Auris Nasus Larynx 42 (2015) 167–169
Contents lists available at ScienceDirect
Auris Nasus Larynx journal homepage: www.elsevier.com/locate/anl
Oncogenic osteomalacia caused by an occult paranasal sinus tumor Tomofumi Okamiya a,*, Katsumasa Takahashi a, Hideo Kamada b, Junko Hirato c, Toru Motoi d, Seiji Fukumoto e, Kazuaki Chikamatsu a a
Department of Otorhinolaryngology – Head and Neck Surgery, Gunma University, Japan Gunma Medical Career Center, Gunma University Hospital, Japan c Department of Pathology, Gunma University Hospital, Japan d Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Japan e Division of Nephrology and Endocrinology, Department of Medicine, University of Tokyo Hospital, Japan b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 2 March 2014 Accepted 2 October 2014 Available online 11 February 2015
Oncogenic osteomalacia (OOM) is a rare bone disease characterized by inadequate bone mineralization and is caused by a humoral factor mainly produced by benign mesenchymal tumors. We report a case of OOM caused by an occult phosphaturic mesenchymal tumor in the paranasal sinus. The causative tumor was small and localized in the ethmoid sinus, and the patient did not exhibit any nasal symptoms. 18Ffluorodeoxyglucose positron emission tomography (FDG-PET) depicted the location of the occult tumor, and systemic venous sampling followed by assessments of the samples’ fibroblast growth factor 23 (FGF23) concentrations confirmed that the tumor secreted FGF23. The tumor was resected via an external surgical approach, resulting in the complete relief of the patient’s symptoms. The combination of FDG-PET and systemic venous sampling to assess serum FGF23 levels is useful for identifying small asymptomatic OOM-associated tumors. Such tumors are rare, but a significant proportion of them develop in the head and neck region, and complete resection is the most effective treatment. It is important that ENT surgeons are aware of the characteristics of OOM. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Oncogenic osteomalacia FDG-PET Systemic venous sampling FGF23
1. Introduction Oncogenic osteomalacia (OOM), which is also known as tumorinduced osteomalacia, is a rare bone disease characterized by inadequate bone mineralization and is caused by a humoral factor usually produced by benign mesenchymal tumors located in soft tissue or bone [1]. Its symptoms include muscle weakness, bone pain, and multiple fractures. Although surgical removal of the causative tumor results in rapid resolution of all painful symptoms, the diagnosis of OOM is often delayed by years because it can be hard to detect the primary tumor [2]. Recently, it has been demonstrated that OOM-associated tumors overexpress fibroblast growth factor 23 (FGF23), which inhibits renal phosphate reabsorption [3]. Thus, high serum FGF23 levels are useful for diagnosing OOM.
* Corresponding author at: Department of Otorhinolaryngology – Head and Neck Surgery, Gunma University, 3-39-22 Showa, Maebashi, Gunma 371-8511, Japan. Tel.: +81 27 220 8358; fax: +81 27 220 8369. E-mail address: [email protected] (T. Okamiya). http://dx.doi.org/10.1016/j.anl.2014.10.001 0385-8146/ß 2014 Elsevier Ireland Ltd. All rights reserved.
We report a case of OOM caused by an occult paranasal sinus tumor and suggest that the combination of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and systemic venous sampling to assess serum FGF23 concentrations is valuable for detecting OOM-associated tumors. 2. Case report A 35-year-old woman was referred to our hospital with an 8month history of lower back pain and gait disturbance. X-ray radiography and whole-body bone scintigraphy depicted multiple fractures of the ulna, ribs, and the ends of the limbs although the patient did not have a history of any other disease nor did she have a family history of bone disease. As for the patient’s laboratory findings, her blood count and liver and kidney functions were all normal; her blood chemistry findings revealed high serum alkaline phosphatase (ALP) levels and low serum phosphate levels, but showed normal serum calcium levels. The patient’s serum 1,25dihydroxyvitamin D [1,25(OH)2D] and intact parathyroid hormone (iPTH) levels were normal, but her maximum rate of tubular phosphate reabsorption to the glomerular filtration rate ratio (TmP/GFR), which is a measure of phosphate reabsorption in the
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proximal renal tubules, was low (1.4 mg/dl; reference range, 2.1–4.3 mg/dl). Accordingly, osteomalacia caused by phosphate wasting in the renal tubules was strongly suspected. The patient also exhibited high serum FGF23 levels (Table 1), which suggested that a hidden tumor was secreting FGF23. Whole-body FDG-PET was carried out, which detected homogeneous radiotracer uptake by a lesion in the left anterior ethmoid sinus (Fig. 1A). In addition, the tumor exhibited a standardized uptake value (SUV) of 7.3, which falls within the range of values exhibited by malignant tumors. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a well-circumscribed hypervascular tumor located in the left anterior ethmoid sinus (Fig. 1B–D). It was considered that the tumor was probably secreting FGF23; therefore, angiography-assisted systemic venous sampling was performed followed by assessments of the samples’ FGF23 concentrations. A total of 18 blood samples, which were obtained from the bilateral subclavian veins, internal jugular veins, brachiocephalic veins, venae cavae, iliac veins, and the femoral veins, were collected through a catheter inserted via the femoral vein. Examinations of the blood samples revealed that the sample collected from the left brachiocephalic vein displayed the highest concentration of FGF23 (285 pg/ml; other veins: 173–257 pg/ml). The fact that the highest FGF23 concentration was detected in the left head and neck region agreed with the detection of a lesion with a high SUV value in the left ethmoid sinus on FDG-PET; therefore, it was concluded that the tumor in the left ethmoid sinus was secreting FGF23 and was responsible for the patient’s OOM. The patient was referred to the Department of Otorhinolaryngology to undergo an excisional biopsy in order to obtain a final pathological diagnosis. However, the clinicians found it difficult to assess the tumor during a nasal endoscopic examination
Table 1 Changes in the patient’s laboratory data before and after surgery. Parameters (reference range)
Pre-ope.
Post-ope.
ALP (115–359 IU/L) P (2.5–4.1 mg/dl) Ca (8.9–10.5 mg/dl) iPTH (15–65 pg/ml) 1,25(OH)2D (20–60 pg/ml) FGF23 (14–40 pg/ml)
738 1.4 9.5 37.4 21 147
244 3.0 9.8 56.6 77 16
Fig. 1. Images of the tumor. (A) FDG-PET detected a tumor in the left anterior ethmoid sinus (arrow). The tumor’s standardized uptake value (SUV) was 7.3, which falls within the range of values exhibited by malignant tumors. (B) A Gd-enhanced MRI scan showed a strongly enhanced hypervascular tumor. The tumor had not invaded the brain. (C and D) Sagittal and coronal contrast-enhanced CT images showed that the tumor was attached to the base of the skull and lamina papyracea, but no bony destruction was observed.
performed via the nostril, so a biopsy involving the removal of the ethmoidal bulla was carried out under general anesthesia. A histopathological examination revealed that the tumor was composed of round, fusiform, and spindle-shaped cells and was fed by delicate capillaries (Fig. 2A). Calcification, fibrosis, and hemorrhaging were observed in the tumor matrix. An immunohistochemical examination demonstrated that the tumor cells expressed FGF23 (Fig. 2B). They were also focally positive for a-smooth muscle actin, but negative for desmin, S-100 protein, keratin, and CD34 (data not shown). The pathological diagnosis was phosphaturic mesenchymal tumor, mixed connective tissue variant [4]. After the final diagnosis of OOM had been made, we attempted a complete resection via an external surgical approach. After removing the anterior wall of the frontal sinus and the frontal process of maxilla, it became possible to view the whole of the tumor, which was a reddish vascular tumor located in the anterior ethmoid sinus and was blocking the nasofrontal duct. The lacrimal bone and lamina papyracea were partially eroded, but the ethmoid roof was intact. The tumor was detached from the eroded bones and completely resected. The patient’s high serum FGF23 levels and low serum phosphate levels improved within a few postoperative days, and her serum ALP levels also gradually normalized (Table 1). She recovered from her lower back pain and gait disturbance within a month. At the three-year follow-up, there was no evidence of a residual tumor in the paranasal sinuses. 3. Discussion FGF23 is a phosphate-regulating hormone derived from bone tissue and is found in the circulation under normal conditions. The serum phosphate levels are maintained through a balance of absorption in the intestine, renal handling, and shift between extracellular phosphate and that in bone or intracellular space. In the proximal renal tubules, the type IIa and IIc sodium-phosphate cotransporters (NaPi-2a,2c) reabsorb approximately 85% of the phosphate filtered by the renal glomerulus, and 1,25(OH)2D stimulates intestinal phosphorus absorption [5]. High serum levels of FGF23 reduce the expression of NaPi-2a,2c and 1,25(OH)2D levels [6], and this in turn leads to the inhibition of both renal phosphate reabsorption and intestinal phosphorus absorption [5]. On the other hand, FGF23 has no influence on the serum calcium concentration. As a result, overexpression of FGF23 leads to high serum ALP levels, low serum phosphate levels, normal to low serum 1,25(OH)2D levels, and unchanged serum calcium levels [7]. Unusual systemic bony pain and multiple fractures combined with high serum ALP levels, low serum phosphate levels without serum calcium abnormalities, and especially high serum FGF23 levels should lead to a suspicion of OOM. In the present study, the first step in the diagnostic process was to determine whether the patient’s low serum phosphate levels were caused by renal or nonrenal abnormalities. This required an assessment of her TmP/GFR value, which is a measure of phosphate reabsorption in the proximal renal tubules [7]. The low TmP/GFR value observed in the present case was indicative of inappropriate renal phosphate wasting. The second diagnostic step was to determine whether the abovementioned renal hypophosphatemia was mediated by FGF23. Thus, we measured the patient’s serum FGF23 level, which was found to be high. FGF23-mediated renal hypophosphatemia can be found in several hypophosphatemic diseases such as hereditary rickets, linear sebaceous nevus syndrome, post-renal transplantation hypophosphatemia, and OOM [7]. Our patient did not have a family history of rickets or a history of renal disease, skin lesions, endocrine abnormalities, or nervous system disease. So, we searched for an FGF23-expressing lesion by performing FDG-PET
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Fig. 2. Histopathological features of the tumor. (A) The tumor contained round and fusiform cells and was fed by delicate capillaries. Calcification was also seen. Bar = 50 mm. Hematoxylin–eosin staining. (B) Almost all of the tumor cells exhibited cytoplasmic positivity for FGF23. Bar = 50 mm. FGF23 immunostaining.
and systemic venous sampling to assess serum FGF23 concentrations as a third diagnostic step, which led us to a final diagnosis of OOM. Although medical management with active vitamin D and phosphate supplements can temporarily relieve the symptoms of OOM, the most effective treatment is surgical removal of the FGF23-expressing tumor, which rapidly resolves any painful symptoms. Nevertheless, the causative tumor is sometimes too small to detect. We applied both FDG-PET and systemic venous sampling followed by assessments of serum FGF23 concentrations to identify the causative tumor. FDG-PET works on the principle that lesions that utilize large amounts of glucose or have an increased blood supply will take up larger amounts of radiolabelled glucose [8]. FDG accumulates not only in malignancies, but also in benign lesions, such as areas of active inflammation and hypermetabolism. Several case reports have described FDG-PET localization in OOM-associated tumors, and strong uptake of radiolabelled glucose might imply hypervascularity and hypermetabolism, which are required for accelerated FGF23 secretion [8,9]. However, the sensitivity rates of FDG-PET on detecting OOMassociated tumors are no more than 50%, as recently reported [10]. Moreover, the modality lacks specificity, and false-positive accumulation in nonspecific inflammatory areas is common [10]. So the positive scan does not necessarily indicate that the depicted tumor is indeed the cause of OOM. In the present case, the highest FGF23 concentration measured in the left head and neck region during systemic venous sampling allowed us to conclude that the occult paranasal sinus tumor identified by FDG-PET was actually secreting FGF23 and causing OOM [11,12]. This combinational procedure confirmed that the detected tumor itself overexpressed FGF23, and proved its functional aspect of this unique tumor. OOM is a rare disease, but a relatively high proportion of OOMassociated tumors occur in the head and neck region; i.e., they occur in the lower extremities, head and neck region, and upper extremities in 45%, 27%, and 17% of cases, respectively [13]. Of OOM-associated head and neck tumors, 57% occur in the sinonasal region and 20% develop in the mandible [14]. Thus, it is important that otorhinolaryngologists are aware of OOM. 4. Conclusion The occult phosphaturic mesenchymal tumor that caused our patient’s OOM was small and was localized in the ethmoid sinus, and the patient did not exhibit any nasal symptoms. In such cases, the combination of FDG-PET and systemic venous sampling to assess serum FGF23 concentrations is useful for identifying small asymptomatic OOM-associated tumors.
Surgical removal of the tumor normalized the patient’s laboratory parameters, and her painful symptoms dramatically improved within a month. Although OOM is a rare disease, we should keep in mind that about 27% of OOM-associated tumors occur in the head and neck region. Due to its scarcity, most surgeons are unaware of the existence of OOM; however, delayed diagnosis results in patients continuing to suffer from painful symptoms. Conflict of interest None declared. References [1] McCance RA. Osteomalacia with Looser’s nodes (Milkman’s syndrome) due to a raised resistance to vitamin D acquired about the age of 15 years. Q J Med 1947;16:33–46. [2] Kominek P, Starek I, Geierova M, Matousek P, Zelenik K. Phosphaturic mesenchymal tumour of the sinonasal area: case report and review of the literature. Head Neck Oncol 2011;3:16. [3] Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A 2001;98:6500–5. [4] Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO classification of tumours of soft tissue and bone. 4th ed. Lyon: IARC Press; 2013. p. 211–2. [5] Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004;19:429–35. [6] Shimada T, Urakawa I, Yamazaki Y, Hasegawa H, Hino R, Yoneya T, et al. FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem Biophys Res Commun 2004;314:409–14. [7] Imel EA, Econs MJ. Approach to the hypophosphatemic patient. J Clin Endocrinol Metab 2012;97:696–706. [8] Khadgawat R, Singh Y, Kansara S, Tandon N, Bal C, Seith A, et al. PET/CT localisation of a scapular haemangiopericytoma with tumour-induced osteomalacia. Singapore Med J 2009;50:55–7. [9] Dupond JL, Mahammedi H, Prie D, Collin F, Gil H, Blagosklonov O, et al. Oncogenic osteomalacia: diagnostic importance of fibroblast growth factor 23 and F-18 fluorodeoxyglucose PET/CT scan for the diagnosis and follow-up in one case. Bone 2005;36:375–8. [10] Jadhav S, Kasaliwal R, Lele V, Rangarajan V, Chandra P, Shah H, et al. Functional imaging in primary tumour-induced osteomalacia: relative performance of FDG PET/CT vs somatostatin receptor-based functional scans: a series of nine patients. Clin Endocrinol 2014;81:31–7. [11] Takeuchi Y, Suzuki H, Ogura S, Imai R, Yamazaki Y, Yamashita T, et al. Venous sampling for fibroblast growth factor-23 confirms preoperative diagnosis of tumor-induced osteomalacia. J Clin Endocrinol Metab 2004;89:3979– 82. [12] Ito N, Shimizu Y, Suzuki H, Saito T, Okamoto T, Hori M, et al. Clinical utility of systemic venous sampling of FGF23 for identifying tumours responsible for tumour-induced osteomalacia. J Intern Med 2010;268:390–4. [13] Ryan EA, Reiss E. Oncogenous osteomalacia. Review of the world literature of 42 cases and report of two new cases. Am J Med 1984;77:501–12. [14] Gonzalez-Compta X, Manos-Pujol M, Foglia-Fernandez M, Peral E, Condom E, Claveguera T, et al. Oncogenic osteomalacia: case report and review of head and neck associated tumours. J Laryngol Otol 1998;112:389–92.
Contents lists available at ScienceDirect
Auris Nasus Larynx journal homepage: www.elsevier.com/locate/anl
Oncogenic osteomalacia caused by an occult paranasal sinus tumor Tomofumi Okamiya a,*, Katsumasa Takahashi a, Hideo Kamada b, Junko Hirato c, Toru Motoi d, Seiji Fukumoto e, Kazuaki Chikamatsu a a
Department of Otorhinolaryngology – Head and Neck Surgery, Gunma University, Japan Gunma Medical Career Center, Gunma University Hospital, Japan c Department of Pathology, Gunma University Hospital, Japan d Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Japan e Division of Nephrology and Endocrinology, Department of Medicine, University of Tokyo Hospital, Japan b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 2 March 2014 Accepted 2 October 2014 Available online 11 February 2015
Oncogenic osteomalacia (OOM) is a rare bone disease characterized by inadequate bone mineralization and is caused by a humoral factor mainly produced by benign mesenchymal tumors. We report a case of OOM caused by an occult phosphaturic mesenchymal tumor in the paranasal sinus. The causative tumor was small and localized in the ethmoid sinus, and the patient did not exhibit any nasal symptoms. 18Ffluorodeoxyglucose positron emission tomography (FDG-PET) depicted the location of the occult tumor, and systemic venous sampling followed by assessments of the samples’ fibroblast growth factor 23 (FGF23) concentrations confirmed that the tumor secreted FGF23. The tumor was resected via an external surgical approach, resulting in the complete relief of the patient’s symptoms. The combination of FDG-PET and systemic venous sampling to assess serum FGF23 levels is useful for identifying small asymptomatic OOM-associated tumors. Such tumors are rare, but a significant proportion of them develop in the head and neck region, and complete resection is the most effective treatment. It is important that ENT surgeons are aware of the characteristics of OOM. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Oncogenic osteomalacia FDG-PET Systemic venous sampling FGF23
1. Introduction Oncogenic osteomalacia (OOM), which is also known as tumorinduced osteomalacia, is a rare bone disease characterized by inadequate bone mineralization and is caused by a humoral factor usually produced by benign mesenchymal tumors located in soft tissue or bone [1]. Its symptoms include muscle weakness, bone pain, and multiple fractures. Although surgical removal of the causative tumor results in rapid resolution of all painful symptoms, the diagnosis of OOM is often delayed by years because it can be hard to detect the primary tumor [2]. Recently, it has been demonstrated that OOM-associated tumors overexpress fibroblast growth factor 23 (FGF23), which inhibits renal phosphate reabsorption [3]. Thus, high serum FGF23 levels are useful for diagnosing OOM.
* Corresponding author at: Department of Otorhinolaryngology – Head and Neck Surgery, Gunma University, 3-39-22 Showa, Maebashi, Gunma 371-8511, Japan. Tel.: +81 27 220 8358; fax: +81 27 220 8369. E-mail address: [email protected] (T. Okamiya). http://dx.doi.org/10.1016/j.anl.2014.10.001 0385-8146/ß 2014 Elsevier Ireland Ltd. All rights reserved.
We report a case of OOM caused by an occult paranasal sinus tumor and suggest that the combination of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and systemic venous sampling to assess serum FGF23 concentrations is valuable for detecting OOM-associated tumors. 2. Case report A 35-year-old woman was referred to our hospital with an 8month history of lower back pain and gait disturbance. X-ray radiography and whole-body bone scintigraphy depicted multiple fractures of the ulna, ribs, and the ends of the limbs although the patient did not have a history of any other disease nor did she have a family history of bone disease. As for the patient’s laboratory findings, her blood count and liver and kidney functions were all normal; her blood chemistry findings revealed high serum alkaline phosphatase (ALP) levels and low serum phosphate levels, but showed normal serum calcium levels. The patient’s serum 1,25dihydroxyvitamin D [1,25(OH)2D] and intact parathyroid hormone (iPTH) levels were normal, but her maximum rate of tubular phosphate reabsorption to the glomerular filtration rate ratio (TmP/GFR), which is a measure of phosphate reabsorption in the
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168
proximal renal tubules, was low (1.4 mg/dl; reference range, 2.1–4.3 mg/dl). Accordingly, osteomalacia caused by phosphate wasting in the renal tubules was strongly suspected. The patient also exhibited high serum FGF23 levels (Table 1), which suggested that a hidden tumor was secreting FGF23. Whole-body FDG-PET was carried out, which detected homogeneous radiotracer uptake by a lesion in the left anterior ethmoid sinus (Fig. 1A). In addition, the tumor exhibited a standardized uptake value (SUV) of 7.3, which falls within the range of values exhibited by malignant tumors. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a well-circumscribed hypervascular tumor located in the left anterior ethmoid sinus (Fig. 1B–D). It was considered that the tumor was probably secreting FGF23; therefore, angiography-assisted systemic venous sampling was performed followed by assessments of the samples’ FGF23 concentrations. A total of 18 blood samples, which were obtained from the bilateral subclavian veins, internal jugular veins, brachiocephalic veins, venae cavae, iliac veins, and the femoral veins, were collected through a catheter inserted via the femoral vein. Examinations of the blood samples revealed that the sample collected from the left brachiocephalic vein displayed the highest concentration of FGF23 (285 pg/ml; other veins: 173–257 pg/ml). The fact that the highest FGF23 concentration was detected in the left head and neck region agreed with the detection of a lesion with a high SUV value in the left ethmoid sinus on FDG-PET; therefore, it was concluded that the tumor in the left ethmoid sinus was secreting FGF23 and was responsible for the patient’s OOM. The patient was referred to the Department of Otorhinolaryngology to undergo an excisional biopsy in order to obtain a final pathological diagnosis. However, the clinicians found it difficult to assess the tumor during a nasal endoscopic examination
Table 1 Changes in the patient’s laboratory data before and after surgery. Parameters (reference range)
Pre-ope.
Post-ope.
ALP (115–359 IU/L) P (2.5–4.1 mg/dl) Ca (8.9–10.5 mg/dl) iPTH (15–65 pg/ml) 1,25(OH)2D (20–60 pg/ml) FGF23 (14–40 pg/ml)
738 1.4 9.5 37.4 21 147
244 3.0 9.8 56.6 77 16
Fig. 1. Images of the tumor. (A) FDG-PET detected a tumor in the left anterior ethmoid sinus (arrow). The tumor’s standardized uptake value (SUV) was 7.3, which falls within the range of values exhibited by malignant tumors. (B) A Gd-enhanced MRI scan showed a strongly enhanced hypervascular tumor. The tumor had not invaded the brain. (C and D) Sagittal and coronal contrast-enhanced CT images showed that the tumor was attached to the base of the skull and lamina papyracea, but no bony destruction was observed.
performed via the nostril, so a biopsy involving the removal of the ethmoidal bulla was carried out under general anesthesia. A histopathological examination revealed that the tumor was composed of round, fusiform, and spindle-shaped cells and was fed by delicate capillaries (Fig. 2A). Calcification, fibrosis, and hemorrhaging were observed in the tumor matrix. An immunohistochemical examination demonstrated that the tumor cells expressed FGF23 (Fig. 2B). They were also focally positive for a-smooth muscle actin, but negative for desmin, S-100 protein, keratin, and CD34 (data not shown). The pathological diagnosis was phosphaturic mesenchymal tumor, mixed connective tissue variant [4]. After the final diagnosis of OOM had been made, we attempted a complete resection via an external surgical approach. After removing the anterior wall of the frontal sinus and the frontal process of maxilla, it became possible to view the whole of the tumor, which was a reddish vascular tumor located in the anterior ethmoid sinus and was blocking the nasofrontal duct. The lacrimal bone and lamina papyracea were partially eroded, but the ethmoid roof was intact. The tumor was detached from the eroded bones and completely resected. The patient’s high serum FGF23 levels and low serum phosphate levels improved within a few postoperative days, and her serum ALP levels also gradually normalized (Table 1). She recovered from her lower back pain and gait disturbance within a month. At the three-year follow-up, there was no evidence of a residual tumor in the paranasal sinuses. 3. Discussion FGF23 is a phosphate-regulating hormone derived from bone tissue and is found in the circulation under normal conditions. The serum phosphate levels are maintained through a balance of absorption in the intestine, renal handling, and shift between extracellular phosphate and that in bone or intracellular space. In the proximal renal tubules, the type IIa and IIc sodium-phosphate cotransporters (NaPi-2a,2c) reabsorb approximately 85% of the phosphate filtered by the renal glomerulus, and 1,25(OH)2D stimulates intestinal phosphorus absorption [5]. High serum levels of FGF23 reduce the expression of NaPi-2a,2c and 1,25(OH)2D levels [6], and this in turn leads to the inhibition of both renal phosphate reabsorption and intestinal phosphorus absorption [5]. On the other hand, FGF23 has no influence on the serum calcium concentration. As a result, overexpression of FGF23 leads to high serum ALP levels, low serum phosphate levels, normal to low serum 1,25(OH)2D levels, and unchanged serum calcium levels [7]. Unusual systemic bony pain and multiple fractures combined with high serum ALP levels, low serum phosphate levels without serum calcium abnormalities, and especially high serum FGF23 levels should lead to a suspicion of OOM. In the present study, the first step in the diagnostic process was to determine whether the patient’s low serum phosphate levels were caused by renal or nonrenal abnormalities. This required an assessment of her TmP/GFR value, which is a measure of phosphate reabsorption in the proximal renal tubules [7]. The low TmP/GFR value observed in the present case was indicative of inappropriate renal phosphate wasting. The second diagnostic step was to determine whether the abovementioned renal hypophosphatemia was mediated by FGF23. Thus, we measured the patient’s serum FGF23 level, which was found to be high. FGF23-mediated renal hypophosphatemia can be found in several hypophosphatemic diseases such as hereditary rickets, linear sebaceous nevus syndrome, post-renal transplantation hypophosphatemia, and OOM [7]. Our patient did not have a family history of rickets or a history of renal disease, skin lesions, endocrine abnormalities, or nervous system disease. So, we searched for an FGF23-expressing lesion by performing FDG-PET
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Fig. 2. Histopathological features of the tumor. (A) The tumor contained round and fusiform cells and was fed by delicate capillaries. Calcification was also seen. Bar = 50 mm. Hematoxylin–eosin staining. (B) Almost all of the tumor cells exhibited cytoplasmic positivity for FGF23. Bar = 50 mm. FGF23 immunostaining.
and systemic venous sampling to assess serum FGF23 concentrations as a third diagnostic step, which led us to a final diagnosis of OOM. Although medical management with active vitamin D and phosphate supplements can temporarily relieve the symptoms of OOM, the most effective treatment is surgical removal of the FGF23-expressing tumor, which rapidly resolves any painful symptoms. Nevertheless, the causative tumor is sometimes too small to detect. We applied both FDG-PET and systemic venous sampling followed by assessments of serum FGF23 concentrations to identify the causative tumor. FDG-PET works on the principle that lesions that utilize large amounts of glucose or have an increased blood supply will take up larger amounts of radiolabelled glucose [8]. FDG accumulates not only in malignancies, but also in benign lesions, such as areas of active inflammation and hypermetabolism. Several case reports have described FDG-PET localization in OOM-associated tumors, and strong uptake of radiolabelled glucose might imply hypervascularity and hypermetabolism, which are required for accelerated FGF23 secretion [8,9]. However, the sensitivity rates of FDG-PET on detecting OOMassociated tumors are no more than 50%, as recently reported [10]. Moreover, the modality lacks specificity, and false-positive accumulation in nonspecific inflammatory areas is common [10]. So the positive scan does not necessarily indicate that the depicted tumor is indeed the cause of OOM. In the present case, the highest FGF23 concentration measured in the left head and neck region during systemic venous sampling allowed us to conclude that the occult paranasal sinus tumor identified by FDG-PET was actually secreting FGF23 and causing OOM [11,12]. This combinational procedure confirmed that the detected tumor itself overexpressed FGF23, and proved its functional aspect of this unique tumor. OOM is a rare disease, but a relatively high proportion of OOMassociated tumors occur in the head and neck region; i.e., they occur in the lower extremities, head and neck region, and upper extremities in 45%, 27%, and 17% of cases, respectively [13]. Of OOM-associated head and neck tumors, 57% occur in the sinonasal region and 20% develop in the mandible [14]. Thus, it is important that otorhinolaryngologists are aware of OOM. 4. Conclusion The occult phosphaturic mesenchymal tumor that caused our patient’s OOM was small and was localized in the ethmoid sinus, and the patient did not exhibit any nasal symptoms. In such cases, the combination of FDG-PET and systemic venous sampling to assess serum FGF23 concentrations is useful for identifying small asymptomatic OOM-associated tumors.
Surgical removal of the tumor normalized the patient’s laboratory parameters, and her painful symptoms dramatically improved within a month. Although OOM is a rare disease, we should keep in mind that about 27% of OOM-associated tumors occur in the head and neck region. Due to its scarcity, most surgeons are unaware of the existence of OOM; however, delayed diagnosis results in patients continuing to suffer from painful symptoms. Conflict of interest None declared. References [1] McCance RA. Osteomalacia with Looser’s nodes (Milkman’s syndrome) due to a raised resistance to vitamin D acquired about the age of 15 years. Q J Med 1947;16:33–46. [2] Kominek P, Starek I, Geierova M, Matousek P, Zelenik K. Phosphaturic mesenchymal tumour of the sinonasal area: case report and review of the literature. Head Neck Oncol 2011;3:16. [3] Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A 2001;98:6500–5. [4] Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO classification of tumours of soft tissue and bone. 4th ed. Lyon: IARC Press; 2013. p. 211–2. [5] Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004;19:429–35. [6] Shimada T, Urakawa I, Yamazaki Y, Hasegawa H, Hino R, Yoneya T, et al. FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem Biophys Res Commun 2004;314:409–14. [7] Imel EA, Econs MJ. Approach to the hypophosphatemic patient. J Clin Endocrinol Metab 2012;97:696–706. [8] Khadgawat R, Singh Y, Kansara S, Tandon N, Bal C, Seith A, et al. PET/CT localisation of a scapular haemangiopericytoma with tumour-induced osteomalacia. Singapore Med J 2009;50:55–7. [9] Dupond JL, Mahammedi H, Prie D, Collin F, Gil H, Blagosklonov O, et al. Oncogenic osteomalacia: diagnostic importance of fibroblast growth factor 23 and F-18 fluorodeoxyglucose PET/CT scan for the diagnosis and follow-up in one case. Bone 2005;36:375–8. [10] Jadhav S, Kasaliwal R, Lele V, Rangarajan V, Chandra P, Shah H, et al. Functional imaging in primary tumour-induced osteomalacia: relative performance of FDG PET/CT vs somatostatin receptor-based functional scans: a series of nine patients. Clin Endocrinol 2014;81:31–7. [11] Takeuchi Y, Suzuki H, Ogura S, Imai R, Yamazaki Y, Yamashita T, et al. Venous sampling for fibroblast growth factor-23 confirms preoperative diagnosis of tumor-induced osteomalacia. J Clin Endocrinol Metab 2004;89:3979– 82. [12] Ito N, Shimizu Y, Suzuki H, Saito T, Okamoto T, Hori M, et al. Clinical utility of systemic venous sampling of FGF23 for identifying tumours responsible for tumour-induced osteomalacia. J Intern Med 2010;268:390–4. [13] Ryan EA, Reiss E. Oncogenous osteomalacia. Review of the world literature of 42 cases and report of two new cases. Am J Med 1984;77:501–12. [14] Gonzalez-Compta X, Manos-Pujol M, Foglia-Fernandez M, Peral E, Condom E, Claveguera T, et al. Oncogenic osteomalacia: case report and review of head and neck associated tumours. J Laryngol Otol 1998;112:389–92.
