Successful Superficial Blood Sampling to Localize a Fibroblast Growth Factor-23-Producing Tumor.

BACKGROUND Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome caused by aberrant fibroblast growth factor-23 (FGF-23)-producing tumors. Early surgical resection is the optimal strategy for preventing TIO progression. Thus, tumor localization is a priority for successful treatment. A simple and safe examination method to identify functional endocrine tumors is essential to achieve better outcomes in patients with TIO. CASE REPORT A 64-year-old Japanese man with recurrent fractures, hypophosphatemia, and elevated alkaline phosphatase and FGF-23 levels (109 pg/mL) was admitted to our university hospital and was diagnosed with FGF23-related hypophosphatemic osteomalacia. Notably, the superficial dorsal vein in the patient's left foot exhibited a high FGF-23 level (7510 pg/mL). Octreotide and ¹8F-fluorodeoxyglucose (FDG) scintigraphy and systemic venous sampling revealed that the tumor in the third basal phalanx of the left foot was responsible for FGF-23 overproduction. Tumor resection resulted in a rapid decrease in serum FGF-23 levels and an increase in serum phosphorus levels. CONCLUSIONS Octreotide scintigraphy, FDG-positron emission tomography, and systemic venous sampling are the standard methods for localizing functional endocrine tumors. However, the limited availability and invasive nature of these examinations hinder effective treatment. Here, we highlight the importance of peripheral superficial blood sampling as an alternative to conventional systemic methods for confirming the presence of FGF-23-producing tumors. Clinicians should consider TIO as a potential cause of acquired hypophosphatemic osteomalacia. Furthermore, peripheral superficial vein blood sampling may be useful for confirming the localization of FGF-23-producing tumors.

Vitamin D deficiency or resistance and hypophosphatemia.

Vitamin D is mainly produced in the skin (cholecalciferol) by sun exposure while a fraction of it is obtained from dietary sources (ergocalciferol). Vitamin D is further processed to 25-hydroxyvitamin D and 1,25-dihydroxy vitamin D (calcitriol) in the liver and kidneys, respectively. Calcitriol is the active form which mediates the actions of vitamin D via vitamin D receptor (VDR) which is present ubiquitously. Defect at any level in this pathway leads to vitamin D deficient or resistant rickets. Nutritional vitamin D deficiency is the leading cause of rickets and osteomalacia worldwide and responds well to vitamin D supplementation. Inherited disorders of vitamin D metabolism (vitamin D-dependent rickets, VDDR) account for a small proportion of calcipenic rickets/osteomalacia. Defective 1α hydroxylation of vitamin D, 25 hydroxylation of vitamin D, and vitamin D receptor result in VDDR1A, VDDR1B and VDDR2A, respectively whereas defective binding of vitamin D to vitamin D response element due to overexpression of heterogeneous nuclear ribonucleoprotein and accelerated vitamin D metabolism cause VDDR2B and VDDR3, respectively. Impaired dietary calcium absorption and consequent calcium deficiency increases parathyroid hormone in these disorders resulting in phosphaturia and hypophosphatemia. Hypophosphatemia is a common feature of all these disorders, though not a sine-qua-non and leads to hypomineralisation of the bone and myopathy. Improvement in hypophosphatemia is one of the earliest markers of response to vitamin D supplementation in nutritional rickets/osteomalacia and the lack of such a response should prompt evaluation for inherited forms of rickets/osteomalacia.

Extended curettage for tumour-induced osteomalacia in the bone.

BACKGROUND: extended curettage is generally used to treat infiltrative bone tumours. However, the extent of the curettage performed in previous studies remains unclear. This study aimed to investigate the efficacy of extended curettage for bone tumour-induced osteomalacia. METHODS: we included 12 patients with tumour-induced osteomalacia who underwent extended curettage at our hospital between 2000 and 2022. Extended curettage was applied in cases where tumour resection could cause functional impairment or necessitate complex reconstruction. We investigated patients' clinical and oncological outcomes. RESULTS: patients had a mean age of 55 (24-81) years, and the median follow-up duration after surgery was 3.9 (1.0-14.0) years. The causative tumours were located in the pelvis and lumbar spine. Imaging revealed the tumours to be of the sclerotic, intertrabecular, lytic and mixed types. Intraoperative 3D fluoroscopy was used in 10 patients. Extended curettage with high-speed burring and adjuvant therapy with cauterization using an electric scalpel and ethanol resulted in a remission rate of 83%; no recurrence or metastasis was observed in cases of early postoperative biochemical remission. In cases where the causative tumour was at the lumbar spine and ischium close to the acetabulum, no postoperative biochemical remission was observed, and conservative treatment was continued. Except for one patient with a tumour in the lumbar spine, all patients could walk without a cane. CONCLUSIONS: extended curettage for bone tumour-induced osteomalacia is oncologically and functionally favourable, especially in cases where resection of the causative tumour could cause functional impairment or necessitate complex reconstruction.

Cytological findings of phosphaturic mesenchymal tumor: Report of a case with summary of prior published cases.

Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm causing tumor-induced osteomalacia (TIO) and is characterized by secretion of FGF23, renal phosphate wasting and hypophosphataemia. It can be completely cured by resection and therefore its diagnosis is of utmost importance. Although the histology is well described, there is sparse literature on cytology of PMT and only three cases have been described so far. A 45-year-old lady presented with a non-tender mass in hard palate for 2 years from which fine-needle aspiration was done. The smears were paucicellular and showed bland spindle cells embedded in osteoid-like stromal matrix in a hemorrhagic background. Here we take the opportunity to describe the cytological findings of PMT along with its cytological differentials and a summary of prior published cases.

Renal histology of Fanconi syndrome associated with adefovir dipivoxil: A case report.

A sporadic occurrence of Fanconi syndrome associated with adefovir dipivoxil (ADV) has been reported, particularly when confirmed by renal biopsy. This study presents the case of a 53-year-old man who had been taking ADV 10 mg daily for 10 years to treat chronic hepatitis B (CHB) and subsequently developed Fanconi syndrome. The clinical manifestations included hypophosphatemic osteomalacia, glucosuria, renal tubular acidosis, low-molecular-weight proteinuria, and renal insufficiency. Renal biopsy revealed significant injury to proximal tubular epithelial cells, including vacuolar degeneration and regeneration of tubular epithelial cells. The ultrastructural pathology indicated severe morphological abnormalities of mitochondria, such as densely packed and enlarged mitochondria, with loss, blunting, and disordered arrangement of cristae. Following discontinuation of ADV and supplementation with oral phosphate, hypophosphatemia, glucosuria, and proteinuria were resolved. These findings support the previous hypothesis that ADV-induced nephrotoxicity may involve mitochondrial injury.

Acquired disorders of phosphaturia: Beyond tumor-induced osteomalacia.

Phosphate is an integral part of human cellular structure and function. Though most recognised disorders of phosphaturia are genetic in origin, phosphate loss due to acquired conditions is commonly encountered in clinical practice. Acquired hypophosphatemia is most commonly due to renal phosphate wasting and can produce significant morbidity. It also heralds future kidney damage, and continued exposure can lead to progressive kidney injury and potentially renal failure. These conditions are a diverse group of disorders with common shared mechanisms causing loss of phosphate in the urine. Renal phosphate loss can occur as an isolated entity or as a part of generalised proximal tubular dysfunction, i.e., Fanconi's syndrome. An insight into the pathophysiological mechanisms of acquired phosphaturia can help clinicians monitor their patients better and avoid potential harms.

Tumor-induced osteomalacia: An overview.

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.

The pathophysiology of hypophosphatemia.

After identification of fibroblast growth factor (FGF) 23 as the pivotal regulator of chronic serum inorganic phosphate (Pi) levels, the etiology of disorders causing hypophosphatemic rickets/osteomalacia has been clarified, and measurement of intact FGF23 serves as a potent tool for differential diagnosis of chronic hypophosphatemia. Additionally, measurement of bone-specific alkaline phosphatase (BAP) is recommended to differentiate acute and subacute hypophosphatemia from chronic hypophosphatemia. This article divides the etiology of chronic hypophosphatemia into 4 groups: A. FGF23 related, B. primary tubular dysfunction, C. disturbance of vitamin D metabolism, and D. parathyroid hormone 1 receptor (PTH1R) mediated. Each group is further divided into its inherited form and acquired form. Topics for each group are described, including "ectopic FGF23 syndrome," "alcohol consumption-induced FGF23-related hypophosphatemia," "anti-mitochondrial antibody associated hypophosphatemia," and "vitamin D-dependent rickets type 3." Finally, a flowchart for differential diagnosis of chronic hypophosphatemia is introduced.

Clinical Characteristics of Malignant Phosphaturic Mesenchymal Tumor Causing Tumor-Induced Osteomalacia.

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.

[FGF23 tumor induced osteomalacia with localization of neoplasm in the tympanic cavity]. / FRF23-indutsirovannaya osteomalyatsiya opukholevogo geneza s lokalizatsiei novoobrazovaniya v barabannoi polosti.

Tumor induced osteomalacia is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients complain of progressive bone pain, muscle weakness and brittle fractures. Delayed diagnosis of osteomalacia caused by a tumor is often found in clinical practice. When verifying the exact localization of the neoplasm, radical removal within healthy tissues is recommended. The article considers a clinical example of FGF23 tumor induced osteomalacia with localization of neoplasm in the tympanic cavity.

Epidemiology of Tumor-Induced Osteomalacia in Germany Based on Real World Data.

Tumor-induced osteomalacia (TIO) is an ultra-rare disease caused mostly by benign tumors that secrete fibroblast growth factor-23. Because of nonspecific symptoms, the diagnostic delay is long, and therapy can be challenging. Moreover, epidemiological data on TIO are scarce owing to its rarity. Therefore, this study aimed to quantify TIO's incidence rates and prevalence in Germany. Retrospective longitudinal and cross-sectional analyses were conducted using anonymized German claims data from the statutory health insurance (SHI) database. This database, which comprises the data of approximately 5 million insurants, is a representative sample of the German population and supports national projections. As there is no unique International Statistical Classification of Diseases and Related Health Problems (ICD) code for TIO, operational categories based on different surrogates were defined to determine the prevalence and incidence rates of TIO among probable patients. This study showed that TIO has a prevalence of (documented code, advanced imaging, medication, or tumor removal) 0.187 per 100,000 persons and an incidence rate of ≤ 0.094 per 100,000 person years. This analysis provides the first epidemiological insight into German patients with TIO. Despite the general limitations associated with the analysis of SHI claims data of ultra-rare diseases, we believe that this analysis provides a sound basis for further analysis, particularly with regard to the care situation of patients with TIO.

Tumor-induced Osteomalacia: A Case Report and Etiological Analysis with Literature Review.

BACKGROUND: Tumor-induced osteomalacia (TIO) belongs to a rare disease of the paraneoplastic syndrome. Phosphate uric mesenchymal tumor (PMT) is the most common cause of TIO, while the possibility of other tumors cannot be excluded. CASE PRESENTATION: We present a case of a 36-year-old female patient with systemic skeletal abnormalities. The woman complained of low back pain with mild motor dysfunction for 2 years. Laboratory examination showed abnormalities in markers of bone metabolism, parathyroid hormone (PTH), vitamin D and serum phosphorus. Pooled imaging examination indicated extension abnormalities in the skeletal system and a single lesion in the right femoral head. The lesion of the right femoral was imaging with somatostatin receptor-positive, which was highly suggestive of a single neuroendocrine tumor. CT guided right femoral tumorectomy and bone grafting were performed when medical treatment failed. Postoperative pathological diagnosis was phosphate urinary mesenchymal tumor secreting fibroblast growth factor 23 (FGF23), which accorded with pre-operative expectations. The postoperative symptoms were effectively relieved, and indicators returned to normal. CONCLUSION: The tumors causing TIO exhibited significant heterogeneity in terms of tissue origin, pathological characteristics and biological behavior, but the unique common characteristic is the secretion of FGF23. With significant progress in diagnosis and treatment, the clinical follow-up of most TIO patients shows a good prognosis, but the prognosis of those with malignant tumors is relatively poor.

Global Health Disparities in Childhood Rickets.

Nutritional rickets is a global health problem reflecting both historical and contemporary health disparities arising from racial, ethnic, environmental, and geopolitical circumstances. It primarily affects marginalized populations and can contribute to long-term morbidity. Deficits in bone health in childhood may also contribute to osteomalacia/osteoporosis. Solutions require a global public health approach.

Increased Uptake of Brown Tumor in 99m Tc-HYNIC-TOC Scintigraphy Mimicking Postoperative Recurrence of Tumor-Induced Osteomalacia.

ABSTRACT: A 61-year-old man underwent a resection of tumor in the left tibia that caused osteomalacia 11 years ago. Postoperative bone pain and fatigue symptoms were briefly relieved but then recurred. To identify potential recurrent tumors, 99m Tc-HYNIC-TOC scintigraphy was performed. Images revealed an osteolytic lesion in the right tibia with increased uptake. The lesion was subsequently resected, which pathologically proved a brown tumor. Symptoms of bone pain and weakness caused by osteomalacia did not relieve 4 months after the operation. Here, we present a rare case of brown tumor with high activity on 99m Tc-HYNIC-TOC SPECT/CT, mimicking a culprit tumor of osteomalacia.

Tumor-induced osteomalacia combined with increased bone resorption postoperatively: A case report.

RATIONALE: Rare tumor-induced osteomalacia (TIO) usually resulted in bone pain, fragility fractures and muscle weakness in clinical, which is caused by the reduced phosphate reabsorption, thus impaired mineralization of the bone matrix and free energy transfer. The specific problems in postsurgical patients are obscure although surgical removal of the tumor is the only definitive treatment. Here, we documented a female TIO patient who suffered more severe bone pain and muscle spasms post-operation. Further, we presented and discussed our explanation for the unexpected symptoms. PATIENT CONCERNS: The main symptoms were whole-body pain and muscle weakness. The patient also presented with osteoporosis and multiple fractures. DIAGNOSIS: Elevated serum fibroblast growth factor 23 (FGF23) level and hypophosphatemia indicated the diagnosis of TIO. Positron emission tomography (PET)/computed tomography (CT) with 68 Ga-DOTATATE located the tumor in the dorsolateral part of the left foot. Histopathological examinations confirmed the diagnosis. INTERVENTIONS: The tumor was surgically removed immediately after the diagnosis of TIO and localization of the tumor. Postoperatively, calcium carbonate supplement treatment was continued. OUTCOMES: Two days after surgery, the serum FGF23 level was decreased to the normal range. Five days after surgery, N-terminal propeptide of type I procollagen and ß-CrossLaps (ß-CTx) had a remarkable increase. A month after surgery, the patient N-terminal propeptide of type I procollagen and ß-CTx levels were decreased obviously, and serum FGF23, phosphate and 24h urinary phosphate were in the normal range. LESSONS: We report a female patient who presented with osteoporosis and fractures. She was found with an elevation of FGF23 and diagnosis with TIO after PET/CT scanning. After surgically removing the tumor, the patient experienced more severe bone pain and muscle spasms. Active bone remodeling might be the reason for the symptoms. Further study will reveal the specific mechanism for this abnormal bone metabolism.

Occipital bone and tumor-induced osteomalacia: a rare tumor site for an uncommon paraneoplastic syndrome.

INTRODUCTION: Tumor-induced osteomalacia (TIO) is an uncommon paraneoplastic syndrome due to the overproduction of fibroblast growth factor 23 (FGF23). It is predominantly caused by mesenchymal tumors and cured upon their complete removal. Non-surgical treatment is an alternative option but limited to specific clinical conditions. METHODS: We report a challenging case of TIO caused by a tumor involving the occipital bone. We also performed a literature review of TIO caused by tumors localized at this site, focusing on clinical findings, treatment, and outcomes. RESULTS: The patient, a 62-year-old male, presented with a long-lasting history of progressive weakness. Biochemical evaluation revealed severe hypophosphatemia due to low renal tubular reabsorption of phosphate with raised intact FGF23 values. A 68 Ga-DOTATATE PET/TC imaging showed a suspicious lesion located in the left occipital bone that MRI and selective venous catheterization confirmed to be the cause of TIO. Stereotactic gamma knife radiosurgery was carried out, but unfortunately, the patient died of acute respiratory failure. To date, only seven additional cases of TIO have been associated to tumors located in the occipital bone. Furthermore, the tumor involved the left side of the occipital bone in all these patients. CONCLUSION: The occipital region is a difficult area to access so a multidisciplinary approach for their treatment is required. If anatomical differences could be the basis for the predilection of the left side of the occipital bone, it remains to be clarified.

FGF23-related hypophosphatemia in a patient with small cell lung cancer: a case report and literature review.

Although there are a few case reports of patients with small cell lung cancer developing hypophosphatemia, detailed information on this condition is scarce. A 52-year-old patient with advanced stage small cell lung cancer developed hypophosphatemia (1.1 mg/dL) during chemotherapy. A reduced level of the tubular reabsorption of phosphate concomitant with an inappropriately elevated level of fibroblast growth factor (FGF) 23 (48.4 pg/mL) was noted, leading to the diagnosis of FGF23-related hypophosphatemia. Laboratory data also showed hypercortisolemia with an elevated ACTH level and hyponatremia with an inappropriately unsuppressed level of antidiuretic hormone (ADH). These data suggested the overproduction of FGF23 in addition to ACTH and ADH. Because the octreotide loading test did not present a suppressive effect on ACTH or FGF23 levels, the patient was treated with phosphate supplementation, active vitamin D and metyrapone, which partially improved the serum phosphate and cortisol levels. Even after two subsequent courses of chemotherapy, the small cell lung cancer progressed, and the FGF23 level was further elevated (83.7 pg/mL). Although it is very rare, FGF23-related hypophosphatemia is one of the hormonal disturbances that could be observed in patients with small cell lung cancer. This article reviews similar clinical conditions and revealed that advanced states of malignancy seemed to be associated with the development of renal wasting hypophosphatemia, especially in lung cancer and prostate cancer. Therefore, the parameters related to hypophosphatemia should be monitored in patients with advanced small cell lung cancer to prevent the development of hypophosphatemic osteomalacia.

Osteomalacia.

Osteomalacia with characteristic histomorphometric, radiographic, laboratory and clinical features is a prominent syndrome of disturbed bone mineralisation in adulthood. From an etiological point of view, osteomalacia is usually caused by substrate (calcium, phosphate) deficiency, presence of excess mineralization inhibitors or deficiency or ineffectivness of mineralization facilitator (vitamin D). In proportion to the high number of congenital and acquired causes of osteomalacia, its clinical and laboratory picture is heterogeneous and rarely fully expressed. The treatment of a particular case is determined by the cause of osteomalacia and may (but does not necessarily) include correction of the underlying disease, administration of calcium and various forms of vitamin D, as well as orthopaedic interventions. For some of the hereditary forms, biological or replacement therapy is prospectively available. The article attempts to cover the whole range of osteomalacia variants, mentioning a fact discussed only in recent years - the occurrence of oligosymptomatic, incompletely expressed forms.