the jaws. A possible alteration in the synthesis or/and activity of these cytokines by the stromal spindle cells in the CGCGs may enhance osteolysis through the stimulation of osteoclast progenitor cells, given the fact that the intraosseous lesions cause bone resorption.

Granulomatosis lesions occurring after diagnosis of primary or secondary immunodeficiency are not accidental and have been described in a small number of patients suffering from various diseases: common variable immunodeficiency (CVID), malignancy (lymphoma and solid tumors), and acquired immunodeficiency syndrome (AIDS). Two types of granulomatosis can appear: true sarcoidosis and sarcoid-like reaction. We report four patients, two with CVID and two with malignancy, in whom clinical granulomatosis appeared a few months to a few years after diagnosis of immunodeficiency. They developed noncaseating granulomas of the lung, spleen and liver associated with conjunctival granulomas and bilateral panuveitis. The granulomatous disorder was diagnosed after immunodeficiency on histopathological studies revealing noncaseating granulomas. Causation agents such as infectious organisms and environmental compounds were excluded. The relationship between sarcoid-like reaction, true sarcoidosis and immunodeficiency is discussed. The underlying pathophysiology responsible for the association between granuloma formation and immunodeficiency in the same patient remains obscure. It may be quite difficult to distinguish true sarcoidosis and sarcoid-like reaction. It is possible that these two entities are the clinical extremes of a common pathological process.

Background: Central giant cell lesion (CGCL) is a reactive lesion of the jaws with an associated inflammatory infiltrate. Since cell circulation allows for intense communication between different compartments in the body, we investigated whether the CGCL would lead to phenotypic and/or functional changes in circulating leukocytes., Methods: We obtained lymphocytes and monocytes from CGCL patients and control subjects, to evaluate cytokine and adhesion molecule expression using flow cytometry., Results: Our results revealed that CD4(+) T cells and CD14(+) monocytes from CGCL express elevated levels of CD11a and CD11b, respectively, when compared with controls. The frequencies of CD4(+) T cells expressing interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha and the frequencies of CD4(+) and CD14(+) cells expressing interleukin (IL)-10 were increased in CGCL group, when compared with controls., Conclusions: Our data indicate that, although CGCL is a localized lesion, the patients show systemic functional alterations in circulating leukocytes, suggesting their role in the inflammatory pathogenesis of CGCL.

Annular elastolytic giant cell granuloma (AEGCG) is characterized by non-palisading granuloma and elastophagocytic giant cells. Granulomas consist of structured masses of macrophages, dendritic cells, and T lymphocytes which play an essential role in granuloma formation. Two lineage systems of dendritic cells and macrophages originated from peripheral blood monocytes have been established in vitro. To know how elastin fragments are involved in the granuloma formation in AEGCG, we tested in vitro whether elastin fragments potentially induce monocyte-derived macrophages or dendritic cells to form granuloma and multinucleated giant cells. Immunohistochemical studies of the lesional skins of AEGCG (n = 5) revealed that the 67-kDa elastin receptor was specifically expressed in the epithelioid or multinucleated giant cells. Proliferation of factor XIIIa(+) cells and CD68(+) cells was also seen in the lesional skins of AEGCG. Factor XIIIa(+) dendritic cells or CD68(+) macrophages were established by the treatment of granulocyte/macrophage-colony stimulating factor (GM-CSF)/interleukin-4 or M-CSF, respectively. Further treatments of these dendritic cells or macrophages with elastin peptide resulted in the formation of granuloma or multinucleated giant cells which were immunoreactive with anti-67-kDa elastin receptor antibody. These findings suggest that elastic tissue induces factor XIIIa(+) cells and CD68(+) macrophages to form granuloma or multinucleated giant cells and plays an essential role in the formation of granuloma in AEGCG.

Immature dendritic cells (DCs) are scattered throughout peripheral tissues and act as sentinels that sample the antigenic environment. After activation, they modify their chemokine receptor profile and migrate toward lymphoid tissues. On arrival, they have matured into chemokine-producing DCs that express co-stimulatory molecules and can prime naive T cells. Normal temporal arteries contain immature DCs that are located at the media-adventitia border. In temporal arteries affected by giant cell arteritis, DCs are highly enriched and activated and have matured into fully differentiated cells producing the chemokines, CCL18, CCL19, and CCL21. In keeping with their advanced maturation, DCs in the granulomatous lesions possess the chemokine receptor, CCR7. CCR7 binds CCL19 and CCL21, causing the highly activated DCs to be trapped in the peripheral tissue site. The co-stimulatory molecule, CD86, which is critical for DC/T-cell interaction, is expressed by a subset of DCs captured in the arterial wall. DC/T-cell interaction does not involve interleukin-12; transcripts for interleukin-12 p40 are absent in the vasculitic infiltrates. We propose that differentiation of DCs and the autocrine and paracrine actions of chemokines in granulomatous lesions misdirect DCs away from their usual journey to lymphoid organs and are critical in maintaining T-cell activation and granuloma formation in giant cell arteritis.

Hypersensitivity pneumonitis (extrinsic allergic alveolitis) caused by inhaled allergens can progress to disabling or even fatal end-stage lung disease. The only truly effective treatment is early recognition and control of exposure. Although patients produce antibody exuberantly, the immunopathogenesis involves cellular immunity--notably, CD8(+) cytotoxic lymphocytes, multinucleate giant cell granulomas, and ultimately interstitial fibrosis. Many causative agents have been recognized in occupational dusts or mists, but most current new cases arise from residential exposure to pet birds (pigeons and parakeets), contaminated humidifiers, and indoor molds. The symptoms and physical findings are nonspecific. Serum IgG containing high titers of specific antibody to the offending antigen is elevated. Pulmonary function tests show restrictive and diffusion defects with hypoxemia, especially after exercise. Occasionally, small airways disease causes obstruction. Radio-graphic changes vary according to the stage of the disease and are best evaluated by means of high-resolution computed tomography. In typical cases, the history of a known exposure and the presence of a characteristic interstitial lung disease with serologic confirmation of IgG antibody to the offending antigen suffice for diagnosis. In more obscure cases, observation of changes after a natural environmental exposure, bronchoalveolar lavage, and lung biopsy might be indicated. Among the many questions that remain are the following: What is the prevalence of hypersensitivity pneumonitis and how often is it the cause of chronic interstitial fibrosis? What is the long-term prognosis? Why do most individuals exposed to these antigens develop a vigorous antibody response whereas only a few develop the disease? How does exposure to endotoxin and cigarette smoking affect the disease? To answer these questions, standardized and validated clinical laboratory immunochemical tests are needed, in addition to a systematic approach to diagnosis, classification of disease severity, risk assessment, and management. This review is limited to the disease caused by airborne allergens and focuses on its immunopathogenesis, eliciting agents, clinical manifestations, diagnosis, management, and prognosis.

Granulomatous interstitial nephritis is a rare condition whose pathogenesis is poorly understood. Of 203 renal biopsies performed between 1974 to 1994 in which interstitial nephritis was the predominant change, granulomata occurred in 12. The authors reviewed the records of these patients and performed immunopathologic and immunohistochemical studies in their biopsies to characterize the phenotype of infiltrating cells. The authors used markers for T cells, B cells, and macrophages, and determined whether they were activated through assessment of upregulation of HLA-DR molecules. Additionally, the authors attempted to delineate whether or not tubules contributed to giant cell formation through assessment of intermediate filament for keratins and macrophage markers in epithelioid cells. Drug (aspirin, gentamycin, or combination of drugs), infection (Echerichia coli or various organisms), and sarcoidosis accounted for granulomatous inflammation in three patients each, Wegener's granulomatosis and oxalosis resulting from intestinal bypass in one patient each, and in one patient the possible cause could not be determined. Except for biopsies of granulomatous inflammation resulting from infection, in which neutrophils predominated, in all other biopsies, T cells and macrophages made up most of the inflammatory cell infiltrate. HLA-DR was upregulated in mononuclear cells infiltrating the interstitium and was expressed in proximal tubular cells and endothelial cells in all but biopsies of patients with sarcoidosis. In no instance was there evidence that tubules contributed epithelial cells to giant cell formation. These findings are consistent with the notion that granulomatous interstitial nephritis is a cell-mediated form of tissue injury in which T cell-macrophage seem to play a major role.

Nine cases of peripheral giant cell granuloma of the oral cavity have been immunohistochemically analyzed to assess the nature of the giant cells. Giant cells were unreactive when tested with antibodies recognizing myelomonocytic and macrophage markers (lysozyme, MAC 387, HAM 56) but showed strong immunoreactivity with MB1, an antibody reactive with osteoclasts. It is concluded that giant cells characterizing giant cell granuloma exhibit a phenotype distinct from other giant cells found in sites of chronic inflammation and may be true osteoclasts.

We report a case of idiopathic granulomatous hypophysitis diagnosed at autopsy in a 69-year-old female who, after endocrine coma, died from gastrointestinal hemorrhage. Immunohistochemical studies disclosed a predominance of T-lymphocytes in the inflammatory pituitary infiltrates. In addition to hypophysitis, lymphocytic thyroiditis and adrenalitis lesions and atrophic gastritis were found. These findings, consistent with autoimmune disease, are similar to those reported for lymphocytic hypophysitis, and raise the possibility that both types of hypophysitis are different aspects of the same condition.

The giant cell granuloma of jaw is a well-vascularised lesion comprising a mononuclear cell infiltrate with a large number of giant cells. It has been suggested that the lesion is reparative in nature, rather than neoplastic, and that the giant cells are phagocytes accumulating in chronic reparative granulation tissue. However, the nature of the multinucleate giant cells never has been established. One possibility is that the constituent giant cells are osteoclasts. The authors assessed expression by the giant cells of several osteoclast-specific characteristics: excavation of bone; motility inhibition by calcitonin (CT); and binding of osteoclast specific monoclonal antibodies. Two tumors were disaggregated and incubated on slices of cortical bone in the presence and absence of CT. Both tumors were found to excavate bone, a function unique to osteoclasts. The giant cells also were responsive to CT, resulting in cytoplasmic quiescence and inhibition of bone resorption. Two osteoclast-specific monoclonal antibodies bound all the giant cells in one central and six peripheral tumors examined immunohistochemically. These results provide strong evidence for the osteoclastic nature of the giant cells. The presence of alkaline phosphatase-positive cells forming woven bone in giant cell granulomas suggests that osteoblasts are present in the lesion. As cells of osteoblastic lineage are known to regulate osteoclastic function, it may be that osteoblasts account for the characteristic infiltration of osteoclasts into giant cell granulomas of jaws, either as part of a reparative response by reactive osteoblasts or as an infiltrate induced by osteoblasts of aberrant function, as suggested for giant cell tumors of bone.

Giant cells are commonly seen in granulomas produced by a wide variety of known and unknown agents. It is widely accepted that giant cell formation results from fusion of mononuclear phagocytes. Both experimental and circumstantial evidence suggests that fusion takes place following the attachment of more than one macrophage to the same endocytic material. This view is in keeping with the consistent observation of giant cell formation in granulomas, where macrophages are actively ingesting material in close apposition to other macrophages. The experimental evidence for this view derives from the finding that if more than one macrophage is attached simultaneously to the same endocytic material in vitro, fusion results. Study of the phagocytic capacity of giant cells formed in vivo suggests that the same mechanism of fusion operates in granulomatous inflammation. Giant cell formation in granulomas thus appears to be the incidental result of macrophages ingesting material in close apposition to other macrophages. The material responsible for fusion may either be the visible particulate cause of granuloma formation or the denatured macromolecules formed by the inflammatory process.

Question: By means of antimacrophage sera it is possible to demonstrate partially common antigenicity of monocytes with peritoneal macrophages, reticulum cells capable of phagocytosis, mast cells and Kupper's cells. The authors continued these studies important for the explantation of cytogenetical interrelations using a special method on epitheloid and giant cells of rats. The experiments aimed for the detection of possible partially common antigenicity with the above mentioned monocytes/macrophages system.

Sixty-six giant cell lesions ranging from inflammatory to neoplastic were evaluated for HLA-DR antigens using formalin/paraffin tissue and a monoclonal antibody labelled by the avidin-biotin peroxidase. HLA-DR antigens were expressed in nearly all lesions, predominantly on round, macrophage-like cells. Granulomatous inflammatory lesions were generally more immunoreactive than non-inflammatory lesions. Multinucleate giant cells were relatively unreactive in non-inflammatory lesions as compared to inflammatory lesions. Determination of HLA-DR expression does not appear to be helpful in discriminating between the various giant cell lesions.

A model for the fusion of macrophages in areas of chronic inflammation in vivo has been presented which is derived from the associations of macrophage fusion in vivo and in vitro. It is suggested that in granulomata, where macrophages are closely packed in the presence of endocytogenic material, this material may on occasion attach simultaneously to more than one macrophage. Ensuing endosome margin formation may then lead to the endosome margins of one macrophage fusing with those of the other. By causing macrophages to phagocytose glutaraldehyde-fixed red blood cells in vitro under circumstances which more closely reflect in-vivo phagocytosis than the phagocytosis of the red cells by macrophages in a glass adherent monolayer, it has been shown that simultaneous attachment leads to macrophage fusion. It is suggested that giant cell formation in vivo in granulomata results from the process of simultaneous attempted endocytosis.

Neonatally thymectomized and intact Holstein calves were inoculated intradermally with bacille Calmette Guérin mycobacteria at 4 to 6 months of age. The immune response of the calves was evaluated by in vitro lymphocyte stimulation, with a purified protein derivative of Mycobacterium bovis, and by a cervical skin test. Eight of te calves had been previously infected at 7 to 15 weeks of age with bovine viral diarrhea virus. The cutaneous and in vitro immune responses were not different in neonatally thymectomized calves, whether or not they had been previously infected with bovine viral diarrhea virus. However, a prominent histologic difference in the nature of the primary granulomatous lesions was observed in the thymectomized calves. These injection sites were characterized by few lymphocytes and an increased number of multinucleated giant cells. These observations were interpreted as manifestations of a deficient thymus-dependent effector response in the thymectomized calves.

Murine multinucleate giant cells and mononuclear phagocytes were examined with various quantitative cytochemical and autoradiographic techniques. No evidence was found that multinucleate giant cells were metabolically effete, in fact they compared favourably with mononuclear phagocytes. In addition, rat multinucleate giant cells consistently expressed surface Ia antigens and to a lesser degree fibronectin. It is suggested that multinucleate giant cells are a differentiated derivative of the mononuclear phagocytic system.

This report presents the ultrastructural features of a congenital epulis. The granular cells of the epulis were packed with numerous membrane bound cytoplasmic granules containing particles, small vesicles, and electron-dense materials. These granules were negative in immunohistochemical reaction for CEA (DAKO PAP KIT). Cytoplasmic organelles such as mitochondria, rough surfaced endoplasmic reticulum, and Golgi apparatus, were absent. Nuclei were markedly indented. Occasionally, banded intracellular collagen fibrils were observed within the cytoplasm. Some of these fibrils were surrounded by a limiting membrane, whereas others appeared to lie free in the cytoplasm. The collagen fibrils were also seen within a deep invagination of the cell surface. There was no basal lamina around the granular cells. Sporadically, mast cells with many granules containing lamellar formations were found between the granular cells. These observations support the idea that granular cells of the congenital epulis are derived from mesenchymal cells, probably fibroblasts.

Mediastinal lymph nodes of 11 patients with Sarcoidosis were studied. The immunoperoxidase technique using monoclonal antibody to HLA-DR antigen revealed on conventional frozen sections epithelioid cell granulomas with intense staining. Localization of this HLA-DR + material on or in cells in these granulomas was possible with 1 mu semithin frozen sections. Epithelioid cells as well as multi nuclear giant cells were seen in these sections with membrane bound HLA-DR antigens. Some problems about HLA-DR antigens in relation with antigen handling, the presence on epithelioid, (and) giant cells and granuloma formation will be discussed.