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Phosphaturic mesenchymal tumors (PMTs) are extremely rare mesenchymal tumors of soft tissue and bone that cause tumor-induced osteomalacia (TIO). Some of these tumors are completely asymptomatic and may grow undetected unless they become large enough to cause pain or discomfort. This type of tumor is crucial to diagnose in patients being treated for phosphate metabolism disorders and are a rare reason why patients seek medical help owing to pain. Here, we report the details of a patient with progressive bone pain caused by a PMT originating in the left femur., Competing Interests: Declaration of conflicting interestsThe authors declare that there is no conflict of interest.

Background: Phosphaturic Mesenchymal Tumors (PMTs) are rare mesenchymal neoplasms known for producing Tumor-induced Osteomalacia (TIO). TIO is an uncommon paraneoplastic syndrome characterized by radiographic evidence of inadequate bone mineralization and analytical abnormalites., Methods: We sought to present a case of TIO caused by skull base PMT with intracranial extension, manifesting with pain, progressive weakness, and multiple bone fractures. Furthermore, a systematic review was performed, following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. A search was conducted in PubMed database with title/abstract keywords "Phosphaturic mesenchymal tumor" and "Osteomalacia." Search results were reviewed looking for intracranial or skull base tumors., Results: Our systematic review included 29 reported cases of intracranial PMT. In the reviewed cases there was a significative female predominance with 22 cases (75,86%). Osteomalacia was presented in 25 cases (86,20%). Bone fractures were present in 10 cases (34,48%). The most common site of involvement was the anterior cranial fossa in 14 cases (48,27%). Surgery was performed in 27 cases (93,10%) with previous tumor embolization in 4 cases (13,79%). Total recovery of the presenting symptoms in the first year was achieved in 21 cases (72,41%). Recurrence of the disease was described in 6 cases (25%)., Conclusions: Skull base PMTs with intracranial extension are extremely rare tumors. Most patients are middle-aged adults with a PMT predominantly located in anterior cranial fossa. Surgery is the current treatment of choice with optimal outcome at 1-year follow-up, although recurrence could be present in almost 25% of the cases., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Phosphaturic mesenchymal tumors are rare, usually benign neoplasms that occur in the soft tissue or bone and are the cause of nearly all cases of tumor-induced osteomalacia. Tumor-induced osteomalacia due to phosphaturic mesenchymal tumor is a challenging diagnosis to make-patients present with variable clinical and radiologic findings and the culprit neoplasm is often small and can occur anywhere head to toe. We present two cases of phosphaturic mesenchymal tumor in the scapular body and plantar foot. In both cases, the patient endured years of debilitating symptoms before a tissue diagnosis was eventually reached. Descriptions of clinical presentation, laboratory workup, surgical resection, and imaging characteristics, with a focus on CT, MRI, and functional imaging, are provided to assist with the diagnosis and management of this rare entity. A brief review of current literature and discussion of the differential diagnoses of phosphaturic mesenchymal tumor is also provided., (© 2023. The Author(s), under exclusive licence to International Skeletal Society (ISS).)

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. 68 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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2023 Copyright: © 2023 Saudi Journal of Kidney Diseases and Transplantation.)

Introduction: Oncogenic osteomalacia is a very rare disease usually caused by a phosphaturic mesenchymal tumor, particularly the "mixed connective tissue type", secreting FGF-23 hormone., Objective: The authors report a case of ethmoid tumor associated with oncogenic osteomalacia and discuss management based on a review of the literature., Case Summary: A 41-year-old woman with multiple fractures causing major disability was diagnosed with early-onset osteoporosis. CT scan followed by MRI, performed due to the concomitant presence of nasal obstruction, showed a right ethmoid tumor in contact with the dura mater and periorbital tissues, but with no signs of invasion. Endoscopic resection was performed with reconstruction of the defect of the cribriform plate by a nasoseptal flap. Nasal and bone symptoms subsequently resolved. Histological examination revealed a phosphaturic mesenchymal tumor., Discussion: Twelve cases of mesenchymal tumor of the ethmoid sinus associated with oncogenic osteomalacia have been reported to date. FGF-23 assay and whole-body MRI with STIR sequence are useful for the diagnosis. A very favorable outcome is observed after surgical treatment in the majority of cases., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

We report the case of a 25-year-old male patient with tumor-induced osteomalacia from a 1.8-cm phosphaturic mesenchymal tumor in the right distal thigh, who was treated at our institution with a single session of CT-guided cryoablation in December 2015, which resulted in biochemical and clinical resolution. We present the clinical history, physical examination, biochemistry, functional imaging, anatomic characterization, and follow-up for clinical outcome. The response to treatment was documented in terms of normalization of serum fibroblastic growth factor 23 (FGF23) and phosphorous levels, symptomatic improvement, as well as normalization of bone mineralization on femur radiographs 3 months after the procedure. Although the first-line treatment for phosphaturic mesenchymal tumor-induced osteomalacia is wide surgical excision, CT-guided cryoablation widens the array of treatment options, especially in those patients who decline surgery or who are otherwise poor surgical candidates.

Phosphaturic mesenchymal tumor (PMT) is a morphologically heterogeneous soft tissue and bone neoplasm, producing a paraneoplastic syndrome due to phosphate wasting. These tumors produce fibroblast growth factor 23, which is implicated in renal tubule phosphate loss. Medical records of patients seen from 1999 to 2013 with osteomalacia associated or not with a tumor were reviewed. Clinical and laboratory data, radiographic studies, and follow-up of 8 patients were tabulated. Histologic features and the immunoprofile of the tumors were analyzed. There were 208 patients with osteomalacia, but only 8 (3.84%) had osteomalacia associated with a tumor. The median age of the patients was 40 years. The tumor size ranged from 1.5 to 4 cm. Five were located in soft tissues and skin; and 3, in bones. Osteomalacia symptoms lasted from 2 to 14 years with a median of 6 years. Laboratory data showed hypophosphatemia and phosphaturia in all patients. All tumors were histologically benign. Histologically, the salient features were a hemangiopericytoid pattern, chronic hemorrhage, and microcystic areas. All neoplasms were diffusely positive for vimentin and focally positive for epithelial membrane antigen, CD34, and S-100 protein. Ki-67 was positive in approximately 10% of neoplastic cells in 2 cases and less than 1% in the remainder. We report 8 cases of PMTs producing osteomalacia, from a single third-level Mexican medical institution. These tumors occurred in soft tissues, skin, and bones. All tumors were benign, small, not easily detected by physical examination and diagnosed due to the metabolic abnormalities., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Hypophosphatemia with osteomalacia may be due to a neoplasm that produces fibroblast growth factor 23 (FGF-23), which inhibits phosphate reabsorption in the kidneys. Most of these tumors occur in bone or soft tissue and occasionally in the head, although intracranial occurrence is very rare. This report describes a tumor that caused hypophosphatemia and osteomalacia and was located entirely in the right anterior cranial fossa. Radiologically, the tumor resembled a meningioma; histologically, it was a low-grade phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT). After gross-total resection, the patient's symptoms abated and laboratory values normalized. The authors also studied another PMTMCT initially diagnosed as a hemangiopericytoma that involved the left anterior cranial fossa and ethmoid sinus, and reviewed reports of 6 other intracranial tumors that induced osteomalacia, 3 entirely in the anterior cranial fossa, 2 involving the anterior cranial fossa and ethmoid sinus, and 1 in the cavernous sinus. In older children or adults who have hypophosphatemia with osteomalacia and no personal or family history of metabolic, renal, or malabsorptive disease, a neoplasm should be suspected and an imaging workup that includes the brain is warranted, with particular attention to the anterior cranial fossa. Additionally, because there are some overlapping histological features between PMTMCTs and hemangiopericytomas, it may be helpful to assess tumoral FGF-23 expression by reverse transcriptase polymerase chain reaction or immunohistochemical analysis in patients with oncogenic osteomalacia from an intracranial tumor diagnosed as, or resembling, hemangiopericytoma.

We present 2 cases of tumor-induced osteomalacia (TIO). Both patients had histories of long-term bone and muscle pain. Laboratory data revealed hypophosphatemia. Whole-body magnetic resonance (MR) imaging (WB-MRI) clearly depicted a small subcutaneous mass in the left thigh of the first patient and a right acetabular mass in the second patient. These lesions were pathologically proven to be hemangiopericytoma-phosphaturic mesenchymal tumors (PMT).

Context: Tumor-induced osteomalacia is a rare condition usually caused by benign mesenchymal tumors. When the tumor can be found, patients are usually managed by wide excision of the tumor., Objective: We report a 51-yr-old male with clinical and biochemical evidence of tumor-induced osteomalacia caused by a mesenchymal tumor in the right iliac bone. He declined surgery and appears to have been successfully managed by computed tomography-guided percutaneous ethanol ablation and percutaneous cryoablation., Results: Our patient appears to have had an excellent clinical and biochemical response to computed tomography-guided percutaneous ethanol ablation and percutaneous cryoablation. We found one prior case of image-guided ablation using radiofrequency ablation for tumor-induced osteomalacia., Conclusions: Although the standard treatment for tumor-induced osteomalacia is wide excision of the tumor, image-guided ablation may be an option in patients who cannot have appropriate surgery or who decline surgery.

Phosphaturic mesenchymal tumor of mixed connective tissue type is a rare, histologically distinctive mesenchymal neoplasm associated with tumor-induced osteomalacia resulting from production of the phosphaturic hormone fibroblast growth factor 23. Because of its rarity, specific genetic alterations that contribute to the pathogenesis of these tumors have yet to be elucidated. Herein, we report the abnormal karyotypes from 2 cases of confirmed phosphaturic mesenchymal tumor of mixed connective tissue type. G-banded analysis demonstrated the first tumor to have a karyotype of 46,Y,t(X;3;14)(q13;p25;q21)[15]/46XY[5], and the second tumor to have a karyotype of 46, XY,add(2)(q31),add(4)(q31.1)[2]/92,slx2[3]/46,sl,der(2)t(2;4)(q14.2;p14),der(4)t(2;4)(q14.2;p14),add(4)(q31.1)[10]/46,sdl,add(13)(q34)[4]/92,sdl2x2[1]. These represent what is, to our knowledge, the first examples of abnormal karyotypes obtained from phosphaturic mesenchymal tumor of mixed connective tissue type., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Tumor-induced osteomalacia (TIO), or oncogenic osteomalacia (OOM), is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recent evidence shows that tumor-overexpressed fibroblast growth factor 23 (FGF23) is responsible for the hypophosphatemia and osteomalacia. The tumors associated with TIO are usually phosphaturic mesenchymal tumor mixed connective tissue variants (PMTMCT). Surgical removal of the responsible tumors is clinically essential for the treatment of TIO. However, identifying the responsible tumors is often difficult. Here, we report a case of a TIO patient with elevated serum FGF23 levels suffering from bone pain and hypophosphatemia for more than three years. A tumor was finally located in first metacarpal bone by octreotide scintigraphy and she was cured by surgery. After complete excision of the tumor, serum FGF23 levels rapidly decreased, dropping to 54.7% of the preoperative level one hour after surgery and eventually to a little below normal. The patient's serum phosphate level rapidly improved and returned to normal level in four days. Accordingly, her clinical symptoms were greatly improved within one month after surgery. There was no sign of tumor recurrence during an 18-month period of follow-up. According to pathology, the tumor was originally diagnosed as "lomangioma" based upon a biopsy sample, "proliferative giant cell tumor of tendon sheath" based upon sections of tumor, and finally diagnosed as PMTMCT by consultation one year after surgery. In conclusion, although an extremely rare disease, clinicians and pathologists should be aware of the existence of TIO and PMTMCT, respectively.

The authors describe a case of oncogenic osteomalacia due to a mesenchymal phosphaturic tumour in the maxillary sinus. This is a paraneoplastic syndrome in which a tumour produces a peptide hormone-like substance (phosphatonin) that causes a urinary loss of phosphates resulting in a debilitating systemic condition. In this case, the patient experienced muscle stiffness, reduction of muscle tone, loss of weight and pathological fractures. Clinical and radiological examination revealed a tumour in the right maxillary sinus; all other results were negative. The diagnosis following pathology examination was mesenchymal phosphaturic tumour with a haemangiopericytoma-like vascular pattern. Different histological types of mesenchymal tumours can be associated with paraneoplastic syndrome, but their localization in the paranasal sinuses is rare. The correct diagnosis allows the appropriate therapeutic approach, which can lead to an almost immediate resolution of the clinical situation after surgical removal of the neoplasm as in the present case. Oncogenic osteomalacia is rare, particularly in the maxillofacial region, and only a few cases have been reported., (Copyright © 2010 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recently, it was reported that tumors associated with TIO produce fibroblast growth factor (FGF) 23, identified as the last member of the FGF family and of which excessive action causes several hypophosphatemic diseases whereas deficient FGF23 activity results in hyperphosphatemic tumoral calcinosis. In this case, although it was difficult to locate the associated tumor, an abnormal mass in the left maxilla was detected by imaging. The tumor was removed by partial resection of the left maxillary alveolar region. Thereafter, serum level of FGF23 rapidly decreased, hypophosphatemia improved, and the clinical symptoms greatly improved. Histopathologic diagnosis of the tumor was phosphaturic mesenchymal tumor, mixed connective tissue variant. Immunohistochemical findings confirmed that the removed tumor produced FGF23. These results indicate that development of osteomalacia in this patient was related to the maxillary tumor, which overexpressed FGF23., (Copyright 2010 Mosby, Inc. All rights reserved.)

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome that results in renal phosphate wasting with hypophosphatemia. In most cases, the underlying cause of TIO is a small mesenchymal neoplasm that is often difficult to detect, resulting in delayed diagnosis. One such neoplasm is the phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT), an unusual entity with unique morphologic and biochemical features. Most of these tumors are found at appendicular sites with only rare cases reported in the jaws. We describe a PMTMCT involving the mandible in a patient with a protracted history of osteomalacia. A review of the current literature is provided with emphasis on the clinical and histologic features, etiopathogenesis, and management of PMTMCT in the setting of TIO.

Phosphaturic mesenchymal tumors of the mixed connective tissue type (PMTMCT) are extremely rare, histologically distinctive neoplasms, which cause tumor-induced osteomalacia (TIO) in most cases through the elaboration of a phosphaturic hormone, fibroblast growth factor-23 (FGF23). Rarely, identical tumors without known TIO may be observed. We studied a large group of PMTMCT for expression of FGF23, using a novel reverse transcription polymerase chain reaction (RT-PCR) assay for FGF23 in formalin-fixed, paraffin-embedded tissues. Twenty-nine PMTMCT (17 with and 12 without TIO) and 23 non-PMTMCT (16 various mesenchymal tumors, including 5 chondromyxoid fibroma, 8 chondroblastoma, 1 hemangiopericytoma, 1 aneurysmal bone cyst, and 1 high grade sarcoma; 5 carcinomas; and 2 non-neoplastic tissues) were retrieved. Total RNA was extracted from formalin-fixed, paraffin-embedded sections for RT-PCR analysis. FGF23 was amplified using 3 sets of primers that spanned the intron/exon boundaries to amplify the 3 exons of FGF23 gene (140, 125, and 175 bp). The housekeeping gene phosphoglycerokinase (189 bp) was coamplified to check the RNA quality. Sixteen of 17 (94%) PMTMCT with TIO were FGF23-positive. Nine of 12 (75%) PMTMCT without TIO were FGF23-positive. Two chondromyxoid fibroma and 1 aneurysmal bone cyst were positive; all other non-PMTMCT were negative. We conclude that RT-PCR for FGF23 is a sensitive and specific means of confirming the diagnosis of PMTMCT both in patients with and without TIO. FGF23 gene expression was present in more than 90% of PMTMCT with known TIO, confirming the role of FGF23 in this syndrome. Rare FGF23-negative PMTMCT with known TIO likely express other phosphaturic hormones (eg, frizzled-related protein 4). Our finding of expression of FGF23 in 75% of histologically identical tumors without known TIO confirms the reproducibility of the diagnosis of PMTMCT, even in the absence of known phosphaturia.

Phosphaturic mesenchymal tumour-mixed connective tissue variant is a rare tumour classically associated with oncogenic osteomalacia. This report describes two patients with this distinct tumour type but with no evidence of the paraneoplastic syndrome.

Phosphaturic mesenchymal tumors that cause the paraneoplastic syndrome known as oncogenic osteomalacia are rare. The authors report on the case of a 57-year-old man with a history of osteomalacia and in whom was diagnosed a thoracic spine tumor at the T-4 level. Complete tumor resection was accomplished. The histological diagnosis was phosphaturic mesenchymal tumor (mixed connective tissue variant). After lesion removal, the paraneoplastic syndrome resolved. At the 24-month follow-up, no recurrence of the disease was observed. The clinical presentation, surgical technique, and follow-up in this case were reviewed in detail.

Tumor-induced osteomalacia (TIO) is a rare paraneoplasic syndrome with overproduction of fibroblast growth factor 23 as a phosphaturic agent, leading to chronic hyperphosphaturia and hypophosphatemia, associated with inappropriately normal or low levels of 1,25-dihydroxyvitamin D. Diagnosis of this disease is often challenging. The following case report described a middle-aged man with symptoms of bone pain and severe muscle weakness, who was found to have TIO. The tumor responsible for the symptoms was localized on his thigh and its resection resulted in normalization of blood chemistry and complaints. Subsequent microscopic examination revealed a phosphaturic mesenchymal tumor, mixed connective tissue type. The authors reinforce the importance of recognition of this disease, as severe disability and even death can be avoided with the surgical removal of the causative tumor.

Fibroblast growth factor 23 (FGF23) overexpression has been identified as a causative factor for tumor-induced osteomalacia (TIO) characterized by hypophosphatemia due to increased renal phosphate wasting, low 1,25(OH)(2)D(3) serum levels, and low bone density. The effects of long-lasting disturbed phosphate homeostasis on bone mineralization are still not well understood. We report on a patient with a 12-year history of TIO, treated with 1,25(OH)(2)D(3) and phosphate, who finally developed hyperparathyroidism with gland hyperplasia before the tumor could be localized in the scapula and removed. During surgery a transiliac bone biopsy was obtained. FGF23 expression in the tumor cells was confirmed by in situ hybridization. Serum FGF23 levels as measured by ELISA were found to be extremely elevated before and decreased after removal of the tumor. Bone histology/histomorphometry and measurement of bone mineralization density distribution using quantitative backscattered electron imaging were performed on the bone biopsy. The data showed important surface osteoidosis and a slightly increased osteoblast but markedly decreased osteoclast number. The mineralized bone volume (-11%) and mineralized trabecular thickness (-18%) were low. The mean degree of mineralization of the bone matrix (-7%), the most frequent calcium concentration (-4.1%), and the amounts of fully mineralized bone (-40.3%) were distinctly decreased, while the heterogeneity of mineralization (+44.5%) and the areas of primary mineralization (+131.6%) were dramatically increased. We suggest that the elevated levels of FGF23 and/or low phosphate concentrations disturb the mineralization kinetics in vivo without affecting matrix mineralization of pre-existing bone packets.

One of the most unusual and uncommon types of osteomalacia is the oncogenic osteomalacia that is predominantly caused by a soft tissue or bone tumour, mostly by a phosphaturic mesenchymal tumour, mixed connective tissue type (PMTMCT). We report a case of a 27-year-old male presented with complaints of progressive and generalized muscle weakness, bone pains and multiple fractures. Intra-articular PMTMCT of the knee was diagnosed and surgically removed. We describe histopathological features of PMTMCT and review the most recent studies concerning this diagnostic problem.

We report a 31-year-old woman with tumor-induced osteomalacia suffering from slowly progressive bilateral muscle weakness predominantly in the proximal muscles and multiple bone pains for the past 2 years. She was unable to walk or raise her arms above the shoulder. We suspected tumor-induced osteomalacia due to decreased serum phosphate and 1alpha, 25 (OH),-vitamin D3 levels, low percentage of tubular reabsorption of phosphate (%TRP), adult onset, and no family history of osteomalacia. Regular imaging examinations could not detect the location of the primary tumor: however, indium-111 octreotide scintigraphy detected the causative primary mesenchymal tumor in the right sole. Pain and muscle weakness improved promptly after tumor resection, and she was able to walk 6 d postoperatively. This is the first case report in Japan describing the detection of the primary tumor site by indium-111 octreotide scintigraphy.

Tumor-induced osteomalacia, also known as oncogenic osteomalacia, is a rare paraneoplastic syndrome in which vitamin D resistant osteomalacia occurs due to the presence of a tumor. The following case report describes a young woman who seeks a second opinion from a rheumatologist and is found to have oncogenic osteomalacia. Not often discussed in the rheumatology literature, oncogenic osteomalacia is a rare and interesting disease entity in which diagnosis is often more challenging than treatment.

Objective: To report the outcomes of tumor-induced osteomalacia after treatment, particularly related to recovery of bone mass., Methods: We review the clinical course of a 61-year-old man extremely debilitated from multiple fractures and neuromuscular weakness due to tumor-induced osteomalacia and report the changes in biochemical markers and bone density after removal of the causative neoplasm., Results: At the time of diagnosis, the patient's serum phosphorus and 1,25 dihydroxyvitamin D levels were depressed, and his fibroblast growth factor-23 level was markedly elevated. These values normalized 2 days after surgery and remained within their respective reference ranges 4 and 12 months after resection of a mesenchymal tumor. Lumbar bone density values (T-scores) were 0.445 g/cm2 (-5.9) preoperatively, 0.939 g/cm2 (-1.4) 4 months after surgery, and 1.152 g/cm2 (0.7) 12 months after surgery. Left femoral neck values at the same time points were 0.525 g/cm2 (-3.0), 1.035 g/cm2 (-0.8), and 1.184 g/cm2 (1.9). Ultra-distal radius values at the same time points were 0.128 g/cm2 (-7.0), 0.191 g/cm2 (-5.9), and 0.259 g/cm2 (-4.8). In addition, he recovered neuromuscular function and was able to leave his wheelchair., Conclusion: Tumor-induced osteomalacia can be an extremely debilitating disease. With successful localization, identification, and resection of the neoplasm, bone mass and physical function can recover.

Background: Tumor-induced osteomalacia (TIO) is an extremely rare paraneoplastic syndrome associated with mesenchymal tumors in the craniofacial region., Methods: We treated a 24-year-old Japanese woman with paranasal sinus tumor and a low serum phosphate level who presented with nasal obstruction and systemic bone fractures. Serum fibroblast growth factor 23 (FGF-23) was measured before and after surgery., Results: After surgery, her symptoms were resolved and the serum phosphate and FGF-23 levels became normalized., Conclusion: FGF-23 is thought to be a useful diagnostic marker in patients with craniofacial tumors associated with multiple systemic fractures.

A 45-year-old man was admitted to our hospital because of bone pain and hypophosphatemia. He had undergone surgery 2 years previously for a "benign unclassified mesenchymal tumor" in the skull, but there were no clinical symptoms related to osteomalacia. His laboratory examination revealed low serum phosphate, high alkaline phosphatase, and normal calcium levels. The diagnosis of tumor-induced osteomalacia due to phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT) was made by re-examining the pathologic specimens. Oral supplementation with phosphate and 1-25-dihydroxyvitamin D relieved his clinical symptoms and laboratory values returned to normal. However, subcutaneous administration of octreotide had no clinical effect. Clinicians and pathologists should be aware of the existence of PMTMCT especially nonphosphaturic or asymptomatic variants of this disorder.

Objective: To study the clinicopathologic features of osteomalacia or rickets-associated mesenchymal tumors., Methods: The clinical and pathologic findings of 10 cases of osteomalacia or rickets-associated mesenchymal tumors were evaluated. Hematoxylin and eosin stain, immunohistochemistry and histochemistry were performed on the archival paraffin sections., Results: Amongst the 10 patients studied, 6 were males and 4 were females. Their age at the time of operation ranged from 28 to 69 years ( mean = 45.6 years). A history of long-standing bone pain, arthralgia, limitation in movement, hypophosphatemia and hyperphosphaturia was present in all cases. The duration of symptoms ranged from 2 to 27 years (mean = 9.6 years). The tumor size ranged from 1 to 7 cm (mean size = 3.52 cm). Microscopically, the tumors were composed of various mesenchymal cells, including spindled fibroblast-like cells, adipocytes, chondroid cells and mucinous cells. The background was rich in blood vessels. In 8 of the 10 cases, there was also dystrophic calcification in an unusual flocculent or "grungy" pattern. Peripheral woven bone shell formation was noted in 2 cases and non-urate crystal deposition in 2 cases. Mitotic figures were rare in 9 cases. In 1 of the 10 cases however, mitotic figures and bizarre cells were commonly encountered. On immunohistochemical study, the tumor cells were all positive for vimentin. There was focal positivity for smooth muscle actin and CD34 in 5 and 3 cases respectively. The staining for desmin, S-100 and AE1/AE3 was negative. Ki-67 proliferation index was less than 4% in 8 cases and 30% in 1 case. Alcian blue-positive mucinous matrix and mucinous degeneration around vessels were noted in 8 cases., Conclusions: Most of the osteomalacia or rickets-associated tumors are either benign or low-grade malignant mesenchymal tumors. They can be mistaken as other neoplasms due to the morphologic heterogeneity present. Thorough understanding of the associated clinical features and laboratory investigation results is helpful in arriving at the correct diagnosis.

Objective: To describe a case of persistent tumor-induced osteomalacia, determine whether serum fibroblast growth factor-23 (FGF-23) levels postoperatively indicate incomplete tumor resection, and report lumbar spine and forearm bone mineral density (BMD) changes during 5 years of follow-up., Methods: We present clinical, radiologic, histologic, and bone densitometry data as well as serum FGF-23 levels (determined with use of a novel C-terminal enzyme-linked immunosorbent assay) from the study patient and discuss these findings in the context of previous literature., Results: A 52-year-old man, who presented with muscle weakness and multiple fractures, was found to have low values for serum phosphorus, serum 1,25-dihydroxyvitamin D, and maximal tubular reabsorption of phosphate per glomerular filtration rate, a high level of serum alkaline phosphatase, and a normal serum concentration of parathyroid hormone, characteristic of tumor-induced osteomalacia. Magnetic resonance imaging to evaluate an abnormality of the left foot revealed a soft tissue mass, biopsy of which confirmed the presence of a benign, phosphaturic, mesenchymal tumor. The baseline serum FGF-23 level (2,050 RU/mL) was more than 17 times the upper limit of normal for adults (23 to 118 RU/mL) and decreased substantially within 1 day after partial resection of the tumor but remained above normal postoperatively. BMD changes indicated rapid substantial recovery of vertebral BMD but ongoing loss of forearm bone density., Conclusion: The serum FGF-23 level is high in a substantial proportion of patients with tumor-induced osteomalacia. The postoperative above normal levels of serum FGF-23 correlated with known persistence of tumor in our study patient. In a patient with normal renal function, such as our study patient, levels of serum FGF-23 studied with use of the C-terminal enzyme-linked immunosorbent assay reached their nadir within 24 hours postoperatively. This result suggests that this assay can provide clinicians with rapid prognostic information in patients with known or suspected residual tumor. BMD should be assessed at both appendicular and axial sites in patients with persistent tumor-induced osteomalacia.

Oncogenic osteomalacia, which is characterized by renal phosphate wasting, low serum 1, 25-dihydroxyvitamin D, and osteomalacia, is caused by mesenchymal neoplasms that are termed phosphaturic mesenchymal tumors (PMTs). As PMTs are usually small and lack specific histological features, the pathological identification of PMTs is difficult. Dentin matrix protein 1 (DMP1) is an acidic phosphoprotein expressed in mineralized tissues including bone, tooth, and hypertrophic cartilage. Increased expression of DMP1 gene in PMTs has been reported by using differential cDNA screening. In the present study, DMP1 expression in PMTs and other soft tissue tumors was analyzed immunohistochemically to verify its utility in the differential diagnosis of PMTs. Anti-DMP1 polyclonal antibody was raised against the C-terminal sequence of DMP1. Three cases with PMTs and 11 other soft tissue tumors (two malignant hemangiopericytomas, three solitary fibrous tumors, three synovial sarcomas, and three malignant peripheral nerve sheath tumors) were analyzed for DMP1 expression. DMP1 expression was observed in all of the three cases with PMTs, but never found in other soft tissue tumors examined. DMP1 was detected in the extracellular matrix with myxomatous features or around capillary vessels, and in dystrophic calcified sites. Paranuclear DMP1 staining in the tumor cells was also observed. These findings indicate that DMP1 immunohistochemistry is a useful tool for identifying PMTs.

Oncogenic osteomalacia is an uncommon syndrome characterized by bone pain, proximal muscle weakness, hypophosphatemia, hyperphosphaturia, and a low plasma concentration of 1,25-dihydroxy-vitamin D. The disease affects both sexes at around 40 years of age, although it can sometimes affect children and adolescents. Generally, the syndrome is associated with a tumor, usually benign, of mesenchymal origin and is resolved after removal of the tumor; this syndrome can sometimes be associated with malignant tumors. These tumors seem to be histologically heterogeneous and are generally localized in soft tissues and bone. In this article, a case of oncogenic osteomalacia associated with a hypophosphaturic mesenchymal tumor of the ethmoid is reported in a 24-year-old man. After surgical and radical removal of the tumor, the patient noted a decrease in the clinical symptoms and signs.

Oncogenic osteomalacia (OO) is a rare paraneoplastic syndrome of osteomalacia due to phosphate wasting. The phosphaturic mesenchymal tumor (mixed connective tissue variant) (PMTMCT) is an extremely rare, distinctive tumor that is frequently associated with OO. Despite its association with OO, many PMTMCTs go unrecognized because they are erroneously diagnosed as other mesenchymal tumors. Expression of fibroblast growth factor-23 (FGF-23), a recently described protein putatively implicated in renal tubular phosphate loss, has been shown in a small number of mesenchymal tumors with known OO. The clinicopathological features of 32 mesenchymal tumors either with known OO (29) or with features suggestive of PMTMCT (3) were studied. Immunohistochemistry for cytokeratin, S-100, actin, desmin, CD34, and FGF-23 was performed. The patients (13 male, 19 female) ranged from 9 to 80 years in age (median 53 years). A long history of OO was common. The cases had been originally diagnosed as PMTMCT (15), hemangiopericytoma (HPC) (3), osteosarcoma (3), giant cell tumor (2), and other (9). The tumors occurred in a variety of soft tissue (21) and bone sites (11) and ranged from 1.7 to 14 cm. Twenty-four cases were classic PMTMCT with low cellularity, myxoid change, bland spindled cells, distinctive "grungy" calcified matrix, fat, HPC-like vessels, microcysts, hemorrhage, osteoclasts, and an incomplete rim of membranous ossification. Four of these benign-appearing PMTMCTs contained osteoid-like matrix. Three other PMTMCTs were hypercellular and cytologically atypical and were considered malignant. The 3 cases without known OO were histologically identical to the typical PMTMCT. Four cases did not resemble PMTMCT: 2 sinonasal HPC, 1 conventional HPC, and 1 sclerosing osteosarcoma. Three cases expressed actin; all other markers were negative. Expression of FGF-23 was seen in 17 of 21 cases by immunohistochemistry and in 2 of 2 cases by RT-PCR. Follow-up (25 cases, 6-348 months) indicated the following: 21 alive with no evidence of disease and with normal serum chemistry, 4 alive with disease (1 malignant PMTMCT with lung metastases). We conclude that most cases of mesenchymal tumor-associated OO, both in the present series and in the reported literature, are due to PMTMCT. Improved recognition of their histologic spectrum, including the presence of bone or osteoid-like matrix in otherwise typical cases and the existence of malignant forms, should allow distinction from other mesenchymal tumors. Recognition of PMTMCT is critical, as complete resection cures intractable OO. Immunohistochemistry and RT-PCR for FGF-23 confirm the role of this protein in PMTMCT-associated OO.

The August 2003 COM. A 47-year-old woman presented with a long history of muscle pain, weakness, and visual disturbances. Over the last year, she developed diplopia and left sixth nerve palsy. No other neuro-ophthalmologic abnormalities were found. Past medical and family history was unremarkable. Laboratory investigation disclosed hypophosphatemia, phosphaturia, elevated serum alkaline phosphatase activity, and normal serum calcium levels. CT scans showed a lobulated mass arising on the meningeal surface of the cavernous sinus, measuring 3x 2 x 2 cm. The lesion was partially resected and microscopic examination revealed a highly vascularized tumor composed of primitive mesenchymal cells arranged whether in a patternless-pattern or surrounding thin-walled, branching vascular spaces and thick-walled hyalinized vessels. Other eye-catching features were microcystic areas, multinucleated osteoclastic-like giant cells, scattered islands of mature adipocytes, foci of hemorrhage, thrombosed medium-sized-to-large vessels, and hemosiderin-laden macrophages. After surgery, the patient recovered from the muscle pain and weakness, with a significant improvement of serum calcium and alkaline phosphatase levels and phosphate blood levels. Taken together, the clinical and pathologic features were consistent with a diagnosis of phosphaturic mesenchymal tumor (mixed connective tissue variant) of the cavernous sinus in a setting of oncogenic osteomalacia. No further treatment was carried out. The patient has been followed for the last 4 years with no evidence of recurrent disease. Oncogenic osteomalacia is a rare clinical entity characterized by hypophosphatemia, phosphaturia, and a low concentration of 1,25-dihydroxyvitamin D(3) caused by a neoplasm. Pathologists should be aware of this entity, because surgical excision of the tumor is usually curative.

Objective: Oncogenic hypophosphatemic osteomalacia (OOM) is a rare disease characterized by hypophosphatemia, inappropriately low levels of circulating 1,25-dihydroxyvitamin D(3) and osteomalacia. The disease is most commonly caused by benign mesenchymal tumors that produce, among several other factors, fibroblast growth factor-23 (FGF-23). Current evidence thus suggests that this protein has an important role in the regulation of phosphate homeostasis. By producing polyclonal antibodies against human FGF-23 protein we wanted to determine the localization of FGF-23 protein in OOM tumors that express FGF-23 mRNA., Design and Methods: Three polyclonal antibodies were raised in rabbits against three different peptides with sequences derived from human FGF-23: [Cys-70]FGF-23(51-69)amide, [Tyr-223]FGF-23(206-222)amide and [Tyr-224]FGF-23(225-244)amide. One of the resulting antisera was subsequently used for immunohistochemistry on sections from five different tumors causing OOM. FGF-23 mRNA expression was confirmed with in situ hybridization., Results: After affinity purification, two of three antisera detected recombinant human FGF-23 by Western blot analysis. Through immunohistochemical analysis using the anti-[Tyr-224]FGF-23(225-244)amide antibody and through in situ hybridization using full-length antisense FGF-23 cRNA as a probe, we showed that abundant amounts of FGF-23 protein and mRNA are present in certain tumor cells of five different OOM tumors., Conclusions: We conclude that OOM tumors express FGF-23 protein and that the immunohistochemical detection of FGF-23 in OOM tumors is feasible and may help in establishing the diagnosis of tumor-induced hypophosphatemia through analysis of biopsies or surgical specimens.