Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome, primarily caused by the overproduction of phosphatonins, such as fibroblast growth factor 23 (FGF23), by mesenchymal tumors. The biochemical hallmark of TIO includes renal phosphate wasting-induced hypophosphatemia, elevated levels of parathyroid hormone (PTH) and alkaline phosphatase (ALP), inappropriately normal or frankly low 1, 25-dihydroxyvitamin D, and inappropriately normal or elevated FGF23 levels (1, 2). The surgical excision of the tumor represents the definitive therapeutic intervention, necessitating the precise detection and localization of the tumors as a prerequisite for the potential curative approach to TIO (3, 4). Nonetheless, these tumors frequently present asymptomatically, are diminutive in size, exhibit slow growth, and can be located anywhere within the body, from the skull to the feet, rendering the diagnostic process exceedingly challenging (5). This necessitates the employment of multimodal imaging techniques for accurate tumor localization. The general unfamiliarity with TIO among clinicians often leads to diagnostic inaccuracies and overlooked diagnoses. ¹⁸F-AlF-NOTA-octreotide (¹⁸F-OC) positron emission tomography/computed tomography (PET/CT) represents a novel molecular imaging modality, targeting somatostatin receptor-expressing tumors, and holds promise for application in evaluating neuroendocrine tumors. However, its efficacy in the assessment of TIO remains to be fully ascertained (6). This article delineates 6 cases of TIO accurately localized and pathologically diagnosed using ¹⁸F-OC PET/CT imaging, coupled with an analytical summary based on relevant literature to augment understanding of this condition.

This study retrospectively collected and analyzed clinical and imaging data for 6 patients with suspected TIO, who underwent ¹⁸F-OC PET/CT imaging at the PET Center of the Second Affiliated Hospital of Zhejiang University School of Medicine between January 2022 and January 2024. All cases were pathologically confirmed as PMT. We gathered data on demographic details (gender and age), clinical manifestations, disease duration, tumor location, and serum levels of phosphate, ALP, PTH,1,25-dihydroxy vitamin D, and FGF23. Additionally, information on tumor biopsy and imaging findings from CT and MRI scans was compiled. The ¹⁸F-OC PET/CT examination data were processed using Siemens syngo software at the imaging station. PMTs typically occur in a wide range of locations, hence patients suspected of having PMTs usually require a PET/CT scan that covers the entire body from the skull to the feet. The tumor region of interest (ROI) was manually delineated, and with a threshold set at a standardized uptake value (SUV) of 2.5, the maximum standardized uptake value (SUVmax), the mean standardized uptake value (SUVmean), and metabolic tumor volume (MTV) were automatically calculated. Informed consent for the publication of case reports and associated images was obtained from all participating patients, who are currently under follow-up. The study received approval from the institutional ethics committee (approval number: 2023–1234).

Hypophosphatemic osteomalacia (HO) consists of hypophosphatemia, elevated ALP, muscular weakness, and bone pain. Misdiagnosis of HO is common, with an average delay of about 5 years before diagnosis (7). It is often caused by severe vitamin D deficiency, hereditary hypophosphatemic rickets syndromes, renal tubular acidosis, primary hyperparathyroidism, medications, and TIO (8). TIO-related tumors primarily originate from mesenchymal tissues, mostly located in bone and soft tissue (5, 9). Zhang et al. (10) reported that among 135 cases, 54.5% of the causative tumors originated from bone, predominantly in the femur and jawbone, while 45.5% originated from soft tissues, located in areas such as the nasal cavity, sinuses, and periosteum. The most common pathological type is PMT, among others like giant cell tumor, prostate cancer, B-cell non-Hodgkin lymphoma, vasopericytoma, neurofibroma, hemangiopericytomas and osteofibrous dysplasia, etc (5, 7, 11–15). In 1947, McCance (16). reported the first case of osteomalacia caused by a femoral tumor, but the relationship between the tumor and osteomalacia was not clear. In 1959, Prader et al. (17) first elucidated the relationship between mesenchymal tumors and osteomalacia. In 1987, Weidner and Santa (18). coined the term ‘phosphaturic mesenchymal tumor-mixed connective tissue variant (PMTMCT)’ for osteomalacia-associated mesenchymal tumors. In 2004, Folpe et al. (19) first proposed classifying the mesenchymal tumor that causes TIO as an independent pathological hisological type, and it was included in the WHO (2013) Classification of Soft Tissue Tumors in 2013 (20).

Despite pathologic confirmation, locating TIO tumors is challenging due to their small size and indolence, requiring advanced imaging such as CT, whole-body MRI, bone scintigraphy, and ¹⁸F-FDG PET/CT (21–23). Conventional anatomical imaging modalities exhibit limited diagnostic accuracy for TIO and typically rely on the guidance provided by functional imaging techniques (24). In 1996, Reubi et al. (25) reported that a variety of mesenchymal-derived tumors express somatostatin receptor (SSTR), especially SSTR2 receptors, establishing SSTR imaging as a pivotal method for identifying causative tumors (26). Agents for single-photon imaging include ¹¹¹In and ^99mTc-labeled SSTR (27–29). Positron imaging agents primarily consist of ⁶⁸Ga-labeled SSTR octreotide variants (27, 30, 31). Particularly, ⁶⁸Ga-DOTA-TATE, with stronger affinity to SSTR2 receptors, has become the preferred imaging choice for detecting causing tumors (32, 33). Zhang et al. (34) reported that in a study of 56 patients suspected of having TIO, the ⁶⁸Ga-DOTA-TATE PET/CT scans demonstrated a sensitivity of 95.13%, and a specificity of 60.00% for detecting TIO. In another study by Zhang et al. (10) involving 159 patients suspected of TIO, the ⁶⁸Ga-DOTA-TATE PET/CT scans achieved a sensitivity of 99.3% (134/135), a specificity of 79.2% (19/24), and an accuracy of 96.2% (153/159) in identifying TIO. These findings highlight the high efficacy and potential of ⁶⁸Ga-DOTA-TATE PET/CT in accurately diagnosing TIO in suspected cases. However, the limited production capacity of ⁶⁸Ga through germanium-gallium generators and the challenges associated with post-elution labeling, with a half-life of 68 minutes, has hindered the widespread use of ⁶⁸Ga-labeled PET tracers, prompting the exploration of other radiotracer for SSTR imaging (35). ¹⁸F, a radionuclide commonly employed in clinical PET imaging, can be produced in bulk by cyclotrons, featuring a relatively longer half-life, thereby offering superior inherent resolution (36). In 2010, Laverman et al. (37, 38) presented a labeling method for ¹⁸F-OC and demonstrated its high in vitro binding affinity to SSTR in a preclinical model. In 2019, Long et al. (6) reported their initial clinical experience with ¹⁸F-OC in three healthy volunteers and twenty-two patients with neuroendocrine neoplasms (NENs). The tracer was proven safe with favorable pharmacokinetics and biodistribution characteristics, offering good detection of tumors with high tumor-to-background ratios. The application of ¹⁸F-OC PET/CT has significantly impacted the clinical diagnosis of neuroendocrine tumors (39–41), marking it as a valuable molecular imaging tool for identifying tumors expressing SSTR. Nonetheless, the use of ¹⁸F-OC PET/CT for the diagnosis and treatment of TIO remains limited by the small number of cases studied (42).

This study details the imaging characteristics of identifying TIO using ¹⁸F-OC PET/CT, underscoring the technique’s proficiency in locating elusive, solitary tumors predominantly found in the lower extremities. These slow-growing tumors, often small in size, can nonetheless provoke systemic symptoms. Our study revealed that among the 6 causative tumors identified, three originated from soft tissue and remaining three from bones, with soft tissue tumors presenting larger volumes than their bony counterparts. Notably, the smallest detected TIO tumor, overlooked by both conventional imaging modalities and ¹⁸F-FDG PET/CT, was successfully identified by ¹⁸F-OC PET/CT. This tumor, nestled in the femoral neck, measured just 1.27 cm³ in volume and 7.8 mm in maximum diameter. This finding supports the notion that the majority of TIO tumors are benign, non-invasive growths confined within bone structures. The study emphasizes that ¹⁸F-OC PET/CT, offering whole-body tomographic imaging from the skull to the feet, is crucial for patients suspected of having TIO, as it can detect tumors that may be missed by conventional imaging techniques focused on specific locations. Moreover, ¹⁸F-OC, serving as a targeted imaging agent, demonstrated higher metabolic uptake than nonspecific agents like ¹⁸F-FDG in TIO tumors, highlighting its utility in detecting tumors with increased SSTR expression. SUVmax and SUVmean are commonly employed to discriminate between malignant tumors and benign lesions, offering insights into the malignancy gradient of the tumor. Meanwhile, MTV is frequently employed to ascertain the metabolic volume of diseases exhibiting high uptake. These three metabolic parameters, ubiquitous in PET imaging, play a critical role in tumor diagnosis and treatment (43). Within this study, ¹⁸F-OC PET/CT identified tumors with SSTR overexpression, with SUVmax ranging from 5.47 to 25.69, SUVmean ranging from 3.43 to 7.26, and MTV ranging from 1.27 to 18.59 cm³. Additionally, the CT component aided in the localization of these tumors, particularly those that might be overlooked due to low metabolic uptake. Despite the benign nature of TIO tumors, there have been instances of malignancy, underscoring the necessity of complete surgical removal for a curative outcome, albeit with a risk of recurrence (44, 45). The study concludes with a follow-up on a patient who experienced tumor recurrence post-surgery, highlighting the importance of ongoing monitoring after treatment.

Whole-body ¹⁸F-OC PET/CT imaging emerges as a groundbreaking SSTR-specific technique pivotal in pinpointing TIO. However, the study acknowledges the limitation posed by its small sample size, advocating for future research encompassing a larger cohort to refine the diagnostic accuracy of ¹⁸F-OC PET/CT for TIO. Such research would furnish clinicians with a more comprehensive diagnostic tool, potentially enhancing patient care, treatment strategies, and prognostic assessments.

Written informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be published in this article.

JL: Writing – original draft, Writing – review & editing.