Phosphaturic Mesenchymal Tumor, Mixed Connective Tissue Variant Research Articles

PHOSPHATURIC MESENCHYMAL TUMOR IN THE MANDIBLE WITH ASSOCIATED ONCOGENIC OSTEOMALACIA: A CASE REPORT

Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm that has been associated with oncogenic osteomalacia. This tumor secretes fibroblast growth factor-23 (FGF-23). Although other mesenchymal tumors can cause oncogenic osteomalacia, PMT is the most common mesenchymal neoplasm associated with oncogenic osteomalacia and accounts for 80% of such cases. Most patients are adults and the tumor can affect both men and women. The most common location for the tumor is the lower extremities followed by the head and neck area. Patients typically present with diffuse bone pain, bone fractures, and progressive muscle weakness. The laboratory studies usually reveal increased levels of FGF-23, hyperphosphaturia, increased alkaline phosphatase, normal serum calcium and parathyroid hormone levels, normal to low levels of 1,25-dihydroxyvitamin D and hypophosphatemia. The four common phosphaturic mesenchymal tumor microscopic subtypes are: phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT), osteoblastoma-like variant, ossifying fibroma-like variant, and non-ossifying fibroma-like variant. The small size of this slow growing tumor and the non-specific clinical presentation may present a diagnostic challenge to clinicians. We present a case of a 48-year-old Haitian male who was diagnosed with PMT in the right angle of the mandible. Fewer than 15 cases of PMT presenting in the oral cavity have been reported in the literature. The clinical presentation, the laboratory findings, imaging characteristics, and the histopathologic features for this case are discussed along with the molecular genetic aspects, treatment and prognosis for this rare neoplasm.

Phosphaturic Mesenchymal Heel Tumor Presenting with Tumor-Induced Osteomalacia

To help clinicians identify and treat patients with tumor-induced osteomalacia (TIO) resulting from a phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT). Describe the history, presentation, laboratory findings, diagnostic studies, treatment, and literature review. A 58-year-old female with no significant past medical history presents with ongoing multiple bone pain for years. She had a bone scan showing multiple focal areas of increased uptake involving bilateral ribs, distal right tibia, and left femoral neck, representing previously healed fractures. Her bilateral lower-extremity magnetic resonance imaging showed stress fractures of the anteromedial cortex, right tibia, and the left femoral neck. Phosphorus was noted to be 1.9 mg/dL (normal range, 2.0 to 4.0 mg/dL), and alkaline phosphatase was 179 U/L (normal range, 25 to 110 U/L). Tubular maximum re-absorption of phosphate to glomerular filtration rate ratio was 0.438, which was low. An outside physician initiated patient on teriparatide, which showed bone mineral density improvement after 1 year, and then the teriparatide was stopped. Later, she developed a nontraumatic pubic ramus fracture; teriparatide was resumed. While on teriparatide, she developed several new rib fractures. Due to declining phosphorus levels, further investigation led to an elevated fibroblast growth factor 23 (FGF-23) level of 243 RU/mL (normal, <50 RU/mL). TIO was strongly suspected, and a nuclear medicine positron emission tomography/computed tomography trunk with 68Ga-1,4,7,10-tetraazacyclododecane 1,4,7,10-tetraacetic acid tyrosine-3-octreotate (i.e., 68Ga-DOTATATE) showed a right heel soft-tissue nodule. Fine-needle aspiration biopsy was performed, confirming PMTMCT, positive for FGF-23 mRNA. After surgery, her symptoms resolved and her phosphorus normalized. TIO is a rare paraneoplastic syndrome characterized by bone pain, muscle weakness, and fractures associated with persistent hypophosphatemia. Clinicians now have new imaging tools to help identify and treat patients with PMTMCT.

Ectopic expression of Klotho in fibroblast growth factor 23 (FGF23)-producing tumors that cause tumor-induced rickets/osteomalacia (TIO)

Tumor-induced rickets/osteomalacia (TIO) is a rare paraneoplastic syndrome caused by tumors that ectopically express fibroblast growth factor 23 (FGF23). FGF23 is a bone-derived hormone that regulates serum phosphate concentrations. Patients with TIO develop hypophosphatemic rickets/osteomalacia due to FGF23 excess and suffer from symptoms such as leg deformities, bone pain, skeletal muscle myopathy, and multiple fractures/pseudofractures. Usually, successful surgical removal of the causative tumors normalizes serum FGF23 and phosphate concentrations in patients with TIO. Most FGF23-producing tumors associated with TIO are histologically called phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT). The precise mechanism by which these tumors ectopically overproduce FGF23 outside of bone is yet to be clarified. Therefore, we performed an RNA sequencing analysis of a PMTMCT that was found in the left parotid gland of a patient with TIO. Among the upregulated genes, we focused on Klotho, the protein product of which is a single pass transmembrane protein that works along with an FGF receptor 1c as a receptor complex for FGF23. Subsequent histological analysis confirmed the ectopic expression of Klotho in other PMTMCTs. From these results, we assume that the ectopic expression of Klotho in PTMMCTs enables a positive feedback loop in FGF23 production via the activation of FGF receptor 1c and exacerbates disease manifestations in TIO.

Tumor-Induced Osteomalacia: Increased Level of FGF-23 in a Patient with a Phosphaturic Mesenchymal Tumor at the Tibia Expressing Periostin.

In our case, a 45-year-old male patient had multiple fractures accompanied by hypophosphatemia. FGF-23 levels were significantly increased, and total body magnetic resonance imaging (MRI) revealed a tumor mass located at the distal tibia leading to the diagnosis of tumor-induced osteomalacia (TIO). After resection of the tumor, hypophosphatemia and the increased levels of FGF-23 normalized within a few days. Subsequent microscopic examination and immunohistochemical analysis revealed a phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT) showing a positive expression of somatostatin receptor 2A (SSTR2A), CD68, and Periostin. Electron microscopy demonstrated a poorly differentiated mesenchymal tumor with a multifocal giant cell component and evidence of neurosecretory-granules. However, the resected margins showed no tumor-free tissue, and therefore a subsequent postoperative radiotherapy was performed. The patient is still in complete remission after 34 months. Tumor resection of PMTMCTs is the therapy of choice. Subsequent radiotherapy in case of incompletely resected tumors can be an important option to avoid recurrence or metastasis even though this occurs rarely. The prognostic value of expression of Periostin has to be evaluated more precisely in a larger series of patients with TIO.

Mandibular Phosphaturic Mesenchymal Tumor–Mixed Connective Tissue Variant in a Young Girl

Phosphaturic mesenchymal tumor-mixed connective tissue variant (PMTMCT) is an extremely rare tumor associated with tumor-induced osteomalacia. The majority occur in middle age and arise from the extremities. This report describes a young girl with PMTMCT arising in the mandible and with no evidence of paraneoplastic syndrome.

Intracranial phosphaturic mesenchymal tumors

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.

Intracranial phosphaturic mesenchymal tumor, mixed connective tissue variant presenting without oncogenic osteomalacia

Background:Phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT) is a rare tumor typically occurring in soft tissues and bone, causing oncogenic (tumor-induced) osteomalacia (TIO) through secretion of the phosphaturic hormone, fibroblast growth factor-23 (FGF-23). Rare tumors identical to PMTMCT occur without known TIO. Intracranial localization of PMTMCT is extremely rare, with only two cases reported in the literature. We present a very unusual case of a patient with an intracranial PMTMCT that presented with neurologic changes without osteomalacia.Case Description:A 67-year-old woman presented with progressive incontinence, apathy, and abulia after having undergone a total knee replacement 1 month earlier. Imaging disclosed a large left frontal anterior fossa mass. She underwent uncomplicated surgical resection of this tumor. Surprisingly, histopathology suggested PMTMCT. Reverse transcription polymerase chain reaction (RT-PCR) assay demonstrating FGF-23 expression in the tumor confirmed the diagnosis. Serum FGF-23 levels postoperatively were normal and she had no clinical or laboratory evidence of osteomalacia or phosphaturia.Conclusion:This report should serve to alert clinicians to the possibility that PMTMCT can be included in the differential diagnosis of intracranial masses even in the absence of tumor-induced osteomalacia.

Tumor-Induced Osteomalacia Caused by Primary Fibroblast Growth Factor 23 Secreting Neoplasm in Axial Skeleton: A Case Report

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.

A 61‐YEAR‐OLD WOMAN WITH OSTEOMALACIA AND A THORACIC SPINE LESION

Phosphaturic mesenchymal tumor, mixed connective tissue variant (PMT-MCT) is a rare, largely benign, mesenchymal neoplasm almost invariably associated with oncogenic osteomalacia. It is generally found in the soft tissue and bone of the extremities. We report a case of a 61-year-old female with long-standing osteomalacia who was found to have PMT-MCT of the thoracic spine. There have been very few previously reported cases of PMT involving the spinal vertebrae and neuropathologists should be aware of this lesion. Recognition of PMT-MCT is critical for optimal patient care since complete surgical resection without additional therapy is curative.

Phosphaturic mesenchymal tumor, mixed connective tissue variant, of the mandible: report of a case and review of the literature

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 Tumor with Symptoms Related to Osteomalacia that Appeared One Year after Tumorectomy

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.

Tumeur du pied et douleurs diffuses : un cas d’ostéomalacie oncogénique

Oncogenic osteomalacia is a rare clinicopathologic entity, linked to a mesenchymal tumor which overexpresses a hypophosphatemic factor, supposed to be the FGF-23. To date, about 100 cases have been published. We report the case of a 40-year-old man who presented an osteomalacic syndrome with no classical etiological diagnosis. The discovery of a subcutaneous tumor of the right foot and a high serum level of FGF-23 suggested the diagnosis of oncogenic osteomalacia. Surgical removal of the tumor resulted in complete reversal of the clinical and biochemical defects. Pathologic examination revealed spindle cells associated with osteoclast-like giant cells, embedded within a myxoid matrix which showed floculent calcification. These observations were compatible with the features of PMTMCT (Phosphaturic mesenchymal tumor mixed connective tissue variant).