Cellular cannibalism in central and peripheral giant cell granuloma

Cellular cannibalism in central and peripheral giant cell granuloma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cellular cannibalism in central and peripheral giant cell granuloma Zeinab Akbarzadeh Fathabadi, Saede Atarbashi-Moghadam This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6600945/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Cellular cannibalism is observed in many lesions containing giant cells, including Peripheral Giant Cell Granuloma (PGCG) and Central Giant Cell Granuloma (CGCG). However, limited information exists on its role in prognosticating the behavior of these lesions. This study aimed to assess the frequency of cellular cannibalism in PGCG and CGCG of the oral cavity. Methods A total of 125 samples with complete clinical and radiographic data were included. Sections were examined under ×400 magnification. A total of 100 giant cells were analyzed per section, and the percentage of cannibalistic cells was recorded. Only giant cells in the central tumor mass were assessed, excluding those near the bone to avoid counting osteoclasts. Data were analyzed using SPSS version 26. Statistical tests included Shapiro–Wilk, Levene’s test, Independent Samples t-test, one-way ANOVA with Tukey’s HSD post-hoc test, Generalized Linear Model (GLM), and Pearson Chi-Square. Results Of the 125 cases, 50.4% were male and 49.6% were female, with a mean age of 38.29 ± 19.18 years. Ninety-one samples were PGCG, and 34 were CGCG (11 non-aggressive, 23 aggressive). All samples showed cellular cannibalism)100%). The mean cellular cannibalism in CGCG (18.68 ± 10.09) was significantly higher than in PGCG (13.41 ± 8.22)(P-value: 0.003). Additionally, aggressive CGCG had a higher mean of cellular cannibalism than non-aggressive CGCG, though this difference was not statistically significant(P-value: 0.163). Conclusion This study suggests that cellular cannibalism may be a potential pathological indicator in evaluating the biological behavior of CGCG and PGCG. Cannibalism Peripheral giant cell granuloma Giant Cell Granuloma Aggressive Figures Figure 1 Figure 2 Figure 3 Background Peripheral Giant Cell Granuloma (PGCG) is a relatively common tumor-like growth in the oral cavity. It is likely not a true neoplasm, but rather a reactive lesion resulting from localized irritation or trauma. PGCG bears close microscopic resemblance to Central Giant Cell Granuloma (CGCG), and some pathologists believe it may represent the soft tissue counterpart of this intraosseous lesion( 1 ). CGCG is an intraosseous lesion of unknown etiology. There has been considerable debate over whether this lesion represents a reactive process or a benign neoplasm. Specifically, genetic studies have identified recurrent somatic mutations in TRPV4, KRAS, or FGFR1 in approximately 70% of the cases examined. These mutations activate the Ras-MAPK pathway and appear to be significant drivers in the development of the disease. Interestingly, similar mutations that activate this pathway have been identified in many other conditions that cause the proliferation of giant cells in the oral cavity( 1 ). The cellular phenomenon in which a living cell is internalized by another viable cell represents a remarkable biological event. The study of cell-in-cell phenomena began with Lewis’s interest in understanding his observations of a non-phagocytic process in which one cell appeared to engulf another. Some of the known forms of this phenomenon include Emperipolesis, Cellular Cannibalism and Entosis( 2 ). Emperipolesis is a condition in which hematopoietic cells, including neutrophils, lymphocytes, and plasma cells, are observed in a viable and intact state within the cytoplasm of a host cell such as a megakaryocyte, monocyte, endothelial cell, fibroblast, or even a malignant cell, without causing any damage. In this phenomenon, since both the engulfing and internalized cells remain alive, there are no physiological or morphological consequences for either of them.( 3 , 4 ) In Entosis, a cell engulfs another cell of the same type. Although the internalized cells are initially viable, most eventually undergo a non-apoptotic form of cell death that requires autophagy-related proteins. This phenomenon has been proposed as a cell-in-cell invasive process with a physiological role in eliminating cells that have detached from a substrate( 5 ). Cannibalism is a closely related phenomenon known as cellular self-consumption or homotypic cell engulfment. The term “cannibalism” originates from the Spanish word caníbal , referring to human cannibalism—a claim associated with the Carib people. In Greek, it is called anthropophagy, meaning a human consuming other humans. Cellular cannibalism also occurs at the cellular level in humans, defined as the ability of one cell to engulf another living cell of the same or different type ( 2 , 6 , 7 ). It is also described as a larger cell engulfing a slightly smaller one within its cytoplasm. Cellular cannibalism has been reported in various cancers, including bladder cancer, breast cancer, lung cancer, gastric cancer, and oral squamous cell carcinoma (OSCC), and it is significantly associated with anaplasia, tumor invasion, histological grading, and metastatic potential( 6 ). In cellular cannibalism, one cell becomes trapped within another and is enclosed in a vacuolated space. This process displaces the nucleus of the host cell toward the periphery. Consequently, Leyden referred to the cells exhibiting this phenomenon as "bird-eye cells" ( 2 , 6 , 7 ). The mechanism of cellular cannibalism is attributed to metabolic alterations in malignant tumor cells, which enable them to engulf other tumor cells under unfavorable conditions such as hypoxia, nutrient deprivation, and acidic environments—thus supporting their survival and progression. In some instances, a malignant cell that has engulfed another may itself be internalized by a third cell, a phenomenon referred to as complex cannibalism. Cannibalistic giant cells and stromal cells express histiocytic markers, while the internalized cells lack Bcl-2 expression, indicating that cell death in the engulfed cells occurs via apoptosis( 7 ). Cellular cannibalism, in addition to being observed in various types of cancers, has also been noted in lesions containing giant cells. These lesions include giant cell tumor of tendon sheath (localized type), CGCG, and PGCG in the oral cavity. Available evidence suggests that the increased frequency of cellular cannibalism in these lesions may indicate enhanced metabolic activity of giant cells and may be associated with more aggressive behavior of these lesions( 2 , 5 ). The aim of the present study is to assess the frequency of cellular cannibalism in CGCG and PGCG lesions. Given that cellular cannibalism is a common feature in many lesions containing giant cells and that there are limited studies on its potential impact on the biological behavior of these lesions, further investigation of this phenomenon could be crucial in evaluating the aggressiveness and clinical prognosis of these lesions. Furthermore, since these morphological features can be easily identified under a light microscope, they may help predict the behavior of these lesions and assist in selecting the appropriate treatment approach, without incurring any additional costs. MATERIALS AND METHODS Case selection Patient records from the Department of Oral and Maxillofacial Pathology at Shahid Beheshti University of Medical Sciences were reviewed over a 10-year period from 2014 to 2023. All cases diagnosed with PGCG and CGCG were included. Patients with incomplete records (i.e., missing more than one demographic detail) or unavailable histological slides were excluded from the study. Initially, 143 patient records were identified. After applying the inclusion criteria, 125 cases were included in the study. This study was approved by the Ethics Committee of Shahid Beheshti Dental School under the code IR.SBMU.DRC.REC.1403.020 and was conducted in compliance with declaration of Helsinki ( 8 ). Criterion for aggressive and non-aggressive CGCG Lesions were classified into aggressive and non-aggressive categories based on the criteria established by Chuong et al.( 9 ) and supported by several subsequent studies evaluating the biological behavior of CGCG ( 5 , 10 ). In this study, non-aggressive lesions were characterized by minimal or no symptoms, slow growth, absence of root resorption or cortical perforation, and low recurrence tendency. In contrast, aggressive lesions presented with pain, rapid growth, root resorption, cortical perforation, and a higher likelihood of recurrence. Quantification of cannibalistic cells Quantification of cannibalistic giant cells (GCs) was performed on hematoxylin and eosin (H&E)-stained sections. Since this phenomenon is readily identifiable in routine staining, additional assessments such as immunohistochemistry (IHC) were deemed unnecessary. The slides were examined under high-power magnification (×400). A zigzag (battlefield) method was employed to prevent double-counting of individual cells. In each section, 100 multinucleated giant cells were evaluated, and the number of cannibalistic cells was recorded as a percentage. Only the GCs located in the central mass of the lesion were considered; any GCs in contact with the bone surface were excluded from analysis to avoid including osteoclasts. Identification of cannibalistic cells Cannibalistic giant cells exhibited partial or complete engulfment of stromal tumor cells(Fig. 1 ). In cases of partial cannibalism, formation of pseudopodia by giant cells was observed. At the contact site between the mononuclear cell and the membrane of the giant cell, a small invagination in the membrane of the giant cell was noted. In complete cannibalism, the engulfed cells were entirely internalized within the cytoplasm of the giant cells and were surrounded by a clear halo. These internalized cells often showed apoptotic features, such as nuclear degradation and increased cytoplasmic density. Since giant cells arise from the fusion of mononuclear cells, it may be hypothesized that the cannibalistic process is associated with the cellular fusion events involved in giant cell formation. However, the distinct morphological characteristics described above allow for a clear distinction between cell cannibalism and cell fusion. Statistical analysis The normality of data distribution was assessed using the Shapiro-Wilk test, and homogeneity of variances was evaluated using Levene's test. Based on the sample size in each group and the results of these tests, the mean percentage of cellular cannibalism between the two lesions (PGCG and CGCG) was compared using the Independent Samples t-test. For comparisons among the three groups (PGCG, aggressive CGCG, and non-aggressive CGCG), One-Way ANOVA followed by Tukey’s HSD post-hoc test was applied. To evaluate the effect of independent variables on the percentage of cannibalistic giant cells in each lesion type, a Generalized Linear Model (GLM) was used. The distribution of gender across lesion types was analyzed using the Pearson Chi-Square test. All statistical analyses were performed using SPSS version 26, and the significance level was set at α = 0.05. Results Among 125 cases with adequate documentation and accessible histopathologic slides, there were 50.4% males and 49.6% females(PGCG: 52.7% male and 47.3% female, aggressive CGCG: 43.5% male and 56.5% female, and non-aggressive CGCG: 45.5% male and 54.5% female) The mean age of the patients was 38.29 ± 19.18 years old (ranging from 5 to 83 years. PGCG:40.21 ± 19.99, aggressive CGCG: 36.30 ± 14.95, and non-aggressive CGCG: 26.55 ± 16.60). Among the PGCG cases, 61 lesions (67%) occurred in the mandibular gingiva and 30 (33%) in the maxillary gingiva. Among the non-aggressive CGCG cases, 7 were located in the mandible and 4 in the maxilla. Among the aggressive CGCG samples, 20 lesions were found in the mandible and 3 in the maxilla. Cannibalism was found in all the cases (100%) (Fig. 1 , 2 ). The findings indicate that the mean cellular cannibalism in the CGCG group is significantly higher than in the PGCG group(P-value: 0.003) (Table 1 ). The difference between PGCG and aggressive CGCG was also statistically significant(P-value: 0.002). Although the frequency of cellular cannibalism was higher in aggressive CGCG compared to the non-aggressive type, this difference was not statistically significant. Similarly, the frequency of cannibalism in non-aggressive CGCG lesions was higher than that in PGCG; however, this difference also did not reach statistical significance (P-value: 0.882)(Fig. 3 ). Cannibalism of two cells or of several cells was also seen. Table 1 Cannibalism percentage by lesion type (PGCG, CGCG) Parameter Number Mean cannibalistic cell frequency ± SD P-value PGCG 91 13.41 ± 8.22 0.003 CGCG 34 18.68 ± 10.09 The radiographic findings indicate that border type (defined vs. undefined) and locularity (unilocular vs. multilocular) do not have a statistically significant effect on the percentage of cellular cannibalism in both aggressive CGCG and non-aggressive CGCG lesions (Table 2 ). The effect of CGCG lesions on the bone cortex was also evaluated, with the most significant observed effect being expansion, thinning, and simultaneous perforation of the cortex. Table 2 Radiographic findings and cannibalism percentage by lesion type (non-aggressive CGCG, aggressive CGCG) Parameter Radiographic border locularity radiographic.size (mean ± SD) cannibalism percentage defined Undefined unilocular multilocular non Aggressive CGCG 6 1 5 2 2.86 ± 2.11 13.29 ± 8.20 Aggressive CGCG 11 2 12 8 4.10 ± 1.83 19.65 ± 10.17 Although radiographic information was available for all cases, the actual radiographic images were accessible in only 27 cases. The mean radiographic size of aggressive lesions was larger than that of non-aggressive lesions. Additionally, radiographic size did not show a significant effect on the percentage of cellular cannibalism in aggressive CGCG lesions, but it did in non-aggressive CGCG lesions. Specifically, for every 1 cm increase in size within this group, a roughly 3% increase in cellular cannibalism was observed. No significant differences were observed in mean age or gender distribution across PGCG and CGCG subtypes. Multivariate analysis revealed no significant effect of age, gender, or lesion location on the percentage of cellular cannibalism in PGCG and non-aggressive CGCG. However, in aggressive CGCG, lesion location was significantly associated with cannibalism frequency (P = 0.021), with higher percentages in maxillary lesions. Discussion Cellular cannibalism is defined as a process in which a larger cell engulfs a smaller cell within its cytoplasm ( 6 ). In this study, all the samples (100%) exhibited cellular cannibalism. Furthermore, the frequency of cellular cannibalism was significantly higher in CGCG compared to PGCG. This finding is consistent with the results of the studies by Sarode et al. and Urs et al. ( 2 , 5 ). Although the number of samples in the present study is greater than in the Sarode study, the alignment of the results remains consistent. In the study by Sarode et al., it was observed that the frequency of occurrence of cannibalistic giant cells in aggressive CGCG was significantly higher than in non-aggressive CGCG ( 5 ). This finding was also confirmed in Sarode's subsequent study( 10 ). Similarly, the findings of the study by Urs et al. were consistent with previous research ( 2 ). These results led the authors of these studies to propose cellular cannibalism as a potential feature in assessing the aggressive behavior of CGCG. The findings of the present study were also in agreement with these results, as the mean cellular cannibalism in aggressive CGCG (20.57 ± 10.47) was higher than in non-aggressive CGCG (14.73 ± 8.33); however, this difference was not statistically significant. Although the clinical criteria used to differentiate these two groups in our study were similar to those in the previous studies, several factors may explain this difference. One such factor could be the difference in the number of cases examined in the various studies. A larger sample size in our study may have reduced the type I error probability, resulting in the lack of a statistically significant difference. Furthermore, biological differences between the study populations could be another influencing factor. Genetic, environmental, and biological factors in different populations can impact the pathological characteristics of lesions. In the present study, we investigated the effect of variables such as gender, age, and lesion location on the frequency of occurrence of cannibalistic giant cells in PGCG, aggressive CGCG, and non-aggressive CGCG. While previous studies provided information on the age, gender, and location of the lesions in their samples ( 2 , 5 , 10 ), they did not specifically assess the potential effects of these variables on the frequency of cellular cannibalism. Our findings showed that the frequency of cellular cannibalism in aggressive CGCG lesions occurring in the maxilla was higher than in those located in the mandible. This observation, considering the anatomical and biological factors associated with each region, can be explained. According to Lange's study, the mechanism of cellular cannibalism in PGCG and CGCG lesions differs from that in tumor lesions. In these types of lesions, giant cells originate from the monocyte-macrophage lineage and function similarly to osteoclasts ( 11 ). Therefore, giant cells in PGCG and CGCG inherently possess phagocytic capabilities, which is the key factor behind the occurrence of the cannibalism of stromal tumor cells( 5 ). One possible explanation for the higher frequency of cellular cannibalism in maxillary CGCG lesions compared to mandibular lesions is the difference in blood supply to these two regions. The maxilla, due to its unique anatomical structure, receives more blood flow than the mandible, which could directly affect the density and activity of blood-derived cells, including cannibalistic giant cells. Since these cells are directly derived from the monocyte-macrophage lineage, increased blood supply may lead to a higher number and activity of these cells in maxillary lesions. This could help explain the findings of the present study; however, further studies are needed for definitive confirmation. Another aspect examined in our study was the analysis of radiographic features of aggressive and non-aggressive CGCG lesions, including border, locularity, and radiographic size, as well as the relationship between these variables and the frequency of cellular cannibalism. Data analysis revealed that in non-aggressive CGCG lesions, for every 1 cm increase in the radiographic size of the lesion, the frequency of cellular cannibalism increases by approximately 3%. This finding is consistent with the results of previous studies by Sarode ( 5 , 10 ). In their studies, it was observed that, firstly, the size of aggressive lesions was, on average, larger than that of non-aggressive lesions, and secondly, the frequency of cannibalism in aggressive lesions was significantly higher than in the non-aggressive type. The analysis of the findings in our study indicates that as CGCG lesions progress from the non-aggressive type to the aggressive type, as defined by clinical criteria, the frequency of cellular cannibalism also shows an increasing trend. This finding is physiologically significant and may serve as a potential marker for evaluating the biological behavior of the lesion as it progresses from a non-aggressive to an aggressive state, warranting further investigation. Multiple studies have investigated the possibility of predicting the aggressive behavior of cancers based on the frequency of cellular cannibalism in microscopic observations( 6 , 12 – 14 ). Research conducted by Jain, Sarode, and Rocha has all shown that more aggressive lesions with higher grades in oral squamous cell carcinoma (OSCC) exhibit a higher frequency of cellular cannibalism. These findings confirm that cellular cannibalism can be considered a reliable predictive marker for the aggressive behavior of OSCC and its potential for metastasis ( 6 , 12 , 13 ). Additionally, one study mentioned that cellular cannibalism is also observed in high-metastatic potential osteosarcomas ( 14 ). The pathogenesis of cellular cannibalism in malignant tumors seems to be linked to the tumor cells' efforts to survive in adverse environmental conditions, such as high acidity, hypoxia, and nutrient deficiency( 6 ). The acidic environment plays a key role in activating proteolytic enzymes, which are directly involved in invasion, metastasis, and the selection of cells that are resistant to these conditions (cannibalistic cells) ( 15 ). However, this mechanism is not directly applicable to benign lesions such as PGCG and CGCG. According to the study by Lange, as mentioned earlier, cellular cannibalism in PGCG and CGCG lesions is more due to the intrinsic characteristics of the cells rather than a mechanism of adaptation to adverse environmental conditions. ( 11 ) However, the findings of Sarode's studies have shown that the increase in the number of cannibalistic giant cells in PGCG and CGCG may indicate higher metabolic activity in these cells, and this metabolic increase could be related to the more aggressive biological behavior of these lesions ( 5 ). This study was limited by a relatively small sample size, missing clinical data, and the unavailability or poor quality of some histologic slides, which may affect the generalizability of the findings. Additionally, the lack of longitudinal follow-up limited our ability to assess the prognostic significance of cellular cannibalism. Future research with larger, more homogenous samples and the use of immunohistochemical techniques is recommended to better understand the underlying mechanisms and potential prognostic value of this phenomenon. Conclusion The findings of this study highlight the potential role of cellular cannibalism as a pathological marker in evaluating the biological behavior of CGCG and PGCG. Specifically, an increase in the size of non-aggressive CGCG lesions was associated with an increased frequency of cellular cannibalism, which may potentially indicate a gradual progression of these lesions towards more aggressive forms. Abbreviations PGCG: Peripheral Giant Cell Granuloma CGCG: Central Giant Cell Granuloma Declarations Ethical declarations Ethics approval consent to participate This study was ethically approved by the ethics committee of Shahid Beheshti University of Medical Sciences (IR.SBMU.DRC.REC.1403.020) and was conducted in compliance with declaration of Helsinki. As this retrospective study involved anonymized patient records with no direct contact with individuals and there is no personal images or clinical details of participants, patient’s informed consent was waived by Shahid Beheshti University of Medical Sciences Ethic Committee. Consent to participate : Not Applicable Data availability: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests: The authors declare that they have no competing interests Funding : This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors' contributions : SAM participated in the conception and design of the study, acquisition of data, analysis of data, critical revision, and final approval of the manuscript. ZAF participated in the conception and design of the study, acquisition of data, analysis of data, drafting of the article, and final approval of the manuscript. Acknowledgements: Not applicable References Boşca AB, Şovrea AS, Miclăuş V, Ruxanda F, Mihu CM, Melincovici CS, et al. Diagnostic and therapeutic approaches in oral cavity granulomas based on new data concerning their origin and pathogenesis. Rom J Morphol Embryol. 2018;59(3):679–90. Urs AB, Yaming P, Malhotra R. An insight into the cannibalistic behavior of giant cell granulomas of the jaws. Journal of oral and Maxillofacial Pathology. 2018;22(3):449. Kruse-Lösler B, Diallo R, Gaertner C, Mischke K-L, Joos U, Kleinheinz J. Central giant cell granuloma of the jaws: a clinical, radiologic, and histopathologic study of 26 cases. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology. 2006;101(3):346–54. Barresi V, Branca G, Ieni A, Rigoli L, Tuccari G, Caruso RA. Phagocytosis (cannibalism) of apoptotic neutrophils by tumor cells in gastric micropapillary carcinomas. World Journal of Gastroenterology: WJG. 2015;21(18):5548. Sarode SC, Sarode GS. Cellular cannibalism in central and peripheral giant cell granuloma of the oral cavity can predict biological behavior of the lesion. Journal of oral pathology & medicine. 2014;43(6):459–63. Jain M. An overview on" cellular cannibalism” with special reference to oral squamous cell carcinoma. Experimental oncology. 2015. Gupta N, Jadhav K, Shah V. Emperipolesis, entosis and cell cannibalism: Demystifying the cloud. Journal of Oral and Maxillofacial Pathology. 2017;21(1):92–8. Association WM. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Jama. 2013;310(20):2191–4. Chuong R, Kaban LB, Kozakewich H, Perez-Atayde A. Central giant cell lesions of the jaws: a clinicopathologic study. Journal of oral and maxillofacial surgery. 1986;44(9):708–13. Sarode GS, Sarode SC, Gawande S, Patil S, Anand R, Patil SG, et al. Cellular cannibalism in giant cells of central giant cell granuloma of jaw bones and giant cell tumors of long bones. Journal of Investigative and Clinical Dentistry. 2017;8(2):e12214. de Lange J, van den Akker HP, van den Berg H. Central giant cell granuloma of the jaw: a review of the literature with emphasis on therapy options. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology. 2007;104(5):603–15. Sarode SC, Sarode GS. Neutrophil‐tumor cell cannibalism in oral squamous cell carcinoma. Journal of oral pathology & medicine. 2014;43(6):454–8. Siquara da Rocha LdO, Souza BSdF, Lambert DW, Gurgel Rocha CdA. Cell-in-cell events in oral squamous cell carcinoma. Frontiers in Oncology. 2022;12:931092. Zargaran M. Cellular Cannibalism: Suggesting a Histopathological Parameter for Predicting Metastasis of Osteosarcoma in Future Studies. Asian Pac J Cancer Prev. 2021;22(7):1985–6. Fais S. Cannibalism: a way to feed on metastatic tumors. Cancer letters. 2007;258(2):155–64. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6600945","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":474760326,"identity":"95e66535-0889-4f34-aed3-0562a430c951","order_by":0,"name":"Zeinab Akbarzadeh Fathabadi","email":"","orcid":"","institution":"Shahid Beheshti University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Zeinab","middleName":"Akbarzadeh","lastName":"Fathabadi","suffix":""},{"id":474760327,"identity":"f3715491-ce30-4220-93ea-5b2c0e896f59","order_by":1,"name":"Saede Atarbashi-Moghadam","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIiWNgGAWjYDCCAxAqgYGBh+HABzCDGC0HoFoOziBZCzMPMVr4bh9g/Pyh5l4ef//Zg4dt2+zy+NkbGD98zMGtRfJcArPEgWPFxRI38hIO57YlF0v2HGCWnLkNtxaDMwwMEgfYEhIbbvAYALUwJ264kcDGzItfC/OPA/8SEuefP2Nw2LKtnigtbBIH2xISNxzIMTjM2HaYsBbJM4xtFmf7EooNb+QYHOw5dzxxZs/BZrx+4TvDfPhGxbeEPLnzZ4w//CirTuxnbz744SMeLQwMjA1IbDZ0EcLgDymKR8EoGAWjYKQAACywXNp94KVmAAAAAElFTkSuQmCC","orcid":"","institution":"Shahid Beheshti University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Saede","middleName":"","lastName":"Atarbashi-Moghadam","suffix":""}],"badges":[],"createdAt":"2025-05-06 08:53:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6600945/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6600945/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85278551,"identity":"68259e4c-f646-4140-b61d-36f45af60e0d","added_by":"auto","created_at":"2025-06-24 07:47:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":660976,"visible":true,"origin":"","legend":"\u003cp\u003ePGCG. A large giant cell engulfs more than one cell (black arrows) (H \u0026amp; E, ×400).\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6600945/v1/5430f1c0b6f3e68bbdbac982.png"},{"id":85278554,"identity":"2c18d3d3-e43a-4692-8035-7e3826b1340c","added_by":"auto","created_at":"2025-06-24 07:47:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":552993,"visible":true,"origin":"","legend":"\u003cp\u003eCGCG. Giant cells show cellular cannibalism. The cannibalized cells are seen with a clear halo (black arrows) (H \u0026amp; E, ×400).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6600945/v1/87879abe7ea1fc44f3760c62.png"},{"id":85278553,"identity":"1fd60d9e-0dec-488b-8339-e44d5892f560","added_by":"auto","created_at":"2025-06-24 07:47:10","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":32629,"visible":true,"origin":"","legend":"\u003cp\u003eCannibalism percentage by lesion type (PGCG, non-aggressive CGCG, aggressive CGCG)\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-6600945/v1/6742819a1f7f587936158a73.png"},{"id":102863506,"identity":"d3e85735-566e-41b7-ad60-b3bed547ef7b","added_by":"auto","created_at":"2026-02-17 16:26:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1840739,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6600945/v1/d24847f1-5999-4585-9343-d8046f44bf72.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cellular cannibalism in central and peripheral giant cell granuloma","fulltext":[{"header":"Background","content":"\u003cp\u003ePeripheral Giant Cell Granuloma (PGCG) is a relatively common tumor-like growth in the oral cavity. It is likely not a true neoplasm, but rather a reactive lesion resulting from localized irritation or trauma. PGCG bears close microscopic resemblance to Central Giant Cell Granuloma (CGCG), and some pathologists believe it may represent the soft tissue counterpart of this intraosseous lesion(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCGCG is an intraosseous lesion of unknown etiology. There has been considerable debate over whether this lesion represents a reactive process or a benign neoplasm. Specifically, genetic studies have identified recurrent somatic mutations in TRPV4, KRAS, or FGFR1 in approximately 70% of the cases examined. These mutations activate the Ras-MAPK pathway and appear to be significant drivers in the development of the disease. Interestingly, similar mutations that activate this pathway have been identified in many other conditions that cause the proliferation of giant cells in the oral cavity(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe cellular phenomenon in which a living cell is internalized by another viable cell represents a remarkable biological event. The study of cell-in-cell phenomena began with Lewis\u0026rsquo;s interest in understanding his observations of a non-phagocytic process in which one cell appeared to engulf another. Some of the known forms of this phenomenon include Emperipolesis, Cellular Cannibalism and Entosis(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEmperipolesis is a condition in which hematopoietic cells, including neutrophils, lymphocytes, and plasma cells, are observed in a viable and intact state within the cytoplasm of a host cell such as a megakaryocyte, monocyte, endothelial cell, fibroblast, or even a malignant cell, without causing any damage. In this phenomenon, since both the engulfing and internalized cells remain alive, there are no physiological or morphological consequences for either of them.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eIn Entosis, a cell engulfs another cell of the same type. Although the internalized cells are initially viable, most eventually undergo a non-apoptotic form of cell death that requires autophagy-related proteins. This phenomenon has been proposed as a cell-in-cell invasive process with a physiological role in eliminating cells that have detached from a substrate(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCannibalism is a closely related phenomenon known as cellular self-consumption or homotypic cell engulfment. The term \u0026ldquo;cannibalism\u0026rdquo; originates from the Spanish word \u003cem\u003ecan\u0026iacute;bal\u003c/em\u003e, referring to human cannibalism\u0026mdash;a claim associated with the Carib people. In Greek, it is called anthropophagy, meaning a human consuming other humans. Cellular cannibalism also occurs at the cellular level in humans, defined as the ability of one cell to engulf another living cell of the same or different type (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). It is also described as a larger cell engulfing a slightly smaller one within its cytoplasm. Cellular cannibalism has been reported in various cancers, including bladder cancer, breast cancer, lung cancer, gastric cancer, and oral squamous cell carcinoma (OSCC), and it is significantly associated with anaplasia, tumor invasion, histological grading, and metastatic potential(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn cellular cannibalism, one cell becomes trapped within another and is enclosed in a vacuolated space. This process displaces the nucleus of the host cell toward the periphery. Consequently, Leyden referred to the cells exhibiting this phenomenon as \"bird-eye cells\" (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe mechanism of cellular cannibalism is attributed to metabolic alterations in malignant tumor cells, which enable them to engulf other tumor cells under unfavorable conditions such as hypoxia, nutrient deprivation, and acidic environments\u0026mdash;thus supporting their survival and progression. In some instances, a malignant cell that has engulfed another may itself be internalized by a third cell, a phenomenon referred to as complex cannibalism. Cannibalistic giant cells and stromal cells express histiocytic markers, while the internalized cells lack Bcl-2 expression, indicating that cell death in the engulfed cells occurs via apoptosis(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCellular cannibalism, in addition to being observed in various types of cancers, has also been noted in lesions containing giant cells. These lesions include giant cell tumor of tendon sheath (localized type), CGCG, and PGCG in the oral cavity. Available evidence suggests that the increased frequency of cellular cannibalism in these lesions may indicate enhanced metabolic activity of giant cells and may be associated with more aggressive behavior of these lesions(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe aim of the present study is to assess the frequency of cellular cannibalism in CGCG and PGCG lesions. Given that cellular cannibalism is a common feature in many lesions containing giant cells and that there are limited studies on its potential impact on the biological behavior of these lesions, further investigation of this phenomenon could be crucial in evaluating the aggressiveness and clinical prognosis of these lesions. Furthermore, since these morphological features can be easily identified under a light microscope, they may help predict the behavior of these lesions and assist in selecting the appropriate treatment approach, without incurring any additional costs.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eCase selection\u003c/h2\u003e \u003cp\u003ePatient records from the Department of Oral and Maxillofacial Pathology at Shahid Beheshti University of Medical Sciences were reviewed over a 10-year period from 2014 to 2023. All cases diagnosed with PGCG and CGCG were included. Patients with incomplete records (i.e., missing more than one demographic detail) or unavailable histological slides were excluded from the study. Initially, 143 patient records were identified. After applying the inclusion criteria, 125 cases were included in the study. This study was approved by the Ethics Committee of Shahid Beheshti Dental School under the code IR.SBMU.DRC.REC.1403.020 and was conducted in compliance with declaration of Helsinki (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCriterion for aggressive and non-aggressive CGCG\u003c/h3\u003e\n\u003cp\u003eLesions were classified into aggressive and non-aggressive categories based on the criteria established by Chuong et al.(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) and supported by several subsequent studies evaluating the biological behavior of CGCG (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn this study, non-aggressive lesions were characterized by minimal or no symptoms, slow growth, absence of root resorption or cortical perforation, and low recurrence tendency.\u003c/p\u003e \u003cp\u003eIn contrast, aggressive lesions presented with pain, rapid growth, root resorption, cortical perforation, and a higher likelihood of recurrence.\u003c/p\u003e\n\u003ch3\u003eQuantification of cannibalistic cells\u003c/h3\u003e\n\u003cp\u003eQuantification of cannibalistic giant cells (GCs) was performed on hematoxylin and eosin (H\u0026amp;E)-stained sections. Since this phenomenon is readily identifiable in routine staining, additional assessments such as immunohistochemistry (IHC) were deemed unnecessary.\u003c/p\u003e \u003cp\u003eThe slides were examined under high-power magnification (\u0026times;400). A zigzag (battlefield) method was employed to prevent double-counting of individual cells. In each section, 100 multinucleated giant cells were evaluated, and the number of cannibalistic cells was recorded as a percentage. Only the GCs located in the central mass of the lesion were considered; any GCs in contact with the bone surface were excluded from analysis to avoid including osteoclasts.\u003c/p\u003e\n\u003ch3\u003eIdentification of cannibalistic cells\u003c/h3\u003e\n\u003cp\u003eCannibalistic giant cells exhibited partial or complete engulfment of stromal tumor cells(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In cases of partial cannibalism, formation of pseudopodia by giant cells was observed. At the contact site between the mononuclear cell and the membrane of the giant cell, a small invagination in the membrane of the giant cell was noted.\u003c/p\u003e \u003cp\u003eIn complete cannibalism, the engulfed cells were entirely internalized within the cytoplasm of the giant cells and were surrounded by a clear halo. These internalized cells often showed apoptotic features, such as nuclear degradation and increased cytoplasmic density.\u003c/p\u003e \u003cp\u003eSince giant cells arise from the fusion of mononuclear cells, it may be hypothesized that the cannibalistic process is associated with the cellular fusion events involved in giant cell formation. However, the distinct morphological characteristics described above allow for a clear distinction between cell cannibalism and cell fusion.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe normality of data distribution was assessed using the Shapiro-Wilk test, and homogeneity of variances was evaluated using Levene's test. Based on the sample size in each group and the results of these tests, the mean percentage of cellular cannibalism between the two lesions (PGCG and CGCG) was compared using the Independent Samples t-test. For comparisons among the three groups (PGCG, aggressive CGCG, and non-aggressive CGCG), One-Way ANOVA followed by Tukey\u0026rsquo;s HSD post-hoc test was applied.\u003c/p\u003e \u003cp\u003eTo evaluate the effect of independent variables on the percentage of cannibalistic giant cells in each lesion type, a Generalized Linear Model (GLM) was used. The distribution of gender across lesion types was analyzed using the Pearson Chi-Square test. All statistical analyses were performed using SPSS version 26, and the significance level was set at α\u0026thinsp;=\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAmong 125 cases with adequate documentation and accessible histopathologic slides, there were 50.4% males and 49.6% females(PGCG: 52.7% male and 47.3% female, aggressive CGCG: 43.5% male and 56.5% female, and non-aggressive CGCG: 45.5% male and 54.5% female)\u003c/p\u003e \u003cp\u003eThe mean age of the patients was 38.29\u0026thinsp;\u0026plusmn;\u0026thinsp;19.18 years old (ranging from 5 to 83 years. PGCG:40.21\u0026thinsp;\u0026plusmn;\u0026thinsp;19.99, aggressive CGCG: 36.30\u0026thinsp;\u0026plusmn;\u0026thinsp;14.95, and non-aggressive CGCG: 26.55\u0026thinsp;\u0026plusmn;\u0026thinsp;16.60).\u003c/p\u003e \u003cp\u003eAmong the PGCG cases, 61 lesions (67%) occurred in the mandibular gingiva and 30 (33%) in the maxillary gingiva. Among the non-aggressive CGCG cases, 7 were located in the mandible and 4 in the maxilla. Among the aggressive CGCG samples, 20 lesions were found in the mandible and 3 in the maxilla.\u003c/p\u003e \u003cp\u003eCannibalism was found in all the cases (100%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e,\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The findings indicate that the mean cellular cannibalism in the CGCG group is significantly higher than in the PGCG group(P-value: 0.003) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The difference between PGCG and aggressive CGCG was also statistically significant(P-value: 0.002). Although the frequency of cellular cannibalism was higher in aggressive CGCG compared to the non-aggressive type, this difference was not statistically significant. Similarly, the frequency of cannibalism in non-aggressive CGCG lesions was higher than that in PGCG; however, this difference also did not reach statistical significance (P-value: 0.882)(Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Cannibalism of two cells or of several cells was also seen.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCannibalism percentage by lesion type (PGCG, CGCG)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMean cannibalistic\u003c/p\u003e \u003cp\u003ecell frequency\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePGCG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e13.41\u0026thinsp;\u0026plusmn;\u0026thinsp;8.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCGCG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e18.68\u0026thinsp;\u0026plusmn;\u0026thinsp;10.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe radiographic findings indicate that border type (defined vs. undefined) and locularity (unilocular vs. multilocular) do not have a statistically significant effect on the percentage of cellular cannibalism in both aggressive CGCG and non-aggressive CGCG lesions (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The effect of CGCG lesions on the bone cortex was also evaluated, with the most significant observed effect being expansion, thinning, and simultaneous perforation of the cortex.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRadiographic findings and cannibalism percentage by lesion type (non-aggressive CGCG, aggressive CGCG)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eRadiographic border\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003elocularity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eradiographic.size (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ecannibalism percentage\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003edefined\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUndefined\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eunilocular\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003emultilocular\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enon Aggressive CGCG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e2.86\u0026thinsp;\u0026plusmn;\u0026thinsp;2.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e13.29\u0026thinsp;\u0026plusmn;\u0026thinsp;8.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAggressive CGCG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e4.10\u0026thinsp;\u0026plusmn;\u0026thinsp;1.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e19.65\u0026thinsp;\u0026plusmn;\u0026thinsp;10.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAlthough radiographic information was available for all cases, the actual radiographic images were accessible in only 27 cases. The mean radiographic size of aggressive lesions was larger than that of non-aggressive lesions. Additionally, radiographic size did not show a significant effect on the percentage of cellular cannibalism in aggressive CGCG lesions, but it did in non-aggressive CGCG lesions. Specifically, for every 1 cm increase in size within this group, a roughly 3% increase in cellular cannibalism was observed.\u003c/p\u003e \u003cp\u003eNo significant differences were observed in mean age or gender distribution across PGCG and CGCG subtypes. Multivariate analysis revealed no significant effect of age, gender, or lesion location on the percentage of cellular cannibalism in PGCG and non-aggressive CGCG. However, in aggressive CGCG, lesion location was significantly associated with cannibalism frequency (P\u0026thinsp;=\u0026thinsp;0.021), with higher percentages in maxillary lesions.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCellular cannibalism is defined as a process in which a larger cell engulfs a smaller cell within its cytoplasm (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn this study, all the samples (100%) exhibited cellular cannibalism. Furthermore, the frequency of cellular cannibalism was significantly higher in CGCG compared to PGCG. This finding is consistent with the results of the studies by Sarode et al. and Urs et al. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Although the number of samples in the present study is greater than in the Sarode study, the alignment of the results remains consistent.\u003c/p\u003e \u003cp\u003eIn the study by Sarode et al., it was observed that the frequency of occurrence of cannibalistic giant cells in aggressive CGCG was significantly higher than in non-aggressive CGCG (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). This finding was also confirmed in Sarode's subsequent study(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Similarly, the findings of the study by Urs et al. were consistent with previous research (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). These results led the authors of these studies to propose cellular cannibalism as a potential feature in assessing the aggressive behavior of CGCG. The findings of the present study were also in agreement with these results, as the mean cellular cannibalism in aggressive CGCG (20.57\u0026thinsp;\u0026plusmn;\u0026thinsp;10.47) was higher than in non-aggressive CGCG (14.73\u0026thinsp;\u0026plusmn;\u0026thinsp;8.33); however, this difference was not statistically significant. Although the clinical criteria used to differentiate these two groups in our study were similar to those in the previous studies, several factors may explain this difference. One such factor could be the difference in the number of cases examined in the various studies. A larger sample size in our study may have reduced the type I error probability, resulting in the lack of a statistically significant difference. Furthermore, biological differences between the study populations could be another influencing factor. Genetic, environmental, and biological factors in different populations can impact the pathological characteristics of lesions.\u003c/p\u003e \u003cp\u003eIn the present study, we investigated the effect of variables such as gender, age, and lesion location on the frequency of occurrence of cannibalistic giant cells in PGCG, aggressive CGCG, and non-aggressive CGCG. While previous studies provided information on the age, gender, and location of the lesions in their samples (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), they did not specifically assess the potential effects of these variables on the frequency of cellular cannibalism. Our findings showed that the frequency of cellular cannibalism in aggressive CGCG lesions occurring in the maxilla was higher than in those located in the mandible. This observation, considering the anatomical and biological factors associated with each region, can be explained.\u003c/p\u003e \u003cp\u003eAccording to Lange's study, the mechanism of cellular cannibalism in PGCG and CGCG lesions differs from that in tumor lesions. In these types of lesions, giant cells originate from the monocyte-macrophage lineage and function similarly to osteoclasts (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Therefore, giant cells in PGCG and CGCG inherently possess phagocytic capabilities, which is the key factor behind the occurrence of the cannibalism of stromal tumor cells(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). One possible explanation for the higher frequency of cellular cannibalism in maxillary CGCG lesions compared to mandibular lesions is the difference in blood supply to these two regions. The maxilla, due to its unique anatomical structure, receives more blood flow than the mandible, which could directly affect the density and activity of blood-derived cells, including cannibalistic giant cells. Since these cells are directly derived from the monocyte-macrophage lineage, increased blood supply may lead to a higher number and activity of these cells in maxillary lesions. This could help explain the findings of the present study; however, further studies are needed for definitive confirmation.\u003c/p\u003e \u003cp\u003eAnother aspect examined in our study was the analysis of radiographic features of aggressive and non-aggressive CGCG lesions, including border, locularity, and radiographic size, as well as the relationship between these variables and the frequency of cellular cannibalism. Data analysis revealed that in non-aggressive CGCG lesions, for every 1 cm increase in the radiographic size of the lesion, the frequency of cellular cannibalism increases by approximately 3%. This finding is consistent with the results of previous studies by Sarode (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). In their studies, it was observed that, firstly, the size of aggressive lesions was, on average, larger than that of non-aggressive lesions, and secondly, the frequency of cannibalism in aggressive lesions was significantly higher than in the non-aggressive type. The analysis of the findings in our study indicates that as CGCG lesions progress from the non-aggressive type to the aggressive type, as defined by clinical criteria, the frequency of cellular cannibalism also shows an increasing trend. This finding is physiologically significant and may serve as a potential marker for evaluating the biological behavior of the lesion as it progresses from a non-aggressive to an aggressive state, warranting further investigation.\u003c/p\u003e \u003cp\u003eMultiple studies have investigated the possibility of predicting the aggressive behavior of cancers based on the frequency of cellular cannibalism in microscopic observations(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Research conducted by Jain, Sarode, and Rocha has all shown that more aggressive lesions with higher grades in oral squamous cell carcinoma (OSCC) exhibit a higher frequency of cellular cannibalism. These findings confirm that cellular cannibalism can be considered a reliable predictive marker for the aggressive behavior of OSCC and its potential for metastasis (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Additionally, one study mentioned that cellular cannibalism is also observed in high-metastatic potential osteosarcomas (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe pathogenesis of cellular cannibalism in malignant tumors seems to be linked to the tumor cells' efforts to survive in adverse environmental conditions, such as high acidity, hypoxia, and nutrient deficiency(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The acidic environment plays a key role in activating proteolytic enzymes, which are directly involved in invasion, metastasis, and the selection of cells that are resistant to these conditions (cannibalistic cells) (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). However, this mechanism is not directly applicable to benign lesions such as PGCG and CGCG.\u003c/p\u003e \u003cp\u003eAccording to the study by Lange, as mentioned earlier, cellular cannibalism in PGCG and CGCG lesions is more due to the intrinsic characteristics of the cells rather than a mechanism of adaptation to adverse environmental conditions. (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) However, the findings of Sarode's studies have shown that the increase in the number of cannibalistic giant cells in PGCG and CGCG may indicate higher metabolic activity in these cells, and this metabolic increase could be related to the more aggressive biological behavior of these lesions (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis study was limited by a relatively small sample size, missing clinical data, and the unavailability or poor quality of some histologic slides, which may affect the generalizability of the findings. Additionally, the lack of longitudinal follow-up limited our ability to assess the prognostic significance of cellular cannibalism. Future research with larger, more homogenous samples and the use of immunohistochemical techniques is recommended to better understand the underlying mechanisms and potential prognostic value of this phenomenon.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe findings of this study highlight the potential role of cellular cannibalism as a pathological marker in evaluating the biological behavior of CGCG and PGCG. Specifically, an increase in the size of non-aggressive CGCG lesions was associated with an increased frequency of cellular cannibalism, which may potentially indicate a gradual progression of these lesions towards more aggressive forms.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003ePGCG: Peripheral Giant Cell Granuloma\u003c/p\u003e\n\u003cp\u003eCGCG: Central Giant Cell Granuloma\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was ethically approved by the ethics committee of Shahid Beheshti University of Medical Sciences (IR.SBMU.DRC.REC.1403.020) and was conducted\u0026nbsp;in compliance with declaration of Helsinki. As this retrospective study involved anonymized patient records with no direct contact with individuals and there is no personal images or clinical details of participants, patient\u0026rsquo;s informed consent was waived by Shahid Beheshti University of Medical Sciences Ethic Committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e: Not Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e:\u0026nbsp;This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e:\u0026nbsp;SAM participated in the conception and design of the study, acquisition of data, analysis of data, critical revision, and final approval\u003cstrong\u003e\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003eof the manuscript.\u003c/p\u003e\n\u003cp\u003eZAF participated in the conception and design of the study, acquisition of data, analysis of data, drafting of the article, and final approval\u003cstrong\u003e\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003eof the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e Not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBoşca AB, Şovrea AS, Miclăuş V, Ruxanda F, Mihu CM, Melincovici CS, et al. Diagnostic and therapeutic approaches in oral cavity granulomas based on new data concerning their origin and pathogenesis. Rom J Morphol Embryol. 2018;59(3):679\u0026ndash;90.\u003c/li\u003e\n\u003cli\u003eUrs AB, Yaming P, Malhotra R. An insight into the cannibalistic behavior of giant cell granulomas of the jaws. Journal of oral and Maxillofacial Pathology. 2018;22(3):449.\u003c/li\u003e\n\u003cli\u003eKruse-L\u0026ouml;sler B, Diallo R, Gaertner C, Mischke K-L, Joos U, Kleinheinz J. Central giant cell granuloma of the jaws: a clinical, radiologic, and histopathologic study of 26 cases. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology. 2006;101(3):346\u0026ndash;54.\u003c/li\u003e\n\u003cli\u003eBarresi V, Branca G, Ieni A, Rigoli L, Tuccari G, Caruso RA. Phagocytosis (cannibalism) of apoptotic neutrophils by tumor cells in gastric micropapillary carcinomas. World Journal of Gastroenterology: WJG. 2015;21(18):5548.\u003c/li\u003e\n\u003cli\u003eSarode SC, Sarode GS. Cellular cannibalism in central and peripheral giant cell granuloma of the oral cavity can predict biological behavior of the lesion. Journal of oral pathology \u0026amp; medicine. 2014;43(6):459\u0026ndash;63.\u003c/li\u003e\n\u003cli\u003eJain M. An overview on\u0026quot; cellular cannibalism\u0026rdquo; with special reference to oral squamous cell carcinoma. Experimental oncology. 2015.\u003c/li\u003e\n\u003cli\u003eGupta N, Jadhav K, Shah V. Emperipolesis, entosis and cell cannibalism: Demystifying the cloud. Journal of Oral and Maxillofacial Pathology. 2017;21(1):92\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eAssociation WM. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Jama. 2013;310(20):2191\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003eChuong R, Kaban LB, Kozakewich H, Perez-Atayde A. Central giant cell lesions of the jaws: a clinicopathologic study. Journal of oral and maxillofacial surgery. 1986;44(9):708\u0026ndash;13.\u003c/li\u003e\n\u003cli\u003eSarode GS, Sarode SC, Gawande S, Patil S, Anand R, Patil SG, et al. Cellular cannibalism in giant cells of central giant cell granuloma of jaw bones and giant cell tumors of long bones. Journal of Investigative and Clinical Dentistry. 2017;8(2):e12214.\u003c/li\u003e\n\u003cli\u003ede Lange J, van den Akker HP, van den Berg H. Central giant cell granuloma of the jaw: a review of the literature with emphasis on therapy options. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology. 2007;104(5):603\u0026ndash;15.\u003c/li\u003e\n\u003cli\u003eSarode SC, Sarode GS. Neutrophil‐tumor cell cannibalism in oral squamous cell carcinoma. Journal of oral pathology \u0026amp; medicine. 2014;43(6):454\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eSiquara da Rocha LdO, Souza BSdF, Lambert DW, Gurgel Rocha CdA. Cell-in-cell events in oral squamous cell carcinoma. Frontiers in Oncology. 2022;12:931092.\u003c/li\u003e\n\u003cli\u003eZargaran M. Cellular Cannibalism: Suggesting a Histopathological Parameter for Predicting Metastasis of Osteosarcoma in Future Studies. Asian Pac J Cancer Prev. 2021;22(7):1985\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eFais S. Cannibalism: a way to feed on metastatic tumors. Cancer letters. 2007;258(2):155\u0026ndash;64.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Cannibalism, Peripheral giant cell granuloma, Giant Cell Granuloma, Aggressive","lastPublishedDoi":"10.21203/rs.3.rs-6600945/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6600945/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCellular cannibalism is observed in many lesions containing giant cells, including Peripheral Giant Cell Granuloma (PGCG) and Central Giant Cell Granuloma (CGCG). However, limited information exists on its role in prognosticating the behavior of these lesions. This study aimed to assess the frequency of cellular cannibalism in PGCG and CGCG of the oral cavity.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA total of 125 samples with complete clinical and radiographic data were included. Sections were examined under \u0026times;400 magnification. A total of 100 giant cells were analyzed per section, and the percentage of cannibalistic cells was recorded. Only giant cells in the central tumor mass were assessed, excluding those near the bone to avoid counting osteoclasts. Data were analyzed using SPSS version 26. Statistical tests included Shapiro\u0026ndash;Wilk, Levene\u0026rsquo;s test, Independent Samples t-test, one-way ANOVA with Tukey\u0026rsquo;s HSD post-hoc test, Generalized Linear Model (GLM), and Pearson Chi-Square.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOf the 125 cases, 50.4% were male and 49.6% were female, with a mean age of 38.29\u0026thinsp;\u0026plusmn;\u0026thinsp;19.18 years. Ninety-one samples were PGCG, and 34 were CGCG (11 non-aggressive, 23 aggressive). All samples showed cellular cannibalism)100%). The mean cellular cannibalism in CGCG (18.68\u0026thinsp;\u0026plusmn;\u0026thinsp;10.09) was significantly higher than in PGCG (13.41\u0026thinsp;\u0026plusmn;\u0026thinsp;8.22)(P-value: 0.003). Additionally, aggressive CGCG had a higher mean of cellular cannibalism than non-aggressive CGCG, though this difference was not statistically significant(P-value: 0.163).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis study suggests that cellular cannibalism may be a potential pathological indicator in evaluating the biological behavior of CGCG and PGCG.\u003c/p\u003e","manuscriptTitle":"Cellular cannibalism in central and peripheral giant cell granuloma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-24 07:47:06","doi":"10.21203/rs.3.rs-6600945/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"32e36673-bd64-4952-b9ea-58a365f23846","owner":[],"postedDate":"June 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-17T16:26:01+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-24 07:47:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6600945","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6600945","identity":"rs-6600945","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}