Oral Focal Epithelial Hyperplasia in a Patient with Graft-versus-host Disease: A Case Report

Oral Focal Epithelial Hyperplasia in a Patient with Graft-versus-host Disease: 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 Oral Focal Epithelial Hyperplasia in a Patient with Graft-versus-host Disease: A Case Report Jiaqi Huang, Qiaozhi Jiang, Jiaxuan Liu, Guocheng Mei, Renchuan Tao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6217913/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Jul, 2025 Read the published version in BMC Oral Health → Version 1 posted 13 You are reading this latest preprint version Abstract Patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT) frequently experience immunodeficiency, predisposing them to graft-versus-host disease (GVHD) and viral infection. The oral cavity is a common organ affected by chronic GVHD(cGVHD), which can lead to the development of secondary malignant tumors such as verruciform xanthoma and oral squamous cell carcinoma (OSCC). Focal epithelial hyperplasia (FEH), an uncommon and asymptomatic condition caused by human papillomavirus (HPV) types 13 or 32, can affect the oral mucosa. This case report describes a patient with cGVHD following allo-HSCT who developed extensive FEH in the oral mucosa. This observation underscores the importance of regular oral examinations for transplant recipients, particularly those with cGVHD, to monitor HPV infection and the potential development of FEH. Oral focal epithelial hyperplasia Hematopoietic stem cell transplantation Graft-versus-host Disease case report Figures Figure 1 Figure 2 Introduction Allogenetic hematopoietic stem cell transplantation (allo-HSCT) is an effective means to treat malignant hematological diseases such as leukemia [ 5 ]. Graft-versus-host disease (GVHD) is a common and serious complication. The oral cavity is one of the common organs affected by cGVHD. In addition to the characteristic reticular white stripe lesions, dry mouth and erythema lesions were the most common manifestations of oral cGVHD. Patients with oral cGVHD are prone to fungal and herpes virus infections as well as secondary malignant tumors such as verruciform xanthoma and oral squamous cell carcinoma (OSCC) [ 6 , 7 ]. Focal epithelial hyperplasia (FEH), also known as Heck's disease, is a ondition associated with human papillomavirus (HPV) types 13 or 32. It was first described in 1965 based on the observations of isolated or multiple soft papular and nodular eruptions on the oral mucosa of Navajo Xavante Indian and Alaska Eskimo children [ 1 , 2 , 3 ]. An etiological link has been established between HPV infection and FEH. Clinically, FEH manifests as multiple or single pink mucosal papules, typically measuring 1–10 mm in diameter [ 4 ]. No reports of secondary FEH in oral cGVHD have been presented. Here, we firstly report a case of a patient with oral cGVHD who developed extensive oral FEH, which was manifested as P16 positive and had a favorable prognosis after surgical resection and skin grafting. Our case indicates that patients with oral cGVHD might have higher risk to HPV infection and extensive FEH. Stomatologists should be vigilant to such suspicious patients, make early diagnoses and treatments, and enhance the prognosis and quality of life of patients. Case report In October 2020, a 46-year-old male presented at our department with a chief complaint of persistent oral mucosal swelling for approximately one and a half years, The swelling had begun to increase rapidly over the preceding six months. A previous biopsy had been inconclusive. His medical history revealed that he had underwent allo-HSCT in 1996 following combined chemotherapy and total body irradiation (TBI) for the treatment of acute lymphoblastic leukemia (ALL). His HLA-matched sibling donor was his younger brother. Post-transplantation, there was no evidence of acute GVHD (aGVHD), but cyclosporine A was administered for GVHD prophylaxis for six months. Subsequently, the patient developed cutaneous cGVHD. Later, he experienced oral ulceration accompanied by significant pain and was diagnosed with oral cGVHD, which gradually improved over the course of a year. On physical examination, a well-circumscribed, asymptomatic, exophytic tumor was observed on the right buccal mucosa and hard palate, characterized by white granular papules on the surface (Fig. 1 A-C). We recommended surgical intervention for this condition. In November 2020, the patient underwent tumor resection, abdominal free skin grafting, and biofilm implantation (Fig. 1 D-F). Histopathological examination revealed verrucous hyperplasia of the surface epithelial hyperplasia with downward keratinized clefts. Keratinized pearls were observed within the epithelial nail processes, ndicative of acanthosis change. Papillary hyperplasia was observed in certain areas of the epithelium, with superficial cells frequently exhibiting hollow cell-like alterations and occasional mitotic figures. The lamina propria demonstrated varying degrees of lymphocyte infiltration. (Fig. 2 A, B) Based on these findings, the pathologic diagnosis was consistent with FEH. Immunohistochemical analysis showed positive staining for HPV marker p16 and programmed cell death-ligand 1 (PD-L1), characterized by dense brown nuclear immunoreactivity (Fig. 2 C-F). Discussion For patients with hematopoietic malignancies, allo-HSCT represents a critically important therapeutic option. Post-transplant oral complications frequently include chronic graft-versus-host disease (cGVHD) and secondary viral, fungal, and bacterial infections [ 12 ]. Among them, viral infections remain a major cause of post-transplantation morbidity and mortality in allo-HSCT recipients [ 9 , 10 ]. HPV infection following transplantation is more prevalent in the female genitalia compared to the oral cavity, leading to a relative lack of attention to oral HPV infection from both clinicians and patients [ 11 , 13 ]. A previous study showed that three patients post HSCT exhibited papillomatous lesions indicative of HPV infection alongside cGVHD features characterized by dense subepithelial lymphoid infiltration, suggesting that a cGVHD condition may facilitate HPV infection [ 14 ]. Previous studies have shown an association between FEH and immune deficiency. Specifically, FEH has been documented in two patients with leukocyte adhesion deficiency and in some adults infected with HIV following immunosuppression therapy, indicating an increased likelihood of HPV and FEH infections in immunocompromised individuals [ 8 ]. Although the interaction between HPV and systemic immunosuppression therapy remains not fully elucidated, it is known that HPV can lead to persistent infection under systemic immunosuppression, which cannot be cleared by the compromised immune system, thereby promoting mucosal damage and tumor development [ 15 ]. We report a case of atypical clinical features of HPV infection following allo-HSCT. The final diagnosis was based on clinical oral examination and pathological findings. Immunohistochemical examination revealed strong positive of p16 in FEH tissue, suggested HPV infection, which may explain the broader extent and faster progression of FEH lesions in this patient compared to previously reported cases. Studies have indicated that the activation of PD-L1 checkpoint inhibitors may increase the risk of GVHD [ 16 ]. One of the key mechanisms for evading immune surveillance involves the overexpression of PD-L1 in tumor cells. Previous studies have shown that PD-L1 may play a role in evading immune surveillance during persistent HPV infection and malignant progression [ 17 , 18 , 19 ]. In oropharyngeal cancer and OSCC, HPV infection is closely associated with the expression of PD-L1 [ 17 , 20 , 21 ]. In our case, strong PD-L1 positivity was observed, which may contribute to HPV infection and pathological progression. The management of FEH is not always necessary as these lesions are often asymptomatic and may spontaneously regress over a period of months to years without undergoing malignant transformation. The first-line treatments for FEH typically include surgical excision, cryotherapy, CO2 laser ablation, electrocoagulation, or electrodessication [ 23 , 24 ]. Among these options, surgical excision is the most commonly utilized method. Topical or systemic interferon has been reported to offer potential benefits, particularly in case of diffuse involvement. Other therapeutic modalities that have been explored include imiquimod 5% cream and systemic retinoids such as acitretin [ 22 , 25 ]. In our case, due to the rapid progression and extensive involvement of the lesion, which occupied the entire right cheek, surgical resection was deemed necessary. This case underscores the importance of recognizing that the immune status of patients following allo-HSCT may render them more susceptible to HPV infection. Particularly, patients with oral cGVHD are at an increased risk for developing FEH, and the disease progression can be rapid. Consequently, dentists should advise regular examinations for these patients to facilitate early diagnosis and treatment of any suspicious lesions, thereby potentially improving prognosis. Abbreviations allo-HSCT: allogeneic hematopoietic stem cell transplantation; GVHD: graft-versus-host disease; cGVHD: chronic GVHD; OSCC: oral squamous cell carcinoma; FEH: Focal epithelial hyperplasia; HPV: human papillomavirus; TBI: total body irradiation; ALL: acute lymphoblastic leukemia; PD-L1: programmed cell death-ligand 1; HE: hematoxylin and eosin Declarations Ethics approval and consent to participate Not applicable Consent for publication A written informed consent for publication was obtained from the patient to publish all clinical details and any accompanying images. Availability of data and materials The data used to support the findings of this study are available from the corresponding author upon request. Competing Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding This study was supported by the National Natural Science Foundation of China(No.82370959, 82160180), Youth Science Foundation Project of Guangxi Natural Science Foundation(No.2024GXNSFBA010284), Key Project of Guangxi Natural Science Foundation (2023GXNSFDA026018), Youth Science Foundation Project of Guangxi Medical University Natural Science Foundation(GXMUYSF202431) and First-class discipline innovation-driven talent program of Guangxi Medical University. The funding organization played role in the data collection of this case report. Authors’ contributions Jiaqi Huang and Qiaozhi Jiang designed the case report and wrote the main manuscript text. Jiaqi Huang and Jiaxuan Liu prepared figures 2. Jiaqi Huang and Guocheng Mei prepared figures 1. Renchuan Tao mainly supervised the work and revised the main manuscript. All authors reviewed the manuscript. Acknowledgements Not applicable References Pfister H, Heltich J, Runne U, Chilf GN. Characterization of human papillomavirus type 13 from focal epithelial Heck lesions. J Virol 1983; 47:363-6. Archard HO, Heck JW, Stanley HR. Focal epithelial hyperplasia: an unusual oral mucosal lesion found in Indian children. Oral Surg Oral Med Oral Pathol 1965;20:201-12. Moerman M, Danielides VG, Nousia CS, Van Wanzeele F, Forsyth R, Vermeersch H. Recurrent focal epithelial hyperplasia due to HPV13 in an HIV positive patient. Dermatology 2001;203:339-41. Said AK, Leao JC, Fedele S, Porter SR. Focal epithelial hyperplasia-an update. J Oral Pathol Med . 2013;42(6):435-442. Tefferi A. Primary myelofibrosis: 2021 update on diagnosis, risk stratification and management[J]. Am J Hematol, 2021, 96(1):145-162. Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report[J]. Biol Blood Marrow Transplant, 2015, 21(3):389-401. Atsuta Y, Suzuki R, Yamashita T, et al. Continuing increased risk of oral/esophageal cancer after allogeneic hematopoietic stem cell transplantation in adults in association with chronic graft-versus-host disease[J]. Ann Oncol, 2014, 25(2):435-441. Artac H, Göktürk B, Bozdemir SE, et al. Late-onset adenosine deaminase deficiency presenting with Heck's disease. Eur J Pediatr . 2010;169(8):1033-1036. doi:10.1007/s00431-009-1131-9 T zannou I, Papadopoulou A, Naik S, et al. Off-the-Shelf Virus-Specific T Cells to Treat BK Virus, Human Herpesvirus 6, Cytomegalovirus, Epstein-Barr Virus, and Adenovirus Infections After Allogeneic Hematopoietic Stem-Cell Transplantation. J Clin Oncol. 2017;35(31):3547-3557. Epstein JB, Gharapetian S, Rejali AR, et al. Complex management of resistant oral herpes simplex virus infection following hematopoietic stem cell transplantation: potential role of topical cidofovir. Support Care Cancer. 2016;24:3603-3606. Elad S, Ranna V, Ariyawardana A, et al. Viral Infections Section, Oral Care Study Group, Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO). A systematic review of oral herpetic viral infections in cancer patients: commonly used outcome measures and interventions. Support Care Cancer. 2017;25:687-700. Ramos GA, Piragibe MMM, Moreira MCR, et al. Polymicrobial infection of the oral mucosa after hematopoietic stem cell transplantation. Case report. Hematol Transfus Cell Ther. 2019;41:360-364 Bauer D, Tüchler R, Lawitschka A, Dörfler D. Human papillomavirus in female adolescents and young adults after allogeneic hematopoietic stem cell transplantation-Not a problem prior to coitarche. Transpl Infect Dis. 2020;22(4):e13307. Socié G, Scieux C, Gluckman E, et al. Squamous cell carcinomas after allogeneic bone marrow transplantation for aplastic anemia: further evidence of a multistep process. Transplantation.1998;66:667–670 Laffort C, Le Deist F, Favre M, et al. Severe cutaneous papillomavirus disease after haemopoietic stem-cell transplantation in patients with severe combined immune deficiency caused by common gammac cytokine receptor subunit or JAK-3 deficiency. Lancet. 2004;363(9426):2051-2054. Kasai S, Itonaga H, Niino D, et al. Programmed death 1 ligand (PD-L1) in solid cancers after allogeneic hematopoietic stem cell transplantation: a retrospective analysis by the Nagasaki Transplant Group [published correction appears in Int J Hematol. 2020 Dec;112(6):906. A.M. Hong, P. Ferguson, T. Dodds, D. Jones, M. Li, J. Yang, et al., Significant association of PD-L1 expression with human papillomavirus positivity and its prognostic impact in oropharyngeal cancer, Oral Oncol 92 (2019) 33–39. O.C. Ukpo, W.L. Thorstad, J.S. Lewis Jr., B7-H1 expression model for immune evasion in human papillomavirus-related oropharyngeal squamous cell carcinoma, Head Neck Pathol 7 (2013) 113–121. S. Allouch, A. Malki, A. Allouch, I. Gupta, S. Vranic, A.E. Al Moustafa, High-risk HPV oncoproteins and PD-1/PD-L1 interplay in human cervical cancer: recent evidence and future directions, Front. Oncol. 10 (2020) 914. J. He, X.F. Chen, M.G. Xu, J. Zhao, Relationship of programmed death ligand-1expression with clinicopathological features and prognosis in patients with oral squamous cell carcinoma: a meta-analysis, Arch. Oral Biol. 114 (2020), 104717. A.M. Hong, R.E. Vilain, S. Romanes, J. Yang, E. Smith, D. Jones, et al., PD-L1 expression in tonsillar cancer is associated with human papillomavirus positivity and improved survival: implications for anti-PD1 clinical trials, Oncotarget 7 (2016) 77010–77020. Bozca, B.; Ozbudak, I.; Alpsoy, E. A case of Heck’s disease with primary intestinal lymphangiectasia treated with imiquimod.Indian J. Dermatol. Venereol. Leprol. 2020, 86, 724–725. Puriene, A.; Rimkevicius, A.; Gaigalas, M. Focal Epithelial Hyperplasia: Case Report. Stomatologija 2011, 13, 102–106. Nallanchakrava, S.; Sreebala, N.; LNU, B.; Sindgi, F. Laser Excision of Focal Epithelial Hyperplasia (Heck’s Disease): A Rare Case Report. Int. J. Clin. Pediatr. Dent. 2018, 11, 526–528. Vilmer C, Cavelier-Balloy B, Pinquier L, Blanc F, Dubertret L. Focal epithelial hyperplasia and multifocal human papilloma virus infection in an HIV-seropositive man. J Am Acad Dermatol 1994; 30: 497–8. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 01 Jul, 2025 Read the published version in BMC Oral Health → Version 1 posted Editorial decision: Revision requested 09 Apr, 2025 Reviews received at journal 08 Apr, 2025 Reviewers agreed at journal 06 Apr, 2025 Reviews received at journal 06 Apr, 2025 Reviewers agreed at journal 04 Apr, 2025 Reviewers agreed at journal 01 Apr, 2025 Reviews received at journal 31 Mar, 2025 Reviewers agreed at journal 31 Mar, 2025 Reviewers invited by journal 31 Mar, 2025 Editor assigned by journal 31 Mar, 2025 Editor invited by journal 31 Mar, 2025 Submission checks completed at journal 30 Mar, 2025 First submitted to journal 30 Mar, 2025 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. 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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-6217913","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":440478110,"identity":"da02edd3-f2aa-4970-9d9f-8463e782700e","order_by":0,"name":"Jiaqi Huang","email":"","orcid":"","institution":"Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jiaqi","middleName":"","lastName":"Huang","suffix":""},{"id":440478111,"identity":"f94f59e5-0b6c-44fd-864f-9f2236f45b89","order_by":1,"name":"Qiaozhi Jiang","email":"","orcid":"","institution":"Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qiaozhi","middleName":"","lastName":"Jiang","suffix":""},{"id":440478112,"identity":"6548592e-fb56-42cc-85e6-6889ce560a8b","order_by":2,"name":"Jiaxuan Liu","email":"","orcid":"","institution":"Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jiaxuan","middleName":"","lastName":"Liu","suffix":""},{"id":440478113,"identity":"1da0df2f-29d9-4152-b0ea-3da0529d1382","order_by":3,"name":"Guocheng Mei","email":"","orcid":"","institution":"Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Guocheng","middleName":"","lastName":"Mei","suffix":""},{"id":440478114,"identity":"31e71edf-bd8d-420a-bc32-58b7f27cc315","order_by":4,"name":"Renchuan Tao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8ElEQVRIiWNgGAWjYBCDBCBmfADlGOBVyoOkhRmmlHgtbBJEabFnP3zsw8cddnkGx88eq/zati2xgb15mwRDzR3ctvCkJc+ceSa52OBMXtptmTO3Ext4jpVJMBx7hsdhOcbMvG0HEjccyDG7LVEB1CKRYybB2HAYtxb+N8bMf0Fazr8xK5YwAGqRf0NAiwTQFkaQlhs5ZowfwLbwENBy41kyY29bcuLMG2+MpRnO3DZu40krtkg4hlsLe3/yYYafbXaJfedzDD/+bLst289+eOONDzW4taAAZlAssYFYCcRpAKaYH8SqHAWjYBSMghEFAI0BV28NEAD2AAAAAElFTkSuQmCC","orcid":"","institution":"Guangxi Medical University","correspondingAuthor":true,"prefix":"","firstName":"Renchuan","middleName":"","lastName":"Tao","suffix":""}],"badges":[],"createdAt":"2025-03-13 08:23:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6217913/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6217913/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12903-025-06333-3","type":"published","date":"2025-07-01T15:57:17+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82010299,"identity":"7bd55833-a227-4779-af35-fa982f606e5e","added_by":"auto","created_at":"2025-05-06 01:29:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":384454,"visible":true,"origin":"","legend":"\u003cp\u003eA-C, Clinical manifestations on the oral mucosa of the patient. Extensive acanthoid lesions were observed in his buccal and palate mucosa on the initial visit in October 2020.\u003c/p\u003e\n\u003cp\u003eD-F, The process of the tumor resection and skin graft surgery. D) Resection of the tumor with partial excision of the right buccal region. E) Harvesting of a non-vascularized abdominal flap for transplantation. \u0026nbsp;F) Reconstruction of the right buccal region using the transplanted flap.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6217913/v1/788c3a7fd756ee3c5edc8927.png"},{"id":82010300,"identity":"91493710-f990-40a3-b99e-773e4ac505e6","added_by":"auto","created_at":"2025-05-06 01:29:06","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1426486,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathological and immunohistochemical characteristics of oral tissue specimens obtained from the patient. A, B) Photomicrograph of hematoxylin and eosin (HE)-stained histological sections illustrating the predominant morphological features observed in the lesion. Superficial cells frequently exhibited concave nuclear changes and occasional mitotic figures. The lamina propria demonstrated varying degrees of lymphocytic infiltration. Surface epithelial hyperplasia was verrucous, characterized by downward keratinized clefts and the presence of keratinized pearls within the epithelial rete pegs, indicative of acanthosis. In certain regions, the epithelium displayed a papillary configuration. (C,D) Immunohistochemical staining positive expression of p16 in the epithelium (magnification, A ×100, B ×200). (E, F) Additionally, immunohistochemical staining revealed positive expression of PD-L1 in the epithelium. (magnification, A ×100, B ×200).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6217913/v1/22236d37a8a7fefbcbf80267.png"},{"id":86179156,"identity":"2da1ed3c-ee95-4548-a0df-7a9a0c6f323b","added_by":"auto","created_at":"2025-07-07 16:16:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2152264,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6217913/v1/8c5270d1-d792-4cc1-a453-1519eac8adf2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eOral Focal Epithelial Hyperplasia in a Patient with Graft-versus-host Disease: A Case Report\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAllogenetic hematopoietic stem cell transplantation (allo-HSCT) is an effective means to treat malignant hematological diseases such as leukemia [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Graft-versus-host disease (GVHD) is a common and serious complication. The oral cavity is one of the common organs affected by cGVHD. In addition to the characteristic reticular white stripe lesions, dry mouth and erythema lesions were the most common manifestations of oral cGVHD. Patients with oral cGVHD are prone to fungal and herpes virus infections as well as secondary malignant tumors such as verruciform xanthoma and oral squamous cell carcinoma (OSCC) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFocal epithelial hyperplasia (FEH), also known as Heck's disease, is a ondition associated with human papillomavirus (HPV) types 13 or 32. It was first described in 1965 based on the observations of isolated or multiple soft papular and nodular eruptions on the oral mucosa of Navajo Xavante Indian and Alaska Eskimo children [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. An etiological link has been established between HPV infection and FEH. Clinically, FEH manifests as multiple or single pink mucosal papules, typically measuring 1\u0026ndash;10 mm in diameter [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNo reports of secondary FEH in oral cGVHD have been presented. Here, we firstly report a case of a patient with oral cGVHD who developed extensive oral FEH, which was manifested as P16 positive and had a favorable prognosis after surgical resection and skin grafting. Our case indicates that patients with oral cGVHD might have higher risk to HPV infection and extensive FEH. Stomatologists should be vigilant to such suspicious patients, make early diagnoses and treatments, and enhance the prognosis and quality of life of patients.\u003c/p\u003e"},{"header":"Case report","content":"\u003cp\u003eIn October 2020, a 46-year-old male presented at our department with a chief complaint of persistent oral mucosal swelling for approximately one and a half years, The swelling had begun to increase rapidly over the preceding six months. A previous biopsy had been inconclusive. His medical history revealed that he had underwent allo-HSCT in 1996 following combined chemotherapy and total body irradiation (TBI) for the treatment of acute lymphoblastic leukemia (ALL). His HLA-matched sibling donor was his younger brother. Post-transplantation, there was no evidence of acute GVHD (aGVHD), but cyclosporine A was administered for GVHD prophylaxis for six months. Subsequently, the patient developed cutaneous cGVHD. Later, he experienced oral ulceration accompanied by significant pain and was diagnosed with oral cGVHD, which gradually improved over the course of a year. On physical examination, a well-circumscribed, asymptomatic, exophytic tumor was observed on the right buccal mucosa and hard palate, characterized by white granular papules on the surface (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA-C). We recommended surgical intervention for this condition.\u003c/p\u003e \u003cp\u003eIn November 2020, the patient underwent tumor resection, abdominal free skin grafting, and biofilm implantation (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD-F). Histopathological examination revealed verrucous hyperplasia of the surface epithelial hyperplasia with downward keratinized clefts. Keratinized pearls were observed within the epithelial nail processes, ndicative of acanthosis change. Papillary hyperplasia was observed in certain areas of the epithelium, with superficial cells frequently exhibiting hollow cell-like alterations and occasional mitotic figures. The lamina propria demonstrated varying degrees of lymphocyte infiltration. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA, B) Based on these findings, the pathologic diagnosis was consistent with FEH. Immunohistochemical analysis showed positive staining for HPV marker p16 and programmed cell death-ligand 1 (PD-L1), characterized by dense brown nuclear immunoreactivity (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC-F).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eFor patients with hematopoietic malignancies, allo-HSCT represents a critically important therapeutic option. Post-transplant oral complications frequently include chronic graft-versus-host disease (cGVHD) and secondary viral, fungal, and bacterial infections [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Among them, viral infections remain a major cause of post-transplantation morbidity and mortality in allo-HSCT recipients [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. HPV infection following transplantation is more prevalent in the female genitalia compared to the oral cavity, leading to a relative lack of attention to oral HPV infection from both clinicians and patients [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. A previous study showed that three patients post HSCT exhibited papillomatous lesions indicative of HPV infection alongside cGVHD features characterized by dense subepithelial lymphoid infiltration, suggesting that a cGVHD condition may facilitate HPV infection [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrevious studies have shown an association between FEH and immune deficiency. Specifically, FEH has been documented in two patients with leukocyte adhesion deficiency and in some adults infected with HIV following immunosuppression therapy, indicating an increased likelihood of HPV and FEH infections in immunocompromised individuals [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Although the interaction between HPV and systemic immunosuppression therapy remains not fully elucidated, it is known that HPV can lead to persistent infection under systemic immunosuppression, which cannot be cleared by the compromised immune system, thereby promoting mucosal damage and tumor development [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. We report a case of atypical clinical features of HPV infection following allo-HSCT. The final diagnosis was based on clinical oral examination and pathological findings. Immunohistochemical examination revealed strong positive of p16 in FEH tissue, suggested HPV infection, which may explain the broader extent and faster progression of FEH lesions in this patient compared to previously reported cases. Studies have indicated that the activation of PD-L1 checkpoint inhibitors may increase the risk of GVHD [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. One of the key mechanisms for evading immune surveillance involves the overexpression of PD-L1 in tumor cells. Previous studies have shown that PD-L1 may play a role in evading immune surveillance during persistent HPV infection and malignant progression [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In oropharyngeal cancer and OSCC, HPV infection is closely associated with the expression of PD-L1 [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In our case, strong PD-L1 positivity was observed, which may contribute to HPV infection and pathological progression. The management of FEH is not always necessary as these lesions are often asymptomatic and may spontaneously regress over a period of months to years without undergoing malignant transformation. The first-line treatments for FEH typically include surgical excision, cryotherapy, CO2 laser ablation, electrocoagulation, or electrodessication [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Among these options, surgical excision is the most commonly utilized method. Topical or systemic interferon has been reported to offer potential benefits, particularly in case of diffuse involvement. Other therapeutic modalities that have been explored include imiquimod 5% cream and systemic retinoids such as acitretin [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In our case, due to the rapid progression and extensive involvement of the lesion, which occupied the entire right cheek, surgical resection was deemed necessary.\u003c/p\u003e \u003cp\u003eThis case underscores the importance of recognizing that the immune status of patients following allo-HSCT may render them more susceptible to HPV infection. Particularly, patients with oral cGVHD are at an increased risk for developing FEH, and the disease progression can be rapid. Consequently, dentists should advise regular examinations for these patients to facilitate early diagnosis and treatment of any suspicious lesions, thereby potentially improving prognosis.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eallo-HSCT: allogeneic hematopoietic stem cell transplantation; GVHD: graft-versus-host disease; cGVHD: chronic GVHD; OSCC: oral squamous cell carcinoma; FEH: Focal epithelial hyperplasia; HPV: human papillomavirus; TBI: total body irradiation; ALL: acute lymphoblastic leukemia; PD-L1: programmed cell death-ligand 1; HE: hematoxylin and eosin\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA written informed consent for publication was obtained from the patient to publish all clinical details and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used to support the findings of this study are available from the corresponding author upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the National Natural Science Foundation of China(No.82370959, 82160180), Youth Science Foundation Project of Guangxi Natural Science Foundation(No.2024GXNSFBA010284), Key Project of Guangxi Natural Science Foundation (2023GXNSFDA026018), Youth Science Foundation Project of Guangxi Medical University Natural Science \u0026nbsp;Foundation(GXMUYSF202431) and First-class discipline innovation-driven talent program of Guangxi Medical University. The funding organization played role in the data collection of this case report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJiaqi Huang and Qiaozhi Jiang designed the case report and wrote the main manuscript text. Jiaqi Huang and Jiaxuan Liu prepared figures 2. Jiaqi Huang and Guocheng Mei prepared figures 1. Renchuan Tao mainly supervised the work and revised the main manuscript. All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePfister H, Heltich J, Runne U, Chilf GN. Characterization of human papillomavirus type 13 from focal epithelial Heck lesions. J Virol 1983; 47:363-6.\u003c/li\u003e\n\u003cli\u003eArchard HO, Heck JW, Stanley HR. Focal epithelial hyperplasia: an unusual oral mucosal lesion found in Indian children. Oral Surg Oral Med Oral Pathol 1965;20:201-12.\u003c/li\u003e\n\u003cli\u003eMoerman M, Danielides VG, Nousia CS, Van Wanzeele F, Forsyth R, Vermeersch H. Recurrent focal epithelial hyperplasia due to HPV13 in an HIV positive patient. Dermatology 2001;203:339-41.\u003c/li\u003e\n\u003cli\u003eSaid AK, Leao JC, Fedele S, Porter SR. Focal epithelial hyperplasia-an update. \u003cem\u003eJ Oral Pathol Med\u003c/em\u003e. 2013;42(6):435-442.\u003c/li\u003e\n\u003cli\u003eTefferi A. Primary myelofibrosis: 2021 update on diagnosis, risk stratification and management[J]. Am J Hematol, 2021, 96(1):145-162.\u003c/li\u003e\n\u003cli\u003eJagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report[J]. 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Complex management of resistant oral herpes simplex virus infection following hematopoietic stem cell transplantation: potential role of topical cidofovir. Support Care Cancer. 2016;24:3603-3606.\u003c/li\u003e\n\u003cli\u003eElad S, Ranna V, Ariyawardana A, et al. Viral Infections Section, Oral Care Study Group, Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO). A systematic review of oral herpetic viral infections in cancer patients: commonly used outcome measures and interventions. Support Care Cancer. 2017;25:687-700.\u003c/li\u003e\n\u003cli\u003eRamos GA, Piragibe MMM, Moreira MCR, et al. Polymicrobial infection of the oral mucosa after hematopoietic stem cell transplantation. Case report. Hematol Transfus Cell Ther. 2019;41:360-364\u003c/li\u003e\n\u003cli\u003eBauer D, T\u0026uuml;chler R, Lawitschka A, D\u0026ouml;rfler D. 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Programmed death 1 ligand (PD-L1) in solid cancers after allogeneic hematopoietic stem cell transplantation: a retrospective analysis by the Nagasaki Transplant Group [published correction appears in Int J Hematol. 2020 Dec;112(6):906.\u003c/li\u003e\n\u003cli\u003eA.M. Hong, P. Ferguson, T. Dodds, D. Jones, M. Li, J. Yang, et al., Significant association of PD-L1 expression with human papillomavirus positivity and its prognostic impact in oropharyngeal cancer, Oral Oncol 92 (2019) 33\u0026ndash;39.\u003c/li\u003e\n\u003cli\u003eO.C. Ukpo, W.L. Thorstad, J.S. Lewis Jr., B7-H1 expression model for immune evasion in human papillomavirus-related oropharyngeal squamous cell carcinoma, Head Neck Pathol 7 (2013) 113\u0026ndash;121.\u003c/li\u003e\n\u003cli\u003eS. Allouch, A. Malki, A. Allouch, I. Gupta, S. Vranic, A.E. Al Moustafa, High-risk HPV oncoproteins and PD-1/PD-L1 interplay in human cervical cancer: recent evidence and future directions, Front. 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Stomatologija 2011, 13, 102\u0026ndash;106.\u003c/li\u003e\n\u003cli\u003eNallanchakrava, S.; Sreebala, N.; LNU, B.; Sindgi, F. Laser Excision of Focal Epithelial Hyperplasia (Heck\u0026rsquo;s Disease): A Rare Case Report. Int. J. Clin. Pediatr. Dent. 2018, 11, 526\u0026ndash;528.\u003c/li\u003e\n\u003cli\u003eVilmer C, Cavelier-Balloy B, Pinquier L, Blanc F, Dubertret L. Focal epithelial hyperplasia and multifocal human papilloma virus infection in an HIV-seropositive man. J Am Acad Dermatol 1994; 30: 497\u0026ndash;8.\u003c/li\u003e\n\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-oral-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ohea","sideBox":"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ohea/default.aspx","title":"BMC Oral Health","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Oral focal epithelial hyperplasia, Hematopoietic stem cell transplantation, Graft-versus-host Disease, case report","lastPublishedDoi":"10.21203/rs.3.rs-6217913/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6217913/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePatients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT) frequently experience immunodeficiency, predisposing them to graft-versus-host disease (GVHD) and viral infection. The oral cavity is a common organ affected by chronic GVHD(cGVHD), which can lead to the development of secondary malignant tumors such as verruciform xanthoma and oral squamous cell carcinoma (OSCC). Focal epithelial hyperplasia (FEH), an uncommon and asymptomatic condition caused by human papillomavirus (HPV) types 13 or 32, can affect the oral mucosa. This case report describes a patient with cGVHD following allo-HSCT who developed extensive FEH in the oral mucosa. This observation underscores the importance of regular oral examinations for transplant recipients, particularly those with cGVHD, to monitor HPV infection and the potential development of FEH.\u003c/p\u003e","manuscriptTitle":"Oral Focal Epithelial Hyperplasia in a Patient with Graft-versus-host Disease: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-06 01:29:01","doi":"10.21203/rs.3.rs-6217913/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-09T07:50:22+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-08T14:38:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"237438099642896585633119250861571463976","date":"2025-04-06T21:14:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-06T18:14:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"267285862308541528483816599493019136370","date":"2025-04-04T07:17:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"186586014553406810033501741681453546213","date":"2025-04-01T04:21:33+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-01T03:52:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"124244513974186741250514681786393131870","date":"2025-03-31T22:45:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-31T19:42:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-31T19:40:48+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-03-31T08:30:09+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-30T10:05:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Oral Health","date":"2025-03-30T10:04:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-oral-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ohea","sideBox":"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ohea/default.aspx","title":"BMC Oral Health","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d312489a-eb56-48b7-9ef3-bab779c6062e","owner":[],"postedDate":"May 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-07T16:06:25+00:00","versionOfRecord":{"articleIdentity":"rs-6217913","link":"https://doi.org/10.1186/s12903-025-06333-3","journal":{"identity":"bmc-oral-health","isVorOnly":false,"title":"BMC Oral Health"},"publishedOn":"2025-07-01 15:57:17","publishedOnDateReadable":"July 1st, 2025"},"versionCreatedAt":"2025-05-06 01:29:01","video":"","vorDoi":"10.1186/s12903-025-06333-3","vorDoiUrl":"https://doi.org/10.1186/s12903-025-06333-3","workflowStages":[]},"version":"v1","identity":"rs-6217913","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6217913","identity":"rs-6217913","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}