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Tumour induced osteomalacia and Phosphatonin (FGF23) having a role in resection of mesenchymal tumor.
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124.10.2013
Dr.Mohan T Shenoy
DM Resident in Endocrinology
AIMS-Kochi
2
• 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
3
• 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
4
5
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
6
7
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Fibroblast growth factor 23
• The most extensively studied phosphatonin is FGF-23, a 251-
amino 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 1-
hydroxylase 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.
9
• 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
Fibroblast growth factor 23
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Differential diagnosis of
hypophosphatemia
14Jan de Beur, S. M. JAMA 2005;294:1260-1267.
Mechanisms of FGF-23 Excess in Renal Phosphate-Wasting Syndromes
15
Proposed pathogenesis of renal phosphate wasting
Strewler G J PNAS 2001;98:5945-5946
©2001 by National Academy of Sciences
16
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
17
• 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.
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Clinical evaluation
19
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
urine and blood samples taken at the same time. and is independent of plasma
phosphate and renal function.
20
• 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
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• 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
22
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
23
Diagnosis confirmation
• Localizing studies: functional imaging
– FDG-PET/CT,
– Octreotide scintigraphy,
– 68Ga-DOTANOC PET/CT
• Localizing studies: anatomical imaging
– CXR,
– CT,
– MRI
• Venous sampling
24
Diagnosis
Genitourinary-associated
tracer
Tumor
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Venous
Sampling
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Treatment
• Surgical resection
• Medical treatment
-phosphate and calcitriol supplementation
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28
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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
30
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
31
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 mesenchymalcomponent (H and E, x40)
32
• 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.
33Phosphaturic mesenchymal tumor. Syncytial mesenchymal component composed of bland oval and spindle shaped stromalcells situated around variably sized microcystic spaces, thin walled blood vessels, and eosinophilic dystrophic calcified debris (H and E, x100)
34
35
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.
36
THANK YOU