Phosphaturic mesenchymal tumor of the right thigh

Elevated Fibroblast Growth Factor 23 in a Patient With Metastatic Prostate Cancer and Hypophosphatemia

Disclosure: M. Patil: None. S. Wangsiricharoen: None. A. Lazar: None. T.A. Guise: None. Tumor induced osteomalacia (TIO) is a rare paraneoplastic phenomenon. Fibroblast growth factor-23 (FGF23) secretion from phosphaturic mesenchymal tumor (PMT) is implicated as the cause for hypophosphatemia and osteomalacia. Other rare conditions associated with dysregulated FGF23 production include fibrous dysplasia (FD). Coexistence of two unusual conditions which could increase FGF23 concentrations is rare. We report a case of PMT causing TIO in a patient with evidence of FD. A 79-year-old male was evaluated for worsening rib and right flank pain of more than one year duration. He also complained of generalized muscle weakness. His total alkaline phosphatase (ALP) levels were noted to be increased for many years. Computed tomography (CT) showed scattered sclerosis within ribs, and lytic lesions with cortical bone destruction in right iliac bone (4.3 x1.5 cm) and L4 vertebra. Biopsy of the right iliac lesion revealed findings compatible with PMT. Positron Emission Tomography (PET) showed fluorodeoxyglucose (FDG) avid lesion of the right anterior iliac wing, diffuse osteomalacia, insufficiency fractures of the ribs, as well as FDG avid lesions in left supra-acetabular area and in L4 vertebral body concerning for metastatic disease. Laboratory evaluation revealed ALP 306 (40-129 U/L), bone specific ALP 99 (0-20 mcg/L), phosphorus 1.5 (2.5-4.5 mg/dL), 25-(OH)-vitamin D 27 (30- 100 ng/mL), 24 hour urinary phosphorus 0.6 (0.4-1.3 g/24 hr), PTH 51.3 (15-65 pg/mL), FGF23 303 (<180 RU/mL), Calcium 10.3 (8.4-10.2 mg/dL), albumin 4.4 (3.5- 5.2 gm/dL), C-terminal telopeptide of type 1 collagen (CTX) 1611 (10-854 pg/mL). CT-guided cryoablation of the right iliac lesion was performed. Also, biopsy and cryoablation of the left supra-acetabular lesion was performed; pathology showed fibrous dysplasia (FD). Mutation analysis confirmed a mutation in exon 8 of GNAS gene. Post ablation, FGF23 dropped to 102 RU/mL and phosphorus increased to 3.0 mg/dL. The patient had significant improvement in bone pain and weakness. The patient with classic features of TIO improved with simultaneous cryoablation of both the PMT as well as the FD lesions. The unusual feature of the case is co-existence of PMT and FD. Malignant transformation of FD lesions is a rare complication. We confirmed that the PMT did not have GNAS mutation and is unlikely to arise from FD. And FGF23 in situ hybridization was strongly positive in the PMT and negative in the FD, ruling out FD as a contributor to patient’s hypophosphatemia. We plan to perform DOTATATE scan to differentiate PMT from FD in the L4 lesion. This is a unique case of coexistence of two separate conditions, both of which could secrete intact FGF23. Our studies suggest that PMT is the only etiology of hypophosphatemia and TIO. Presentation: Thursday, June 15, 2023

We report the case of a 66-year-old woman with tumor-induced osteomalacia (TIO) caused by fibroblast growth factor 23 (FGF-23) secreting mesenchymal tumor localized in a lumbar vertebra and review other cases localized to the axial skeleton. She presented with nontraumatic low back pain and spontaneous bilateral femur fractures. Laboratory testing was remarkable for low serum phosphorus, phosphaturia, and significantly elevated serum FGF-23 level. Magnetic resonance imaging (MRI) of the lumbar spine showed a focal lesion in the L-4 vertebra which was hypermetabolic on positron emission tomography (PET) scan. A computed tomography (CT) guided needle biopsy showed a low grade spindle cell neoplasm with positive FGF-23 mRNA expression by reverse transcriptase polymerase chain reaction (RT-PCR), confirming the diagnosis of a phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT). The patient elected to have surgery involving anterior resection of L-4 vertebra with subsequent normalization of serum phosphorus. Including the present case, we identified 12 cases of neoplasms localized to spine causing TIO. To our knowledge, this paper represents the first documented case of lumbar vertebra PMT causing TIO. TIO is a rare metabolic bone disorder that carries a favorable prognosis. When a lesion is identifiable, surgical intervention is typically curative.

BackgroundPhosphaturic mesenchymal tumors (PMTs) are rare neoplasms that are often associated with tumor-induced osteomalacia (TIO) due to excessive serum levels of fibroblast growth factor 23 (FGF23). PMTs share overlapping histologic features with other types of tumors; thus, accurate pathological diagnosis may be challenging. We performed an immunohistochemical examination of FGF23 expression in PMTs and other types of tumors, together with pertinent molecular analyses.MethodsSeven PMTs (5 with TIO and 2 without TIO) and 46 other types of bone and soft tissue tumors were retrieved, and immunohistochemistry was performed using a commercially available anti-FGF23 antibody. In addition, FGF23 mRNA expression was detected by reverse transcription-polymerase chain reaction (RT-PCR), using RNA extracted from formalin-fixed, paraffin-embedded tissues.ResultsImmunohistochemical analysis of FGF23 expression showed distinct, punctate staining in the cytoplasm in 5 PMTs with TIO, whereas FGF23 expression was negative in the 2 PMTs without TIO and the other 46 tumors. FGF23 mRNA expression was detected in all 4 PMTs examined, as well as in 1 chondromyxoid fibroma and 1 myxoid liposarcoma. The real-time RT-PCR data showed that the relative expression levels of the FGF23 mRNA tended to be higher in PMTs with TIO than in PMTs without TIO, or in the chondromyxoid fibroma specimen.ConclusionsOur data suggested that the feasibility of immunohistochemical detection of FGF23 may depend on the level of secreted FGF23 from tumor cells. Thus, immunohistochemistry for FGF23 is an useful diagnostic adjunct for PMT, although its utility appears to be limited in cases without TIO.

Tumor induced osteomalacia secondary to anaplastic thyroid carcinoma: A case report and review of the literature

Phosphaturic mesenchymal tumors (PMTs) are very rare tumors which are frequently associated with Tumor Induced Osteomalacia (TIO), a paraneoplastic syndrome that manifests as renal phosphate wasting. The tumor cells produce a peptide hormone-like substance known as fibroblast growth factor 23 (FGF23), a physiologic regulator of phosphate levels. FGF23 decreases proximal tubule reabsorption of phosphates and inhibits 1-α-hydroxylase, which reduces levels of 1-α, 25-dihydroxyvitamine D3. Thus, overexpression of FGF23 by the tumor cells leads to increased excretion of phosphate in the urine, mobilization of calcium and phosphate from bones, and the reduction of osteoblastic activity, ultimately resulting in widespread osteomalacia. Patients typically present with gradual muscular weakness and diffuse bone pain from pathologic fractures. The diagnosis is often delayed due to the non-specific nature of the symptoms and lack of clinical suspicion. While serum phosphorus and FGF23 testing can assist in making a clinical diagnosis of PMT, the responsible tumor is often difficult to locate. The pathologic diagnosis is often missed due to the rarity of PMTs and histologic overlap with other mesenchymal neoplasms. While patients can experience severe disabilities without treatment, excision is typically curative and results in a dramatic reversal of symptoms. Histologically, PMT has a variable appearance and can resemble other low grade mesenchymal tumors. Even though very few cases of PMT have been reported in the world literature, it is very important to consider this diagnosis in all patients with hypophosphatemic osteomalacia. Here we present a patient who suffered for almost 5 years without a diagnosis. Ultimately, the PMT was located on a 68Ga-DOTA TATE PET/CT scan and subsequently confirmed by histologic and immunohistologic study. Interestingly, strong positivity for FGFR1 by IHC might be related to the recently described FN1-FGFR1 fusion. Upon surgical removal, the patient’s phosphate and FGF23 levels returned to normal and the patient’s symptoms resolved.

Tumor-induced osteomalacia (TIO) is a subtype of paraneoplastic syndrome associated with hypophosphatemia due to renal phosphate wasting in adults. The humoral factor responsible for clinical picture known as fibroblast growth factor 23 (FGF23) is most often secreted by benign yet elusive mesenchymal tumors, difficult to localize, access, and excise completely; rarely, they are multiple and malignant. Paradoxical inappropriately normal or low levels of 1,25-dihydroxyvitamin D in the setting of hypophosphatemia is due to suppressive effect of FGF23. The following case report describes a 31-year-old male with symptoms of multiple fractures and severe muscle weakness, hypophosphatemia with elevated tubular maximum reabsorption of phosphate/glomerular filtration rate with low active Vitamin D, prompted assay for C-terminal FGF23, which was elevated multifold. The tumor was localized with whole body 68-Gadolinium DOTANOC positron emission tomography-computed tomography fusion scan in the left nasal cavity with ipsilateral maxillary antrum. It was excised through transnasal approach and found to be mesenchymal tumor on histopathology. At 1 week of follow-up, serum phosphate became normalized without supplementation. The patient is in follow-up for further measurement of FGF23 level and signs of recurrence. Because the occurrence of such a condition is rare and most often misdiagnosed or mismanaged for years, it is important to recognize this condition in differential diagnosis as potential curative surgical option is a reality.

BackgroundTumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Phosphaturic mesenchymal tumor (PMT) is a novel histopathologic entity that has been identified as a separate cause of TIO. Clinically, PMT is typically diagnosed late due to its rarity.Case presentationThe paper reports on a patient with a sustained left-sided sub-trochanteric femur fracture in 2018 who subsequently underwent fracture reduction and internal fixation placement. Six years postoperatively, the patient developed a recurrent femoral stem fracture accompanied by internal fixation device failure on the left side of the femur with no apparent causative factors. Based on the patient’s history of multiple fractures, a series of tests were performed and he was diagnosed with a rare disease recognized as TIO. A PET-CT scan conducted prior to surgery revealed that the lesion was located in the right suprapatellar bursa, so the mass was palpated on the body surface and surgically excised.ConclusionsIt is the first reported case of TIO in a patient with internal fixation device failure. Following a thorough review of the patient’s medical history, examination findings, and associated literature, the study concluded that the patient’s long-term osteomalacia and hypophosphatemia would significantly compromise the stability of the internal fixation. Specifically, we determined that the primary tumor lesion in this case was the primary cause of internal fixation failure. Therefore, patients found to have difficult-to-correct hypophosphatemia with multiple fractures in clinical practice should be further investigated for the primary etiology, such as TIO as mentioned in this case, before fracture surgery is performed. Enhancing 68 Ga-DOTA-TATE Positron Emission Tomography/ Computed Tomography (PET/CT) is also recommended to provide a more precise diagnosis of the tumor. For definite tumor lesions, total excisional surgery is considered to be a viable treatment for TIO.

In cancer patients, positron emission tomography/ computed tomography (PET/CT) fused images present less variability in target contouring, respect to use only CT images, respectively. However, the gold standard has not yet been clearly established between radiation oncologists with regard to PET images and the methodology of contouring targets with confidence using PET/CT fused images. The aim of this study was to determine whether integrated PET/CT fused images provide advantages in virtual simulation compared with morphological contouring only with CT. Thirty cancer patients were evaluated in an adapted PET/CT hybrid in radiotherapy (RT) setup position, with 20 of them being suitable for RT: 17 were suitable for curative intent, which was the group of interest in this study. All image series were sent to the RT work station (WS) where CT and PET series were automatically fused by Digital Imaging and Communications in Medicine (DICOM) in each case. PET series were threshold and were subjected to source-to-background contrast algorithms to fi nally redefine the original tumour description. Three different radiotherapy plans (RTP) for each patient were compared after targets were contoured: [1] planning over metabolic (PET) contoured targets, [2] planning over only morphologic (CT) targets, and [3] planning over targets obtained for treatment based on fused PET/CT images. PET/CT findings altered initial-stage planning in four patients (23.5%) because they had been undergoing chemotherapy. Gross target volume (GTV) and planning target volume (PTV) based only on PET showed more homogeneity to obtain mean doses (p = 0.025) with respect to those based on PET/CT, respectively. However, no percentage differences were observed in median PTV doses between the planning methods, although there was higher variability in PET/CT planning. Morphological (CT) and PET/ CT target volumes were more voluminous than metabolic (PET) volumes. On the other hand, 20% of metabolic (PET) PTV were out of those defined by PET/CT. Thoracic RT plans based on PET preserved better bilateral lung [percentage volume of lung irradiated with a dose of 20 Gy (V20); significance, R(2) = 0.559, p = 0.006]. For our physicians, PET/CT fused images allowed better contouring of primary tumours in 40% of head and neck cancers and 34% of thoracic cancers. PET/CT provides useful information for virtual simulation therapy. Image treatment and planning in an RT workstation is mandatory.

Breast cancer (BC) accounts for one-third of all cases of cancer in women in the UK. Current strategies for the detection of BC recurrence include computed tomography (CT), magnetic resonance imaging (MRI) and bone scintigraphy. Positron emission tomography (PET) and, more recently, positron emission tomography/computed tomography (PET/CT) are technologies that have been shown to have increasing relevance in the detection and management of BC recurrence. To review the accuracy of PET and PET/CT for the diagnosis of BC recurrence by assessing their value compared with current practice and compared with each other. MEDLINE and EMBASE were searched from inception to May 2009. Studies were included if investigations used PET or PET/CT to diagnose BC recurrence in patients with a history of BC and if the reference standard used to define the true disease status was histological diagnosis and/or long-term clinical follow-up. Studies were excluded if a non-standard PET or PET/CT technology was used, investigations were conducted for screening or staging of primary breast cancer, there was an inadequate or undefined reference standard, or raw data for calculation of diagnostic accuracy were not available. Quality assessment and data extraction were performed independently by two reviewers. Direct and indirect comparisons were made between PET and PET/CT and between these technologies and methods of conventional imaging, and meta-analyses were carried out. Analysis was conducted separately on patient- and lesion-based data. Subgroup analysis was conducted to investigate variation in the accuracy of PET in certain populations or contexts and sensitivity analysis was conducted to examine the reliability of the primary outcome measures. Of the 28 studies included in the review, 25 presented patient-based data and 7 presented lesion-based data for PET and 5 presented patient-based data and 1 presented patient- and lesion-based data for PET/CT; 16 studies conducted direct comparisons with 12 comparing the accuracy of PET or PET/CT with conventional diagnostic tests and 4 with MRI. For patient-based data (direct comparison) PET had significantly higher sensitivity [89%, 95% confidence interval (CI) 83% to 93% vs 79%, 95% CI 72% to 85%, relative sensitivity 1.12, 95% CI 1.04 to 1.21, p = 0.005] and significantly higher specificity (93%, 95% CI 83% to 97% vs 83%, 95% CI 67% to 92%, relative specificity 1.12, 95% CI 1.01 to 1.24, p = 0.036) compared with conventional imaging tests (CITs)--test performance did not appear to vary according to the type of CIT tested. For patient-based data (direct comparison) PET/CT had significantly higher sensitivity compared with CT (95%, 95% CI 88% to 98% vs 80%, 95% CI 65% to 90%, relative sensitivity 1.19, 95% CI 1.03 to 1.37, p = 0.015), but the increase in specificity was not significant (89%, 95% CI 69% to 97% vs 77%, 95% CI 50% to 92%, relative specificity 1.15, 95% CI 0.95 to 1.41, p = 0.157). For patient-based data (direct comparison) PET/CT had significantly higher sensitivity compared with PET (96%, 95% CI 90% to 98% vs 85%, 95% CI 77% to 91%, relative sensitivity 1.11, 95% CI 1.03 to 1.18, p = 0.006), but the increase in specificity was not significant (89%, 95% CI 74% to 96% vs 82%, 95% CI 64% to 92%, relative specificity 1.08, 95% CI 0.94 to 1.20, p = 0.267). For patient-based data there were no significant differences in the sensitivity or specificity of PET when compared with MRI, and, in the one lesion based study, there was no significant differences in the sensitivity or specificity of PET/CT when compared with MRI. Studies reviewed were generally small and retrospective and this may have limited the generalisability of findings. Subgroup analysis was conducted on the whole set of studies investigating PET and was not restricted to comparative studies. Conventional imaging studies that were not compared with PET or PET/CT were excluded from the review. Available evidence suggests that for the detection of BC recurrence PET, in addition to conventional imaging techniques, may generally offer improved diagnostic accuracy compared with current standard practice. However, uncertainty remains around its use as a replacement for, rather than an add-on to, existing imaging technologies. In addition, PET/CT appeared to show clear advantage over CT and PET alone for the diagnosis of BC recurrence. Future research should include: prospective studies with patient populations clearly defined with regard to their clinical presentation; a study of diagnostic accuracy of PET/CT compared with conventional imaging techniques; a study of PET/CT compared with whole-body MRI; studies investigating the possibility of using PET/CT as a replacement for rather than an addition to CITs; and using modelling of the impact of PET/CT on patient outcomes to inform the possibility of conducting large-scale intervention trials.

Tumour Induced Osteomalacia (TIO) caused by a Fibroblast-Growth- Factor-23 (FGF-23) secreting tumour is a rare paraneoplastic disorder. Patients often present with non-specific complaints of pain and stiffness however findings of hypophosphataemia and inappropriately suppressed 1,25 dihidroxyvitamin D are almost pathognemonic of this condition. We present a previously healthy 51-year-old man who presented with an 18 month history of body aches, hypophosphataemia, and an incidental finding of atraumatic foot fractures on x-ray. Technetium bone scan identified diffuse skeletal pathologic fractures. He was further found to have persistent hypophosphataemia, suppressed 1-25-dihidroxyvitamin-D, renal phosphate wasting with reduced Tubular Reabsorption of Phosphate (TRP), and an FGF-23 level more than twice the upper limit of normal. Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET), Gallium-68 Dotatate PET and magnetic resonance imaging further identified and characterised a 40 mm FDG and Dotatate-avid lesion in the right third rib. Histopathological examination of a biopsy specimen revealed phosphaturic mesenchymal tumour with positive FGF-23 immunohistochemical staining arising in a background consistent with osteomalacia. After tumour resection, the patient’s hypophosphataemia, reduced TRP and elevated FGF- 23 normalised and he made an excellent recovery with rehabilitation. This case report illustrates the importance of a diagnosis of hypophosphataemia in a patient with musculo-skeletal aches and alerts clinicians of the differential diagnosis of TIO.

Mutations in fibroblast growth factor 23 (FGF-23) cause autosomal dominant hypophosphatemic rickets. Clinical and laboratory findings in this disorder are similar to those in oncogenic osteomalacia, in which tumors abundantly express FGF-23 messenger RNA, and to those in X-linked hypophosphatemia, which is caused by inactivating mutations in a phosphate-regulating endopeptidase called PHEX. Recombinant FGF-23 induces phosphaturia and hypophosphatemia in vivo, suggesting that it has a role in phosphate regulation. To determine whether FGF-23 circulates in healthy persons and whether it is elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, an immunometric assay was developed to measure it. Using affinity-purified, polyclonal antibodies against [Tyr223]FGF-23(206-222)amide and [Tyr224]FGF-23(225-244)amide, we developed a two-site enzyme-linked immunosorbent assay that detects equivalently recombinant human FGF-23, the mutant form in which glutamine is substituted for arginine at position 179 (R179Q), and synthetic human FGF-23(207-244)amide. Plasma or serum samples from 147 healthy adults (mean [+/-SD] age, 48.4+/-19.6 years) and 26 healthy children (mean age, 10.9+/-5.5 years) and from 17 patients with oncogenic osteomalacia (mean age, 43.0+/-13.3 years) and 21 patients with X-linked hypophosphatemia (mean age, 34.9+/-17.2 years) were studied. Mean FGF-23 concentrations in the healthy adults and children were 55+/-50 and 69+/-36 reference units (RU) per milliliter, respectively. Four patients with oncogenic osteomalacia had concentrations ranging from 426 to 7970 RU per milliliter, which normalized after tumor resection. FGF-23 concentrations were 481+/-528 RU per milliliter in those with suspected oncogenic osteomalacia and 353+/-510 RU per milliliter (range, 31 to 2335) in those with X-linked hypophosphatemia. FGF-23 is readily detectable in the plasma or serum of healthy persons and can be markedly elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, suggesting that this growth factor has a role in phosphate homeostasis. FGF-23 measurements might improve the management of phosphate-wasting disorders.

Lessons learnt from delayed diagnosis of FGF-23-producing tumour-induced osteomalacia and post-operative hungry bone syndrome

Clinical features and treatment of hypophosphatemia and associated complications induced by Phosphaturic mesenchymal tumors: A case series of six patients.

Tumor-induced osteomalacia is characterized by hypophosphatemia and fragility fractures caused by fibroblast growth factor 23 (FGF23)-producing tumors. We report a case of tumor-induced osteomalacia in which the tumor location could be determined by gallium 68 (68Ga)-DOTATOC positron emission tomography (PET)/computed tomography (CT). A 74-year-old woman had recurrent fractures and bone pain. Blood tests showed hypophosphatemia and elevated serum alkaline phosphatase and FGF23 levels and CT and bone scintigraphy showed multiple bone fractures. Tumor-induced osteomalacia was therefore suspected. Indium 111 (111In)-pentetreotide scintigraphy showed focus of increased activity in the head, and CT and magnetic resonance images showed a mass-like lesion in the posterior ethmoidal sinus. However, in systemic venous sampling, serum FGF23 level was highest in the left common iliac vein. 68Ga-DOTATOC PET/CT clearly demonstrated focal uptake in the left anterior inferior iliac spine consistent with systemic venous sampling. Retrospectively analyzed, focal uptake in the head was considered to be a physiological uptake in the pituitary gland. The tumor was resected and the pathological diagnosis was phosphaturic mesenchymal tumor. A combination of systemic venous sampling and 68Ga-DOTATOC PET/CT was useful in detection of a small FGF23-producing tumor. Precise tumor localization in such cases requires careful interpretation of scintigraphy.