TUMOR-INDUCED OSTEOMALACIA DUE TO PHOSPHATURIC MESENCHYMAL TUMOR, MIXED CELL TYPE, OF THE SPHENOID BONE

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1 Case Report TUMOR-INDUCED OSTEOMALACIA DUE TO PHOSPHATURIC MESENCHYMAL TUMOR, MIXED CELL TYPE, OF THE SPHENOID BONE C.V. Harinarayan, MBBS, MD, DM, FAMS, FRCP, FACE 1 ; Swaroop Gopal, MBBS, MCh 2 ; Chandrashekar Puttaswamygowda, MBBS, MS 3 ; Khalida Parveen Adnan, MBBS, MD 4 ; Nandita Ghosal MBBS, MD 5 ; Shabnam Roohi, MBBS, MD 4 ; Anisha Tandon, MBBS, DMRD, DNB 6 ; Prashant GR, MBBS, DRM 6 ABSTRACT Objective: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by small endocrine tumors that secrete fibroblast growth factor 23 (FGF23), a phosphaturic hormone. Methods: A 44-year-old male was evaluated following complaints of progressive leg pain, difficulty walking, and muscle pain over the previous 9 years. Biochemical evaluation showed low serum phosphorus, high urine phosphorus, and elevated FGF23 levels. These findings were suggestive of TIO. A whole-body (68)Gallium-labeled (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-1-nai(3)-octreotide positron emission tomography computed tomography scan revealed a large vascular lesion in the anterior squamous portion of the right temporal lobe and right greater wing of the sphenoid bone, involving the posterolateral wall of the right orbit. Axial T1-weighted magnetic resonance imaging revealed isointense lesions Submitted for publication September 18, 2015 Accepted for publication November 9, 2015 From the 1 Institute of Endocrinology, Diabetes, Thyroid and Osteoporosis Disorders, 2 Institute of Neurological Sciences, 3 Institute of Orthopedics, 4 Department of Laboratory Medicine, 5 Department of Pathology, Sarka World Hospitals, Bangalore, India, and 6 Department of Nuclear Medicine, Health Care Global Hospitals, Bangalore, India. Address correspondence to Prof. Dr. C.V. Harinarayan, Director, Institute of Endocrinology, Diabetes, Thyroid and Osteoporosis Disorders, Sarka World Hospitals, Sy No 52/2 & 53/3, Deverabeesanahalli (opp Intel, Outer Ring Road), Varathur Hobili, Marathahalli, Bangalore , Karnataka State, India. cvhari5endo@rediffmail.com. DOI: /EP CR To purchase reprints of this article, please visit: Copyright 2016 AACE. containing multiple vascular channels. The histomorphologic feature of the excised tumor was compatible with a phosphaturic mesenchymal tumor, mixed cell type. Serum phosphorus and FGF23 levels normalized after excision of the tumor and resulted in healing of the fractured femur. Results: We report a large vascular lesion in the anterior squamous portion of the right temporal lobe and right greater wing of the sphenoid bone, involving the posterolateral wall of the right orbit as a cause of TIO. Conclusion: TIO is a fascinating paraneoplastic syndrome and is an important cause of adult-onset hypophosphatemia. Localization of tumors in cases of TIO is difficult and a stepwise approach with functional and anatomic imaging is usually successful in 90% of the cases. Excision of the tumor cures this debilitating disease, although recurrence is possible. (AACE Clinical Case Rep. 2016;2:e290-e295) Abbreviations: CT = computed tomography; FGF23 = fibroblast growth factor 23; Ga68-DOTANOC = (68)Galliumlabeled (1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid)-1-nai(3)-octreotide; MRI = magnetic resonance imaging; PET = positron emission tomography; PMTMCT = primitive appearing mixed connective tissue tumors; SSR = somatostatin receptor; TIO = tumor-induced osteomalacia CASE REPORT A 44-year-old male complaining of leg pain and difficulty walking over the previous 9 years had been diagnosed with hypophosphatemia 7 years prior and was prescribed phosphate, vitamin D, and calcium supplements (no medical records available). The patient was no longer receiving therapy when he presented to us at the endo- e290 AACE CLINICAL CASE REPORTS Vol 2 No. 4 Autumn 2016 Copyright 2016 AACE

2 Copyright 2016 AACE Hemangiopericytoma of Sphenoid Bone, AACE Clinical Case Rep. 2016;2(No. 4) e291 crinology outpatient department with complaints of bone pain, muscle weakness, and a limp in gait for re-evaluation of his symptoms. There was no history of smoking, ethanol intake, antiseizure medication, antacid abuse, steroid intake, bisphosphonate intake, or antidiabetic medications. Because of his ailment he had relinquished his job. There was no family history of similar illness. On clinical examination, the patient had kyphoscoliosis with a limp in his gait towards the right, and there were no palpable subcutaneous nodules anywhere in the body. Biochemical examination showed hypophosphatemia (serum phosphorus of 0.8 mg/dl) and abnormal tubular re-absorption of phosphorus (a phosphate excretion index [PEI] of 1.21 [normal, 0.5 to +0.5]) (1). Fibroblast growth factor 23 (FGF23) levels were 44 pg/ml (normal <6.5 pg/ml) (Table 1). Radiologic survey revealed a fracture in the subtrochanteric region of the right femur. Lateral radiograph of the dorsal spine showed multiple wedge compression fractures of the dorsal vertebral bodies with significant loss of vertebral body height and resultant kyphosis (Fig. 1). Computed tomography (CT) bone windows showed an expansile lytic lesion in the right greater wing of the sphenoid bone, with cortical destruction. Axial T1-weighted magnetic resonance imaging (MRI) showed the lesion to be isointense, containing multiple vascular channels. A whole-body (68)Gallium-labeled (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-1-nai(3)-octreotide (Ga68-DOTANOC) positron emission tomography (PET)- CT scan revealed a lesion (standardized uptake value = 14.4) in the anterior squamous portion of the right temporal lobe and right greater wing of the sphenoid bone, involving the posterolateral wall of the right orbit (Fig. 2). Right frontotemporal craniotomy revealed a firm, reddish brown vascular lesion interspersed within the bony trabeculae. The inner table of the calvarium was extremely thin and the lesion was highly vascular, with multiple channels. A biopsy of the lesion was taken and the procedure was abandoned. Later, an angiogram and elective embolization of the lesion was performed prior to excision. Digital subtraction angiogram revealed a vascular calvarial lesion in the region of the right pterion being fed by the branches of the right external carotid artery (middle meningeal artery, internal maxillary artery, and ascending pharyngeal artery). There were large venous channels within the lesion draining into the cavernous sinus region and into the infratemporal venous plexus. There was no blood supply from the internal carotid or vertebral arteries. Larger feeders were successfully cannulated. The tumor was progressively embolized until the vascular blush and flow into the tumor were progressively reduced to satisfactory levels (Fig. 2). Re-exploration craniotomy was performed for complete tumor excision. From the previ- Reference interval Table 1 Biochemical Parameters Before and After Surgery SI GU Pre-operative Units 5 days postsurgery 75 days postsurgery Reference interval Units GU (SI) GU (SI) GU (SI) S Albumin g/l g/dl 4.9 (49) 4.8 (48) 4.3 (43) S Creatinine mmol/l mg/dl 0.62 (54.81) 0.57 (50.39) 0.74 (65.42) S Calcium mmol/l mg/dl 9.3 (2.33) 10.2 (2.55) 10.3 (2.58) S Phosphorus mmol/l mg/dl 0.8 (0.26) 4.2 (1.36) 3.8 (1.23) S ALP IU/L IU/L S 25(OH) Vitamin D nmol/l ng/ml 25 (62.4) 21.9 (54.66) 34.6 (86.36) S PTH (intact) ng/l pg/ml 79.7 (79.7) (122.3) 43.3 (43.3) 24 h U Creatinine 24 h U Phosphate mmol/day 800-2,000 mg/24 h 1,148.8 (101.55) 1,403 (124) 1, (112.77) mmol/day 400-1,300 mg/24 h (21.6) (21.36) (27.14) 24 h U Calcium mmol/day mg/24 h 99.2 (2.48) (3.41) (8.77) PEI to TRP FEp Abbreviations: ALP = alkaline phosphatase; FEp = fractional excretion of phosphorous; GU = gravimetric units; PEI = phosphate excretion index; PTH = parathyroid hormone; S = serum; SI = International System of Units; TRP = tubular re-absorption of phosphate; U = urinary.

3 e292 Hemangiopericytoma of Sphenoid Bone, AACE Clinical Case Rep. 2016;2(No. 4) Copyright 2016 AACE Fig. 1. (A) Lateral radiograph of the dorsal spine showing multiple wedge compression fractures of the dorsal vertebral bodies (arrows) with significant loss of vertebral body height and resultant kyphosis. (B) Anteroposterior (AP) radiograph of the pelvis showing a horizontal fracture of the proximal shaft of the right femur (horizontal arrow). There is significant flattening of the left femoral head (vertical arrow) with sclerotic changes seen in both femoral heads (vertical arrow). (C) Frontal chest radiograph showing significant chest wall deformity due to softening of the ribs and multiple healed rib fractures (vertical arrow). (D) AP radiograph of the right femur at 75 days postsurgery showing a metallic rod and screws bridging the fracture that shows signs of healing. A C E G B D F H Fig. 2. (A) Computed tomography (CT) scan bone window showing an expansile lytic lesion in the greater wing of the right sphenoid bone, with cortical destruction (vertical arrow). (B) Coronal T2W magnetic resonance imaging (MRI) showing the lesion with a very low signal (vertical arrow). (C) Axial T1W MRI showing the lesion to be isointense, containing multiple vascular channels (vertical arrow). (D) Contrast T1W axial MRI showing intense contrast enhancement within the lesion (vertical arrow). (E) Lateral skull digital subtraction angiogram (DSA) image showing tumor blush, supplied by branches of the right middle meningeal artery (vertical arrow). (F) Postembolization lateral skull DSA image showing significant resolution of the blush (vertical arrow). (G) Pre-operative positron emission tomography (PET)-CT showing expansile osteolysis of the anterior squamous portion of the right temporal bone and greater wing of the right sphenoid bone involving the posterolateral wall of the right orbit. A peripheral moth-eaten pattern of osteolysis and centrally enhanced soft tissue component were observed on the CT scan, in addition to avid (68)Gallium-labeled (1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid)-1-nai(3)-octreotide (Ga68-DOTATOC) uptake/somatostatin receptor expression on the PET scan, suggestive of a mesenchymal tumor. Similar lesions were not seen elsewhere in the body. (H) Postoperative image showing right anterior temporal craniotomy with surgical resection of the previously noted expansile osteolytic lesion of the anterior squamous portion of the right temporal bone and right greater wing of the sphenoid bone. No obvious soft tissue lesion or evidence of abnormal Ga68-DOTATOC accumulation was observed in this region.

4 Copyright 2016 AACE Hemangiopericytoma of Sphenoid Bone, AACE Clinical Case Rep. 2016;2(No. 4) e293 ous right frontotemporal skin wound, the tumor was seen below the attachment of the temporalis muscle. The tumor appeared greyish yellow, pale, and relatively avascular compared to its appearance on previous exploration. This relatively avascular tumor was internally decompressed and excised completely. The tumor was soft to firm, relatively avascular with intermixed areas of chunky calcifications or bony islands, and contained areas of hemorrhage and whitish embolized particles within the feeding vessels. The tumor was adherent to the underlying dura from which it was separated with difficulty. Histopathologic examination of the lesion showed fragments of lamellar bone with the focus of the tumor composed of oval to spindle cells with a rich vascular network, occasionally showing a staghorn-like configuration resembling hemangiopericytoma-like areas. In addition, focal collections of osteoclastic giant cells, thickwalled vessels, dilated vascular spaces with hyalinized vessel walls, and fresh hemorrhage were seen. The tumor had infiltrated between the bony trabeculae along with small foci of osseous metaplasia. No whorl formation, mitosis, or necrosis was seen. Reticulin stain showed individual tumor cells wrapped with reticulin. Immunohistochemistry for CD34 showed patchy but strong positivity in tumor cells. Immunostaining was negative for epithelial membrane antigen and S-100 protein, and the MIB-1 labeling index was less than 1%. The histomorphologic features were compatible with a phosphaturic mesenchymal tumor, mixed cell type (Fig. 3). Biochemical re-evaluation at 75 days postsurgery revealed a normalization of serum phosphorus (3.8 mg/dl) and PEI ( 0.16) (Table 1). The FGF23 level on postoperative day 5 was relative units (RU)/mL (reference range, 21.6 to 91.0 RU/mL). The fracture in the right femur was repaired with a cephalomedullary nail, which was followed by normal bone healing and mineralization as indicated by an increase in bone density in subsequent radiographs (Fig. 1). DISCUSSION Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome that presents with hypophosphatemia, myopathy, bone pain, and fractures. TIO, also known as oncogenic osteomalacia, is an acquired form of hypophosphatemia that usually presents in the fourth and fifth decade of life. Both males and females are equally affected by TIO (2). The major symptoms of TIO include weakness, difficulty walking, height loss, pathologic fractures in the ribs, femur, and vertebrae, pseudo fractures of the pubic rami, and pelvic deformities (2). All regions of the body are potentially affected by TIO. TIO is suspected when there is hypophosphatemia with hyperphosphaturia in a nonazotemic adult in the absence of acidosis. In the present patient, the absence of glucose or amino acids in the urine ruled out Fanconi syndrome. Patients with TIO have hyperphosphaturia due to the inhibition of tubular reabsorption of phosphate as a result of increased levels of circulating FGF23 produced by the tumor. The systemic bone demineralization caused by renal phosphate wasting is often due to excessive production of FGF23. FGF23, a phosphatonin responsible for phosphate wasting in TIO (3,4), is a peptide synthesized by the osteocytes which inhibits Na-Pi-II transporters in the intestines and kidneys leading to hyperphosphaturia. FGF23 also directly inhibits 1α-hydroxylase expression and thereby inhibits the activation of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Low levels of 1,25-dihydroxyvitamin D leads to decreased intestinal absorption of phosphate (5,6). In this patient, biochemical FGF23 evaluation confirmed TIO and PET scanning localized the tumor. Excision of the patient s tumor resulted in normalization of phosphaturia and healing of the fractured femur. FGF23-producing mesenchymal tumors are often benign lesions that are usually very small and difficult to identify (7). Because of the small size of these tumors, their localization and diagnosis of TIO can be challenging. In an effort to localize FGF23-producing mesenchymal tumors, various imaging modalities have been employed including bone scanning, MRI, CT, Indium-111 pentetreotide or octreotide scintigraphy, and PET (7,8). Around 40% of these tumors originate from bone and 55% have soft tissue origin. It has been shown that 56% of these tumors are found in the lower extremities and 31% are found in the head (8). Due to their varied locations, functional localizations of these tumors by PET scanning should be preceded by conventional CT or MRI (2). Tumors responsible for TIO are often small and exist within the bone, making them difficult to locate, and various imaging modalities may be required for their detection. Some mesenchymal tumors express somatostatin receptors (SSR), including hemangiopericytomas, which have high levels of SSR expression. Ga68-DOTANOC PET/CT is useful in documenting SSR expression and, hence, is the imaging modality of choice to localize such tumors (9). PET/CT with Ga68-DOTANOC is highly sensitive (90%) and specific (82%) for the detection of neuroendocrine tumors (10). Imaging is successful in 80% of TIO cases (11). Resection of the tumor in cases of TIO leads to curing of the disease, although the tumor can recur locally and occasionally metastasize. In a study by Jiang et al (2), among 39 tumors in cases of TIO, 12 were localized in the head, 8 in the mandible, and 4 in the nasal sinus. To the best of our knowledge, including an extensive search of the literature, a large vascular lesion in the anterior squamous portion of the right temporal lobe and right greater wing of the sphenoid bone involving the posterolateral wall of the right orbit has not been previously reported as a cause of TIO. On histopathologic examination various differential diagnoses were considered, including hemangiopericytoma, aneurysmal bone cyst, meningioma, ossifying fibroma,

5 e294 Hemangiopericytoma of Sphenoid Bone, AACE Clinical Case Rep. 2016;2(No. 4) Copyright 2016 AACE Fig. 3. Paraffin-embedded section of phosphaturic mesenchymal tumor showing (A) ovoid to spindle shaped cells with prominent interspersed vascularity, (B) accentuated CD34 immunostaining, (C) focal area resembling an aneurysmal bone cyst with vascular spaces (curved arrow) showing osteoclastic giant cells (straight arrow) in the wall, and (D) prominent metaplastic bone formation (vertical arrow) (A, C, and D: hematoxylin & eosin [100 ], B: avidin-biotin complex immunoperoxidase method [100 ]). and schwannoma. Under light microscopy there were foci that resembled hemangiopericytoma; however, this possibility was ruled out by the presence of osteoclastic giant cells, osseous metaplasia, and thick walled blood vessels that occasionally contained osteoclastic giant cells within the wall similar to an aneurysmal bone cyst. The absence of whorl formation and immunonegativity for epithelial membrane antigen ruled out meningioma. Similarly, hemangiopericytoma-like areas ruled out the possibility of a pure aneurysmal bone cyst. The absence of Verocay bodies, Antoni A and B areas, and immunonegativity for S-100 protein ruled out a schwannoma. Phosphaturic mesenchymal tumors (PMTs) are classified as four distinct morphologic types: (1) primitive appearing mixed connective tissue tumors (PMTMCTs), (2) osteoblastoma-like tumors, (3) nonossifying fibroma-like tumors, and (4) ossifying fibroma-like tumors (12,13). PMTMCTs typically show hemangiopericytoma-like and aneurysmal bone cyst like areas. Recently, PMTMCTs have been recognized as the major pathologic category of TIO, characterized by a distinctive admixture of spindle cells, microcysts, osteoclast-like giant cells, cartilage-like matrix, prominent blood vessels, and metaplastic bone (2,4,12,13). CONCLUSION In summary, TIO is a fascinating paraneoplastic syndrome and is an important cause of adult-onset hypophosphatemic osteomalacia due to unregulated oversecretion of FGF23. While the localization of the causative tumor in cases of TIO is difficult, a stepwise approach involving functional and anatomic imaging typically results in a successful diagnosis in 90% of cases. Excision of the tumor with wide margins cures this debilitating disease. ACKNOWLEDGMENT We thank ScienceDocs Inc ( com) for language editing. DISCLOSURE The authors have no multiplicity of interest to disclose. REFERENCES 1. Nordin BE, Bulusu L. A modified index of phosphate excretion. Postgrad Med J. 1968;44: Jiang Y, Xia WB, Xing XP, et al. Tumor-induced osteomalacia: an important cause of adult-onset hypophosphatemic osteomalacia in China: Report of 39 cases and review of the literature. J Bone Miner Res. 2012;27: White KE, Jonsson KB, Carn G, et al. The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting. J Clin Endocrinol Metab. 2001;86: Farrow EG, White KE. Tumor-induced osteomalacia. Expert Rev Endocrinol Metab. 2009;4:

6 Copyright 2016 AACE Hemangiopericytoma of Sphenoid Bone, AACE Clinical Case Rep. 2016;2(No. 4) e Bergwitz C, Jüppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med. 2010;61: Mount, D, Yu, A. Phosphate transport. In: Brenner B, ed. Brenner & Rector s The Kidney. 8th ed. Philadelphia, PA: Saunders Elsevier; 2008: Whyte MP, Liberman UA. Rickets and osteomalacia (acquired and heritable forms) and skeletal dysplasias. In: Wass JAH, Stewart PM, eds. Oxford Textbook of Endocrinology and Diabetes. 2nd ed. New York, NY: Oxford University Press; 2011: De Beur SM, Finnegan RB, Vassiliadis J, et al. Tumors associated with oncogenic osteomalacia express genes important in bone and mineral metabolism. J Bone Miner Res. 2002;17: Rodrigues NR, Calich AL, Etchebehere M, et al. Wholebody (99m)Tc-octreotide scintigraphy with SPECT/CT to detect occult tumor inducing paraneoplastic osteomalacia. Clin Nucl Med. 2015;40: Arnold R, Chen YJ, Costa F, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: follow-up and documentation. Neuroendocrinology. 2009;90: Bhavani N, Reena Asirvatham A, Kallur K, et al. Utility of Gallium-68 DOTANOC PET/CT in the localization of Tumour-induced osteomalacia. Clin Endocrinol (Oxf). 2016;84: Weidner N, Bar RS, Weiss D, Strottmann MP. Neoplastic pathology of oncogenic osteomalacia/rickets. Cancer. 1985;55: Weidner N, Santa Cruz D. Phosphaturic mesenchymal tumors. A polymorphous group causing osteomalacia or rickets. Cancer. 1987;59: