Xanthoma Combining Osteonecrosis in Knee Joint: A Case Report

Xanthoma Combining Osteonecrosis in Knee Joint: A Case Report | 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 Case Report Xanthoma Combining Osteonecrosis in Knee Joint: A Case Report Hai Su, Yichen Gong, Lei Chen, Haojing Zhou, Hua Huang, Shengxu Yu, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3889868/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Aug, 2024 Read the published version in BMC Musculoskeletal Disorders → Version 1 posted 10 You are reading this latest preprint version Abstract Xanthoma typically occurs in the subcutaneous tissues, with rare cases of osseous xanthoma. However, the occurrence of knee joint osteonecrosis combined with xanthoma is even more uncommon. To the best of our knowledge, this is the first reported case. In this article, we describe a 50-year-old female patient who developed xanthoma on the basis of osteonecrosis of the knee joint. The primary clinical symptoms were knee joint pain and limited mobility. Despite conventional treatments for osteonecrosis, there was no significant improvement. Subsequently, she underwent arthroscopic excision of the knee joint xanthoma. Following the procedure, her VAS score decreased from 7 to 2, and knee joint mobility increased from 10-103° to 10-140°. Through our follow-up, the patient did not exhibit symptom recurrence. This case is valuable and provides a feasible therapeutic approach for future clinical applications. Xanthoma Osteonecrosis Knee Bone infarction case report Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Background Xanthoma (or yellow fibroma) is a benign proliferative lesion commonly found in patients with hyperlipidemia, primarily occurring in soft tissues such as the skin, tendons, and fascia. Pathologically, the gradual intracellular accumulation of lipids captured by specific receptors or phagocytic mechanisms leads to the presence of macrophage-like mononuclear cells, multinucleated giant cells, and a significant number of foam cells formed by macrophages 1 . Currently, the report of xanthomas in bone tissue is rare. On the other hand, osteonecrosis is a common pathological condition affecting the metaphysis or diaphysis of long bones. The etiology of osteonecrosis is not fully understood, but risk factors such as decompression sickness, glucocorticoid use, alcohol abuse, and dyslipidemia are considered contributory 2 . Clinically, osteonecrosis can manifest as joint pain and swelling 3 . However, the occurrence of xanthoma in patients with osteonecrosis of the knee joint is even more rare. To the best of our knowledge, there have been no reported cases of osteonecrosis combined with xanthoma previously. Therefore, we present a case report detailing the diagnosis and treatment process of a patient with osteonecrosis of the knee joint complicated by xanthoma. A comprehensive discussion is provided, incorporating clinical, radiological, and histopathological perspectives. Case presentation The patient, a 50-year-old female, presented to our hospital in 2018 with recurrent bilateral knee joint pain and swelling, complained about standing and walking difficulty. Specialized examination revealed tenderness around both knee joints, slightly elevated skin temperature, and a limited flexion-extension range of 10-120°. To establish a diagnosis, a bilateral knee MRI was performed, indicating osteonecrotic changes in the both knee joints(Figure 1) (Figure 2). Bone tissue biopsy was performed and the biopsy suggests osteonecrosis. Immunohistochemistry results confirmed the diagnosis of osteonecrosis, showing CKpan(-), Vim(+), CD79a(-), CD3(-), EMA(-), P53(-), and Ki-67(-) (Figure 3). Despite a four-year history of oral steroid use from 2005~2008, the distant nature of the medication led us to exclude steroid-induced causes. Regarding the treatments, intra-articular anesthesia and sodium hyaluronate injection to alleviate swelling, inflammation, pain and enhance microcirculation. Elcatonin, caltrate, vitamin D, denosumab, alendronate sodium were applied to suppress bone degradation and hyperbaric oxygen therapy. After slight improvements in patient’s symptoms, she was discharged from hospital. In 2022, the patient's left knee joint symptoms worsened while right joint never deteriorated since 2019, prompting another visit to our hospital. MRI of the left knee joint suggested osteonecrosis, synovial hyperplasia and benign hyperplastic lesion. Combining the imaging findings, we suspected a benign tumor within the knee joint, thus arthroscopic intervention was recommended. However, the patient opted to continue the current conservative treatment, including anti-osteoporosis measures, anti-inflammatory medications, and analgesic support. In 2023, the patient's left knee joint symptoms kept deteriorating, accompanied by significant swelling and movement disorder. Regarding physical examination, a positive floating patella test, and tenderness were observed. The VAS score was 7, and knee joint movement was limited to 10-103°. Muscle strength in the left lower limb was graded as IV, with reduced skin sensation in the left inguinal region. After discussed with the patient, a left knee arthroscopy performed under general anesthesia on November 10, 2023. Substantial tissue was extracted during the procedure (Figure 4). Postoperative pathology revealed chronic synovitis with synovial hyperplasia, foam cell reaction, and multinucleated giant cell reaction, suggesting xanthoma-like proliferation. Immunohistochemistry results indicated Ki-67(5%+), CD138(focal+), CD68(+), CD163(+), S-100(-), EMA(-), and CKpan(-) (Figure 5). The final diagnosis was xanthoma. Postoperatively, the left knee joint swelling and pain reduced (VAS score: 3), and flexion-extension range increased to 10-140°. The patient has a history of inflammatory pseudotumor in the orbital region and received oral prednisone 4 mg daily from 2005 to 2008. There is also a four-year history of hypertension, and currently, blood pressure is within normal range. In 2021, the patient was diagnosed as hyperlipidemia, and no medications were applied. In 2022, the patient underwent left kidney resection at our hospital. Results and Discussions The occurrence of osteonecrosis combined with xanthoma in the knee joint is an extremely rare condition, with no reported cases in previous literature. This is the first case report featuring the combination of osteonecrosis and xanthoma in knee joint. Osteonecrosis typically manifests as bone necrosis in the diaphysis and epiphysis 4 . It is commonly believed to result from local blood circulation disorders, such as thrombosis, trauma, excessive glucocorticoid use, lipid metabolism abnormalities, among other factors. Clinically, it may present with focal pain, swelling, and even restricted mobility of adjacent joints. Additionally, characteristic features of infectious diseases, such as recurrent fever and increased white blood cell count, may also be observed. Initially, we attributed the patient's symptoms to osteonecrosis. However, after conventional treatments, we observed significant improvement in the symptoms of the right knee joint, while the left knee showed less notable improvement. Subsequent MRI images revealed an abnormal mass in the knee joint (Figure 1) (Figure 2). This led us to suspect whether this abnormal mass was the cause of the symptoms. Following consent from the patient, we performed arthroscopic surgery. Postoperatively, the patient experienced gradual relief of pain in the left knee joint, with the VAS score decreased, and the range of motion increased. The postoperative pathological results confirmed the presence of xanthoma. There are currently two theories regarding the formation of xanthoma 5 . The first theory suggests that local trauma or bleeding leads to the flow of fat into surrounding tissues, subsequently engulfed by macrophages, resulting in the accumulation of fat within these cells and the eventual appearance of foam-like macrophages. Extracellular cholesterol crystals induce giant cell inflammatory reactions and fibrosis. The second theory proposes that circulating lipid nutrients in the blood of patients with autoimmune diseases may cause undifferentiated mesenchymal cells to undergo xanthoma-like transformation through a series of inflammatory reactions, followed by the accumulation of engulfed tissue cells. Studies have classified bone xanthoma as a variant change in benign or malignant lesions in the late stage of skeletal yellow tumor; secondary osseous xanthoma in type 2 or 3 hyperlipidemic patients; and primary xanthoma with normal lipid metabolism 6 . Previous research has found that high cholesterol increases osteoclast differentiation and bone resorption, potentially leading to the occurrence of osteoarthritis 7 . Additionally, some studies indicate a certain correlation between elevated triglycerides and knee joint pain 8 . In our patient, we compared bone metabolism markers before and after the increase in triglycerides. We found that bone resorption was active when triglycerides increased, while the vitality of bone formation decreased, similar to the results of previous studies (Figure 6). In our case, the patient exhibited elevated triglycerides and total cholesterol in hematological tests. Therefore, we believe that the xanthoma in this patient is attributed to hyperlipidemia. In this case, we believe that the symptoms in the patient's left knee joint may caused by xanthoma. The synovitis caused by xanthoma and the occupation within the joint led to the patient experiencing knee joint pain, limited functional activity, and an elevated level of inflammation 9,10 . Through arthroscopic surgery, after removing a significant portion of the xanthoma and synovial tissue, inflammatory factors were reduced within the knee joint, resulting in a significant improvement in the symptoms of the patient's left knee joint. Additionally, considering the correlation between xanthoma and hyperlipidemia, we advised the patient to maintain a low-fat diet in their daily life to improve their hyperlipidemia status and prevent recurrence. After discharge, we conducted a two-month follow-up and did not observe an exacerbation of knee joint pain in the patient. The VAS score was 2, and knee joint flexion and extension reached 10-150°. Through this case, when clinicians encounter similar patients, it is crucial to determine whether the patient's symptoms are caused by osteonecrosis or xanthoma. Our report may provide a feasible treatment approach for patients with osteonecrosis combined with xanthoma in knee joint. There are a few limits of the study. Current research on xanthoma is mainly focused on dermatology, and the reason for its occurrence between knee joints is still unknown. Furthermore, whether the patient's hyperlipidemia is caused by dietary factors or abnormalities in bone metabolism has not been sufficiently studied. Therefore, future research may require more animal experiments or genetic studies to explore the relationship between osteonecrosis and xanthoma and whether there is a genetic connection. However, there is currently no study explaining whether changes in bone metabolism can lead to abnormalities in lipid metabolism. Conclusion In summary, osteonecrosis combined with xanthoma in the knee joint is an exceptionally rare condition. This case suggests that, for patients with osteonecrosis combined with xanthoma, arthroscopic removal of the xanthoma in the knee joint is a feasible approach. It can alleviate knee joint pain and improve joint mobility. Considering that both conditions may manifest similar symptoms in the knee joint, it is crucial to identify their primary pathogenic causes. Declarations Funding statement The research was supported by Traditional Chinese Medicine Science and Technology Program of Zhejiang Province (No. 2023ZL367) and National Nature Science Foundation of Zhejiang Province (No.LY24H270001). Conflict of interest disclosure The authors stated that they had no interests which might be perceived as posing a conflict or bias. Patient consent statement Informed consent was obtained from all individual participants included in the study。 Consent for publication : Written Informed consent was obtained from patients to publish the study. Ethics approval statement: Approval was granted by the Ethics Committee of The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine) (Date: April 12, 2023/No. 2023-KLS-130-01). Authorship declaration: All authors listed meet the authorship criteria according to the latest guidelines of the International Committee of Medical Journal Editors, and all authors agree with the publication of the manuscript. Availability of data and materials : The datasets used and/or analyzed 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 statement: This work was financially supported by Zhejiang Provincial Project of Administration of Chinese Medicine under Grant No. 2023ZL369. Authors' contributions: Hai Su and Yichen Gong wrote the paper. Lei Chen and Haojin Zhou collected the medical record. Hua Huang, Shengxu Yu and Peijian Tong performed the surgery. Chundan Wang conducted the pathological examination. Taotao Xu funded the study and reviewed the paper. Acknowledgements: Not applicable. References Kazmi A, Frewen J, McDonald B, Davison J. O'Toole, E. Tuberous xanthoma secondary to homozygous familial hypercholesterolaemia: a life-threatening diagnosis. Clin Exp Dermatol. 2022;47:2336–8. Chang C, Greenspan A, Gershwin ME. The pathogenesis, diagnosis and clinical manifestations of steroid-induced osteonecrosis. J Autoimmun. 2020;110:102460. Gorbachova T, Melenevsky Y, Cohen M, Cerniglia BW. Osteochondral Lesions of the Knee: Differentiating the Most Common Entities at MRI. Radiographics: Rev publication Radiological Soc North Am Inc. 2018;38:1478–95. Mont MA, Marker DR, Zywiel MG, Carrino JA. Osteonecrosis of the knee and related conditions. J Am Acad Orthop Surg. 2011;19:482–94. Muthusamy KA, et al. Bilateral temporal bone xanthoma. Case report. J Neurosurg. 2008;108:361–4. Mottola E et al. Xanthoma of rib: a case report and review of the literature. J Cardiothorac Surg 18, 205, (2023). Song Y, Liu J, Zhao K, Gao L, Zhao J. Cholesterol-induced toxicity: An integrated view of the role of cholesterol in multiple diseases. Cell Metabol. 2021;33:1911–25. Pan F, Tian J, Cicuttini F, Jones G. Metabolic syndrome and trajectory of knee pain in older adults. Osteoarthr Cartil. 2020;28:45–52. Dainese P, et al. Association between knee inflammation and knee pain in patients with knee osteoarthritis: a systematic review. Osteoarthr Cartil. 2022;30:516–34. Wang X, et al. Synovitis mediates the association between bone marrow lesions and knee pain in osteoarthritis: data from the Foundation for the National Institute of Health (FNIH) Osteoarthritis Biomarkers Consortium. Osteoarthr Cartil. 2022;30:1270–7. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 24 Aug, 2024 Read the published version in BMC Musculoskeletal Disorders → Version 1 posted Editorial decision: Revision requested 07 Mar, 2024 Reviews received at journal 21 Feb, 2024 Reviewers agreed at journal 21 Feb, 2024 Reviews received at journal 14 Feb, 2024 Reviewers agreed at journal 03 Feb, 2024 Reviewers invited by journal 03 Feb, 2024 Editor assigned by journal 03 Feb, 2024 Editor invited by journal 31 Jan, 2024 Submission checks completed at journal 31 Jan, 2024 First submitted to journal 22 Jan, 2024 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. 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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-3889868","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":270192535,"identity":"b97b7723-e85f-457d-a2b3-c0878771c586","order_by":0,"name":"Hai Su","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)","correspondingAuthor":false,"prefix":"","firstName":"Hai","middleName":"","lastName":"Su","suffix":""},{"id":270192536,"identity":"5a14631e-0c0a-4a08-b7f2-8b2ecb1cb9f2","order_by":1,"name":"Yichen Gong","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)","correspondingAuthor":false,"prefix":"","firstName":"Yichen","middleName":"","lastName":"Gong","suffix":""},{"id":270192537,"identity":"ef8772c0-e951-4c33-8b8f-e69dc1b7b9d1","order_by":2,"name":"Lei Chen","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)","correspondingAuthor":false,"prefix":"","firstName":"Lei","middleName":"","lastName":"Chen","suffix":""},{"id":270192538,"identity":"9d490344-9703-45ac-93b7-ea22a383f1be","order_by":3,"name":"Haojing Zhou","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)","correspondingAuthor":false,"prefix":"","firstName":"Haojing","middleName":"","lastName":"Zhou","suffix":""},{"id":270192539,"identity":"88c9367e-3fe5-4e8b-abea-13b8dca4f74d","order_by":4,"name":"Hua Huang","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)","correspondingAuthor":false,"prefix":"","firstName":"Hua","middleName":"","lastName":"Huang","suffix":""},{"id":270192540,"identity":"013aae6c-1fa0-46d5-97c3-26f5ee3a1b36","order_by":5,"name":"Shengxu Yu","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)","correspondingAuthor":false,"prefix":"","firstName":"Shengxu","middleName":"","lastName":"Yu","suffix":""},{"id":270192541,"identity":"fb2dbdc6-ee36-46c6-bcfc-59400cc6dc95","order_by":6,"name":"Chundan Wang","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)","correspondingAuthor":false,"prefix":"","firstName":"Chundan","middleName":"","lastName":"Wang","suffix":""},{"id":270192542,"identity":"dd09419e-0c0f-4153-aea5-60b9562d49dd","order_by":7,"name":"Peijian Tong","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)","correspondingAuthor":false,"prefix":"","firstName":"Peijian","middleName":"","lastName":"Tong","suffix":""},{"id":270192543,"identity":"601398cf-eef8-4999-a788-02a44d52cb9a","order_by":8,"name":"Taotao Xu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAqElEQVRIiWNgGAWjYHACxgdQhgGxOpiZYUqJ18ImQZoWgxv5xyp/1GxLbGBv3ibBUHOHsBbJGclsNySO3U5s4DlWJsFw7BlhLfwSQC2GDUAtEjlmEowNhwlrYQNqKUgEaZF/Q6QWkC0MB8G28BCpRbLnsbFkw7Hbxm08acUWCceI0GJwPPHhxx81t2X72Q9vvPGhhggtcMAGIhJI0DAKRsEoGAWjAA8AAG8fNfK4Yx3dAAAAAElFTkSuQmCC","orcid":"","institution":"The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)","correspondingAuthor":true,"prefix":"","firstName":"Taotao","middleName":"","lastName":"Xu","suffix":""}],"badges":[],"createdAt":"2024-01-23 04:44:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3889868/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3889868/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12891-024-07776-5","type":"published","date":"2024-08-24T15:57:38+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":50513017,"identity":"1b2d686e-e43a-4f84-9f47-a7e61fc42c43","added_by":"auto","created_at":"2024-02-01 16:22:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":448641,"visible":true,"origin":"","legend":"\u003cp\u003eMRI of the left knee at different times (T1). a: Captured in the year 2018; b: preoperative, captured in the year 2022; c: postoperative, captured in the year 2023.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3889868/v1/969e0f92d64b05f1c1e4bf3a.png"},{"id":50513018,"identity":"ceb262bb-4737-45ea-b14c-2bce2b24cc43","added_by":"auto","created_at":"2024-02-01 16:22:26","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":549694,"visible":true,"origin":"","legend":"\u003cp\u003eMRI of the left knee at different times (T2). a: Captured in the year 2018; b: preoperative, captured in the year 2022; c: postoperative, captured in the year 2023.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-3889868/v1/26e141899881073421fa8859.png"},{"id":50513019,"identity":"c3ec8ea2-c9f8-4c61-9f64-47e8f7dfa638","added_by":"auto","created_at":"2024-02-01 16:22:26","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":442471,"visible":true,"origin":"","legend":"\u003cp\u003eBone tissue biopsy. Fragmented bone tissue with necrosis and fibrosis.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-3889868/v1/bdbe4fdc8a3fc1c8275496cc.png"},{"id":50513021,"identity":"6d751535-7061-4c71-bd2a-f87ee81765bd","added_by":"auto","created_at":"2024-02-01 16:22:26","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":143160,"visible":true,"origin":"","legend":"\u003cp\u003eTissue removed from the joint.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-3889868/v1/3e5ae0a7257135ed6eb5c683.png"},{"id":50513022,"identity":"8ab30767-a393-4a1b-943b-28f7f6375396","added_by":"auto","created_at":"2024-02-01 16:22:26","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":2747138,"visible":true,"origin":"","legend":"\u003cp\u003eXanthoma biopsy. Stained with H\u0026amp;E at a magnification of 10X under a microscope, there is chronic inflammation in the synovial tissue accompanied by synovial tissue hyperplasia, foam cell reaction, and multinucleated giant cell reaction, suggesting tumor-like proliferation.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-3889868/v1/6c9b0f3f2f9a07314cce7006.png"},{"id":50513882,"identity":"5f17610e-7862-4d26-8888-f5f1e79cb44a","added_by":"auto","created_at":"2024-02-01 16:30:26","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":169779,"visible":true,"origin":"","legend":"\u003cp\u003eBone metabolism and lipid metabolism. PINP: Procollagen I N-Terminal Propeptide.\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-3889868/v1/b29e23cc78dff4c4c46428d6.png"},{"id":63300266,"identity":"423bb0b4-ce80-4b30-9779-b2a9cb4710a7","added_by":"auto","created_at":"2024-08-26 16:13:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6099185,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3889868/v1/ff0ed14f-c75b-4176-b676-98a56796ae29.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Xanthoma Combining Osteonecrosis in Knee Joint: A Case Report","fulltext":[{"header":"Background","content":"\u003cp\u003eXanthoma (or yellow fibroma) is a benign proliferative lesion commonly found in patients with hyperlipidemia, primarily occurring in soft tissues such as the skin, tendons, and fascia. Pathologically, the gradual intracellular accumulation of lipids captured by specific receptors or phagocytic mechanisms leads to the presence of macrophage-like mononuclear cells, multinucleated giant cells, and a significant number of foam cells formed by macrophages\u003csup\u003e1\u003c/sup\u003e. Currently, the report of xanthomas in bone tissue is rare.\u003c/p\u003e\n\u003cp\u003eOn the other hand, osteonecrosis is a common pathological condition affecting the metaphysis or diaphysis of long bones. The etiology of osteonecrosis is not fully understood, but risk factors such as decompression sickness, glucocorticoid use, alcohol abuse, and dyslipidemia are considered contributory\u003csup\u003e2\u003c/sup\u003e. Clinically, osteonecrosis can manifest as joint pain and swelling\u003csup\u003e3\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eHowever, the occurrence of xanthoma in patients with osteonecrosis of the knee joint is even more rare. To the best of our knowledge, there have been no reported cases of osteonecrosis combined with xanthoma previously. Therefore, we present a case report detailing the diagnosis and treatment process of a patient with osteonecrosis of the knee joint complicated by xanthoma. A comprehensive discussion is provided, incorporating clinical, radiological, and histopathological perspectives.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eThe patient, a 50-year-old female, presented to our hospital in 2018 with recurrent bilateral knee joint pain and swelling, complained about standing and walking difficulty. Specialized examination revealed tenderness around both knee joints, slightly elevated skin temperature, and a limited flexion-extension range of 10-120\u0026deg;. To establish a diagnosis, a bilateral knee MRI was performed, indicating osteonecrotic changes in the both knee joints(Figure 1) (Figure 2).\u003c/p\u003e\n\u003cp\u003eBone tissue biopsy was performed and the biopsy suggests osteonecrosis. Immunohistochemistry results confirmed the diagnosis of osteonecrosis, showing CKpan(-), Vim(+), CD79a(-), CD3(-), EMA(-), P53(-), and Ki-67(-) (Figure 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDespite a four-year history of oral steroid use from 2005~2008, the distant nature of the medication led us to exclude steroid-induced causes. Regarding the treatments, intra-articular anesthesia and sodium hyaluronate injection to alleviate swelling, inflammation, pain and enhance microcirculation. Elcatonin, caltrate, vitamin D, denosumab, alendronate sodium were applied to suppress bone degradation and hyperbaric oxygen therapy. After slight improvements in patient\u0026rsquo;s symptoms, she was discharged from hospital.\u003c/p\u003e\n\u003cp\u003eIn 2022, the patient\u0026apos;s left knee joint symptoms worsened while right joint never deteriorated since 2019, prompting another visit to our hospital. MRI of the left knee joint suggested osteonecrosis, synovial hyperplasia and benign hyperplastic lesion. Combining the imaging findings, we suspected a benign tumor within the knee joint, thus arthroscopic intervention was recommended. However, the patient opted to continue the current conservative treatment, including anti-osteoporosis measures, anti-inflammatory medications, and analgesic support.\u003c/p\u003e\n\u003cp\u003eIn 2023, the patient\u0026apos;s left knee joint symptoms kept deteriorating, accompanied by significant swelling and movement disorder. Regarding physical examination, a positive floating patella test, and tenderness were observed. The VAS score was 7, and knee joint movement was limited to 10-103\u0026deg;. Muscle strength in the left lower limb was graded as IV, with reduced skin sensation in the left inguinal region. After discussed with the patient, a left knee arthroscopy performed under general anesthesia on November 10, 2023. Substantial tissue was extracted during the procedure (Figure 4).\u003c/p\u003e\n\u003cp\u003ePostoperative pathology revealed chronic synovitis with synovial hyperplasia, foam cell reaction, and multinucleated giant cell reaction, suggesting xanthoma-like proliferation. Immunohistochemistry results indicated Ki-67(5%+), CD138(focal+), CD68(+), CD163(+), S-100(-), EMA(-), and CKpan(-) (Figure 5).\u003c/p\u003e\n\u003cp\u003eThe final diagnosis was xanthoma. Postoperatively, the left knee joint swelling and pain reduced (VAS score: 3), and flexion-extension range increased to 10-140\u0026deg;.\u003c/p\u003e\n\u003cp\u003eThe patient has a history of inflammatory pseudotumor in the orbital region and received oral prednisone 4 mg daily from 2005 to 2008. There is also a four-year history of hypertension, and currently, blood pressure is within normal range. In 2021, the patient was diagnosed as hyperlipidemia, and no medications were applied. In 2022, the patient underwent left kidney resection at our hospital.\u003c/p\u003e"},{"header":"Results and Discussions","content":"\u003cp\u003eThe occurrence of osteonecrosis combined with xanthoma in the knee joint is an extremely rare condition, with no reported cases in previous literature. This is the first case report featuring the combination of osteonecrosis and xanthoma in knee joint.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOsteonecrosis typically manifests as bone necrosis in the diaphysis and epiphysis\u003csup\u003e4\u003c/sup\u003e. It is commonly believed to result from local blood circulation disorders, such as thrombosis, trauma, excessive glucocorticoid use, lipid metabolism abnormalities, among other factors. Clinically, it may present with focal pain, swelling, and even restricted mobility of adjacent joints. Additionally, characteristic features of infectious diseases, such as recurrent fever and increased white blood cell count, may also be observed. Initially, we attributed the patient\u0026apos;s symptoms to osteonecrosis. However, after conventional treatments, we observed significant improvement in the symptoms of the right knee joint, while the left knee showed less notable improvement. Subsequent MRI images revealed an abnormal mass in the knee joint (Figure 1) (Figure 2). This led us to suspect whether this abnormal mass was the cause of the symptoms. Following consent from the patient, we performed arthroscopic surgery. Postoperatively, the patient experienced gradual relief of pain in the left knee joint, with the VAS score decreased, and the range of motion increased. The postoperative pathological results confirmed the presence of xanthoma.\u003c/p\u003e\n\u003cp\u003eThere are currently two theories regarding the formation of xanthoma\u003csup\u003e5\u003c/sup\u003e. The first theory suggests that local trauma or bleeding leads to the flow of fat into surrounding tissues, subsequently engulfed by macrophages, resulting in the accumulation of fat within these cells and the eventual appearance of foam-like macrophages. Extracellular cholesterol crystals induce giant cell inflammatory reactions and fibrosis. The second theory proposes that circulating lipid nutrients in the blood of patients with autoimmune diseases may cause undifferentiated mesenchymal cells to undergo xanthoma-like transformation through a series of inflammatory reactions, followed by the accumulation of engulfed tissue cells. Studies have classified bone xanthoma as a variant change in benign or malignant lesions in the late stage of skeletal yellow tumor; secondary osseous xanthoma in type 2 or 3 hyperlipidemic patients; and primary xanthoma with normal lipid metabolism\u003csup\u003e6\u003c/sup\u003e. Previous research has found that high cholesterol increases osteoclast differentiation and bone resorption, potentially leading to the occurrence of osteoarthritis\u003csup\u003e7\u003c/sup\u003e. Additionally, some studies indicate a certain correlation between elevated triglycerides and knee joint pain\u003csup\u003e8\u003c/sup\u003e. In our patient, we compared bone metabolism markers before and after the increase in triglycerides. We found that bone resorption was active when triglycerides increased, while the vitality of bone formation decreased, similar to the results of previous studies (Figure 6).\u003c/p\u003e\n\u003cp\u003eIn our case, the patient exhibited elevated triglycerides and total cholesterol in hematological tests. Therefore, we believe that the xanthoma in this patient is attributed to hyperlipidemia.\u003c/p\u003e\n\u003cp\u003eIn this case, we believe that the symptoms in the patient\u0026apos;s left knee joint may caused by xanthoma. The synovitis caused by xanthoma and the occupation within the joint led to the patient experiencing knee joint pain, limited functional activity, and an elevated level of inflammation\u003csup\u003e9,10\u003c/sup\u003e. Through arthroscopic surgery, after removing a significant portion of the xanthoma and synovial tissue, inflammatory factors were reduced within the knee joint, resulting in a significant improvement in the symptoms of the patient\u0026apos;s left knee joint. Additionally, considering the correlation between xanthoma and hyperlipidemia, we advised the patient to maintain a low-fat diet in their daily life to improve their hyperlipidemia status and prevent recurrence. After discharge, we conducted a two-month follow-up and did not observe an exacerbation of knee joint pain in the patient. The VAS score was 2, and knee joint flexion and extension reached 10-150\u0026deg;.\u003c/p\u003e\n\u003cp\u003eThrough this case, when clinicians encounter similar patients, it is crucial to determine whether the patient\u0026apos;s symptoms are caused by osteonecrosis or xanthoma. Our report may provide a feasible treatment approach for patients with osteonecrosis combined with xanthoma in knee joint.\u003c/p\u003e\n\u003cp\u003eThere are a few limits of the study. Current research on xanthoma is mainly focused on dermatology, and the reason for its occurrence between knee joints is still unknown. Furthermore, whether the patient\u0026apos;s hyperlipidemia is caused by dietary factors or abnormalities in bone metabolism has not been sufficiently studied. Therefore, future research may require more animal experiments or genetic studies to explore the relationship between osteonecrosis and xanthoma and whether there is a genetic connection. However, there is currently no study explaining whether changes in bone metabolism can lead to abnormalities in lipid metabolism.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, osteonecrosis combined with xanthoma in the knee joint is an exceptionally rare condition. This case suggests that, for patients with osteonecrosis combined with xanthoma, arthroscopic removal of the xanthoma in the knee joint is a feasible approach. It can alleviate knee joint pain and improve joint mobility. Considering that both conditions may manifest similar symptoms in the knee joint, it is crucial to identify their primary pathogenic causes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThe research was supported by Traditional Chinese Medicine Science and Technology Program of Zhejiang Province (No. 2023ZL367) and National Nature Science Foundation of Zhejiang Province (No.LY24H270001).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest disclosure\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eThe authors stated that they had no interests which might be perceived as posing a conflict or bias.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003ePatient consent statement\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eInformed consent was obtained from all individual participants included in the study。\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e Written Informed consent was obtained from patients to publish the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval statement:\u0026nbsp;\u003c/strong\u003eApproval was granted by the Ethics Committee of The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine) (Date: April 12, 2023/No. 2023-KLS-130-01).\u003cbr\u003e\u003cstrong\u003eAuthorship declaration:\u0026nbsp;\u003c/strong\u003eAll authors listed meet the authorship criteria according to the latest guidelines of the International Committee of Medical Journal Editors, and all authors agree with the publication of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding statement: This work was financially supported by Zhejiang Provincial Project of Administration of Chinese Medicine under Grant No. 2023ZL369.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u0026nbsp;\u003c/strong\u003e\u003cem\u003eHai Su\u003c/em\u003e and \u003cem\u003eYichen Gong\u003c/em\u003e wrote the paper. \u003cem\u003eLei Chen\u0026nbsp;\u003c/em\u003eand \u003cem\u003eHaojin Zhou\u0026nbsp;\u003c/em\u003ecollected the medical record. \u003cem\u003eHua Huang, Shengxu Yu\u003c/em\u003e and \u003cem\u003ePeijian Tong\u003c/em\u003e performed the surgery. \u003cem\u003eChundan Wang\u003c/em\u003e conducted the pathological examination. \u003cem\u003eTaotao Xu\u003c/em\u003e funded the study and reviewed the paper.\u003c/p\u003e\n\u003ch4\u003eAcknowledgements: Not applicable.\u003c/h4\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKazmi A, Frewen J, McDonald B, Davison J. O'Toole, E. Tuberous xanthoma secondary to homozygous familial hypercholesterolaemia: a life-threatening diagnosis. Clin Exp Dermatol. 2022;47:2336\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChang C, Greenspan A, Gershwin ME. The pathogenesis, diagnosis and clinical manifestations of steroid-induced osteonecrosis. J Autoimmun. 2020;110:102460.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGorbachova T, Melenevsky Y, Cohen M, Cerniglia BW. Osteochondral Lesions of the Knee: Differentiating the Most Common Entities at MRI. Radiographics: Rev publication Radiological Soc North Am Inc. 2018;38:1478\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMont MA, Marker DR, Zywiel MG, Carrino JA. Osteonecrosis of the knee and related conditions. J Am Acad Orthop Surg. 2011;19:482\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMuthusamy KA, et al. Bilateral temporal bone xanthoma. Case report. J Neurosurg. 2008;108:361\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMottola E et al. Xanthoma of rib: a case report and review of the literature. J Cardiothorac Surg 18, 205, (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSong Y, Liu J, Zhao K, Gao L, Zhao J. Cholesterol-induced toxicity: An integrated view of the role of cholesterol in multiple diseases. Cell Metabol. 2021;33:1911\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePan F, Tian J, Cicuttini F, Jones G. Metabolic syndrome and trajectory of knee pain in older adults. Osteoarthr Cartil. 2020;28:45\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDainese P, et al. Association between knee inflammation and knee pain in patients with knee osteoarthritis: a systematic review. Osteoarthr Cartil. 2022;30:516\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang X, et al. Synovitis mediates the association between bone marrow lesions and knee pain in osteoarthritis: data from the Foundation for the National Institute of Health (FNIH) Osteoarthritis Biomarkers Consortium. Osteoarthr Cartil. 2022;30:1270\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-musculoskeletal-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmsd","sideBox":"Learn more about [BMC Musculoskeletal Disorders](http://bmcmusculoskeletdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://author-welcome.nature.com/12891","title":"BMC Musculoskeletal Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Xanthoma, Osteonecrosis, Knee, Bone infarction, case report","lastPublishedDoi":"10.21203/rs.3.rs-3889868/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3889868/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Xanthoma typically occurs in the subcutaneous tissues, with rare cases of osseous xanthoma. However, the occurrence of knee joint osteonecrosis combined with xanthoma is even more uncommon. To the best of our knowledge, this is the first reported case. In this article, we describe a 50-year-old female patient who developed xanthoma on the basis of osteonecrosis of the knee joint. The primary clinical symptoms were knee joint pain and limited mobility. Despite conventional treatments for osteonecrosis, there was no significant improvement. Subsequently, she underwent arthroscopic excision of the knee joint xanthoma. Following the procedure, her VAS score decreased from 7 to 2, and knee joint mobility increased from 10-103° to 10-140°. Through our follow-up, the patient did not exhibit symptom recurrence. This case is valuable and provides a feasible therapeutic approach for future clinical applications.","manuscriptTitle":"Xanthoma Combining Osteonecrosis in Knee Joint: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-01 16:22:21","doi":"10.21203/rs.3.rs-3889868/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-03-07T12:19:23+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-02-21T15:04:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"81e03e1b-e3a6-4d39-8512-e268aa3d2002","date":"2024-02-21T14:19:37+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-02-14T11:58:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"b32faadf-3db7-471e-809c-212846287a9d","date":"2024-02-04T04:17:25+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-02-04T02:42:10+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-02-04T02:37:33+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-01-31T07:16:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-01-31T07:12:49+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Musculoskeletal Disorders","date":"2024-01-23T04:38:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-musculoskeletal-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmsd","sideBox":"Learn more about [BMC Musculoskeletal Disorders](http://bmcmusculoskeletdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://author-welcome.nature.com/12891","title":"BMC Musculoskeletal Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e94ab7b2-7855-48e2-b9a5-ce28d03a4355","owner":[],"postedDate":"February 1st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-26T16:03:33+00:00","versionOfRecord":{"articleIdentity":"rs-3889868","link":"https://doi.org/10.1186/s12891-024-07776-5","journal":{"identity":"bmc-musculoskeletal-disorders","isVorOnly":false,"title":"BMC Musculoskeletal Disorders"},"publishedOn":"2024-08-24 15:57:38","publishedOnDateReadable":"August 24th, 2024"},"versionCreatedAt":"2024-02-01 16:22:21","video":"","vorDoi":"10.1186/s12891-024-07776-5","vorDoiUrl":"https://doi.org/10.1186/s12891-024-07776-5","workflowStages":[]},"version":"v1","identity":"rs-3889868","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3889868","identity":"rs-3889868","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}