Tumour induced osteomalacia
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Tumour induced osteomalacia

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Tumour induced osteomalacia and Phosphatonin (FGF23) having a role in resection of mesenchymal tumor.

Tumour induced osteomalacia and Phosphatonin (FGF23) having a role in resection of mesenchymal tumor.

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  • FGF23, a phosphatonin, is the most important player that is implicated in the pathogenesis of most of the disorders with hypophosphatemic rickets/osteomalacia. It binds to FGF receptor 1c (FGFR1c) on cell membranes. Klotho is another important protein in the phosphate homeostasis. Interaction of Klotho with the FGFR1c converts it into a receptor specific for FGF23 function.Decrease in the serum phosphorus level decreases FGF23 and PTH levels, while 1,25(OH)2D level is increased. Increase in serum phosphorus leads to opposite changes. Calcitriol [1,25(OH)2D] increases serum phosphorus and FGF23, while it decreases PTH. Increase in FGF23 leads to decrease in PTH and calcitriol levels. PTH increases calcitriol and FGF23 levels

Tumour induced osteomalacia Tumour induced osteomalacia Presentation Transcript

  • Dr.Mohan T Shenoy DM Resident in Endocrinology AIMS-Kochi 24.10.2013 1
  • • Rare and fascinating paraneoplastic syndrome • Paraneoplastic syndromes refer to the disorders that accompany benign or malignant tumors but are not directly related to mass effects or invasion by the primary tumor or its metastases. • Abnormal phosphate and vitamin D metabolism • Caused by typically small endocrine tumors that secrete the phosphaturic hormone, fibroblast growth factor 23 2
  • • TIO is counted among the ranks of endocrine neoplasms that have a striking presentation and, when resected, a dramatic and satisfying resolution. • Seen in association with other diseases such as prostate cancer, oat cell cancer, hematologic malignancies, neurofibromatosis, epidermal nevus syndrome, and polyostotic fibrous dysplasia of bone 3
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  • Phosphate homeostasis • Role in intracellular signaling, membrane function, energy metabolism, and bone mineralization • absorbed in the duodenum and jejunum • stored in the skeleton • phosphate reabsorption takes place in the proximal renal tubule 5
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  • Fibroblast growth factor 23 • The most extensively studied phosphatonin is FGF-23, a 251amino acid secreted protein with a halflife of ~45 min and disappears rapidly from the circulation. • Recombinant FGF-23 administered intraperitoneally to mice or rats induces phosphaturia and inhibits 25-OH vitamin D 1hydroxylase activity. • Secretion is still being defined, but probably serum phosphorus acts by binding to target cells via an FGF receptor (probably FGFR1) on the basal cell surface of proximal tubule cells. 8
  • Fibroblast growth factor 23 • Predominantly expressed in osteocytes in the bone and endothelial cells of bone marrow and thymus • There is evidence that the phosphaturic action is to some extent PTH-dependent. • Gupta et al. (2004) found that both FGF23 and serum phosphorus were high in the blood of patients with hypoparathyroidism, indicating that in the absence of PTH, FGF23 was unable to adequately lower blood phosphorus level. This led to the notion that medically induced hypoparathyroidism may be a potential treatment for TIO 9
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  • Differential diagnosis of hypophosphatemia 13
  • Mechanisms of FGF-23 Excess in Renal PhosphateWasting Syndromes Jan de Beur, S. M. JAMA 2005;294:1260-1267. 14
  • Proposed pathogenesis of renal phosphate wasting Strewler G J PNAS 2001;98:5945-5946 ©2001 by National Academy of Sciences 15
  • Clinical presentation • frequently present with multiple fractures, height loss, and generalized debilitated status. • Pain, weakness, gait abnormalities, and low phosphorus levels. • muscle weakness, and multiple bone pain • Pediatric patients can develop rickets and growth retardation 16
  • • Biochemical hallmarks of the disorder : – hypophosphatemia due to Renal phosphate wasting – inappropriately normal or low 1,25-OH vitamin D, – elevated or inappropriately normal plasma FGF23. 17
  • Clinical evaluation 18
  • Urinary phosphate wasting • Two ways – Percent tubular reabsorption of phosphate (%TRP) – tubular maximum for phosphate corrected for glomerular filtration rate (TmP/GFR) {by using normograms} TmP/GFR can be calculated only in the fasting state, typically from second morning-void 19 urine and blood samples taken at the same time. and is independent of plasma
  • • Bidjovet’s normogram for calculation of TMP GFR ; • mg/dl is on left of each axis and mmol/l is on right of each axis 20
  • • The formula used to calculate TmP/GFR is dependent on the value of TRP and can be calculated using the formulas below: • If %TRP≤ 0:86; TmP/GFR=TRP phosphate • If > 0:86; 0.3 TRP(1-0.8 TRP) phosphate 21
  • Radiological Diagnosis Imaging studies for detecting/localizing neoplasms associated with tumor-induced osteomalacia Plain films CT MRI F-18 FDG PET-CT Indium 111-pentetreotide scintigraphy Technetium-99m PET 22
  • Diagnosis confirmation • Localizing studies: functional imaging – FDG-PET/CT, – Octreotide scintigraphy, – 68Ga-DOTANOC PET/CT • Localizing studies: anatomical imaging – CXR, – CT, – MRI • Venous sampling 23
  • Diagnosis Genitourinary-associated tracer Tumor 24
  • Venous Sampling 25
  • Treatment • Surgical resection • Medical treatment -phosphate and calcitriol supplementation 26
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  • • A new treatment approach that holds promise, but needs additional study for confirmation of efficacy and establishment of safety, is cinacalcet, an agonist of the calcium-sensing receptor that lowers blood PTH levels. • The use of cinacalcet was advocated on the basis of evidence that FGF23 action was PTH-dependent. • However, Urinary calcium must be monitored carefully to avoid nephrocalcinosis and/or nephrolithiasis. • Sometimes necessitating the addition of a thiazide diuretic 29
  • Histopathology • nuclear grade is low, and mitotic activity is usually absent or very low. • The cells are typically embedded within a myxoid or myxochondroid matrix with ‘grungy’ calcification • hemangiopericytoma, sarcomas, ossifying fibromas, granulomas, giant cell tumors, and osteoblastomas 30
  • Histology Phosphaturic mesenchymal tumor, low magnification. Prominent fragments of eosinophilic calcification/dystrophic bone formation surrounded by microcystic spaces, variably sized thin walled vessels, and moderately cellular mesenchymal 31 component (H and E, x40)
  • • PMTMCT are a group of tumors with a spectrum of histopathologic findings that include a background of spindle/stellate cells with low nuclear and mitotic activity. This is true even in cases of metastatic disease. • Prominent vascularity is common and includes vessels of different sizes and patterns, consistent with the fact that they are most commonly classified as hemangiopericytomas. •Osteoclast-like giant cells are frequently seen in these tumors and mature fat or lamellar bone can be present as well. •FGF23 staining is positive and appears in the cytoplasm of the tumor cells. 32
  • Phosphaturic mesenchymal tumor. Syncytial mesenchymal component composed of bland oval and spindle shaped stromal 33 cells situated around variably sized microcystic spaces, thin walled blood vessels, and eosinophilic dystrophic calcified debris
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  • SUMMARY • TIO is a debilitating disease that is cured with excision of tumor. • The benign-appearing histopathology typically seen in these tumors can be misleading, as even clinically proven metastatic disease can have benign cellular features. • Excision with wide margins important to avoid late recurrence. • When tumors cannot be identified, medical treatment can be successful though periodic surveillance is necessary. 35
  • THANK YOU 36