Phosphaturic mesenchymal tumors show positive staining for somatostatin receptor 2A (SSTR2A)
Departement de Biopathologie, Centre Leon Berard, 69373 Lyon France. Electronic address: . Human pathology
(Impact Factor: 2.77).
09/2013; 44(12). DOI: 10.1016/j.humpath.2013.07.016
Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome associated with tumors that secrete phosphaturic hormones, most notably fibroblast growth factor 23 (FGF23). The majority of tumors associated with this syndrome show stereotypical histological features and are now known as phosphaturic mesenchymal tumors (PMTs). We postulated that immunohistochemistry for somatostatin receptor 2A (SSTR2A) could be used to definitively identify PMTs or other tumors that cause TIO. Immunohistochemistry for FGF23 and SSTR2A was performed on 15 tumors from 14 patients with a definite diagnosis of TIO. All showed positive staining for both markers. While FGF23 staining was quite focal in some tumors, SSTR2A showed diffuse strong expression. In 40 control tumors not known to be associated with the clinical or biochemical features of TIO, FGF23 expression was found in 2 cases (one aneurysmal bone cyst and one osteosarcoma). SSTR2A expression was found in 9 control tumors (4 synovial sarcomas, 2 hemangiomas, 2 aneurysmal bone cysts and one osteosarcoma). Only one tumor (an aneurysmal bone cyst) showed positive staining for both FGF23 and SSTR2A. SSTR2A also commonly stained neoplastic and non-neoplastic endothelial cells. We conclude that neither FGF23 nor SSTR2A expression are specific for the diagnosis of PMT. However both stains are highly sensitive. Because of its diffuse strong expression and widespread availability, immunohistochemistry for SSTR2A is useful to confirm the diagnosis of PMT in an appropriate setting particularly if material is limited. Negative staining can serve as an excellent rule out test for this diagnosis.
Available from: Anke Hautmann
- "They concluded that a positive staining for both markers is highly sensitive to PMTs, but not specific. A negative staining can serve as an excellent rule-out test for this diagnosis . In our case, the immunohistochemical staining for SSTR2A, CD 68, and Periostin was positive (Figures 2(c)–2(e)); the staining for FGF-23 could not be established. "
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ABSTRACT: 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.1. IntroductionTumor-induced osteomalacia (TIO) is a rare, acquired paraneoplastic disorder characterized by a renal phosphate leak leading to hypophosphatemia and deranged bone turnover. The typical biochemical pattern of TIO includes normal circulating levels of calcium and parathormone (PTH), normal or low levels of 1.25-dihydroxyvitamin D (1.25-(OH)2D), and elevated levels of alkaline phosphatase [1–6]. The renal phosphate leak manifests itself in hypophosphatemia. Typically, patients with TIO complain of progressive musculoskeletal pain and muscle weakness. During the diagnostic procedure fractures in various localizations are found frequently. The cause of TIO are usually small, slowly growing tumors of mesenchymal origin (phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT) [5, 7–10].In TIO most tumors overexpress the protein fibroblast growth factor-23 (FGF-23) inhibiting renal phosphate reabsorption in the proximal tubules and acting as a phosphaturic factor [1, 3, 11]. In these cases, FGFR-23 levels are increased and immunohistochemical analysis of the tumor is positive [1, 3, 11]. The primary transport protein responsible for phosphate reabsorption in the kidney is the type II sodium-phosphate cotransporter (NPT2a) localized in the proximal tubule. High circulating FGF-23 levels produce renal phosphate wasting through the downregulation of NPT2a [2, 3, 9]. Matrix extracellular phosphoglycoprotein (MEPE)  and frizzled related protein-4 (FRP-4) have emerged as candidate mediators of the bone-renal pathophysiology as well but are rarely described in literature, so far [11, 12].Diagnosis of TIO is often extremely difficult since tumors can be too small for detection by conventional radiological methods. High-resolution magnetic resonance imaging (MRI) of the whole body is the currently proposed method of choice to confirm the location of the tumor. F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) is a very sensitive method [9, 10, 13] but also nonspecific. Mesenchymal tumors often express somatostatin receptors ; therefore, octreotide scintigraphy is another functional imaging modality. In recent literature, Gallium Dotatate PET has emerged as a virtually ideal investigation to localize tumors causing TIO as well and performed better than F-FDG PET/CT in some studies and seems to be a promising diagnostic tool in patients in whom 111In-octreotide SPECT/CT prior failed to detect a tumor [15, 16]. Further studies with larger patient population are warranted to validate the data.In rare cases, a venous sampling of FGF-23 is necessary to detect the tumor [9, 17]. For tumors that cannot be located, medical treatment with phosphate supplements and active vitamin D (calcitriol or alpha calcitriol) is a therapeutic option .If the responsible neoplasm is surgically removed, the abnormalities in phosphate wasting and in vitamin D metabolism typically dissolve in a few days.2. Materials and Methods
The described patient has given written consent for publication of the data and the photographs of the histopathology of the tumor. The following antibodies were used for the immunohistochemical analysis performed at the Institute for Surgical Pathology in Zurich: somatostatin receptor 2A (SSTR2A), polyclonal antibody, dilution 1 : 100, Zytomed Systems; OSF-2/Periostin, monoclonal antibody, dilution 1 : 1000, R&D Systems; CD 68, monoclonal antibody, dilution 1 : 50, DAKO A/S. Human FGF-23 c-terminal was measured in the laboratories of Synlab Weiden, Germany. An ELISA kit of the Company, Immutopics, Inc., was used.3. Case ReportA 45-year-old man was admitted to our tertiary Rheumatology center due to acute aggravation of systemic bone pain. The symptoms (pain predominantly in knees, heels, and costosternal joints) worsened gradually during the last weeks but had developed one year previously. The patient had a medical history of hypertension and denied any family history of metabolic bone disease.Upon physical examination (weight: 96 kg, height: 173 cm, and BMI: 32 kg/m2), only painful knees and heels without swelling were conspicuous. Laboratory data are shown in Table 1. A 24-hour urine sample revealed an increased phosphate clearance of 44.7 mL/min (normal range: 5–16 mL/min). Fractional excretion of phosphate was increased with 19.2% (normal range: <5% in the setting of hypophosphatemia). Radiological images revealed beginning degenerative signs. A 700 MBq technetium-Teceos bone scan demonstrated increased uptake in the proximal right tibia and fibula, the right calcaneus, the ventral ribs, and both femoral necks. An MRI of the right knee and right calcaneus showed several months old fracture of the proximal tibia and a capillary fracture of the calcaneus.
Available from: Frank Timo Beil
- "Tumors in TIO are known to express somatostatin receptors (SSTR); in particular, SSTR2/2A has been found to be the predominant subtype in TIO causing tumors   . Thus, recent studies reported improved tumor localization in patients with TIO by using somatostatin receptor imaging methods such as 111 Indium-octreotide scintigraphy ( "
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ABSTRACT: Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome characterized by renal phosphate wasting, hypophosphatemia and low calcitriol levels as well as clinical symptoms like diffuse bone and muscle pain, fatigue fractures or increased fracture risk. Conventional imaging methods, however, often fail to detect the small tumors. Lately, tumor localization clearly improved by somatostatin-receptor (SSTR) imaging, such as octreotide scintigraphy or octreotide SPECT/CT. However, recent studies revealed that still a large number of tumors remained undetected by octreotide imaging. Hence, studies focused on different SSTR imaging methods such as 68Ga DOTA-NOC, 68Ga DOTA-TOC and 68Ga DOTA-TATE PET/CT with promising first results. Studies comparing different SSTR imaging methods for tumor localization in TIO are rare and thus little is known about diagnostic alternatives once a particular method failed to detect a tumor in patients with TIO.
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