Homeostatic medicine, new thinking on etiological treatment of large cyst-like periapical lesions: Case series and literature review

Homeostatic medicine, new thinking on etiological treatment of large cyst-like periapical lesions: Case series and literature review | 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 Homeostatic medicine, new thinking on etiological treatment of large cyst-like periapical lesions: Case series and literature review Dongjia Lin, Fang Huang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6760722/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objectives: The view that auxiliary surgical resection is needed for the large cystic periapical lesions (LCPLs) treatment is based more on theoretical hypotheses than clinical evidence. This study questions the necessity of surgical treatment of LCPLs via providing strong clinical evidence and new theoretical supports from the perspective of homeostatic medicine (HM). Methods: Nonsurgical treatment was performed in two LCPL cases (lesion diameter > 20 mm), and long-term follow-up was obtained (> 8 years, up to 18 years in one case). The PubMed, Web of Science, CINAHL, Embase and Cochrane CENTRAL databases were electronically searched (01-01-2003 to 07-31-2023). Studies on LCPLs with at least six months of postoperative review according to clinical and radiological criteria were summarized. Meta-analysis of the non-surgical treatment success rate was performed with RStudio software. Results: Two LCPL cases showed complete periapical lesion resolution after non-surgical treatment. Fourteen studies fulfilled the inclusion criteria, with no obvious publication bias. The worldwide nonsurgical treatment success rate of LCPLs was estimated as 89% (95% CI=85%-94%) in 288 teeth. Conclusions: The pathological hypothesis of true and bay cysts is meaningless for clinical decision-making of LCPLs. Nonsurgical root canal treatment removes the bacterial infection and can achieve successful outcomes even if large bone defects exist. Periapical diseases Large cystic periapical lesions Homeostatic medicine Etiological treatment Case report Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Highlights • There is no clinical therapeutic significance in distinguishing between true and false apical cysts. • Nonsurgical treatment removes bacterial infection and can achieve successful outcomes of large cystic periapical lesions. • Surgical treatment is not a necessary option for large cystic periapical lesions. • Homeostatic medicine would be one of the important directions for the future development of medicine. 1. Introduction Large cystic periapical lesions (LCPLs) are diagnosed by one or more nonvital teeth being affected, area greater than 200 mm 2 , and straw-coloured exudates upon root canal or lesion aspiration. These lesions are related to soft tissue swelling (buccal, palatal, or both), intraoral sinus draining and cortical bone expansion/erosion [1, 2]. The occurrence of LCPLs is extremely rare. Therefore, its treatment remains controversial. First, the incidence of apical cysts is 100% with a radiographic lesion area over 200 mm 2 [3]. The apical cyst has been identified as a true cyst, a completely separate cavity with no continuousness or linking to the root canal, or a bay (also known as a pocket) cyst, communicating openly with the root canal system with the root apex protruding into it [4]. True and bay cysts are half of the various periapical cysts [4, 5]. Traditional opinion assumed that true cyst was a self-sustaining lesion that cannot repair after nonsurgical treatment [4, 6–10]. Second, defects longer than 10 mm or resulting in more than 50% loss of the boundary of the bone are considered critical. Such defects may disturb the natural healing phases and prevent bone from healing without surgical intervention [11–13]. Thus, the treatment of LCPLs is often adjunctive to surgical resection [14]. But is this necessary? An apical periodontitis cannot form by itself [15]. First, apical homeostasis is facilitated by a balanced immune response in root canals. Microbiome dysbiosis in root canals can lead to local inflammatory immune response in periodontal tissue, which ultimately results in apical disorder [16]. Second, an apical cyst is categorized as an inflammatory and not a neoplastic lesion in the World Health Organization (WHO) Histological Typing of Odontogenic Tumours, Jaw Cysts, and Allied Lesions [17–19]. Different from epithelial cells of an odontogenic keratocyst [20, 21], the basal cells of an apical cyst are not able to self-proliferation without stimulus by peripheral signals such as inflammatory mediators, proinflammatory cytokines, and growth factors produced by various immune cells [22]. It is self-limiting and reversible if the bacterial is removed by nonsurgical treatment [23–25]. These pathological features of LCPLs contradict the hypothesis of true cysts, which are not conducive to clinical decision-making. In fact, apical infections are essentially the same as systemic infections. For example, under the conditions of COVID-19 infection, the body temperature set point can increase to 40°C, a procedure acknowledged as fever. However, the set point for body temperature could be completely reversed when the infection is controlled. In this situation, fever helps the body deal with peripheral infection. Similarly, under the conditions of bacterial infection, a healthy periapical tissue can turn into an inflammatory state, a process known as periapical lesion. However, the inflammation could be totally reversed when the infection is controlled. In this situation, inflammation helps the body deal with intense infection. Homeostatic regulation is the capability of the human body to adjust biological indicators to fit different requirements under certain environments [26, 27]. Homeostatic medicine (HM) is a new science that studies the maintenance of homeostasis in the body. Unlike traditional symptomatic treatment, HM focuses more on etiological treatment of the disease [28]. It emphasizes the nature of diseases and guides us to rethink with a biologic awareness of LCPLs. That is, if the cause can be removed with nonsurgical treatment, surgical intervention may not be necessary for LCPLs. Also, differentiation of true or bay cysts would be of no clinical implication. Thus, the study aims to provide strong clinical support and question whether surgical treatment is necessary for LCPLs or not via two long-term follow-up LCPL cases and a literature review. The null hypothesis is that LCPLs can respond successfully to non-surgical endodontic treatment. The histopathological type and size of LCPLs maybe not be the determining factors for surgical treatment. 2. Case series presentation 2.1 Case one A 16-year-old girl presented with repeated episodes of painful swelling in the maxillary anterior sulcus for 2 months. The patient reported trauma 8 years prior without any treatment of the teeth. Intraoral examination revealed painful swelling of the labial mucosa adjacent to teeth 11 and 21. Discomfort in teeth 11 and 21 was found on vertical percussion and apical palpation, while adjacent teeth presented normal responses. Teeth 11 and 21 were discoloured, but areas of decay and periodontal pockets were absent. A periapical radiograph (Fig. 1A-B) showed an extensive radiolucent area extending from the distal aspect of tooth 11, including the periapical region of tooth 21 and reaching the distal surface of tooth 22. The extent of the periapical radiolucent area was 25 × 22 mm, with a thin radiopaque line forming a circumscribed, well-defined boundary. Meanwhile, sparse white obturation and an open apex (Nolla stage 9) were observed in teeth 11 and 21. A diagnosis of symptomatic LCPL of traumatic origin in teeth 11 and 21 was established. Mineral trioxide aggregate (MTA) apical barrier and root canal treatment (RCT) was performed on teeth 11 and 21 after obtaining informed consent from the patient’s parents. After gaining coronal access under a rubber dam on teeth 11 and 21, the previous obturation in the root canals was removed by retreatment files (ProTaper, Dentsply Sirona, USA). A clear, straw-coloured fluid exuded continuously, and the canals were unable to dry. After copious irrigation with 5.25% sodium hypochlorite, the root canal was filled with calcium hydroxide paste (LELE ® , Shanghai Eryi & Zhangjiang Biomaterial Co., Ltd., Shanghai, China). Between appointments, the coronal cavity was temporarily filled with Caviton (GC Co., Tokyo, Japan). The intracanal dressing was maintained for two weeks. After the second dressing change, there was no pain or mucosal swelling. Gutta-percha was used to measure the working length of tooth 11 (Fig. 1B). Following these procedures, the MTA apical barrier was applied (Fig. 1C) under surgical and dental microscopes (M525 F20, Leica, USA). After two days, the root canals were permanently obturated using Cortisomol sealer (Morita, Osaka, Honshu, Japan) with warm vertical condensation technique (Fig. 1D). One week later, teeth 11 and 21 were permanently restored with composite resin (Z350 XT, 3 M, USA). 2.2 Case two A 12-year-old boy presented with severe pain in the condylar area for 2 days. The patient reported trauma 8 years prior without any treatment of the teeth. Extraoral examination showed painful swelling in the condylar area (Fig. 2A). Intraoral examination revealed gingival swelling and overflow adjacent to teeth 32-42 (Fig. 2B). Symptoms on vertical percussion and apical palpation occurred in teeth 32-42, while adjacent teeth presented normal responses. Severe tooth mobility (degree 3) was observed in teeth 31 and 41, and moderate tooth mobility (degree 2) was observed in teeth 32 and 42. Electronic (Vitality Scanner; Analytic Technology, Glendora, CA, USA) and thermal (Endo-Ice; The Hygenic Corporation, OH, USA) pulp sensitivity tests were negative for teeth 31 and 41, while teeth 32 and 42 presented dullness. Areas of decay and periodontal pockets were absent. A periapical radiograph and dental panoramic tomograph (DPT) showed a widened periodontal ligament space for teeth 31 and 41 (Fig. 2C-D). A diagnosis was established as an acute apical abscess of traumatic origin in teeth 31 and 41. RCT was performed for teeth 31 and 41 after obtaining informed consent from the patient’s parents. After access cavity preparation, yellow pus exuded from the canals of teeth 31 and 41. Drainage was performed for two days until discharge through the canal ceased. When the pain and swelling subsided and drainage ceased, the root canals were finally instrumented using nickel-titanium rotary files (ProFile®, Dentsply Maillefer, New York, PA, US) and copious irrigation with 5.25% sodium hypochlorite under rubber dam isolation. Calcium hydroxides paste (LELE ® , Shanghai Eryi & Zhangjiang Biomaterial Co., Ltd., Shanghai, China) was applied to the canals. Between appointments, the coronal cavity was temporarily filled with Caviton (GC Co., Tokyo, Japan). Two weeks later, the root canals were obturated with Cortisomol sealer (Morita, Osaka, Honshu, Japan) with warm vertical condensation technique (Dentsply Sirona, USA, Fig. 2E) and restored with composite resin (Z350 XT, 3 M, USA) after one week. However, the patient returned with recurrent painful swelling in the mandibular anterior gingiva after one year. A periapical radiograph and DPT demonstrated a large radiolucent lesion around teeth 32 to 42 (Fig. 2F-G). Cone-beam computed tomography (CBCT) showed a large, well-defined expansive radiolucent lesion at the apices of teeth 32-42 (Fig. 3A-B). The maximal size of the radiographic lesion was 20 × 15 × 17 mm. The labial cortical plate was completely disrupted in localized areas (Fig. 3A-B). Unexpectedly, a missed lingual canal was observed in both teeth 31 and 41 (Fig. 3C). The affected teeth showed no obvious root resorption. A diagnosis was established to be previously treated symptomatic apical periodontitis. Retreatment was discussed with the patient’s parents. A microscopic endodontic technique was performed to remove the gutta-percha from the labial root canals and probe the lingual root canals of teeth 31 and 41 with minimal invasion (Fig. 4A). After instrumenting missed lingual root canals, calcium hydroxides paste (LELE ® , Shanghai Eryi & Zhangjiang Biomaterial Co., Ltd., Shanghai, China) was applied to the canals (Fig. 4B). The follow-up radiographs showed continuous bone formation at 3 months (Fig. 4C), 6 months (Fig. 4D), and 9 months (Fig. 4E-G). One-year follow-up CBCT showed bony repair of the labial cortical plate (Fig. 5). The lesion size was reduced to 4.5 × 9.5 × 9.5 mm. Finally, permanent obturation of the canals was performed (Fig. 4H-I). One week later, teeth 31 and 41 were permanently restored with composite resin (Z350 XT, 3 M, USA). 2.3 Literature review and analysis Longitudinal clinical studies in English studying the outcomes of nonsurgical treatments for LCPLs published from January 1, 2003, to July 31, 2023, were recognized using the following electronic databases: PubMed, Web of Science, CINAHL, Embase and Cochrane CENTRAL. Keywords and search strategies provided by Burns [29] and Ng et al. [30, 31] were applied to improve the search strategy of our study (Table S1). Studies were removed for duplicate using Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia; available at: www.covidence.org). 2.3.1 Inclusion criteria Clinical studies (mainly case reports and prospective cohort studies) were selected according to revisions of the inclusion criteria used by Burns [29] and Ng et al. [30, 31]. 1. Data allowing for tooth-level outcome assessment. 2. Lesion size of at least 10 mm in diameter. 3. Sample size provided. 4. At least 6 months of postoperative follow-up. 5. Success determined according to clinical and radiographic criteria. a. Clinical success demarcated as the absence of clinical symptoms, as outlined in the individual study. b. Radiographic success differentiated by either “strict” or “loose” criteria. (i) “Strict” radiographic criteria of success: the absence of periapical radiolucency on follow-up assessment. (ii) “Loose” radiographic criteria of success: decrease in the size of periapical radiolucency on follow-up assessment. 2.3.2 Study selection and data extraction The title and abstract screening were performed independently by two reviewers (Lin and Huang). General information (author, year, title, journal); study design (sample size, follow-up period, outcome criteria and assessment); noted medical conditions of patients; and pre, intra- and postoperative factors were extracted. 2.3.3 Analysis To investigate the success rate of nonsurgical treatment for LCPLs, meta-analysis was chosen. To estimate the variance and heterogeneity among trials, the Higgins I 2 test was employed, with a value between 25 and 50% considered to indicate slight heterogeneity; between 50% and 75%, moderate heterogeneity; and >75%, high heterogeneity [32]. 3. Results 3.1 Case one The follow-up at 3 months (Fig. 1 E) and 12 months (Fig. 1 F) showed a “loose” outcome. The follow-up at 7 years (Fig. 1 G), 8 years (Fig. 1 H), 11 years (Fig. 1 I) and 18 years (Fig. 1 J) showed radiographic evidence of a “strict” outcome. 3.2 Case two At the one-year follow-up after retreatment, CBCT depicted “strict” outcomes on sagittal sections (Fig. 5 A), coronal sections (Fig. 5 B), and axial sections (Fig. 5 C) of teeth 31 and 41. The follow-up at 8 years (Fig. 5 E) showed a stable outcome. 3.3 Literature review and analysis The electronic searches generated 4878 results: PubMed (2123), Web of Science (884), CINAHL (726), Embase (929) and Cochrane CENTRAL (216). 3604 abstracts remained after removing duplicates. 26 studies were selected for full text review after abstract screening. 12 studies were excluded for the reasons given in Table S2 after full text review. Finally, 14 studies fulfilled the inclusion criteria and were analysed. Table 1 includes seven articles in which the lesion size was between 10 mm and 20 mm in diameter. Table 2 includes another seven articles in which the lesion size was over 20 mm in diameter. Of the 14 included studies, 12 (85.7%) were case reports, and 2 (14.3%) were prospective cohort studies. The duration of follow-up after completion of treatment ranged from 6 months to 14 years. Only three studies reported over 4 years of follow-up. The 14 studies included 288 LCPLs, with successful outcomes of RCT for 254 LCPLs. The overall calculated success rate of LCPLs was 89% (95% CI = 85–94%, Fig. 6 ). 4. Discussion 4.1 Homeostatic medicine theory [28] The theory of bodily balance can be traced back to around 460 BC when Hippocrates first proposed the theory of the Four Humours to describe the body's equilibrium state [33]. Hippocrates believed that the body could heal itself, and it was the liability of the physician to remove barriers and restore the body to its natural state [34]. Like the concept of internal balance in Western medicine, traditional Chinese medicine tracks the theory of Yin and Yang [28]. More importantly, balance is restored by eliminating the causes of illness. Over-treatment should be avoided to prevent disrupting the balance of Yin and Yang [35]. The relatively dynamic balance depends on nearly 50% of the body's physiological potential that is not utilized, known as the body's functional reserve. Only when facing exceptional circumstances or exterior challenges can the excess reserves of physiological potential be mobilized to enable the body to cope with excessive workloads, thereby facilitating rapid recovery of internal balance [36]. This fifty percent concept of homeostasis provides a new theoretical and biological basis for the cure of diseases, including LCPLs. 4.2 The hypothesis of true and bay cysts is meaningless for clinical decision-making of LCPLs The empirical clinical evidence for how to minimally-invasive treat LCPLs is poor; rather, strategies are based upon theoretical assumptions [37]. True and bay cysts are half of the periapical cysts [4, 5]. If true cysts are not influenced by nonsurgical treatment, the treatment success rate of LCPLs would be less 50%. In fact, our cases and literature analysis suggested that the worldwide success rate of LCPLs with nonsurgical treatment was 89% (95% CI = 85%-94%), the same as the success rate of non-LCPLs with primary nonsurgical endodontic treatments [29]. Recently, a study also found that true cysts and bay cysts showed no significant differences in any evaluated variable [5]. In addition, clinician cannot figure out the cyst types without serial sectioning evaluation of a biopsy specimen. Even if a true cyst requires surgical resection, this theory has no clinical guiding meaning. The hypothesis is speculative, without scientific support or biological plausibility [15, 22]. Therefore, it seems rational to suppose that root apical cysts of any type can heal as long as the epithelial proliferative source (i.e., the root canal infection) is eliminated. Periapical lesions, whether granulomas, abscesses, or cysts, cannot heal after nonsurgical treatment due to the same reason, namely, internal and/or external root infection. Thus, in these cases of posttreatment disease, endodontic strategies should be developed with microbicidal intent. For instance, our second patient returned with recurrent painful swelling in the mandibular anterior gingiva after one year. CBCT showed that untreated lingual root canals for both teeth 31 and 41, with uncontrolled infection. After carefully cleaning, shaping, and filling the missed lingual canals with a microscopic technique, follow-up at 3 months and 9 months demonstrated excellent regeneration of the periapical lesion. Our cases highlight that root canal (re)treatment outcomes are dominantly influenced by the nature of prior dynamic host/infection interactions (etiological factors) [38]. On the one hand, the active repair of periapical lesions requires a reduction in the bacterial load of root canals; on the other hand, it is necessary to rely on the host's immune response to eliminate residual pathogenic microorganisms and achieve homeostasis of the body. Thus, endodontists should focus on the active efficacy of RCTs in maintaining microbial ecological transitions (intraoperative therapeutic factors) and reducing periapical inflammation, as well as the passive ability of functional teeth (and their prosthetic margins) to maintain their integrity and resist infection reversal (postoperative recovery factors). 4.3 The lesion volume may not be a determining factor in the surgical treatment of LCPLs Success can be predictably and consistently achieved in LCPLs with etiological treatment. In our two LCPLs cases (>20mm), excellent long-term outcomes were achieved after RCT, even in one case with a complete labial cortical plate defect. The presence of a preoperative cortical bone defect may have no influence on success or failure of LCPLs nonsurgical treatment. This conclusion was strongly supported in 14 LCPLs studies of our literature review (Table 1 and Table 2). Based on the theory of HM, we suggest that once an LCPL is established, the size of the lesion may not affect the treatment outcome, but a larger lesion may require an extended period for complete regression. A recent study [1] found that 62% LCPLs had bilateral cortical bone defects, and the presence of a palatal cortical bone defect may affect bone healing period. Because the periosteum plays a crucial role in endogenous bone repair and remodelling, as it serves as a reservoir of osteogenic periosteal-derived progenitor cells [39–41]. Damage to the periosteum during the infection process and subsequent erosion of the cortical bone may lead to prolonged healing time. Therefore, the European Society of Endodontology recommends assessing the lesion size to remain unchanged or to diminish until its regression or at least for 4 years [1, 29–31, 42]. However, thus far, only three LCPLs studies have reported over 4 years of follow-up (Table 1 and Table 2). Our cases provided strongly clinical evidence with long-term follow-ups (> 8 years, up to 18 years in one case). 4.4 Limitations and strengths There are limitations to the study. First, given the nature of case reports, limitations in terms of reliability of data collection and selection bias should be noted. Another limitation is the small number of cases with long-term follow-up and lesions > 20mm in size. Third, we did not use CBCT for the first case; thus, we lost detailed information, such as the extension/devastation of the overlying cortical bone and the intensity of the lesion. Despite these limitations, this study has three strengths. First, its novelty, being the first report to consider the aetiology of LCPLs from the perspective of HM. Second, this is the first study proposes that the histopathological type may not influence the outcome of LCPLs treatment. Third, this is the first paper to provide strong clinical evidence by summarizing the outcomes of LCPLs with nonsurgical treatment from January 1, 2003, to July 31, 2023. Regardless, upcoming high-quality clinical experiments with large sample sizes and long follow-up periods are expected to confirm these conclusions. 5. Conclusions There is no clinical therapeutic significance in distinguishing between true and false apical cysts. Surgical treatment is not a necessary option for LCPLs. HM advocates “etiological treatment” rather than “symptomatic treatment” of LCPLs and recommends endodontists wait for sufficient recovery time after removing the cause. Declarations Funding This work was supported by the Guangdong Financial Fund for High-Caliber Hospital Construction [grant No. 174-2018-XMZC-0001-03-0125/D-02]; the Natural Science Foundation of Guangdong Province [grant No. 2021A1515011779]; and the National Natural Science Foundation of China [grant No. 81870737]. Ethical statement Informed consent was acquired from the patient and that the patient consented to the publishing of all images, clinical data, and other data included in the manuscript. Data availability statement No data was used for the research described in the article. CRediT authorship contribution statement Dongjia Lin : Conceptualization, Methodology, Software, Formal analysis, Investigation, Writing–original draft, Visualization. Fang Huang : Conceptualization, Validation, Resources, Writing-review and editing, Supervision, Project administration, Funding acquisition. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 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Innervation of periosteum and bone by sympathetic vasoactive intestinal peptide-containing nerve fibers. Science, 232 (4752) (1986), pp. 868 − 71. European Society of E. Quality guidelines for endodontic treatment: consensus report of the European Society of Endodontology. Int Endod J, 39 (12) (2006), pp. 921 − 30. Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.xlsx Table2.xlsx SupplementalTable1.docx SupplementalTable2.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-6760722","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":471352255,"identity":"73130c92-2099-4eff-917e-433ecd77ad61","order_by":0,"name":"Dongjia Lin","email":"","orcid":"","institution":"Sun Yat-Sen University","correspondingAuthor":false,"prefix":"","firstName":"Dongjia","middleName":"","lastName":"Lin","suffix":""},{"id":471352256,"identity":"549cb523-da8d-4c45-ac40-2e64825bef13","order_by":1,"name":"Fang Huang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIiWNgGAWjYBACA+YDQLKCgYGNHS6WQEALG0jBGaAWZpK0MLYBWURrMWdjfvbw67xt8nzMDMyfef4cZuBnzzFg+LkDtxbLNjZzY9lttw3bmBnYpHnbDjNI9rwxYOw9g8dh9xvMpCW33WYEaWHmbTjMYHAjx4AZ7FRcWo6xf5OWnHPbvg3mMHvCWnjMJD823E4EamGQ5mED2iJBWEuZNMOx28ltQGWSc9vSeSTOPCs42IvfYdskf9Tctp3f3nz4w5s/1nL87ckbH/zEowUEmHnAFGMDE5ABZh/ArwGo9gc6YxSMglEwCkYBMgAAbo5Kk1kdt3AAAAAASUVORK5CYII=","orcid":"","institution":"Sun Yat-Sen University","correspondingAuthor":true,"prefix":"","firstName":"Fang","middleName":"","lastName":"Huang","suffix":""}],"badges":[],"createdAt":"2025-05-27 15:08:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6760722/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6760722/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":84922695,"identity":"bb237dc0-4081-4ccc-995d-715a84aadb26","added_by":"auto","created_at":"2025-06-18 20:23:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":447571,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIOPA showed the treatment and bone healing process of teeth 11 and 21 in case one.\u003c/strong\u003e \u003cstrong\u003eA-B.\u003c/strong\u003e IOPA showed an extensive radiolucent area extending from the mesial aspect of tooth 12, including the periapical region of teeth 11 and 21 and reaching the distal surface of tooth 22. The extent of periapical radiolucency was 25 × 22 mm with a circumscribed, well-defined radiolucent area bound by a thin radiopaque line. \u003cstrong\u003eB.\u003c/strong\u003e Gutta-percha was used to measure the working length of tooth 11 before its apical barrier. \u003cstrong\u003eC.\u003c/strong\u003e MTA apical barrier of teeth 11 and 21. \u003cstrong\u003eD.\u003c/strong\u003e Root canal obturation of teeth 11 and 21. \u003cstrong\u003eE.\u003c/strong\u003e IOPA at\u003cstrong\u003e \u003c/strong\u003ethe 3-month follow-up showed a reduction in the size of apical radiolucency. \u003cstrong\u003eF.\u003c/strong\u003e IOPA at\u003cstrong\u003e \u003c/strong\u003ethe 12-month follow-up. \u003cstrong\u003eG.\u003c/strong\u003e IOPA at the\u003cstrong\u003e \u003c/strong\u003e7-yearfollow-up showed the absence of apical radiolucency. \u003cstrong\u003eH.\u003c/strong\u003e IOPA at\u003cstrong\u003e \u003c/strong\u003ethe 8-year follow-up. \u003cstrong\u003eI.\u003c/strong\u003e IOPA at the\u003cstrong\u003e \u003c/strong\u003e11-year follow-up. \u003cstrong\u003eJ.\u003c/strong\u003e IOPA at\u003cstrong\u003e \u003c/strong\u003ethe\u003cstrong\u003e \u003c/strong\u003e18-year follow-up.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6760722/v1/7ce81f56fa3fef7f4e210ea9.png"},{"id":84922711,"identity":"642ee2cd-87cd-444c-85d1-07e1a9404b96","added_by":"auto","created_at":"2025-06-18 20:23:21","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":405190,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFirst RCT and lesion recurrence of teeth 31 and 41 in case two. A. \u003c/strong\u003eClinical examination showed painful swelling in the condylararea. \u003cstrong\u003eB.\u003c/strong\u003e Intraoral examination revealed gingival swelling and overflow adjacent to teeth 32-42. \u003cstrong\u003eC.\u003c/strong\u003e A diagnostic periapical radiograph showed a widened periodontal ligament space of teeth 31 and 41. \u003cstrong\u003eD.\u003c/strong\u003e DPT showed a slightly radiolucent area extending from the distal aspect of tooth 42 to the distal surface of tooth 32. \u003cstrong\u003eE.\u003c/strong\u003e Root canal obturation of teeth 31 and 41. \u003cstrong\u003eF.\u003c/strong\u003e IOPA at\u003cstrong\u003e \u003c/strong\u003ethe\u003cstrong\u003e \u003c/strong\u003e12-month follow-up demonstrated a recurrent radiolucent lesion around the apices from tooth 32 to tooth 42. \u003cstrong\u003eG.\u003c/strong\u003e DPT showed a recurrent critical apical defect from tooth 32 to tooth 42.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6760722/v1/0c4fe9120468b72516044964.png"},{"id":84922716,"identity":"eb682412-6714-4bf3-8c1f-79144ee5d5fd","added_by":"auto","created_at":"2025-06-18 20:23:22","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":310803,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMultiplanar reconstructed CBCT images showed recurrent apical lesions and missed lingula root canals of teeth 31 and 41 in case two.\u003c/strong\u003e \u003cstrong\u003eA.\u003c/strong\u003e From left to right, up to down are coronal, sagittal, and axial sectionsof tooth 41. \u003cstrong\u003eB.\u003c/strong\u003e From left to right, up to down shows coronal, sagittal, and axial sectionsof tooth 31. \u003cstrong\u003eC.\u003c/strong\u003e Untreated lingula root canals were observed in both teeth 31 and 41. The labial cortical plate was completely defective.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-6760722/v1/4f58c370e25ac92ea1e85301.png"},{"id":84922708,"identity":"bbaf1cbe-5142-443b-8057-d2ae935bfcd5","added_by":"auto","created_at":"2025-06-18 20:23:21","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":343273,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRoot canal retreatment to missed lingula root canals of teeth 31 and 41 in case two. A.\u003c/strong\u003eMicroscopic endodontic technique to remove the gutta-perchas from the labial root canals and probe the lingual root canals of teeth 31 and 41 with minimal invasion. \u003cstrong\u003eB.\u003c/strong\u003e Vitapex dressing in both labial and lingula canals of teeth 31 and 41. \u003cstrong\u003eC.\u003c/strong\u003e IOPA at\u003cstrong\u003e \u003c/strong\u003ethe 3-month follow-up after Vitapex dressing. \u003cstrong\u003eD.\u003c/strong\u003e IOPA at\u003cstrong\u003e \u003c/strong\u003ethe 6-month follow-up after Vitapex dressing. \u003cstrong\u003eE.\u003c/strong\u003e IOPA at\u003cstrong\u003e \u003c/strong\u003ethe 9-month follow-up after Vitapex dressing. \u003cstrong\u003eF.\u003c/strong\u003e Intraoral photograph at the 9-month follow-up with Vitapex dressing. \u003cstrong\u003eG.\u003c/strong\u003e Clinical examination at the 9-month follow-up with Vitapex dressing. \u003cstrong\u003eH.\u003c/strong\u003e IOPA at\u003cstrong\u003e \u003c/strong\u003ethe\u003cstrong\u003e \u003c/strong\u003e16-month follow-up after Vitapex dressing and gutta-percha were used to measure the working length of teeth 31 and 41. \u003cstrong\u003eI.\u003c/strong\u003e Root canal obturation at 16 months.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-6760722/v1/ed2060f7f41d26d183b99e70.png"},{"id":84922706,"identity":"856fff2d-e490-41f7-a753-3b547b85f242","added_by":"auto","created_at":"2025-06-18 20:23:21","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":361785,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMultiplanar reconstructed CBCT images of the first RCT, Vitapex dressing, and root canal retreatment at the one-year follow-up showed continuous bone formation. A.\u003c/strong\u003e CBCT images depicted completely resolved LCPL after root canal retreatment at sagittal sections of teeth 31 and 41.\u003cstrong\u003eB.\u003c/strong\u003e CBCT images depicted completely resolved LCPL after root canal retreatment at coronal sections of teeth 31 and 41.\u003cstrong\u003e C.\u003c/strong\u003e CBCT images depicted completely resolved LCPL after root canal retreatment at axial sections of teeth 31 and 41.\u003cstrong\u003e D.\u003c/strong\u003e 3D reconstruction showed complete bone regeneration of the labial cortical plate of teeth 31 and 41. \u003cstrong\u003eE.\u003c/strong\u003e IOPA Root at 8-year follow-up after canal reobturation.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-6760722/v1/78a613e39c0dd605b181b695.png"},{"id":84922719,"identity":"2b7c1c43-1981-41f8-81d3-52409275aa98","added_by":"auto","created_at":"2025-06-18 20:23:22","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":153695,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot of the success rate of LCPLs in all included studies at 2-year follow-up.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-6760722/v1/29c0df5e135b69d2521131a1.png"},{"id":87178276,"identity":"d82cf195-98c9-4a71-aa59-0853e441c3bd","added_by":"auto","created_at":"2025-07-21 09:17:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3895140,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6760722/v1/e3416357-e38a-48f3-873f-f4a8e0bc931f.pdf"},{"id":84922720,"identity":"8e20c410-dd11-4488-923e-40dda6cae225","added_by":"auto","created_at":"2025-06-18 20:23:22","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":17009,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6760722/v1/be170ac468ef07c280d99188.xlsx"},{"id":84922898,"identity":"ae0697eb-1b40-4d7d-8b50-ea7c923585a5","added_by":"auto","created_at":"2025-06-18 20:31:21","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":17036,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6760722/v1/4b79f83b6523fba508531fe1.xlsx"},{"id":84922894,"identity":"0c4beb08-6fe7-4636-ac11-c09cfdbc9ae9","added_by":"auto","created_at":"2025-06-18 20:31:20","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":15901,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6760722/v1/c9113934d472ceeec9c36cf3.docx"},{"id":84922717,"identity":"e16d68a0-69e9-4d71-a35c-241af2ae34a5","added_by":"auto","created_at":"2025-06-18 20:23:22","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":15694,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTable2.docx","url":"https://assets-eu.researchsquare.com/files/rs-6760722/v1/2f2986152012602e45e26ffa.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Homeostatic medicine, new thinking on etiological treatment of large cyst-like periapical lesions: Case series and literature review","fulltext":[{"header":"Highlights","content":"\u003cp\u003e\u0026bull; There is no clinical therapeutic significance in distinguishing between true and false apical cysts.\u003c/p\u003e\u003cp\u003e\u0026bull; Nonsurgical treatment removes bacterial infection and can achieve successful outcomes of large cystic periapical lesions.\u003c/p\u003e\u003cp\u003e\u0026bull; Surgical treatment is not a necessary option for large cystic periapical lesions.\u003c/p\u003e\u003cp\u003e\u0026bull; Homeostatic medicine would be one of the important directions for the future development of medicine.\u003c/p\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eLarge cystic periapical lesions (LCPLs) are diagnosed by one or more nonvital teeth being affected, area greater than 200 mm\u003csup\u003e2\u003c/sup\u003e, and straw-coloured exudates upon root canal or lesion aspiration. These lesions are related to soft tissue swelling (buccal, palatal, or both), intraoral sinus draining and cortical bone expansion/erosion [1, 2]. The occurrence of LCPLs is extremely rare. Therefore, its treatment remains controversial. First, the incidence of apical cysts is 100% with a radiographic lesion area over 200 mm\u003csup\u003e2\u003c/sup\u003e [3]. The apical cyst has been identified as a true cyst, a completely separate cavity with no continuousness or linking to the root canal, or a bay (also known as a pocket) cyst, communicating openly with the root canal system with the root apex protruding into it [4]. True and bay cysts are half of the various periapical cysts [4, 5]. Traditional opinion assumed that true cyst was a self-sustaining lesion that cannot repair after nonsurgical treatment [4, 6\u0026ndash;10]. Second, defects longer than 10 mm or resulting in more than 50% loss of the boundary of the bone are considered critical. Such defects may disturb the natural healing phases and prevent bone from healing without surgical intervention [11\u0026ndash;13]. Thus, the treatment of LCPLs is often adjunctive to surgical resection [14]. But is this necessary?\u003c/p\u003e \u003cp\u003eAn apical periodontitis cannot form by itself [15]. First, apical homeostasis is facilitated by a balanced immune response in root canals. Microbiome dysbiosis in root canals can lead to local inflammatory immune response in periodontal tissue, which ultimately results in apical disorder [16]. Second, an apical cyst is categorized as an inflammatory and not a neoplastic lesion in the World Health Organization (WHO) Histological Typing of Odontogenic Tumours, Jaw Cysts, and Allied Lesions [17\u0026ndash;19]. Different from epithelial cells of an odontogenic keratocyst [20, 21], the basal cells of an apical cyst are not able to self-proliferation without stimulus by peripheral signals such as inflammatory mediators, proinflammatory cytokines, and growth factors produced by various immune cells [22]. It is self-limiting and reversible if the bacterial is removed by nonsurgical treatment [23\u0026ndash;25]. These pathological features of LCPLs contradict the hypothesis of true cysts, which are not conducive to clinical decision-making.\u003c/p\u003e \u003cp\u003eIn fact, apical infections are essentially the same as systemic infections. For example, under the conditions of COVID-19 infection, the body temperature set point can increase to 40\u0026deg;C, a procedure acknowledged as fever. However, the set point for body temperature could be completely reversed when the infection is controlled. In this situation, fever helps the body deal with peripheral infection. Similarly, under the conditions of bacterial infection, a healthy periapical tissue can turn into an inflammatory state, a process known as periapical lesion. However, the inflammation could be totally reversed when the infection is controlled. In this situation, inflammation helps the body deal with intense infection. Homeostatic regulation is the capability of the human body to adjust biological indicators to fit different requirements under certain environments [26, 27]. Homeostatic medicine (HM) is a new science that studies the maintenance of homeostasis in the body. Unlike traditional symptomatic treatment, HM focuses more on etiological treatment of the disease [28]. It emphasizes the nature of diseases and guides us to rethink with a biologic awareness of LCPLs. That is, if the cause can be removed with nonsurgical treatment, surgical intervention may not be necessary for LCPLs. Also, differentiation of true or bay cysts would be of no clinical implication.\u003c/p\u003e \u003cp\u003eThus, the study aims to provide strong clinical support and question whether surgical treatment is necessary for LCPLs or not via two long-term follow-up LCPL cases and a literature review. The null hypothesis is that LCPLs can respond successfully to non-surgical endodontic treatment. The histopathological type and size of LCPLs maybe not be the determining factors for surgical treatment.\u003c/p\u003e"},{"header":"2. Case series presentation","content":"\u003cp\u003e2.1 Case one\u003c/p\u003e\n\u003cp\u003eA 16-year-old girl presented with repeated episodes of painful swelling in the maxillary anterior sulcus for 2 months. The patient reported trauma 8 years prior without any treatment of the teeth. Intraoral examination revealed painful swelling of the labial mucosa adjacent to teeth 11 and 21. Discomfort in teeth 11 and 21 was found on vertical percussion and apical palpation, while adjacent teeth presented normal responses. Teeth 11 and 21 were discoloured, but areas of decay and periodontal pockets were absent. A periapical radiograph (Fig. 1A-B) showed an extensive radiolucent area extending from the distal aspect of tooth 11, including the periapical region of tooth 21 and reaching the distal surface of tooth 22. The extent of the periapical radiolucent area was 25 \u0026times; 22 mm, with a thin radiopaque line forming a circumscribed, well-defined boundary. Meanwhile, sparse white obturation and an open apex (Nolla stage 9) were observed in teeth 11 and 21. A diagnosis of symptomatic LCPL of traumatic origin in teeth 11 and 21 was established. Mineral trioxide aggregate (MTA) apical barrier and root canal treatment (RCT) was performed on teeth 11 and 21 after obtaining informed consent from the patient\u0026rsquo;s parents.\u003c/p\u003e\n\u003cp\u003eAfter gaining coronal access under a rubber dam on teeth 11 and 21, the previous obturation in the root canals was removed by retreatment files (ProTaper, Dentsply Sirona, USA). A clear, straw-coloured fluid exuded continuously, and the canals were unable to dry. After copious irrigation with 5.25% sodium hypochlorite, the root canal was filled with calcium hydroxide paste (LELE\u003csup\u003e\u0026reg;\u003c/sup\u003e, Shanghai Eryi \u0026amp; Zhangjiang Biomaterial Co., Ltd., Shanghai, China). Between appointments, the coronal cavity was temporarily filled with Caviton (GC Co., Tokyo, Japan). The intracanal dressing was maintained for two weeks. After the second dressing change, there was no pain or mucosal swelling. Gutta-percha was used to measure the working length of tooth 11 (Fig. 1B). Following these procedures, the MTA apical barrier was applied (Fig. 1C) under surgical and dental microscopes (M525 F20, Leica, USA). After two days, the root canals were permanently obturated using Cortisomol sealer (Morita, Osaka, Honshu, Japan) with warm vertical condensation technique (Fig. 1D). One week later, teeth 11 and 21 were permanently restored with composite resin (Z350 XT, 3 M, USA).\u003c/p\u003e\n\u003cp\u003e2.2 Case two\u003c/p\u003e\n\u003cp\u003eA 12-year-old boy presented with severe pain in the condylar area for 2 days. The patient reported trauma 8 years prior without any treatment of the teeth. Extraoral examination showed painful swelling in the condylar area (Fig. 2A). Intraoral examination revealed gingival swelling and overflow adjacent to teeth 32-42 (Fig. 2B). Symptoms on vertical percussion and apical palpation occurred in teeth 32-42, while adjacent teeth presented normal responses. Severe tooth mobility (degree 3) was observed in teeth 31 and 41, and moderate tooth mobility (degree 2) was observed in teeth 32 and 42. Electronic (Vitality Scanner; Analytic Technology, Glendora, CA, USA) and thermal (Endo-Ice; The Hygenic Corporation, OH, USA) pulp sensitivity tests were negative for teeth 31 and 41, while teeth 32 and 42 presented dullness. Areas of decay and periodontal pockets were absent. A periapical radiograph and dental panoramic tomograph (DPT) showed a widened periodontal ligament space for teeth 31 and 41 (Fig. 2C-D). A diagnosis was established as an acute apical abscess of traumatic origin in teeth 31 and 41. RCT was performed for teeth 31 and 41 after obtaining informed consent from the patient\u0026rsquo;s parents.\u003c/p\u003e\n\u003cp\u003eAfter access cavity preparation, yellow pus exuded from the canals of teeth 31 and 41. Drainage was performed for two days until discharge through the canal ceased. When the pain and swelling subsided and drainage ceased, the root canals were finally instrumented using nickel-titanium rotary files (ProFile\u0026reg;, Dentsply Maillefer, New York, PA, US) and copious irrigation with 5.25% sodium hypochlorite under rubber dam isolation. Calcium hydroxides paste (LELE\u003csup\u003e\u0026reg;\u003c/sup\u003e, Shanghai Eryi \u0026amp; Zhangjiang Biomaterial Co., Ltd., Shanghai, China) was applied to the canals. Between appointments, the coronal cavity was temporarily filled with Caviton (GC Co., Tokyo, Japan). Two weeks later, the root canals were obturated with Cortisomol sealer (Morita, Osaka, Honshu, Japan) with warm vertical condensation technique (Dentsply Sirona, USA, Fig. 2E) and restored with composite resin (Z350 XT, 3 M, USA) after one week.\u003c/p\u003e\n\u003cp\u003eHowever, the patient returned with recurrent painful swelling in the mandibular anterior gingiva after one year. A periapical radiograph and DPT demonstrated a large radiolucent lesion around teeth 32 to 42 (Fig. 2F-G). Cone-beam computed tomography (CBCT) showed a large, well-defined expansive radiolucent lesion at the apices of teeth 32-42 (Fig. 3A-B). The maximal size of the radiographic lesion was 20 \u0026times; 15 \u0026times; 17 mm. The labial cortical plate was completely disrupted in localized areas (Fig. 3A-B). Unexpectedly, a missed lingual canal was observed in both teeth 31 and 41 (Fig. 3C). The affected teeth showed no obvious root resorption. A diagnosis was established to be previously treated symptomatic apical periodontitis. Retreatment was discussed with the patient\u0026rsquo;s parents.\u003c/p\u003e\n\u003cp\u003eA microscopic endodontic technique was performed to remove the gutta-percha from the labial root canals and probe the lingual root canals of teeth 31 and 41 with minimal invasion (Fig. 4A). After instrumenting missed lingual root canals, calcium hydroxides paste (LELE\u003csup\u003e\u0026reg;\u003c/sup\u003e, Shanghai Eryi \u0026amp; Zhangjiang Biomaterial Co., Ltd., Shanghai, China) was applied to the canals (Fig. 4B). The follow-up radiographs showed continuous bone formation at 3 months (Fig. 4C), 6 months (Fig. 4D), and 9 months (Fig. 4E-G). One-year follow-up CBCT showed bony repair of the labial cortical plate (Fig. 5). The lesion size was reduced to 4.5 \u0026times; 9.5 \u0026times; 9.5 mm. Finally, permanent obturation of the canals was performed (Fig. 4H-I). One week later, teeth 31 and 41 were permanently restored with composite resin (Z350 XT, 3 M, USA).\u003c/p\u003e\n\u003cp\u003e2.3 Literature review and analysis\u003c/p\u003e\n\u003cp\u003eLongitudinal clinical studies in English studying the outcomes of nonsurgical treatments for LCPLs published from January 1, 2003, to July 31, 2023, were recognized using the following electronic databases: PubMed, Web of Science, CINAHL, Embase and Cochrane CENTRAL. Keywords and search strategies provided by Burns [29] and Ng et al. [30, 31] were applied to improve the search strategy of our study (Table S1). Studies were removed for duplicate using Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia; available at: www.covidence.org).\u003c/p\u003e\n\u003cp\u003e2.3.1 Inclusion criteria\u003c/p\u003e\n\u003cp\u003eClinical studies (mainly case reports and prospective cohort studies) were selected according to revisions of the inclusion criteria used by Burns [29] and Ng et al. [30, 31].\u003c/p\u003e\n\u003cp\u003e1. Data allowing for tooth-level outcome assessment.\u003c/p\u003e\n\u003cp\u003e2. Lesion size of at least 10 mm in diameter.\u003c/p\u003e\n\u003cp\u003e3. Sample size provided.\u003c/p\u003e\n\u003cp\u003e4. At least 6 months of postoperative follow-up.\u003c/p\u003e\n\u003cp\u003e5. Success determined according to clinical and radiographic criteria.\u003c/p\u003e\n\u003cp\u003ea. Clinical success demarcated as the absence of clinical symptoms, as outlined in the individual study.\u003c/p\u003e\n\u003cp\u003eb. Radiographic success differentiated by either \u0026ldquo;strict\u0026rdquo; or \u0026ldquo;loose\u0026rdquo; criteria.\u003c/p\u003e\n\u003cp\u003e(i) \u0026ldquo;Strict\u0026rdquo; radiographic criteria of success: the absence of periapical radiolucency on follow-up assessment.\u003c/p\u003e\n\u003cp\u003e(ii) \u0026ldquo;Loose\u0026rdquo; radiographic criteria of success: decrease in the size of periapical radiolucency on follow-up assessment.\u003c/p\u003e\n\u003cp\u003e2.3.2 Study selection and data extraction\u003c/p\u003e\n\u003cp\u003eThe title and abstract screening were performed independently by two reviewers (Lin and Huang). General information (author, year, title, journal); study design (sample size, follow-up period, outcome criteria and assessment); noted medical conditions of patients; and pre, intra- and postoperative factors were extracted.\u003c/p\u003e\n\u003cp\u003e2.3.3 Analysis\u003c/p\u003e\n\u003cp\u003eTo investigate the success rate of nonsurgical treatment for LCPLs, meta-analysis was chosen. To estimate the variance and heterogeneity among trials, the Higgins \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e test was employed, with a value between 25 and 50% considered to indicate slight heterogeneity; between 50% and 75%, moderate heterogeneity; and \u0026gt;75%, high heterogeneity [32].\u0026nbsp;\u003c/p\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Case one\u003c/h2\u003e \u003cp\u003eThe follow-up at 3 months (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE) and 12 months (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF) showed a \u0026ldquo;loose\u0026rdquo; outcome. The follow-up at 7 years (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eG), 8 years (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eH), 11 years (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eI) and 18 years (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eJ) showed radiographic evidence of a \u0026ldquo;strict\u0026rdquo; outcome.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Case two\u003c/h2\u003e \u003cp\u003eAt the one-year follow-up after retreatment, CBCT depicted \u0026ldquo;strict\u0026rdquo; outcomes on sagittal sections (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA), coronal sections (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eB), and axial sections (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eC) of teeth 31 and 41. The follow-up at 8 years (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eE) showed a stable outcome.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Literature review and analysis\u003c/h2\u003e \u003cp\u003eThe electronic searches generated 4878 results: PubMed (2123), Web of Science (884), CINAHL (726), Embase (929) and Cochrane CENTRAL (216). 3604 abstracts remained after removing duplicates. 26 studies were selected for full text review after abstract screening. 12 studies were excluded for the reasons given in Table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e after full text review. Finally, 14 studies fulfilled the inclusion criteria and were analysed. Table\u0026nbsp;1 includes seven articles in which the lesion size was between 10 mm and 20 mm in diameter. Table\u0026nbsp;2 includes another seven articles in which the lesion size was over 20 mm in diameter.\u003c/p\u003e \u003cp\u003eOf the 14 included studies, 12 (85.7%) were case reports, and 2 (14.3%) were prospective cohort studies. The duration of follow-up after completion of treatment ranged from 6 months to 14 years. Only three studies reported over 4 years of follow-up. The 14 studies included 288 LCPLs, with successful outcomes of RCT for 254 LCPLs. The overall calculated success rate of LCPLs was 89% (95% CI\u0026thinsp;=\u0026thinsp;85\u0026ndash;94%, Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Homeostatic medicine theory [28]\u003c/h2\u003e \u003cp\u003eThe theory of bodily balance can be traced back to around 460 BC when Hippocrates first proposed the theory of the Four Humours to describe the body's equilibrium state [33]. Hippocrates believed that the body could heal itself, and it was the liability of the physician to remove barriers and restore the body to its natural state [34]. Like the concept of internal balance in Western medicine, traditional Chinese medicine tracks the theory of Yin and Yang [28]. More importantly, balance is restored by eliminating the causes of illness. Over-treatment should be avoided to prevent disrupting the balance of Yin and Yang [35]. The relatively dynamic balance depends on nearly 50% of the body's physiological potential that is not utilized, known as the body's functional reserve. Only when facing exceptional circumstances or exterior challenges can the excess reserves of physiological potential be mobilized to enable the body to cope with excessive workloads, thereby facilitating rapid recovery of internal balance [36]. This fifty percent concept of homeostasis provides a new theoretical and biological basis for the cure of diseases, including LCPLs.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e4.2 The hypothesis of true and bay cysts is meaningless for clinical decision-making of LCPLs\u003c/h2\u003e \u003cp\u003eThe empirical clinical evidence for how to minimally-invasive treat LCPLs is poor; rather, strategies are based upon theoretical assumptions [37]. True and bay cysts are half of the periapical cysts [4, 5]. If true cysts are not influenced by nonsurgical treatment, the treatment success rate of LCPLs would be less 50%. In fact, our cases and literature analysis suggested that the worldwide success rate of LCPLs with nonsurgical treatment was 89% (95% CI\u0026thinsp;=\u0026thinsp;85%-94%), the same as the success rate of non-LCPLs with primary nonsurgical endodontic treatments [29]. Recently, a study also found that true cysts and bay cysts showed no significant differences in any evaluated variable [5]. In addition, clinician cannot figure out the cyst types without serial sectioning evaluation of a biopsy specimen. Even if a true cyst requires surgical resection, this theory has no clinical guiding meaning. The hypothesis is speculative, without scientific support or biological plausibility [15, 22]. Therefore, it seems rational to suppose that root apical cysts of any type can heal as long as the epithelial proliferative source (i.e., the root canal infection) is eliminated.\u003c/p\u003e \u003cp\u003ePeriapical lesions, whether granulomas, abscesses, or cysts, cannot heal after nonsurgical treatment due to the same reason, namely, internal and/or external root infection. Thus, in these cases of posttreatment disease, endodontic strategies should be developed with microbicidal intent. For instance, our second patient returned with recurrent painful swelling in the mandibular anterior gingiva after one year. CBCT showed that untreated lingual root canals for both teeth 31 and 41, with uncontrolled infection. After carefully cleaning, shaping, and filling the missed lingual canals with a microscopic technique, follow-up at 3 months and 9 months demonstrated excellent regeneration of the periapical lesion. Our cases highlight that root canal (re)treatment outcomes are dominantly influenced by the nature of prior dynamic host/infection interactions (etiological factors) [38]. On the one hand, the active repair of periapical lesions requires a reduction in the bacterial load of root canals; on the other hand, it is necessary to rely on the host's immune response to eliminate residual pathogenic microorganisms and achieve homeostasis of the body. Thus, endodontists should focus on the active efficacy of RCTs in maintaining microbial ecological transitions (intraoperative therapeutic factors) and reducing periapical inflammation, as well as the passive ability of functional teeth (and their prosthetic margins) to maintain their integrity and resist infection reversal (postoperative recovery factors).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e4.3 The lesion volume may not be a determining factor in the surgical treatment of LCPLs\u003c/h2\u003e \u003cp\u003eSuccess can be predictably and consistently achieved in LCPLs with etiological treatment. In our two LCPLs cases (\u0026gt;20mm), excellent long-term outcomes were achieved after RCT, even in one case with a complete labial cortical plate defect. The presence of a preoperative cortical bone defect may have no influence on success or failure of LCPLs nonsurgical treatment. This conclusion was strongly supported in 14 LCPLs studies of our literature review (Table\u0026nbsp;1 and Table\u0026nbsp;2). Based on the theory of HM, we suggest that once an LCPL is established, the size of the lesion may not affect the treatment outcome, but a larger lesion may require an extended period for complete regression. A recent study [1] found that 62% LCPLs had bilateral cortical bone defects, and the presence of a palatal cortical bone defect may affect bone healing period. Because the periosteum plays a crucial role in endogenous bone repair and remodelling, as it serves as a reservoir of osteogenic periosteal-derived progenitor cells [39\u0026ndash;41]. Damage to the periosteum during the infection process and subsequent erosion of the cortical bone may lead to prolonged healing time. Therefore, the European Society of Endodontology recommends assessing the lesion size to remain unchanged or to diminish until its regression or at least for 4 years [1, 29\u0026ndash;31, 42]. However, thus far, only three LCPLs studies have reported over 4 years of follow-up (Table\u0026nbsp;1 and Table\u0026nbsp;2). Our cases provided strongly clinical evidence with long-term follow-ups (\u0026gt;\u0026thinsp;8 years, up to 18 years in one case).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e4.4 Limitations and strengths\u003c/h2\u003e \u003cp\u003eThere are limitations to the study. First, given the nature of case reports, limitations in terms of reliability of data collection and selection bias should be noted. Another limitation is the small number of cases with long-term follow-up and lesions\u0026thinsp;\u0026gt;\u0026thinsp;20mm in size. Third, we did not use CBCT for the first case; thus, we lost detailed information, such as the extension/devastation of the overlying cortical bone and the intensity of the lesion.\u003c/p\u003e \u003cp\u003eDespite these limitations, this study has three strengths. First, its novelty, being the first report to consider the aetiology of LCPLs from the perspective of HM. Second, this is the first study proposes that the histopathological type may not influence the outcome of LCPLs treatment. Third, this is the first paper to provide strong clinical evidence by summarizing the outcomes of LCPLs with nonsurgical treatment from January 1, 2003, to July 31, 2023. Regardless, upcoming high-quality clinical experiments with large sample sizes and long follow-up periods are expected to confirm these conclusions.\u003c/p\u003e \u003c/div\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eThere is no clinical therapeutic significance in distinguishing between true and false apical cysts. Surgical treatment is not a necessary option for LCPLs. HM advocates \u0026ldquo;etiological treatment\u0026rdquo; rather than \u0026ldquo;symptomatic treatment\u0026rdquo; of LCPLs and recommends endodontists wait for sufficient recovery time after removing the cause.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Guangdong Financial Fund for High-Caliber Hospital Construction [grant No. 174-2018-XMZC-0001-03-0125/D-02]; the Natural Science Foundation of Guangdong Province [grant No. 2021A1515011779]; and the National Natural Science Foundation of China [grant No. 81870737].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was acquired from the patient and that the patient consented to the publishing of all images, clinical data, and other data included in the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo data was used for the research described in the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRediT authorship contribution statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDongjia Lin\u003c/strong\u003e: Conceptualization, Methodology, Software, Formal analysis, Investigation, Writing\u0026ndash;original draft, Visualization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFang Huang\u003c/strong\u003e: Conceptualization, Validation, Resources, Writing-review and editing, Supervision, Project administration, Funding acquisition.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of competing interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank PhD Wei Dong from the Guanghua School of Stomatology, Sun Yat-sen University, and PhD Shanshan Zhu from the School of Public Health, Sun Yat-sen University, for their support with Meta-analysis.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSaini A, Nangia D, Sharma S, Kumar V, Chawla A, Logani A, et al. 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Int J Dent, 2012 (2012), pp. 717816.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMa Z, Guo K, Chen L, Chen X, Zou D, Yang C. Role of periosteum in alveolar bone regeneration comparing with collagen membrane in a buccal dehiscence model of dogs. Sci Rep, 13 (1) (2023), pp. 2505.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHohmann EL, Elde RP, Rysavy JA, Einzig S, Gebhard RL. Innervation of periosteum and bone by sympathetic vasoactive intestinal peptide-containing nerve fibers. Science, 232 (4752) (1986), pp. 868\u0026thinsp;\u0026minus;\u0026thinsp;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEuropean Society of E. Quality guidelines for endodontic treatment: consensus report of the European Society of Endodontology. Int Endod J, 39 (12) (2006), pp. 921\u0026thinsp;\u0026minus;\u0026thinsp;30.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Periapical diseases, Large cystic periapical lesions, Homeostatic medicine, Etiological treatment, Case report","lastPublishedDoi":"10.21203/rs.3.rs-6760722/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6760722/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eObjectives: The view that auxiliary surgical resection is needed for the large cystic periapical lesions (LCPLs) treatment is based more on theoretical hypotheses than clinical evidence. This study questions the necessity of surgical treatment of LCPLs via providing strong clinical evidence and new theoretical supports from the perspective of homeostatic medicine (HM).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMethods: Nonsurgical treatment was performed in two LCPL cases (lesion diameter \u0026gt; 20 mm), and long-term follow-up was obtained (\u0026gt; 8 years, up to 18 years in one case). The PubMed, Web of Science, CINAHL, Embase and Cochrane CENTRAL databases were electronically searched (01-01-2003 to 07-31-2023). Studies on LCPLs with at least six months of postoperative review according to clinical and radiological criteria were summarized. Meta-analysis of the non-surgical treatment success rate was performed with RStudio software.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResults: Two LCPL cases showed complete periapical lesion resolution after non-surgical treatment. Fourteen studies fulfilled the inclusion criteria, with no obvious publication bias. The worldwide nonsurgical treatment success rate of LCPLs was estimated as 89% (95% CI=85%-94%) in 288 teeth.\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eConclusions: The pathological hypothesis of true and bay cysts is meaningless for clinical decision-making of LCPLs. Nonsurgical root canal treatment removes the bacterial infection and can achieve successful outcomes even if large bone defects exist.\u003c/p\u003e","manuscriptTitle":"Homeostatic medicine, new thinking on etiological treatment of large cyst-like periapical lesions: Case series and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-18 20:23:14","doi":"10.21203/rs.3.rs-6760722/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"840f7121-c399-45cf-b789-857492896b8b","owner":[],"postedDate":"June 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-21T09:08:48+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-18 20:23:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6760722","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6760722","identity":"rs-6760722","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}