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Best Practice & Research. Clinical... Mar 2024Tumor-induced osteomalacia (TIO) is rare paraneoplastic syndrome of hypophosphatemic osteomalacia, caused by phosphaturic factors secreted by small mesenchymal origin... (Review)
Review
Tumor-induced osteomalacia (TIO) is rare paraneoplastic syndrome of hypophosphatemic osteomalacia, caused by phosphaturic factors secreted by small mesenchymal origin tumors with distinct pathological features, called 'phosphaturic mesenchymal tumors'. FGF23 is the most well-characterized of the phosphaturic factors. Tumors are often small and located anywhere in the body from head to toe, which makes the localisation challenging. Functional imaging by somatostatin receptor-based PET imaging is the first line investigation, which should be followed with CT or MRI based anatomical imaging. Once localised, complete surgical excision is the treatment of choice, which brings dramatic resolution of symptoms. Medical management in the form of phosphate and active vitamin D supplements is given as a bridge to surgical management or in inoperable/non-localised patients. This review provides an overview of the epidemiology, pathophysiology, pathology, clinical features, diagnosis, and treatment of TIO, including the recent advances and directions for future research in this field.
Topics: Humans; Neoplasms, Connective Tissue; Osteomalacia; Mesenchymoma; Paraneoplastic Syndromes
PubMed: 37935612
DOI: 10.1016/j.beem.2023.101834 -
ANZ Journal of Surgery Oct 2023
Topics: Humans; Mesenchymoma; Adrenal Glands; Adrenal Gland Neoplasms
PubMed: 37249155
DOI: 10.1111/ans.18514 -
Modern Pathology : An Official Journal... Dec 2023Phosphaturic mesenchymal tumors (PMT) are uncommon neoplasms that cause hypophosphatemia/osteomalacia mainly by secreting fibroblast growth factor 23. We previously...
Phosphaturic mesenchymal tumors (PMT) are uncommon neoplasms that cause hypophosphatemia/osteomalacia mainly by secreting fibroblast growth factor 23. We previously identified FN1::FGFR1/FGF1 fusions in nearly half of the PMTs and frequent KL (Klotho or α-Klotho) overexpression in only those with no known fusion. Here, we studied a larger cohort of PMTs for KL expression and alterations. By FN1 break-apart fluorescence in situ hybridization (FISH) and reappraisal of previous RNA sequencing data, 6 tumors previously considered "fusion-negative" (defined by negative results of FISH for FN1::FGFR1 fusion and FGF1 break-apart and/or of RNA sequencing) were reclassified as fusion-positive PMTs, including 1 containing a novel FN1::ZACN fusion. The final cohort of fusion-negative PMTs included 33 tumors from 32 patients, which occurred in the bone (n = 18), soft tissue (n = 10), sinonasal tract (n = 4), and brain (n = 1). In combination with previous work, RNA sequencing, RNA in situ hybridization, and immunohistochemistry showed largely concordant results and demonstrated KL/α-Klotho overexpression in 17 of the 28 fusion-negative and none of the 10 fusion-positive PMTs studied. Prompted by a patient in this cohort harboring germline KL upstream translocation with systemic α-Klotho overexpression and multifocal PMTs, FISH was performed and revealed KL rearrangement in 16 of the 33 fusion-negative PMTs (one also with amplification), including 14 of the 17 cases with KL/α-Klotho overexpression and none of the 11 KL/α-Klotho-low fusion-negative and 11 fusion-positive cases studied. Whole genomic sequencing confirmed translocation and inversion in 2 FISH-positive cases involving the KL upstream region, warranting further investigation into the mechanism whereby these rearrangements may lead to KL upregulation. Methylated DNA immunoprecipitation and sequencing suggested no major role of promoter methylation in KL regulation in PMT. Interestingly, KL-high/-rearranged cases seemed to form a clinicopathologically homogeneous group, showing a predilection for skeletal/sinonasal locations and typically matrix-poor, cellular solitary fibrous tumor-like morphology. Importantly, FGFR1 signaling pathways were upregulated in fusion-negative PMTs regardless of the KL status compared with non-PMT mesenchymal tumors by gene set enrichment analysis, perhaps justifying FGFR1 inhibition in treating this subset of PMTs.
Topics: Humans; In Situ Hybridization, Fluorescence; Fibroblast Growth Factor 1; Soft Tissue Neoplasms; Mesenchymoma; Translocation, Genetic; Paranasal Sinuses
PubMed: 37742927
DOI: 10.1016/j.modpat.2023.100336 -
The Journal of Clinical Endocrinology... Feb 2024Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome usually caused by oversecretion of fibroblast growth factor 23 (FGF23) from a phosphaturic mesenchymal...
CONTEXT
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome usually caused by oversecretion of fibroblast growth factor 23 (FGF23) from a phosphaturic mesenchymal tumor (PMT). PMTs are usually benign neoplasms but some of them show malignant characteristics.
OBJECTIVE
The aim of this study was to compare the clinical characteristics of benign and malignant PMTs inducing TIO.
METHODS
On March 31, 2023, we performed a systematic review of individual patient data analysis in Medline, Google Scholar, Google book, and Cochrane Library using the terms "tumor induced osteomalacia," "oncogenic osteomalacia," "hypophosphatemia," with no language restrictions and according to Preferred Reporting Items for Systematic reviews and Meta-Analyses criteria.
RESULTS
Overall, we collected data from 837 patients with TIO in which the diagnosis of benign and malignant PMT was specified. Of them, 89 were affected by malignant PMT and 748 by benign PMT. Patients with malignant PMTs were younger and presented bone pain, functional impairment, and bone deformities more frequently. Malignant PMTs showed higher values of intact FGF23 and a higher mortality rate.
CONCLUSION
The study results identify the clinical characteristics of patients with malignant TIO, permitting the early identification of patients with PMT at increased risk of malignancy. This may significantly improve the diagnostic approach to disease. Further experimental studies are mandatory to clarify the role of FGF23 in the pathogenesis of malignancy in PMTs.
Topics: Humans; Osteomalacia; Neoplasms, Connective Tissue; Fibroblast Growth Factors; Paraneoplastic Syndromes; Soft Tissue Neoplasms; Mesenchymoma
PubMed: 38006315
DOI: 10.1210/clinem/dgad690 -
BMC Surgery Aug 2023To summarize and discuss the guiding role of endoscopic ultrasound (EUS) in selecting endoscopic treatments for submucosal tumors (SMTs) in the upper gastrointestinal...
OBJECTIVE
To summarize and discuss the guiding role of endoscopic ultrasound (EUS) in selecting endoscopic treatments for submucosal tumors (SMTs) in the upper gastrointestinal tract.
METHODS
A retrospective investigation was conducted on 156 SMT patients who received endoscopic resection guided by EUS in the endoscopy center of the Second Affiliated Hospital of Guangzhou University of Chinese Medicine from May 2019 to September 2021. Next, the size, pathological type, and distribution of lesions were analyzed; the correlation of the tumor origin with distribution of lesions and selection of treatments was explored; and the consistency of preoperative EUS diagnosis and postoperative pathological diagnosis was summarized and analyzed.
RESULTS
The tumor diameters of the included SMT patients ranged from 0.3 to 4 cm, with a mean diameter of 0.95 cm; the lesions were mostly located in the esophagus, gastric fundus or fundic cardia and gastric body. As for the pathological types, liomyoma was the most common tumor in the esophagus, liomyoma and mesenchymoma were mainly located in the fundic cardia and gastric body, and heterotopic pancreas was mostly discovered in the gastric sinus. Among 38 esophageal SMT patients, some with lesions originating from muscularis mucosa and submucosa under EUS mainly underwent endoscopic submucosal dissection (ESD) and endoscope band ligation (EBL); while others with lesions originated from muscularis propria mainly received submucosal tunneling endoscopic resection (STER). Of 115 gastric SMT patients under EUS, some with lesion origins from the muscularis mucosa and submucosa mainly underwent endoscopic submucosal excavation (ESE), while others from muscularis propria mainly underwent ESE, ESD, and endoscopic full-thickness resection (EFTR). Besides, 3 duodenal SMT patients with lesion origins from submucosa and muscularis propria under EUS were given ESD and ESE, respectively. Additionally, 121 cases showed a consistency between the EUS diagnosis and the postoperative pathological nature, and the consistency rate was 84.6%.
CONCLUSION
Clarifying the origin layer, size, growth pattern, and pathological nature of the lesion through preoperative EUS can guide the precise selection of endoscopic treatments, thereby ensuring a safe, effective, and complete surgical outcomes and reducing complications.
Topics: Humans; Retrospective Studies; Upper Gastrointestinal Tract; Endosonography; Endoscopy; Neoplasms
PubMed: 37635257
DOI: 10.1186/s12893-023-02164-7 -
BMJ Case Reports Sep 2023Tumour-induced osteomalacia is a rare cause of osteomalacia, the majority of which is of mesenchymal origin. Oncogenic osteomalacia is a potentially curable condition...
Tumour-induced osteomalacia is a rare cause of osteomalacia, the majority of which is of mesenchymal origin. Oncogenic osteomalacia is a potentially curable condition caused by phosphaturic mesenchymal tumours. We present the case of a woman in her 30s with a sinonasal phosphaturic mesenchymal tumour, treated with surgical excision followed by adjuvant intensity-modulated radiotherapy and subsequent adjuvant chemotherapy. The patient experienced minimal adverse effects during radiation. There was good local control and cosmetic outcomes with no radiation-related toxicity at a follow-up period of 32 months.
Topics: Female; Humans; Radiation Oncologists; Soft Tissue Neoplasms; Adjuvants, Immunologic; Chemotherapy, Adjuvant; Mesenchymoma; Radiation Injuries
PubMed: 37723097
DOI: 10.1136/bcr-2023-255896 -
The Journal of Dermatology Nov 2023Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm that causes tumor-induced osteomalasia (TIO) in most affected patients, usually through the production of...
Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm that causes tumor-induced osteomalasia (TIO) in most affected patients, usually through the production of fibroblast growth factor 23 (FGF23). This tumor is often misdiagnosed due to its relative rarity and its widely varied histomorphologic spectrum. Here we describe a case of a 78-year-old woman who presented with a left middle tumor without symptoms of TIO. The histological features resembled chondromyxoid fibroma with smudgy calcification in the tumor matrix. In addition, we evaluated FGF23 expression through immunohistochemical study and reverse transcription polymerase chain reaction. PMT with chondromyxoid fibroma features are extremely rare. Examining the expression of FGF23 is useful in the diagnosis of PMT.
Topics: Female; Humans; Aged; Neoplasms, Connective Tissue; Paraneoplastic Syndromes; Fibroblast Growth Factors; Osteomalacia; Soft Tissue Neoplasms; Mesenchymoma; Fibroma
PubMed: 37350024
DOI: 10.1111/1346-8138.16870 -
Saudi Journal of Kidney Diseases and... Nov 2023Tumor-induced osteomalacia (TIO) is a disorder in which the clinical signs and symptoms of osteomalacia and the biochemical abnormalities of hypophosphatemia,...
Tumor-induced osteomalacia (TIO) is a disorder in which the clinical signs and symptoms of osteomalacia and the biochemical abnormalities of hypophosphatemia, phosphaturia, and low serum levels of 1,25(OH)2 Vitamin D3 are secondary to a neoplasm. A 33-year-old woman presented with musculoskeletal pain and proximal myopathy with a duration of 2.5 years which was treated with Vitamin D supplements. On the basis of the biochemical tests and histopathology, she was reevaluated and found to have TIO secondary to a phosphaturic mesenchymal tumor. The tumor was resected (limb salvage with endoprosthesis), and she had no pain or weakness at followup. The case reminds the readers to consider the possibility of TIO when evaluating patients with isolated hypophosphatemia, which may lead to long-term disability and prolonged morbidity if untreated. Early recognition and diagnosis of TIO is crucial since resection of the tumor usually reverses its manifestations.
Topics: Humans; Female; Adult; Osteomalacia; Paraneoplastic Syndromes; Hypophosphatemia; Muscular Diseases; Mesenchymoma; Treatment Outcome; Limb Salvage; Biopsy; Neoplasms, Connective Tissue
PubMed: 38725216
DOI: 10.4103/sjkdt.sjkdt_250_23 -
Indian Journal of Pathology &... Apr 2024Phosphaturic mesenchymal tumors (PMTs) are rare mesenchymal tumors, associated with long-standing, non-specific but often debilitating symptoms in the affected patients.... (Review)
Review
BACKGROUND
Phosphaturic mesenchymal tumors (PMTs) are rare mesenchymal tumors, associated with long-standing, non-specific but often debilitating symptoms in the affected patients. These tumors display characteristic histopathological features and in case, identified timely, can be a boon for patients, given an excision is completely curative.
AIMS
To evaluate the clinical and histopathological features of 10 PMTs, diagnosed at our institution, along with clinical outcomes in those patients.
MATERIALS AND METHODS
This was a retrospective study, wherein 10 PMTs, diagnosed from January 2013 to July 2022, were included.
RESULTS
The average age at the time of diagnosis was 40 years with an M:F ratio of 4:1. Clinical features included lumps, weakness, bone pain, difficulty in moving and walking, and pathologic fractures. The biochemical analysis showed normal serum calcium levels (average = 9.5 mg/dL), with low serum phosphorus (average = 2.2 mg/dL) and raised serum fibroblast growth factor 23 (FGF23) levels, in all the cases, wherever available. On histopathology, all tumors showed cells arranged in a hemangiopericytomatous pattern, including oval to short spindle forms. Multinucleate giant cells were present in nine tumors, and characteristic "grungy calcifications" was observed in eight tumors. Prominent pseudo cystic spaces were seen in eight tumors. A significant number of mitotic figures and tumor necrosis were not seen in any tumor. In five cases where follow-up was available, there was complete resolution of symptoms post-resection with no recurrence or metastasis. All those patients were free of disease until the last follow-up.
CONCLUSION
This constitutes the first largest comprehensive study on these rare tumors from our country. PMTs can be diagnosed based on certain histopathological features and correlation with clinicoradiological and biochemical findings. These are invariably benign neoplasms. Patients are relieved of their debilitating symptoms after adequate surgical tumor resection. Therefore, their correct and timely diagnosis is crucial.
Topics: Adult; Female; Humans; Male; Middle Aged; Young Adult; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Hypophosphatemia; Mesenchymoma; Phosphorus; Retrospective Studies; Treatment Outcome
PubMed: 38394416
DOI: 10.4103/ijpm.ijpm_295_23 -
World Neurosurgery Apr 2024Spinal phosphaturic mesenchymal tumor (PMT) is a rare disorder but can be cured once the diagnosis is clear and a complete removal by surgery is performed. To the best... (Review)
Review
BACKGROUND
Spinal phosphaturic mesenchymal tumor (PMT) is a rare disorder but can be cured once the diagnosis is clear and a complete removal by surgery is performed. To the best of our knowledge, only 22 cases in the spine have been described, and we report a case with the largest number of spinal segments (T12-L5) affected among spine PMT cases.
METHODS
A comprehensive literature search was performed until May 23, 2023, following the Preferred Reporting Items for Systematic Reviews guidelines. Studies were chosen through relevant PubMed, Web of Science, and EMBASE searches to prioritize obtaining the largest studies. The Medical Subject Headings and Boolean operators employed for this search were ("PMT" or "TIO" or "Tumor-induced osteomalacia" or "phosphaturic mesenchymal tumor") and ("spine" or "spinal"). Two researchers (L.S.Z. and D.B.C) independently reviewed and evaluated the included articles. Any differing opinions were discussed until a consensus was reached. A total of 18 studies were included. A case report is also presented.
RESULTS
We report a case of spinal PMT. The full text of the relevant articles was construed. A total of 18 studies were reviewed and consolidated. These articles are roughly divided into the following 5 subcategories: 1) clinical features and baseline distribution, 2) laboratory and imaging findings, 3) pathological manifestations, and 4) surgical methods and treatment options.
CONCLUSIONS
Spinal PMT is very rare with a high rate of misdiagnosis and debilitating complications, so it is of significance to increase awareness of the disease among spine surgeons consulted by patients with spinal PMT. Ga-DOTATOC-PET/CT shows very high sensitivity to the spinal PMT but there is no way to exactly determine the location of the tumor. PMT has unique immunohistochemical characteristics and malignant PMT is rare. Once diagnosed, complete surgical excision is the recommended treatment. Burosumab is one of the available options, especially in cases that are recurrent and difficult to surgically resect.
Topics: Humans; Neoplasms, Connective Tissue; Positron Emission Tomography Computed Tomography; Mesenchymoma; Soft Tissue Neoplasms; Spine
PubMed: 38218444
DOI: 10.1016/j.wneu.2024.01.032