Exploration of Treatment Strategies for Nodular Goiter Complicated with Parathyroid Carcinoma: Experience Summary Based on a Single Case

Exploration of Treatment Strategies for Nodular Goiter Complicated with Parathyroid Carcinoma: Experience Summary Based on a Single Case | 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 Exploration of Treatment Strategies for Nodular Goiter Complicated with Parathyroid Carcinoma: Experience Summary Based on a Single Case Le Sun, Ye Zhang, Zhiqing Zhang, Yingqian Zhou, Hao Liu, Yue Qu, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8856468/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 Purpose Parathyroid carcinoma (PC) is an exceedingly rare malignancy that poses significant diagnostic challenges. This case report delineates the clinical presentation, diagnostic evaluation, and multidisciplinary management of PC, highlighting the pivotal role of complete surgical excision and the diagnostic difficulties arising from its overlapping features with benign thyroid and parathyroid conditions. Methods We report the case of a 58-year-old male with a five-year history of a thyroid mass and progressive bilateral lower limb pain. Diagnostic investigations encompassed comprehensive biochemical analysis, thyroid and parathyroid ultrasonography, contrast-enhanced computed tomography (CT), and parathyroid scintigraphy. The patient had bilateral thyroid masses resected, and postoperative pathology showed right parathyroid carcinoma and left nodular goiter. Therefore, the patient underwent further surgery, including resection of the right thyroid lobe and isthmus, as well as central lymph node dissection. Results Preoperative assessment revealed severe hypercalcemia (4.58 mmol/L) and a markedly elevated parathyroid hormone level (3224 ng/L). Imaging examination revealed nodules in both lobes of the thyroid gland. Histopathological examination of the initial specimen confirmed PC, with positive immunostaining for PTH and a high Ki-67 index (25%). The secondary resection demonstrated PC infiltration into the right thyroid parenchyma; no lymph node metastasis was detected (0/2). Postoperative calcium and PTH levels returned to normal, and no recurrence was observed during the two-year follow-up. Conclusion This case emphasizes that PC should be considered in patients presenting with severe hypercalcemia and a cervical mass. Accurate diagnosis requires integration of biochemical, imaging, and histopathological findings. En bloc surgical resection with clear margins constitutes the cornerstone of curative management and can yield favorable long-term outcomes. Parathyroid tumor parathyroid carcinoma secondary hyperparathyroidism hypercalcemia Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Parathyroid carcinoma (PC) is an exceedingly rare and highly aggressive endocrine malignancy that accounts for less than 1% of all cases of primary hyperparathyroidism (PHPT) and an even smaller fraction of overall cancers 1, 2 . Despite its rarity, PC poses significant clinical challenges due to its often-severe manifestations and complex diagnostic and therapeutic considerations. Clinically, PC typically presents with symptoms of profound hypercalcemia, the most common and life -threatening complication of this malignancy 3 . Frequently, patients exhibit markedly elevated serum calcium and parathyroid hormone (PTH) levels, which often exceed those observed in benign parathyroid adenomas (PA) or hyperplasia 4, 5 . These biochemical abnormalities lead to multi-organ involvement, including renal dysfunction, skeletal lesions such as osteitis fibrosa cystica and brown tumors, gastrointestinal symptoms, neuropsychiatric disturbances, and, in rare cases, acute pancreatitis 6-8 . The clinical situation is often complicated by the overlap of these features with benign parathyroid diseases, rendering preoperative diagnosis challenging. We herein present a case of parathyroid carcinoma complicated by nodular goiter and discuss the disease characteristics and management strategies based on a literature review. Case report A 58-year-old male presented with a 5-year history of thyroid mass and pain in both lower legs, with symptoms worsening in the past six months. Initially, he only had a thyroid mass and mild pain in the lower legs. In the past six months, the pain worsened, accompanied by various discomforts such as joint pain, weight loss, and skin itching. In the past two months, nausea and other symptoms emerged. Based on the physical and imaging findings, the patient presents with thyroid nodule and a biochemical profile highly suggestive of primary hyperparathyroidism. Physical examination disclosed firm masses in both thyroid lobes that moved during swallowing. Thyroid ultrasound showed enlargement with multiple TI-RADS 3 nodules, while contrast-enhanced CT shows a complex nodule (35 x 30 x 47 mm) in the right thyroid lobe with progressive enhancement and internal septations. The left lobe contains hypodense nodules (largest 21 x 28 x 25 mm) demonstrating peripheral enhancement with non-enhancing components (Fig. 1A-B). Crucially, parathyroid scintigraphy localized a hyperfunctioning parathyroid gland dorsal to the right lower pole. This is further supported by markedly elevated PTH (3224 ng/L) and significant hypercalcemia (4.58 mmol/L), alongside elevated alkaline phosphatase (985 U/L) and creatinine (166.0 µmol/L), indicating potential renal and bone involvement. The profile is compounded by other abnormalities, including hypokalemia, hypomagnesemia, dyslipidemia, and altered thyroid function. The patient underwent excision of the bilateral parathyroid mass. Intraoperative frozen section pathology revealed a parathyroid tumor with intratumoral collagenous fiber hyperplasia and no evidence of vascular invasion. A definitive distinction between benign and malignant could not be established, pending permanent section analysis. Consequently, only a parathyroid tumor excision was performed (Fig. 1C). Figure1 1A-B Right lobe complex nodule (35*30*47 mm) with progressive enhancement and septations, left lobe hypodense nodules (max 21*28*25 mm) showing peripheral enhancement and non-enhancing areas; 1C Gross appearance of the intraoperative parathyroid mass. Histopathological examination confirmed the mass in the right lobe was PC, while the mass in the left lobe was diagnosed as nodular goiter. For the diagnosis of PC, the immunohistochemical staining of the specimen was positive for PTH, CgA, and CK8/18, but negative for CK19. The Ki-67 proliferation index was 25% (Fig. 2 ). Postoperative PET-CT imaging revealed a mild heterogeneous increase in FDG uptake at the thyroid surgical site, with a maximum SUV of 4.4. Elevated FDG metabolism was also observed in the right 11th rib and pelvis, findings consistent with secondary bone changes associated with hyperparathyroidism (Fig. 3 ). Two weeks later, the patient proceeded to a second procedure, which included a right thyroid lobectomy with isthmusectomy and central compartment lymph node dissection. Postoperative pathology revealed infiltration of the PC into the right thyroid parenchyma. One perithyroidal lymph node was identified and was negative for metastatic carcinoma. Immunohistochemistry of the thyroid specimen showed positivity for CK19 and CK8/18, while results were negative for CgA, Syn, PTH, and calcitonin. The Ki-67 index was significantly lower at 2%. CD68 immunostaining highlighted histiocytes. Special stains were notable for Masson's trichrome (highlighting fibrosis) and Congo red (negative for amyloid deposition). Examination of the right central compartment lymph nodes confirmed no metastasis (0/2 nodes). Serum levels of calcium, phosphorus, and PTH measured preoperatively and postoperatively are presented in Fig. 4 , while blood pressure fluctuations are illustrated in Fig. 5 . The patient developed severe hypotension postoperatively, requiring norepinephrine infusion for vasopressor support. Blood pressure normalized by postoperative day 8. During the two-year postoperative follow-up period, the patient remained asymptomatic with no evidence of disease recurrence, indicating a stable clinical status. Discussion 1. Clinical Manifestations and Epidemiology of PC PC is an extremely rare endocrine malignancy with a historically low global incidence, though recent years have shown a gradual increase. A nationwide Korean cohort study from 2002 to 2017 reported an age-standardized incidence rate rising from 3.8 per 10 million person-years in 2003 to 6.6 per 10 million person-years in 2016, highlighting a notable upward trend 9 . Similarly, U.S. SEER database analyses confirm PC's rarity, representing only about 0.005% of all malignancies, with a slight male predominance and an average diagnosis age in the early 60s 10 . Overall, PC typically affects middle-aged to older adults without a strong gender preference, though regional differences may influence demographic patterns. PC often presents with clinical manifestations primarily related to severe hypercalcemia due to excessive secretion of PTH. Patients with primary hyperparathyroidism often present with severe symptoms caused by high calcium levels in the blood, which can become dangerous if not treated promptly. A key feature is bone pain, along with skeletal issues like broken bones and bone lesions known as osteitis fibrosa cystica, showing how excess PTH damages bone health. Kidney problems, such as kidney stones and calcium buildup in kidney tissue, are also frequent due to excessive calcium in the urine and deposits in the kidneys 6 , 11 , 12 . Moreover, non-functioning PCs, which do not secrete significant amounts of PTH, have been described and are associated with a silent clinical course, further complicating clinical recognition 13 . In these cases, the primary clinical sign may be a neck mass or incidental imaging finding rather than biochemical abnormalities or symptoms of hypercalcemia. The clinical presentation of PC may also overlap with other parathyroid pathologies, such as atypical PA and giant PA, which can exhibit similar biochemical and clinical profiles, including severe hypercalcemia and skeletal involvement 14 , 15 . In summary, PC presents a diverse clinical spectrum, ranging from severe cases characterized by marked hypercalcemia with multisystem involvement—manifesting as bone pain, renal calculi, neuropsychiatric symptoms, and gastrointestinal discomfort—to asymptomatic cases incidentally discovered as neck masses or through imaging findings 16 , 17 . 2. Diagnostic Challenges and Imaging Advances in PC Imaging plays a pivotal role in the diagnosis, localization, and differential diagnosis of PC. The preoperative diagnosis of PC is notably difficult due to significant overlap in clinical presentation and biochemical markers with benign PA 18 . Imaging modalities such as ultrasound, sestamibi scintigraphy, and computed tomography (CT) are routinely employed for localization of parathyroid lesions preoperatively. Yet, their ability to distinguish carcinoma from adenoma is limited. Ultrasound may reveal a large hypoechoic lesion with irregular borders in PC, but similar features can be seen in atypical adenomas or large benign tumors 19 . Advanced imaging techniques like 18F-fluorocholine PET/CT have shown promise in localizing hyperfunctioning parathyroid tissue with high sensitivity but still lack specificity for carcinoma 20 . Positron emission tomography/computed tomography (PET/CT) with various tracers, such as 18F-fluorodeoxyglucose (18F-FDG), 18F-fluorocholine (18F-FCH), and novel agents like 18F-FAPI, has shown promising sensitivity in detecting hyperfunctioning parathyroid tissue and metastatic lesions. 99mTc-sestamibi scintigraphy, often combined with single-photon emission computed tomography/computed tomography (SPECT/CT), provides functional imaging by detecting mitochondrial-rich PA or carcinomas and is especially useful in cases with ectopic glands or multiglandular disease. Notably, 99mTc-sestamibi SPECT/CT has demonstrated utility in detecting both primary lesions and metastatic sites, such as lung metastases, as reported in rare cases of PC with distant spread 21 , 22 . Histopathological examination remains the gold standard for definitive diagnosis, often only available postoperatively. Intraoperative frozen section analysis is limited by sampling errors and interpretative difficulties, with discordance rates noted in some studies 23 . Immunohistochemical markers such as parafibromin and GATA-3 have been investigated to aid diagnosis, but their utility preoperatively is constrained 24 . Molecular subtyping of PC has emerged as a pivotal approach to refine diagnosis, prognostication, and personalized treatment, addressing the challenges posed by this rare and heterogeneous malignancy. Advances in genomic and transcriptomic profiling have revealed distinct molecular signatures that differentiate PC from benign PA and atypical parathyroid tumors, thereby aiding early and accurate diagnosis. For instance, mutations in the CDC73 gene, encoding the tumor suppressor parafibromin, are prevalent in up to 80% of sporadic PCs and serve as a hallmark of malignancy, distinguishing PC from benign lesions 25 . Mutations in CDC73 are highly prevalent in PC, with mutation frequencies reported up to 80% in both familial and sporadic cases. These mutations often lead to loss of parafibromin expression, which is strongly associated with malignant transformation and poor prognosis in parathyroid tumors 16 . 3. Surgical Treatment and Management of PC Surgical resection remains the cornerstone and only potentially curative treatment for PC. En bloc resection with negative margins at the initial surgery offers the best chance for long-term disease control and survival 1 , 2 . Many studies emphasize the importance of achieving negative surgical margins during the first operation, as incomplete resection is associated with higher rates of local recurrence and poorer outcomes 26 , 27 . Intraoperative PTH monitoring can assist in confirming removal of hyperfunctioning tissue, although its role specifically in PC surgery is less well defined compared to benign hyperparathyroidism 28 . When preservation in situ is not feasible, autotransplantation of parathyroid tissue into the sternocleidomastoid muscle or forearm is a recognized technique to maintain parathyroid function, with evidence suggesting that auto transplantation does not increase the risk of permanent hypoparathyroidism 29 . The inferior parathyroid glands, which are more difficult to preserve due to their variable location, are often candidates for autotransplantation 30 . Intraoperative neuromonitoring of the recurrent laryngeal nerve is recommended to minimize the risk of vocal cord paralysis, especially in cases requiring extensive neck dissection due to suspected local invasion 31 . Radiotherapy, while occasionally considered, has not demonstrated consistent benefit in improving disease-free or overall survival 32 . A national cancer database analysis involving over 1,000 PC patients found no association between adjuvant radiotherapy and improved overall survival, underscoring the limited impact of radiation on long-term outcomes 33 . Chemotherapy for PC has similarly failed to demonstrate meaningful efficacy and is generally reserved for palliative purposes rather than curative intent. Chemotherapy is primarily utilized in cases of metastatic or unresectable disease to manage symptoms or control hypercalcemia indirectly 34 . However, due to diagnostic uncertainties, many patients undergo incomplete resection, leading to high rates of local recurrence and metastasis 1 . The recurrence rate ranges from 30% to 67%, with recurrent disease often causing refractory hypercalcemia, which is the predominant cause of morbidity and mortality in PC patients 4 . The management of recurrent and metastatic PC poses significant clinical challenges due to the limited efficacy of adjuvant therapies such as chemotherapy and radiotherapy. Nevertheless, the mainstay of treatment remains surgical, and reoperation is recommended for patients with resectable local recurrences or metastases 2 , 35 . For unresectable or metastatic disease, emerging systemic therapies such as tyrosine kinase inhibitors (e.g., sorafenib) and immunotherapy (e.g., pembrolizumab, nivolumab) have shown promise in controlling disease progression and hypercalcemia, though evidence is currently limited to case reports and small series 36 , 37 . Management of hypercalcemia involves aggressive medical therapy, including fluid replacement, bisphosphonates, calcimimetics such as evocalcet, and, in refractory cases, denosumab 38 , 39 . Emerging therapeutic modalities, including radiofrequency ablation, external beam radiation therapy, and targeted agents such as tyrosine kinase inhibitors and immune checkpoint inhibitors, have shown promise in locally advanced or metastatic settings 36 , 40 . Nevertheless, there is no established standard systemic therapy, and treatment decisions are often individualized in multidisciplinary centers of excellence 35 . In addition, postoperative hypotension following parathyroid carcinoma resection is a clinically significant event that may arise from rapid biochemical shifts after tumor removal. In this case, the patient developed significant hypotension following the initial resection of the parathyroid tumor, which may be attributed to the rapid decline in PTH and subsequent acute hypocalcemia. PC is frequently associated with severe hypercalcemia due to excessive PTH secretion, which can contribute to hypertension through vascular and renal mechanisms 41 . Surgical resection, particularly en bloc excision, leads to a sharp decline in PTH levels, subsequently resulting in acute hypocalcemia 42 . This abrupt normalization of calcium levels may reduce peripheral vascular resistance and myocardial contractility, potentially precipitating hypotension. Additionally, extensive resection may cause inadvertent damage to remaining parathyroid tissue or adjacent structures, further exacerbating electrolyte imbalances. Recent advances in molecular profiling have opened avenues for targeted therapies, including tyrosine kinase inhibitors (TKIs), temozolomide, and immune checkpoint inhibitors (ICIs), offering hope for improved management of advanced PC. Moreover, immune checkpoint blockade with agents such as pembrolizumab has shown promise in PCs characterized by high tumor mutational burden and APOBEC signature overactivation, indicating an immunogenic tumor microenvironment amenable to ICIs 43 . These findings underscore the potential of precision oncology approaches in this rare malignancy. In summary, the exploration of TKIs, temozolomide, and ICIs represents a promising frontier in the management of advanced PC. Molecular profiling has been pivotal in identifying actionable targets, enabling the application of precision medicine approaches that have shown clinical benefit in select cases. Continued research and clinical trials are essential to validate these therapies, optimize their use, and improve outcomes for patients with this challenging malignancy. 4. Comorbidity of PC and Other Thyroid Diseases 4.1 Synchronous Occurrence of PC and Thyroid Carcinoma The synchronous occurrence of PC and thyroid carcinoma, particularly papillary thyroid carcinoma (PTC), is an exceptionally rare clinical phenomenon that poses significant diagnostic and therapeutic challenges. The diagnostic difficulty arises because PC can mimic thyroid malignancies both clinically and radiologically, especially when tumors are located adjacent to or within the thyroid gland. For instance, intrathyroidal PC has been reported, which can be misdiagnosed preoperatively as thyroid carcinoma due to overlapping imaging features and anatomical proximity 44 . Moreover, PC may present with severe hypercalcemia and markedly elevated PTH levels, which can aid in raising suspicion for parathyroid malignancy, but these biochemical markers alone are not definitive. Surgical management typically involves en bloc resection of the parathyroid tumor with ipsilateral thyroid lobectomy or total thyroidectomy, depending on the extent of thyroid involvement, to achieve complete tumor clearance and control hyperparathyroidism 45 . While the short-term prognosis may be favorable with early diagnosis and appropriate surgical intervention, long-term outcomes depend on the completeness of resection and the biological behavior of both tumors. Currently, no standardized guidelines exist for managing synchronous parathyroid and thyroid carcinomas, and treatment strategies are individualized based on tumor characteristics and patient factors. 46 4.2 Differentiation of PC from PA and Hyperplasia Differentiating PC from PA and hyperplasia remains a significant clinical and pathological challenge due to substantial overlap in their presentations. Clinically, all three entities can manifest with primary hyperparathyroidism characterized by hypercalcemia and elevated PTH levels, leading to symptoms such as bone pain, fractures, fatigue, renal complications, and neuropsychiatric disturbances 47 . Histologically, PC is defined by unequivocal evidence of malignancy, such as angioinvasion, perineural invasion, local invasion into adjacent structures, or metastasis. However, these features are often absent or difficult to identify in small biopsy specimens or early-stage tumors, leading to diagnostic ambiguity 48 . Given the diagnostic challenges posed by overlapping features, several important criteria and strategies have been identified to aid differentiation between PC, adenoma, and hyperplasia. Clinically, suspicion for carcinoma should be heightened in patients presenting with severe hypercalcemia (often > 14 mg/dL), markedly elevated PTH levels, palpable neck masses, and evidence of local invasion or metastasis 27 . Imaging cannot definitively distinguish carcinoma from adenoma. Histopathological examination remains the gold standard for diagnosis, with carcinoma defined by invasive features such as angioinvasion, perineural invasion, and local tissue infiltration; however, these are often only confirmed postoperatively. Immunohistochemical markers such as parafibromin loss, Ki-67 proliferation index, and cancer-derived immunoglobulin G (CIgG) expression have shown promise in distinguishing carcinoma from benign lesions and predicting prognosis 49 . Given the complexity and rarity of PC, multidisciplinary collaboration involving endocrinologists, radiologists, pathologists, and surgeons is essential for accurate diagnosis and optimal management. Conclusion In summary, PC presents a significant clinical challenge due to its diagnostic ambiguity and overlapping features with benign disorders. Current management relies on comprehensive preoperative evaluation integrating biochemical profiling and advanced imaging, with complete surgical resection remaining the cornerstone of curative treatment. Molecular characterization, particularly of CDC73 mutations, has enhanced diagnostic precision and reveals potential therapeutic targets. However, managing advanced or recurrent disease requires multidisciplinary collaboration and individualized approaches. Future efforts should focus on elucidating molecular pathogenesis, validating emerging systemic therapies through multicenter trials, and integrating novel biomarkers into clinical practice to ultimately improve patient outcomes. Declarations Author contributions Le Sun and Yue Qu conceived and designed the work; Yubin Ji and Le Sun were responsible for patient treatment and follow-up; Ye Zhang, Zhiqing Zhang, and Yingqian Zhou acquired the data and prepared the figures; and Le Sun and Yue Qu wrote the paper. Funding The author(s) declare that no financial support was received for the research and/or publication of this article. Competing interests The authors declare no competing interests. Ethics statement According to the National Health Commission- Human beings biomedical research ethics audit method (2023), by the Beijing Tsinghua Changgung Hospital Ethics Committee Ethics audit for the publication of any potentially identifiable images or data included in this article (No25992-6-01). Written informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article. Data availability The dataset supporting the conclusions of this article is included within the article. References Sawhney S, Vaish R, Jain S, et al. Parathyroid Carcinoma: a Review. Indian J Surg Oncol. 2022;13(1):133-142. Fingeret AL. Contemporary Evaluation and Management of Parathyroid Carcinoma. JCO Oncol Pract. 2021;17(1):17-21. 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Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling. Mol Oncol. 2023;17(7):1343-1355. Otake K, Kondo Y, Tsukamoto K, et al. Parathyroid carcinoma detected within the thyroid. Nagoya J Med Sci. 2021;83(2):367-374. Gui SY, Zhang CN, Ling L, et al. Parathyroid carcinoma located in the thyroid gland: A case report. World J Clin Cases. 2024;12(18):3609-3614. Scerrino G, Paladino NC, Orlando G, et al. The Nexus of Hyperparathyroidism and Thyroid Carcinoma: Insights into Pathogenesis and Diagnostic Challenges-A Narrative Review. J Clin Med. 2023;13(1). Terro JJ, El-Helou E, El-Khoury E, et al. Giant parathyroid adenoma presenting with a pathological left clavicular fracture: An extremely rare case report. Int J Surg Case Rep. 2020;75:311-316. Erickson LA, Mete O, Juhlin CC, et al. Overview of the 2022 WHO Classification of Parathyroid Tumors. Endocr Pathol. 2022;33(1):64-89. Cui M, Hu Y, Zheng B, et al. Cancer-derived immunoglobulin G: A novel marker for differential diagnosis and relapse prediction in parathyroid carcinoma. Clin Endocrinol (Oxf). 2020;92(5):461-467. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8856468","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":594093444,"identity":"d10055d2-2742-47aa-b1d7-344b0e54c9c6","order_by":0,"name":"Le Sun","email":"","orcid":"","institution":"Tsinghua University","correspondingAuthor":false,"prefix":"","firstName":"Le","middleName":"","lastName":"Sun","suffix":""},{"id":594093446,"identity":"17f52dfd-a66f-4b2e-b486-6ba6014f8d98","order_by":1,"name":"Ye Zhang","email":"","orcid":"","institution":"National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Ye","middleName":"","lastName":"Zhang","suffix":""},{"id":594093447,"identity":"cd3b13d6-1ef6-44f6-bc1e-10ab862f5d9f","order_by":2,"name":"Zhiqing Zhang","email":"","orcid":"","institution":"Rongcheng County People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhiqing","middleName":"","lastName":"Zhang","suffix":""},{"id":594093450,"identity":"bd6bdabd-9f74-47d2-91c6-48d05edb67d2","order_by":3,"name":"Yingqian Zhou","email":"","orcid":"","institution":"Tsinghua University","correspondingAuthor":false,"prefix":"","firstName":"Yingqian","middleName":"","lastName":"Zhou","suffix":""},{"id":594093452,"identity":"516c39a4-184d-424e-9b77-453f169c3f0a","order_by":4,"name":"Hao Liu","email":"","orcid":"","institution":"Tsinghua University","correspondingAuthor":false,"prefix":"","firstName":"Hao","middleName":"","lastName":"Liu","suffix":""},{"id":594093454,"identity":"afae8b96-c5b7-4dd8-8647-3fadd7c25cb8","order_by":5,"name":"Yue Qu","email":"","orcid":"","institution":"Tsinghua University","correspondingAuthor":false,"prefix":"","firstName":"Yue","middleName":"","lastName":"Qu","suffix":""},{"id":594093456,"identity":"5f42fb5f-0fb8-4b98-bf5a-bf66df14f54c","order_by":6,"name":"Yubin Ji","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8UlEQVRIie3SPQrCMBiA4S8UdAm6KoV6ha8ERNDNiyQIutTiDawIdVFwTG/h6Fjp4FL3ioseQCk4iQ624uJg7OiQd0vCA/kD0On+MOJRAI4dq1Se56NsKixC0lGfVWlMvEIEgAKRaSQC6RQkhhxurhQjhvvz9nhbg1VJOLmOVBuTbs+kOLDw4IrJIgZWT7hhSiVxMCNthgfHnhIfxCrhJYOqCbtTNMRqH7/IuAhp1iV2s+PTF+H4k8wv/VaK+SW7Ilj4NTuIT1NTRezZMEr4I3/KXZje/E6jsu1ld6giS/4xrsH7D3yvUQ2V6zqdTqcDeAIUDVHq5CQuJgAAAABJRU5ErkJggg==","orcid":"","institution":"Tsinghua University","correspondingAuthor":true,"prefix":"","firstName":"Yubin","middleName":"","lastName":"Ji","suffix":""}],"badges":[],"createdAt":"2026-02-12 01:39:54","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8856468/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8856468/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103506029,"identity":"13b58c68-5743-4a7f-bbdf-3a3f2caba034","added_by":"auto","created_at":"2026-02-26 13:33:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":588120,"visible":true,"origin":"","legend":"\u003cp\u003eA-B Right lobe complex nodule (35*30*47 mm) with progressive enhancement and septations, left lobe hypodense nodules (max 21*28*25 mm) showing peripheral enhancement and non-enhancing areas; 1C Gross appearance of the intraoperative parathyroid mass.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8856468/v1/1aab76a54cdb6b92f0f2412f.png"},{"id":103259088,"identity":"79bf5960-0dc0-462d-86e3-93b9a1e55528","added_by":"auto","created_at":"2026-02-23 17:36:26","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1416474,"visible":true,"origin":"","legend":"\u003cp\u003eimmunohistochemical staining of the specimen was positive for PTH, CgA, and CK8/18, but negative for CK19. The Ki-67 proliferation index was 25%.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8856468/v1/7dfdd6fcde7b789d92b8957b.png"},{"id":103259086,"identity":"33309f3f-1328-472b-964f-91b534be1a03","added_by":"auto","created_at":"2026-02-23 17:36:26","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":316949,"visible":true,"origin":"","legend":"\u003cp\u003eFocal FDG uptake at thyroid bed (SUV max 4*4) with concurrent bony metastases (right 11th rib/pelvis) consistent with hyperathyroidism-related changes.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8856468/v1/b83ff28adf2371cb62348040.png"},{"id":103505547,"identity":"fc8e6a5f-1688-401c-a947-596d608e0df2","added_by":"auto","created_at":"2026-02-26 13:31:43","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":163156,"visible":true,"origin":"","legend":"\u003cp\u003eSerum levels of Ca, P and PTH measured preoperatively and postoperatively\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8856468/v1/eada799419dc870a080563c4.png"},{"id":103505883,"identity":"1f6174ac-a784-4249-9f61-7c8fcfb12808","added_by":"auto","created_at":"2026-02-26 13:33:21","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":103634,"visible":true,"origin":"","legend":"\u003cp\u003ePerioperative Blood Pressure Trends Following Parathyroid Carcinoma Resection\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-8856468/v1/34dd21d000b477d1ecd235cd.png"},{"id":103509608,"identity":"b955c389-b1e4-40d4-a4b8-cdc793eca35e","added_by":"auto","created_at":"2026-02-26 14:00:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3478701,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8856468/v1/b4a4cd2c-7c68-4a0d-bdb9-a6f3b2705637.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Exploration of Treatment Strategies for Nodular Goiter Complicated with Parathyroid Carcinoma: Experience Summary Based on a Single Case","fulltext":[{"header":"Introduction","content":"\u003cp\u003eParathyroid carcinoma (PC) is an exceedingly rare and highly aggressive endocrine malignancy that accounts for less than 1% of all cases of primary hyperparathyroidism (PHPT) and an even smaller fraction of overall cancers\u003csup\u003e1, 2\u003c/sup\u003e. Despite its rarity, PC poses significant clinical challenges due to its often-severe manifestations and complex diagnostic and therapeutic considerations. Clinically, PC typically presents with symptoms of profound hypercalcemia, the most common and life -threatening complication of this malignancy\u003csup\u003e3\u003c/sup\u003e. Frequently, patients exhibit markedly elevated serum calcium and parathyroid hormone (PTH) levels, which often exceed those observed in benign parathyroid adenomas (PA) or hyperplasia\u003csup\u003e4, 5\u003c/sup\u003e. These biochemical abnormalities lead to multi-organ involvement, including renal dysfunction, skeletal lesions such as osteitis fibrosa cystica and brown tumors, gastrointestinal symptoms, neuropsychiatric disturbances, and, in rare cases, acute pancreatitis\u003csup\u003e6-8\u003c/sup\u003e. The clinical situation is often complicated by the overlap of these features with benign parathyroid diseases, rendering preoperative diagnosis challenging. We herein present a case of parathyroid carcinoma complicated by nodular goiter and discuss the disease characteristics and management strategies based on a literature review.\u003c/p\u003e"},{"header":"Case report","content":"\u003cp\u003eA 58-year-old male presented with a 5-year history of thyroid mass and pain in both lower legs, with symptoms worsening in the past six months. Initially, he only had a thyroid mass and mild pain in the lower legs. In the past six months, the pain worsened, accompanied by various discomforts such as joint pain, weight loss, and skin itching. In the past two months, nausea and other symptoms emerged. Based on the physical and imaging findings, the patient presents with thyroid nodule and a biochemical profile highly suggestive of primary hyperparathyroidism. Physical examination disclosed firm masses in both thyroid lobes that moved during swallowing. Thyroid ultrasound showed enlargement with multiple TI-RADS 3 nodules, while contrast-enhanced CT shows a complex nodule (35 x 30 x 47 mm) in the right thyroid lobe with progressive enhancement and internal septations. The left lobe contains hypodense nodules (largest 21 x 28 x 25 mm) demonstrating peripheral enhancement with non-enhancing components (Fig.\u0026nbsp;1A-B). Crucially, parathyroid scintigraphy localized a hyperfunctioning parathyroid gland dorsal to the right lower pole. This is further supported by markedly elevated PTH (3224 ng/L) and significant hypercalcemia (4.58 mmol/L), alongside elevated alkaline phosphatase (985 U/L) and creatinine (166.0 \u0026micro;mol/L), indicating potential renal and bone involvement. The profile is compounded by other abnormalities, including hypokalemia, hypomagnesemia, dyslipidemia, and altered thyroid function.\u003c/p\u003e \u003cp\u003eThe patient underwent excision of the bilateral parathyroid mass. Intraoperative frozen section pathology revealed a parathyroid tumor with intratumoral collagenous fiber hyperplasia and no evidence of vascular invasion. A definitive distinction between benign and malignant could not be established, pending permanent section analysis. Consequently, only a parathyroid tumor excision was performed (Fig.\u0026nbsp;1C). \u003c/p\u003e \u003cp\u003eFigure1 1A-B Right lobe complex nodule (35*30*47 mm) with progressive enhancement and septations, left lobe hypodense nodules (max 21*28*25 mm) showing peripheral enhancement and non-enhancing areas; 1C Gross appearance of the intraoperative parathyroid mass.\u003c/p\u003e \u003cp\u003eHistopathological examination confirmed the mass in the right lobe was PC, while the mass in the left lobe was diagnosed as nodular goiter. For the diagnosis of PC, the immunohistochemical staining of the specimen was positive for PTH, CgA, and CK8/18, but negative for CK19. The Ki-67 proliferation index was 25% (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePostoperative PET-CT imaging revealed a mild heterogeneous increase in FDG uptake at the thyroid surgical site, with a maximum SUV of 4.4. Elevated FDG metabolism was also observed in the right 11th rib and pelvis, findings consistent with secondary bone changes associated with hyperparathyroidism (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTwo weeks later, the patient proceeded to a second procedure, which included a right thyroid lobectomy with isthmusectomy and central compartment lymph node dissection. Postoperative pathology revealed infiltration of the PC into the right thyroid parenchyma. One perithyroidal lymph node was identified and was negative for metastatic carcinoma. Immunohistochemistry of the thyroid specimen showed positivity for CK19 and CK8/18, while results were negative for CgA, Syn, PTH, and calcitonin. The Ki-67 index was significantly lower at 2%. CD68 immunostaining highlighted histiocytes. Special stains were notable for Masson's trichrome (highlighting fibrosis) and Congo red (negative for amyloid deposition). Examination of the right central compartment lymph nodes confirmed no metastasis (0/2 nodes). Serum levels of calcium, phosphorus, and PTH measured preoperatively and postoperatively are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e, while blood pressure fluctuations are illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003e. The patient developed severe hypotension postoperatively, requiring norepinephrine infusion for vasopressor support. Blood pressure normalized by postoperative day 8. During the two-year postoperative follow-up period, the patient remained asymptomatic with no evidence of disease recurrence, indicating a stable clinical status.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\n\u003ch3\u003e1. Clinical Manifestations and Epidemiology of PC\u003c/h3\u003e\n\u003cp\u003ePC is an extremely rare endocrine malignancy with a historically low global incidence, though recent years have shown a gradual increase. A nationwide Korean cohort study from 2002 to 2017 reported an age-standardized incidence rate rising from 3.8 per 10\u0026nbsp;million person-years in 2003 to 6.6 per 10\u0026nbsp;million person-years in 2016, highlighting a notable upward trend\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Similarly, U.S. SEER database analyses confirm PC's rarity, representing only about 0.005% of all malignancies, with a slight male predominance and an average diagnosis age in the early 60s\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Overall, PC typically affects middle-aged to older adults without a strong gender preference, though regional differences may influence demographic patterns.\u003c/p\u003e \u003cp\u003ePC often presents with clinical manifestations primarily related to severe hypercalcemia due to excessive secretion of PTH. Patients with primary hyperparathyroidism often present with severe symptoms caused by high calcium levels in the blood, which can become dangerous if not treated promptly. A key feature is bone pain, along with skeletal issues like broken bones and bone lesions known as osteitis fibrosa cystica, showing how excess PTH damages bone health. Kidney problems, such as kidney stones and calcium buildup in kidney tissue, are also frequent due to excessive calcium in the urine and deposits in the kidneys\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Moreover, non-functioning PCs, which do not secrete significant amounts of PTH, have been described and are associated with a silent clinical course, further complicating clinical recognition\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. In these cases, the primary clinical sign may be a neck mass or incidental imaging finding rather than biochemical abnormalities or symptoms of hypercalcemia. The clinical presentation of PC may also overlap with other parathyroid pathologies, such as atypical PA and giant PA, which can exhibit similar biochemical and clinical profiles, including severe hypercalcemia and skeletal involvement\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn summary, PC presents a diverse clinical spectrum, ranging from severe cases characterized by marked hypercalcemia with multisystem involvement\u0026mdash;manifesting as bone pain, renal calculi, neuropsychiatric symptoms, and gastrointestinal discomfort\u0026mdash;to asymptomatic cases incidentally discovered as neck masses or through imaging findings\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003e2. Diagnostic Challenges and Imaging Advances in PC\u003c/h3\u003e\n\u003cp\u003eImaging plays a pivotal role in the diagnosis, localization, and differential diagnosis of PC. The preoperative diagnosis of PC is notably difficult due to significant overlap in clinical presentation and biochemical markers with benign PA \u003csup\u003e18\u003c/sup\u003e. Imaging modalities such as ultrasound, sestamibi scintigraphy, and computed tomography (CT) are routinely employed for localization of parathyroid lesions preoperatively. Yet, their ability to distinguish carcinoma from adenoma is limited. Ultrasound may reveal a large hypoechoic lesion with irregular borders in PC, but similar features can be seen in atypical adenomas or large benign tumors\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Advanced imaging techniques like 18F-fluorocholine PET/CT have shown promise in localizing hyperfunctioning parathyroid tissue with high sensitivity but still lack specificity for carcinoma\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Positron emission tomography/computed tomography (PET/CT) with various tracers, such as 18F-fluorodeoxyglucose (18F-FDG), 18F-fluorocholine (18F-FCH), and novel agents like 18F-FAPI, has shown promising sensitivity in detecting hyperfunctioning parathyroid tissue and metastatic lesions. 99mTc-sestamibi scintigraphy, often combined with single-photon emission computed tomography/computed tomography (SPECT/CT), provides functional imaging by detecting mitochondrial-rich PA or carcinomas and is especially useful in cases with ectopic glands or multiglandular disease. Notably, 99mTc-sestamibi SPECT/CT has demonstrated utility in detecting both primary lesions and metastatic sites, such as lung metastases, as reported in rare cases of PC with distant spread\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Histopathological examination remains the gold standard for definitive diagnosis, often only available postoperatively. Intraoperative frozen section analysis is limited by sampling errors and interpretative difficulties, with discordance rates noted in some studies\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Immunohistochemical markers such as parafibromin and GATA-3 have been investigated to aid diagnosis, but their utility preoperatively is constrained\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMolecular subtyping of PC has emerged as a pivotal approach to refine diagnosis, prognostication, and personalized treatment, addressing the challenges posed by this rare and heterogeneous malignancy. Advances in genomic and transcriptomic profiling have revealed distinct molecular signatures that differentiate PC from benign PA and atypical parathyroid tumors, thereby aiding early and accurate diagnosis. For instance, mutations in the CDC73 gene, encoding the tumor suppressor parafibromin, are prevalent in up to 80% of sporadic PCs and serve as a hallmark of malignancy, distinguishing PC from benign lesions\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Mutations in CDC73 are highly prevalent in PC, with mutation frequencies reported up to 80% in both familial and sporadic cases. These mutations often lead to loss of parafibromin expression, which is strongly associated with malignant transformation and poor prognosis in parathyroid tumors\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003e3. Surgical Treatment and Management of PC\u003c/h3\u003e\n\u003cp\u003eSurgical resection remains the cornerstone and only potentially curative treatment for PC. En bloc resection with negative margins at the initial surgery offers the best chance for long-term disease control and survival\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Many studies emphasize the importance of achieving negative surgical margins during the first operation, as incomplete resection is associated with higher rates of local recurrence and poorer outcomes\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Intraoperative PTH monitoring can assist in confirming removal of hyperfunctioning tissue, although its role specifically in PC surgery is less well defined compared to benign hyperparathyroidism\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. When preservation in situ is not feasible, autotransplantation of parathyroid tissue into the sternocleidomastoid muscle or forearm is a recognized technique to maintain parathyroid function, with evidence suggesting that auto transplantation does not increase the risk of permanent hypoparathyroidism\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. The inferior parathyroid glands, which are more difficult to preserve due to their variable location, are often candidates for autotransplantation\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Intraoperative neuromonitoring of the recurrent laryngeal nerve is recommended to minimize the risk of vocal cord paralysis, especially in cases requiring extensive neck dissection due to suspected local invasion\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Radiotherapy, while occasionally considered, has not demonstrated consistent benefit in improving disease-free or overall survival\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. A national cancer database analysis involving over 1,000 PC patients found no association between adjuvant radiotherapy and improved overall survival, underscoring the limited impact of radiation on long-term outcomes\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Chemotherapy for PC has similarly failed to demonstrate meaningful efficacy and is generally reserved for palliative purposes rather than curative intent. Chemotherapy is primarily utilized in cases of metastatic or unresectable disease to manage symptoms or control hypercalcemia indirectly\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, due to diagnostic uncertainties, many patients undergo incomplete resection, leading to high rates of local recurrence and metastasis\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. The recurrence rate ranges from 30% to 67%, with recurrent disease often causing refractory hypercalcemia, which is the predominant cause of morbidity and mortality in PC patients\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. The management of recurrent and metastatic PC poses significant clinical challenges due to the limited efficacy of adjuvant therapies such as chemotherapy and radiotherapy. Nevertheless, the mainstay of treatment remains surgical, and reoperation is recommended for patients with resectable local recurrences or metastases\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. For unresectable or metastatic disease, emerging systemic therapies such as tyrosine kinase inhibitors (e.g., sorafenib) and immunotherapy (e.g., pembrolizumab, nivolumab) have shown promise in controlling disease progression and hypercalcemia, though evidence is currently limited to case reports and small series\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eManagement of hypercalcemia involves aggressive medical therapy, including fluid replacement, bisphosphonates, calcimimetics such as evocalcet, and, in refractory cases, denosumab\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. Emerging therapeutic modalities, including radiofrequency ablation, external beam radiation therapy, and targeted agents such as tyrosine kinase inhibitors and immune checkpoint inhibitors, have shown promise in locally advanced or metastatic settings\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. Nevertheless, there is no established standard systemic therapy, and treatment decisions are often individualized in multidisciplinary centers of excellence\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn addition, postoperative hypotension following parathyroid carcinoma resection is a clinically significant event that may arise from rapid biochemical shifts after tumor removal. In this case, the patient developed significant hypotension following the initial resection of the parathyroid tumor, which may be attributed to the rapid decline in PTH and subsequent acute hypocalcemia. PC is frequently associated with severe hypercalcemia due to excessive PTH secretion, which can contribute to hypertension through vascular and renal mechanisms\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. Surgical resection, particularly en bloc excision, leads to a sharp decline in PTH levels, subsequently resulting in acute hypocalcemia\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. This abrupt normalization of calcium levels may reduce peripheral vascular resistance and myocardial contractility, potentially precipitating hypotension. Additionally, extensive resection may cause inadvertent damage to remaining parathyroid tissue or adjacent structures, further exacerbating electrolyte imbalances.\u003c/p\u003e \u003cp\u003eRecent advances in molecular profiling have opened avenues for targeted therapies, including tyrosine kinase inhibitors (TKIs), temozolomide, and immune checkpoint inhibitors (ICIs), offering hope for improved management of advanced PC. Moreover, immune checkpoint blockade with agents such as pembrolizumab has shown promise in PCs characterized by high tumor mutational burden and APOBEC signature overactivation, indicating an immunogenic tumor microenvironment amenable to ICIs\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. These findings underscore the potential of precision oncology approaches in this rare malignancy. In summary, the exploration of TKIs, temozolomide, and ICIs represents a promising frontier in the management of advanced PC. Molecular profiling has been pivotal in identifying actionable targets, enabling the application of precision medicine approaches that have shown clinical benefit in select cases. Continued research and clinical trials are essential to validate these therapies, optimize their use, and improve outcomes for patients with this challenging malignancy.\u003c/p\u003e\n\u003ch3\u003e4. Comorbidity of PC and Other Thyroid Diseases\u003c/h3\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Synchronous Occurrence of PC and Thyroid Carcinoma\u003c/h2\u003e \u003cp\u003eThe synchronous occurrence of PC and thyroid carcinoma, particularly papillary thyroid carcinoma (PTC), is an exceptionally rare clinical phenomenon that poses significant diagnostic and therapeutic challenges. The diagnostic difficulty arises because PC can mimic thyroid malignancies both clinically and radiologically, especially when tumors are located adjacent to or within the thyroid gland. For instance, intrathyroidal PC has been reported, which can be misdiagnosed preoperatively as thyroid carcinoma due to overlapping imaging features and anatomical proximity\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. Moreover, PC may present with severe hypercalcemia and markedly elevated PTH levels, which can aid in raising suspicion for parathyroid malignancy, but these biochemical markers alone are not definitive. Surgical management typically involves en bloc resection of the parathyroid tumor with ipsilateral thyroid lobectomy or total thyroidectomy, depending on the extent of thyroid involvement, to achieve complete tumor clearance and control hyperparathyroidism\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. While the short-term prognosis may be favorable with early diagnosis and appropriate surgical intervention, long-term outcomes depend on the completeness of resection and the biological behavior of both tumors. Currently, no standardized guidelines exist for managing synchronous parathyroid and thyroid carcinomas, and treatment strategies are individualized based on tumor characteristics and patient factors.\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Differentiation of PC from PA and Hyperplasia\u003c/h2\u003e \u003cp\u003eDifferentiating PC from PA and hyperplasia remains a significant clinical and pathological challenge due to substantial overlap in their presentations. Clinically, all three entities can manifest with primary hyperparathyroidism characterized by hypercalcemia and elevated PTH levels, leading to symptoms such as bone pain, fractures, fatigue, renal complications, and neuropsychiatric disturbances\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. Histologically, PC is defined by unequivocal evidence of malignancy, such as angioinvasion, perineural invasion, local invasion into adjacent structures, or metastasis. However, these features are often absent or difficult to identify in small biopsy specimens or early-stage tumors, leading to diagnostic ambiguity\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e. Given the diagnostic challenges posed by overlapping features, several important criteria and strategies have been identified to aid differentiation between PC, adenoma, and hyperplasia. Clinically, suspicion for carcinoma should be heightened in patients presenting with severe hypercalcemia (often\u0026thinsp;\u0026gt;\u0026thinsp;14 mg/dL), markedly elevated PTH levels, palpable neck masses, and evidence of local invasion or metastasis\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Imaging cannot definitively distinguish carcinoma from adenoma. Histopathological examination remains the gold standard for diagnosis, with carcinoma defined by invasive features such as angioinvasion, perineural invasion, and local tissue infiltration; however, these are often only confirmed postoperatively. Immunohistochemical markers such as parafibromin loss, Ki-67 proliferation index, and cancer-derived immunoglobulin G (CIgG) expression have shown promise in distinguishing carcinoma from benign lesions and predicting prognosis\u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e. Given the complexity and rarity of PC, multidisciplinary collaboration involving endocrinologists, radiologists, pathologists, and surgeons is essential for accurate diagnosis and optimal management.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, PC presents a significant clinical challenge due to its diagnostic ambiguity and overlapping features with benign disorders. Current management relies on comprehensive preoperative evaluation integrating biochemical profiling and advanced imaging, with complete surgical resection remaining the cornerstone of curative treatment. Molecular characterization, particularly of CDC73 mutations, has enhanced diagnostic precision and reveals potential therapeutic targets. However, managing advanced or recurrent disease requires multidisciplinary collaboration and individualized approaches. Future efforts should focus on elucidating molecular pathogenesis, validating emerging systemic therapies through multicenter trials, and integrating novel biomarkers into clinical practice to ultimately improve patient outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLe Sun and Yue Qu conceived and designed the work; Yubin Ji and Le Sun were responsible for patient treatment and follow-up; Ye Zhang, Zhiqing Zhang, and Yingqian Zhou acquired the data and prepared the figures; and Le Sun and Yue Qu wrote the paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author(s) declare that no financial support was received for the research and/or publication of this article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to the National Health Commission- Human beings biomedical research ethics audit method (2023), by the Beijing Tsinghua Changgung Hospital Ethics Committee Ethics audit for the publication of any potentially identifiable images or data included in this article (No25992-6-01). Written informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe dataset supporting the conclusions of this article is included within the article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSawhney S, Vaish R, Jain S, et al. Parathyroid Carcinoma: a Review. Indian J Surg Oncol. 2022;13(1):133-142.\u003c/li\u003e\n \u003cli\u003eFingeret AL. Contemporary Evaluation and Management of Parathyroid Carcinoma. JCO Oncol Pract. 2021;17(1):17-21.\u003c/li\u003e\n \u003cli\u003eCalapkulu M, Gul OO, Cander S, et al. Control of Refractory Hypercalcemia with Denosumab in a Case of Metastatic Parathyroid Carcinoma. J Coll Physicians Surg Pak. 2020;30(7):757-759.\u003c/li\u003e\n \u003cli\u003eAlberti A, Smussi D, Zamparini M, et al. 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Cureus. 2022;14(11):e31757.\u003c/li\u003e\n \u003cli\u003eKartini D, Kurnia A, Yulian ED, et al. Case series of diagnosis and surgery challenges in parathyroid carcinoma. Int J Surg Case Rep. 2022;97:107390.\u003c/li\u003e\n \u003cli\u003eMathey C, Keyzer C, Blocklet D, et al. (18)F-Fluorocholine PET/CT Is More Sensitive Than (11)C-Methionine PET/CT for the Localization of Hyperfunctioning Parathyroid Tissue in Primary Hyperparathyroidism. J Nucl Med. 2022;63(5):785-791.\u003c/li\u003e\n \u003cli\u003eZhu Y, Wang L, You J, et al. Diagnostic value of Tc-99m-MIBI SPECT/CT in parathyroid carcinoma with lung metastasis: a case report and literature review. Front Oncol. 2024;14:1501447.\u003c/li\u003e\n \u003cli\u003eJain V, Saini VK, Narayan ML. Detection of Metastatic Parathyroid Carcinoma with (99m)Tc-Sestamibi SPECT/CT Imaging. Radiol Imaging Cancer. 2025;7(5):e250283.\u003c/li\u003e\n \u003cli\u003eMohamed A, Hassan MM, Zhong W, et al. A Quantitative and Qualitative Assessment of Frozen Section Diagnosis Accuracy and Deferral Rate Across Organ Systems. Am J Clin Pathol. 2022;158(6):692-701.\u003c/li\u003e\n \u003cli\u003eLajmi Z, Bdioui A, Bchir A, et al. The input of GATA-3 in the identification of parathyroid carcinoma diagnosis: Case report with review of literature. Ann Med Surg (Lond). 2021;68:102571.\u003c/li\u003e\n \u003cli\u003eMarini F, Giusti F, Palmini G, et al. Parathyroid carcinoma: molecular therapeutic targets. Endocrine. 2023;81(3):409-418.\u003c/li\u003e\n \u003cli\u003eCunha C, Pinheiro SL, Donato S, et al. Parathyroid carcinoma: Single centre experience. Clin Endocrinol (Oxf). 2022;97(3):250-257.\u003c/li\u003e\n \u003cli\u003eKowalski GJ, Bednarczyk A, Bula G, et al. Parathyroid carcinoma - a study of 29 cases. Endokrynol Pol. 2022;73(1):56-63.\u003c/li\u003e\n \u003cli\u003eLin DX, Zhuo XB, Lin Y, et al. Enhancing parathyroid preservation in papillary thyroid carcinoma surgery using nano-carbon suspension. Sci Rep. 2024;14(1):24680.\u003c/li\u003e\n \u003cli\u003eWang B, Zhu CR, Yao XM, et al. The Effect of Parathyroid Gland Autotransplantation on Hypoparathyroidism After Thyroid Surgery for Papillary Thyroid Carcinoma. Cancer Manag Res. 2021;13:6641-6650.\u003c/li\u003e\n \u003cli\u003eWang B, Zhu CR, Liu H, et al. The inferior parathyroid glands preserved in site recover faster than the superior parathyroid glands preserved in site after thyroid surgery for carcinoma. Medicine (Baltimore). 2020;99(28):e20886.\u003c/li\u003e\n \u003cli\u003eLadsous M, Deguelte S, Hindie E, et al. Chapter 15: Recurrent or persistent primary hyperparathyroidism, parathyromatosis. Ann Endocrinol (Paris). 2025;86(1):101704.\u003c/li\u003e\n \u003cli\u003eBollen H, Decallonne B, Nuyts S. Radiation Treatment for Inoperable Local Relapse of Parathyroid Carcinoma With Symptomatic Hypercalcemia: A Case Report. Front Oncol. 2021;11:733772.\u003c/li\u003e\n \u003cli\u003eGoldner E, Fingeret A. Parathyroid Carcinoma: A National Cancer Database Analysis. J Surg Res. 2023;281:57-62.\u003c/li\u003e\n \u003cli\u003eSilva-Figueroa AM. A Nomogram for Relapse/Death and Contemplating Adjuvant Therapy for Parathyroid Carcinoma. Surg Oncol Clin N Am. 2023;32(2):251-269.\u003c/li\u003e\n \u003cli\u003eDo Cao C, Christou N, Hadoux J, et al. Chapter 8: Management of aggressive forms of primary HPT: Parathyroid carcinoma and atypical parathyroid tumor. Ann Endocrinol (Paris). 2025;86(1):101697.\u003c/li\u003e\n \u003cli\u003eKim NH, Kim CA, Chung SR, et al. Successful Multimodal Treatment of Locally Advanced Parathyroid Carcinoma. JCEM Case Rep. 2024;2(12):luae208.\u003c/li\u003e\n \u003cli\u003eTa B, Bennett MJ. Refractory Hypercalcemia Secondary to Metastatic Parathyroid Carcinoma Treated With Immunotherapy. JCEM Case Rep. 2024;2(7):luae127.\u003c/li\u003e\n \u003cli\u003eMorishita A, Hozumi Y, Ishii H, et al. Effect of early dose increase of evocalcet for intractable hypercalcemia caused by parathyroid carcinoma. Endocrinol Diabetes Metab Case Rep. 2023;2023(1).\u003c/li\u003e\n \u003cli\u003eHaimi M, Yang JW, Kremer R. Refractory hypercalcemia caused by parathyroid-hormone-related peptide secretion from a metastatic pancreatic neuroendocrine tumor: a case report. J Med Case Rep. 2025;19(1):54.\u003c/li\u003e\n \u003cli\u003eViswanath A, Drakou EE, Lajeunesse-Trempe F, et al. Parathyroid carcinoma: New insights. Best Pract Res Clin Endocrinol Metab. 2025;39(2):101966.\u003c/li\u003e\n \u003cli\u003eRodgers SE, Perrier ND. Parathyroid carcinoma. Curr Opin Oncol. 2006;18(1):16-22.\u003c/li\u003e\n \u003cli\u003eVellanki P, Lange K, Elaraj D, et al. Denosumab for management of parathyroid carcinoma-mediated hypercalcemia. J Clin Endocrinol Metab. 2014;99(2):387-390.\u003c/li\u003e\n \u003cli\u003eTeleanu MV, Fuss CT, Paramasivam N, et al. Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling. Mol Oncol. 2023;17(7):1343-1355.\u003c/li\u003e\n \u003cli\u003eOtake K, Kondo Y, Tsukamoto K, et al. Parathyroid carcinoma detected within the thyroid. Nagoya J Med Sci. 2021;83(2):367-374.\u003c/li\u003e\n \u003cli\u003eGui SY, Zhang CN, Ling L, et al. Parathyroid carcinoma located in the thyroid gland: A case report. World J Clin Cases. 2024;12(18):3609-3614.\u003c/li\u003e\n \u003cli\u003eScerrino G, Paladino NC, Orlando G, et al. The Nexus of Hyperparathyroidism and Thyroid Carcinoma: Insights into Pathogenesis and Diagnostic Challenges-A Narrative Review. J Clin Med. 2023;13(1).\u003c/li\u003e\n \u003cli\u003eTerro JJ, El-Helou E, El-Khoury E, et al. Giant parathyroid adenoma presenting with a pathological left clavicular fracture: An extremely rare case report. Int J Surg Case Rep. 2020;75:311-316.\u003c/li\u003e\n \u003cli\u003eErickson LA, Mete O, Juhlin CC, et al. Overview of the 2022 WHO Classification of Parathyroid Tumors. Endocr Pathol. 2022;33(1):64-89.\u003c/li\u003e\n \u003cli\u003eCui M, Hu Y, Zheng B, et al. Cancer-derived immunoglobulin G: A novel marker for differential diagnosis and relapse prediction in parathyroid carcinoma. Clin Endocrinol (Oxf). 2020;92(5):461-467.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Parathyroid tumor, parathyroid carcinoma, secondary hyperparathyroidism, hypercalcemia","lastPublishedDoi":"10.21203/rs.3.rs-8856468/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8856468/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eParathyroid carcinoma (PC) is an exceedingly rare malignancy that poses significant diagnostic challenges. This case report delineates the clinical presentation, diagnostic evaluation, and multidisciplinary management of PC, highlighting the pivotal role of complete surgical excision and the diagnostic difficulties arising from its overlapping features with benign thyroid and parathyroid conditions.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe report the case of a 58-year-old male with a five-year history of a thyroid mass and progressive bilateral lower limb pain. Diagnostic investigations encompassed comprehensive biochemical analysis, thyroid and parathyroid ultrasonography, contrast-enhanced computed tomography (CT), and parathyroid scintigraphy. The patient had bilateral thyroid masses resected, and postoperative pathology showed right parathyroid carcinoma and left nodular goiter. Therefore, the patient underwent further surgery, including resection of the right thyroid lobe and isthmus, as well as central lymph node dissection.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003ePreoperative assessment revealed severe hypercalcemia (4.58 mmol/L) and a markedly elevated parathyroid hormone level (3224 ng/L). Imaging examination revealed nodules in both lobes of the thyroid gland. Histopathological examination of the initial specimen confirmed PC, with positive immunostaining for PTH and a high Ki-67 index (25%). The secondary resection demonstrated PC infiltration into the right thyroid parenchyma; no lymph node metastasis was detected (0/2). Postoperative calcium and PTH levels returned to normal, and no recurrence was observed during the two-year follow-up.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis case emphasizes that PC should be considered in patients presenting with severe hypercalcemia and a cervical mass. Accurate diagnosis requires integration of biochemical, imaging, and histopathological findings. En bloc surgical resection with clear margins constitutes the cornerstone of curative management and can yield favorable long-term outcomes.\u003c/p\u003e","manuscriptTitle":"Exploration of Treatment Strategies for Nodular Goiter Complicated with Parathyroid Carcinoma: Experience Summary Based on a Single Case","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-23 17:36:21","doi":"10.21203/rs.3.rs-8856468/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":"a2cd3f03-4ca5-44bb-a435-f8d75cd4e476","owner":[],"postedDate":"February 23rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-26T05:55:16+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-23 17:36:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8856468","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8856468","identity":"rs-8856468","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}