Trem2-expressing multinucleated giant macrophages are a biomarker of good prognosis in head and neck squamous cell carcinoma
Grégoire GessainAhmed-Amine AnzaliMarvin LerousseauKevin MulderMathilde BiedAnne AupérinDaniel StockholmNicolas SignolleFarah SassiMaria Eugénia Marques Da CostaAntonin MarchaisAlexandre SayadiDaniela WeidnerStefan UderhardtQuentin BlampeySumanth Reddy NakkireddySophie BroutinCharles‐Antoine DutertrePierre BussonThomas WalterAlix MarhicAntoine Moya‐PlanaJoanne GuerlainIngrid BreuskinOdile CasiraghiPhilippe GorpheMarion ClasseJean–Yves ScoazecCamille BlériotFlorent Ginhoux
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Abstract Patients with head and neck squamous cell carcinomas (HNSCC) often have poor outcomes due to suboptimal risk management and treatment strategies; yet integrating novel prognostic biomarkers into clinical practice is challenging. Here, we report the presence of multinucleated giant cells (MGC)—a type of macrophages—in tumors from patients with HNSCC, which are associated with a favorable prognosis in treatment-naive and preoperative chemotherapy–treated patients. Importantly, MGC density increased in tumors following preoperative therapy, suggesting a role of these cells in the antitumoral response. To enable clinical translation of MGC density as a prognostic marker, we developed a deep-learning model to automate its quantification on routinely stained pathological whole slide images. Finally, we used spatial transcriptomic and proteomic approaches to describe the MGC-related tumor microenvironment and observed an increase in central memory CD4 T cells. We defined an MGC-specific signature resembling to TREM2-expressing mononuclear tumor-associated macrophages, which colocalized in keratin tumor niches. Significance: Novel individual biomarkers are needed to guide therapeutic decisions for patients with head and neck cancer. We report for the first time, granulomas of TREM2-expressing multinucleated giant macrophages in keratin-rich tumor niches, as a biomarker of favorable prognosis and developed a deep-learning model to automate its quantification on routinely stained pathological slides.Keywords:
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The Authors report on a case of acute idiopathic giant cell myocarditis, which occurred in a young man without previous history of immunodeficiency or tumours, and displayed a rapidly fatal clinical course. Autoptic examination showed diffuse damage to the myocardium, with myocytolysis, granuloma formation and abundant giant cell reaction. No significant changes were observed in the other organs and systems . Immunohistochemistry revealed that the giant cells strongly reacted with the antibody KP1--raised to the macrophage-associated antigen CD68--whereas they did not stain with the monoclonal against the muscle-specific marker desmin. In the light of their findings and previous reports in the literature, the Authors discuss the possible origin of giant cells, along with the pathogenesis of the condition.
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A case of central giant cell granuloma (CGCG) arising in the mandible of a 27-year-old woman is reported. The lesion was studied immunohistochemically. Histopathologically, CGCG had two main components, mononuclear stromal cells and multinucleated giant cells. Immunoreactivity for CD68 was moderate in most giant cells and weak to moderate in some mononuclear cells. These findings indicate that the giant cells and mononuclear cells originated from macrophages. The related literature on CGCG in Japan is also reviewed and discussed.
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The fibrous histiocytoma is a soft-tissue neoplasm of the biphasic cell population of fibroblasts and histiocytes that affects the dermis and the subcutaneous tissue. The objective of this article is to report a case of benign fibrous histiocytoma (BFH) of the lower lip in a 32-year-old female patient with a chief complaint of swelling in the lower lip for the past 1 month. With diagnostic clinical hypothesis of fibrous hyperplasia, fibrous histiocytoma and mucocele, an excisional biopsy was performed. The histopathological examination revealed a nonencapsulated proliferation of spindle cells with some giant multinucleated cells in the periphery of the lesion. Multinucleated giant cells and lymphocytes were noted throughout the lesion. Immunohistochemical reactions were performed, staining only CD68 in the multinucleated giant cells. According to these characteristics, the final diagnosis was BFH.
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This study investigated whether some components of the extracellular matrix and CD68 expression may drive the differences between the central giant cell granuloma (CGCG) of the jaws and giant cell tumor (GCT) of long bones, which present distinct evolution and clinical behavior.Eight cases of CGCG and 7 cases of GCT were selected and immunohistochemically analyzed to verify the pattern of expression of CD68, tenascin (Tn) and fibronectin (Fn).A large number of the mononuclear cells and multinucleated giant cells CD68+ was observed in both of the studied lesions, indicating histiocyte/ macrophage origin. Seven cases of CGCG of the jaws showed intense staining of Fn, with uniform distribution predominantly. In all 7 cases of GCT of long bones the Fn displayed intense expression, with distribution pattern varying from uniform to reticulate/fibrillar. Six cases of CGCG were intensively stained by Tn, presenting focal expression in half of specimens, and reticulate/ fibrillar pattern of expression in 4 cases. All cases of GCT of the long bones presented intense expression of Tn, uniform distribution, and reticulate/fibrillar pattern of expression in four cases.The immunoexpression of CD68 in mononuclear cells and multinucleated giant cells and staining patterns of Fn and Tn were similar in both entities. These findings indicate that these proteins could not be used to explain the differences between the CGCG of the jaws and GCT of the long bones.
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Central and Peripheral giant cell granulomas of jaws are uncommon, benign, reactive disorders that are characterized by the presence of numerous multinucleated giant cells and mononuclear cells within a stroma. The origin of the multinucleated giant cells is controversial; probably originating from fusion of histiocytes, endothelial cells and fibroblasts.To assess the expression of CD34 and CD68 in central and peripheral giant cell granulomas to understand the origin of these multinucleated giant cells.Twenty cases of Central and Peripheral giant cell granulomas were evaluated immunohistochemically for CD34 and CD68 proteins expression.Immunopositivity for CD34 was seen only in cytoplasm of endothelial cells of blood vessels; whereas, consistent cytoplasmic immunopositivity for CD68 was seen in few stromal cells. Statistical significance was seen in mean number of multinucleated giant cells, mean number of nuclei in multinucleated giant cells, CD68 expression and ratio of macrophages to multinucleated giant cells among two lesions.Although the central giant cell granulomas share some clinical and histopathological similarities with peripheral giant cell granulomas, differences in mean number of nuclei in multinucleated giant cells and CD68 immunoreactivity may underlie the distinct clinical behavior.
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To detect the expression of macrophage inflammatory protein-1alpha (MIP-1alpha), a disintegrin-like and metalloproteinase (ADAM) 8 and 12 and CD68 protein in giant cell lesions of jaw and giant cell tumors of long bone, and to study their effects on the histogenesis of giant cells in such lesions.MIP-1alpha, ADAM8, ADAM12 and CD68 were detected by immunohistochemistry in 24 paraffin-embedded specimens of central giant cell lesions of jaw and giant cell tumors respectively.MIP-1alpha positive signal was located in blood vessels and bone. ADAM8, ADAM12 and CD68 positive signals were located in the cell membrane and cytoplasm of all multinucleated giant cells and some round mononuclear cells in the lesions. In addition, some spindle mononuclear stromal cells were positive for ADAM12 in both lesions.Multinucleated giant cells probably originate from CD68-postive round mononuclear cells, which are recruited from monocyte-macrophage system by chemokines, such as MIP-1alpha, followed by cell fusion mediated by ADAM8 and ADAM12.
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J Oral Pathol Med (2011) 40: 334–337 Background: Giant cell granulomas of the jaws are lesions that arise either peripherally in periodontal ligament and mucoperiosteum or centrally in the bone. The aim of this study was to evaluate expression of CD68 and tartrate-resistant acid phosphatase (TRAP) proteins in multinucleated giant cells and mononuclear cells. Methods: Formalin-fixed and paraffin-embedded tissue section of 20 specimens of central giant cell granuloma and 20 cases of peripheral giant cell granuloma were immunohistochemically analyzed for CD68 and TRAP proteins expression rate using Biotin-Streptavidin method. Result: In central giant cell granuloma, more than 99% of multinucleated giant cells were positive for TRAP antibody and about 90% were positive for CD68. In mononuclear cells of this lesion, 14% of cases were positive with TRAP antibody and 8% with CD68. In peripheral giant cell granuloma, TRAP antibody was positive in 99% of giant cells and in 13% of mononuclear cells. A proportion of 97% of giant cells and 6% of mononuclear cells reacted positively with CD68. Conclusion: Immunohistochemical evidence of this study shows that giant cells and a group of mononuclear cells of stroma in both peripheral and central giant cell granuloma express TRAP antibody severely that is specific for osteoclast. Also, these cells are positive reactive to CD68, which is the macrophage marker and therefore it can be mentioned that giant cells are osteoclast, although their origins are macrophagic/monocytic or their precursors, and maybe mononuclear cells in stroma have a role in formation of giant cells.
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Objective To investigate the possible nature of the multinucleated giant cells (MGCs) in giant cell tumor (GCT) and giant cell granuloma (GCG) of the jaws.Methods Eight cases of GCT and 8 cases of GCG [4 central cases (CGCG) and 4 peripheral cases (PGCG)],1 case of scrofula and 1 case of foreign body giant cell granuloma were undergone immunohistochemical staining to detect CD68, AAT,AACT,lysozyme,MAC-387,vimentin,S-100 and Ki-67 using formalin-paraffin embedded tissue sections.Enzyme histochemical staining for tartrate-resistant acid phosphatase (TRAP),an enzyme marker for osteoclasts,was also performed in all cases.Results MGCs in GCT and GCG lesions possessed both histiocyte/monocyte related antigens (CD68,AAT,AACT) as well as osteoclast specific enzyme (TRAP).Ki67 staining,however,showed that only mononuclear cells,but not the MGCs,were in cell cycle.Conclusion The MGCs in GCT and GCG appeared to express both macrophage and osteoclast associated phenotypes.The exclusively proliferative activity demonstrated in the mononuclear cells and the similar immunocytochemical and histochemical expression in some of the mononuclear elements suggest that these cells may represent precursors of the MGCs.Coalescence or fusion of these precursor cells could result in giant cell formation in the lesion.
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