Tumor induced osteomalacia in head and neck region: single center experience and systematic review

in Endocrine Connections

Correspondence should be addressed to A R Lila: anuraglila@gmail.com

Tumor-induced osteomalacia in the head and neck region remains a challenging diagnosis to manage. Literature pertaining to management and outcome details remains sparse. We describe two cohorts: cohort 1 included seven patients from a single center in Western India with tumors located in paranasal sinuses (n = 3), intracranial (n = 2) and maxilla (n = 2). The unique features from our series is the management of persistent disease with radiation therapy (n = 2) and peptide receptor radionuclide therapy (PRRT) (n = 1). Cohort two has 163 patients identified from 109 publications for systematic review. Paranasal sinuses, mandible, intracranial disease, maxilla and oral cavity, in descending order, are reportedly common tumor sites. Within this cohort, mean age was 46 ± 14 years at presentation with 44.1% having local symptoms. Duration of symptoms varied from 1 to 240 months. Pre-surgery mean serum phosphorus was 1.4 ± 0.4 mg/dL and median FGF-23 levels were 3.6 (IQR:1.8–6.8) times of normal upper limit of normal. Majority (97.5%) were managed primarily with surgical excision; however, primary radiotherapy (n = 2) and surgery combined with radiotherapy (n = 2) were also reported. Twenty patients had persistent disease while nine patients had recurrence, more commonly noted with intracranial and oral cavity tumors. Surgery was the most common second mode of treatment employed succeeded by radiotherapy. Four patients had metastatic disease. The most common histopathological diagnosis reported is PMT mixed connective tissue, while the newer terminology ‘PMT mixed epithelial and connective tissue type’ has been described in 15 patients.

Abstract

Tumor-induced osteomalacia in the head and neck region remains a challenging diagnosis to manage. Literature pertaining to management and outcome details remains sparse. We describe two cohorts: cohort 1 included seven patients from a single center in Western India with tumors located in paranasal sinuses (n = 3), intracranial (n = 2) and maxilla (n = 2). The unique features from our series is the management of persistent disease with radiation therapy (n = 2) and peptide receptor radionuclide therapy (PRRT) (n = 1). Cohort two has 163 patients identified from 109 publications for systematic review. Paranasal sinuses, mandible, intracranial disease, maxilla and oral cavity, in descending order, are reportedly common tumor sites. Within this cohort, mean age was 46 ± 14 years at presentation with 44.1% having local symptoms. Duration of symptoms varied from 1 to 240 months. Pre-surgery mean serum phosphorus was 1.4 ± 0.4 mg/dL and median FGF-23 levels were 3.6 (IQR:1.8–6.8) times of normal upper limit of normal. Majority (97.5%) were managed primarily with surgical excision; however, primary radiotherapy (n = 2) and surgery combined with radiotherapy (n = 2) were also reported. Twenty patients had persistent disease while nine patients had recurrence, more commonly noted with intracranial and oral cavity tumors. Surgery was the most common second mode of treatment employed succeeded by radiotherapy. Four patients had metastatic disease. The most common histopathological diagnosis reported is PMT mixed connective tissue, while the newer terminology ‘PMT mixed epithelial and connective tissue type’ has been described in 15 patients.

Introduction

Tumor-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic syndrome caused by overproduction of fibroblast growth factor 23 (FGF23) by a tumor. FGF-23 plays a vital role in renal phosphate handling and vitamin D synthesis. Hence, TIO is characterized by hypophosphatemia due to renal phosphate wasting, inappropriately normal or low 1,25 dihydroxy vitamin D, and elevated or inappropriately normal plasma FGF-23. These biochemical alterations eventually result in osteomalacia. Due to its rarity, the diagnosis of TIO is delayed with the average time from onset of symptoms to diagnosis being more than 2.5 years (1). As a result, patients often present in a debilitated state with multiple fractures, severe muscle weakness and loss of height due to skeletal deformities. Even with a high index of suspicion, tumor localization remains challenging as the offending tumor may be very small and can be anywhere in the body. Complete tumor resection remains the mainstay of treatment and is known to result in dramatic resolution of symptoms.

The first case of TIO was reported by Robert McCance in 1947 who treated a patient having low phosphorus levels and bone pain with high doses of vitamin D suspecting her to be a case of ‘vitamin D resistance’; however, the symptoms did not completely resolve until a tumor found in the femur was removed (2). Thereafter, more than 300 cases of TIO have been reported in literature with more than 200 being reported since 2000 (3). The most common tumor site is the lower extremity (>40%) followed by the head and neck region (>20%) (4). There have been several reviews on pathological characters of such tumors but there is no comprehensive review describing clinical characteristics and management of patients with TIO in head and neck region. This article aims to describe a single-center experience with TIO involving the head and neck region followed by a comprehensive clinically oriented review of world literature for the same.

Materials and methods

Cohort 1

Medical records of patients attending Department of Endocrinology, KEM Hospital, Mumbai who were diagnosed with TIO from January 2005 till August 2018 were reviewed after obtaining approval from Institutional Ethical Committee II, Seth G S Medical college and KEM Hospital, Mumbai. Informed consent for the photographs, publication of their clinical details and/or imaging was taken. Patients diagnosed with TIO involving the head and neck region were identified and reviewed for inclusion. Concurrently, patients diagnosed with TIO in other regions, and patients with secondary TIO (3) (including neurofibromatosis, epidermal nevus syndrome, and polyostotic fibrous dysplasia of bone) were excluded from the study.

Diagnosis of TIO was considered in patients presenting with features of hypophosphatemia in absence of relevant family history, evidence of renal phosphate wasting (as demonstrated by low % fractional tubular reabsorption of phosphate (TRP) and tubular maximum for phosphate corrected for glomerular filtration rate (TMP/GFR)) with elevated fibroblast growth factor-23 (FGF-23). Only those patients who had anatomical/functional imaging (CT/MRI or Ga-DOTATATE PET/CT) demonstrating localization of tumor in head and neck region have been included for analysis (n = 7).

Biochemical parameters recorded pre-operatively include S. calcium, S. phosphorus, S. alkaline phosphatase (ALP), TMP/GFR, TRP and FGF23 levels, and post-operatively include S. phosphorus and FGF-23 levels. Normal ranges for various parameters at our institute are as follows: S. calcium (9–10.5 mg/dL), S. phosphorus (2.5–5 mg/dL), S. ALP (<117 U/L), TMP/GFR (age- and sex-adjusted values as recommended by Chong et al. (3)), TRP (>85%) and C-terminal FGF-23 (0–150 RU/mL). Furthermore, details from imaging studies done for localization (CT or Ga-DOTATATE PET/CT), treatment modality used, and histopathology reports have been included for analysis. For patients having recurrent disease additional information including time of recurrence following primary management, biochemical profile, localization of recurrent disease and secondary modality of treatment used was documented.

Tubular resorption of phosphate was measured from phosphate and creatinine levels in a spot fasting urine and serum samples at baseline before starting phosphate supplements. TMP/GFR was calculated with use of a nomogram reported by Bijvoet et al. FGF23 was assessed by enzyme-linked immunosorbent assay (FGF23 (C-terminal) kit, Immunotopics, Inc, San Clemente, CA, USA). The kit has sensitivity, an intra-assay coefficient of variation (CV), and an inter-assay CV of 30 RU/mL, 5 and 7.3%, respectively. Serum 1,25(OH)2 vitamin D was assessed by radioimmunoassay (RIA), using a DIA source RIA CT kit by DIA source Immunoassays, SA, with an intra-assay CV of 4.5–9.3% (at 77.3 and 24.5 ng/L concentrations, respectively) and inter-assay CV of 11.3–12.7% (at 33.4 and 13.6 ng/L concentrations, respectively). Whole-body (head to toe) scanning with two acquisitions were obtained 1–1.5 h post intravenous injection of 74–111 MBq of DOTATATE labeled with 68Ga. 68Ga was obtained from an in-house 68Ge/68Ga generator. Scans were acquired on a GE Discovery STE PET/CT with 128 × 128 matrix size and 3 min per bed position of iterative algorithm time. The numbers of bed positions were dependent on the height of the patient, usually 10–12 per patient. CT scans were obtained on a 64-slice Phillips Brilliance CT scanner, while MRI scans were performed on a 1.5 tesla Siemens Sonata (Henkestrabe, Germany) MR scanner.

Cohort 2

We searched for all original and review articles in PubMed till June 2019 (Fig. 1). Individual search was carried out for terms ‘Tumour-Induced Osteomalacia’, ‘Oncogenic Osteomalacia’, and ‘Phosphaturic Mesenchymal Tumour’. All original and review articles published in English were reviewed for inclusion. Only publications describing TIO in head and neck region were included. A secondary search for relevant publications was carried out by handsearching through the reference lists of selected publications. Hence, in addition to the cases described in our series, we reviewed 163 index cases from 109 publications of TIO of head and neck region previously reported in literature. Clinical profile, biochemical investigations, imaging modality used for localization, location of tumor, treatment modalities used, histopathology findings, recurrence and its management, and metastasis if any were noted. Whenever serum levels of calcium, phosphorus, parathyroid hormone (PTH), 1,25 (OH)2 vitamin D3 levels were available in SI units, they were converted to conventional units with online calculators for uniformity in documentation. Serum ALP when available in units/liter only was included for analysis, while values reported in any other units were excluded due to non-availability of a suitable conversion method.

Figure 1
Figure 1

Flowchart of search strategy and selection of studies for inclusion in systematic review.

Citation: Endocrine Connections 8, 10; 10.1530/EC-19-0341

Statistical analysis

Statistical analysis was performed using SPSS software version 23.0. Mean (±standard deviation (s.d.)) was used for continuous variables when they were normally distributed and median (interquartile range (IQR)) was used for variables with skewed distribution. The difference between categorical variables was analyzed using chi-square test. P value <0.05 is considered significant.

Results

Cohort 1

This cohort includes seven index patients with TIO involving head and neck region. Their characteristics are described in Table 1. The cohort comprised four males and three females with mean age of 42.7 ± 10.6 years whose tumors were located in paranasal sinuses (n = 3), maxilla (n = 2), and intra-cranially (n = 2). All patients presented with bone pain and muscle weakness, while pathologic fractures (n = 4) and local symptoms (n = 5) were present in majority of patients. The time lag from onset of symptoms to diagnosis was lengthy (mean: 65.1 ± 50.3 months). In four patients, location of tumor was suspected at initial presentation based on clinical history and examination. Thereafter, tumor location was confirmed with Ga-DOTANOC in two patients, with MRI in one patient and CT in one patient. Three patients were primarily detected on Ga-DOTANOC/DOTATATE PET/CT; one patient had a history of epistaxis elicited retrospectively after tumor localization. Mean tumor size was 3.6 ± 1.3 cm. Except for one patient (who was initially operated at another hospital), pre and post-operative serum phosphorus and FGF-23 levels were available in all patients (Table 1). Three patients were cured with initial surgery, while four had persistent disease. No recurrence was documented in patients cured initially (n = 3) over a mean follow-up of 17 months. Out of four patients with persistent disease, one patient was cured with repeat surgery only, two patients were cured with repeat surgery and external beam radiation therapy (EBRT), and one has stable disease after peptide receptor radionuclide therapy (PRRT). Histopathologic findings revealed phosphaturic mesenchymal tumor mixed connective tissue type (PMTMCT) in four patients, while the remaining three patients had PMT-OF (ossifying fibroma like), hemangiopericytoma, and odontogenic fibroma, respectively. Clinical images of case numbers one, five and six are shown in Figs 2, 3 and 4 respectively.

Figure 2
Figure 2

(Case 1): A 32-year-old female presented with bone pains and multiple fractures for 7 years. On examination, approximately 2 cm-sized round swelling in right upper alveolus was seen (A). Preoperative chest radiograph (image contrast adjusted) showing Looser’s zone along lateral border of scapula (arrows) suggestive of osteomalacia (B). Axial contrast-enhanced CT image soft tissue window showing small enhancing lesion in right upper alveolus (arrow) extending from canine to 1st molar tooth causing erosion of right upper alveolus (C). Ga-DOTATATE PET scan showing increased uptake at the level of right maxillary alveolus (arrow) (D). After excision histopathological examination showing tumor comprising of spindle cells with scattered osteoclastic giant cells bearing histologic semblance to giant cell granuloma (odontogenic fibroma) (E) (H&E, 400×).

Citation: Endocrine Connections 8, 10; 10.1530/EC-19-0341

Figure 3
Figure 3

(Case 5): A 53-year-old female presenting with pain in bilateral groins and difficulty in walking for 3-year duration. As investigations confirmed the diagnosis of FGF-23-dependent hypophosphatemic osteomalacia, 68Ga-DOTATATE PET scan was done to locate the tumor which showed increased uptake in base of skull in left side (dashed arrows) (A). Corresponding axial CT images (B) showing soft tissue density lesion involving occipital bone on left side with erosion of the mastoid and petrous part of adjacent temporal bone. Retromastoid craniotomy with tumor excision was done. Histopathological examination showed hypercellular tumor composed of prominent small blood vessels with areas of hemorrhage (H&E, 200×) (D). Post first surgery repeat 68Ga-DOTATATE scan and corresponding CT images showing residual uptake in base of skull in left side (dashed arrows) in the soft tissue density lesion involving occipital bone on left side with erosion of the mastoid and petrous part of adjacent temporal bone (E). After failed second surgery, patient is now having stable disease after two cycles of PRRT.

Citation: Endocrine Connections 8, 10; 10.1530/EC-19-0341

Figure 4
Figure 4

(Case 6): A 33-year-old female presenting with pain in bilateral groins, difficulty in walking and multiple fractures for 3-year duration. There was past history of dental surgery for some ‘gum swelling’. On examination, there was swelling in right upper alveolar region (A). X-ray right forearm AP view (image contrast adjusted) showing ulnar shaft fracture (B). MRI hip showing bilateral femoral neck insufficiency fractures which was reported as ‘bilateral avascular necrosis’ (C). Ga-DOTANOC scan showing uptake in the right maxillary tumor (D). CECT PNS axial view showing 3 cm tumor in right maxillary region (E). Patient was cured with right maxillectomy and osseous reconstruction. Histopathology showed tumor composed of cellular connective tissue intermixed with woven bone displaying osteoblastic rimming (i.e. ossifying fibroma-like histology) (H&E, 100×).

Citation: Endocrine Connections 8, 10; 10.1530/EC-19-0341

Table 1

Details of cohort 1 patients.

Case no.Age/sexLocation of tumorClinical featuresImaging characteristicsS. Phosphorus (mg/dL)FGF-23 (RU/mL) (0–150)
Local symptomsFeatures of TIODuration (months)Localization withSize of tumor (cm)Pre-opPost-opPre-opPost-op
132/FRight maxillary alveolusSwelling over right alveolusP, F84History and PE1.21.94.3950102
246/MLeft petrous tumorEarache, protruding mass from left earP, MW, F156History and PE51.23.3NA118.6
360/MLeft ethmoid sinusEpistaxisP, MW, F12Ga-DOTANOC4.70.91.864672.5
439/MRight frontal & ethmoid sinusNoP, MW48Ga-DOTANOC2.30.91.03787191
553/FBase of the skullNoP, MW36Ga-DOTATATE3.51.5NA725153
633/FRight maxillaRight upper gum swellingP, MW, F36History and PE30.6

x
1.3889885
736/M Right nasal cavityEpistaxis, nasal obstructionP, MW84History and PE51.94202482
Case no.Surgical managementPersistenceSecond line modalityTotal duration of follow-upStatusHistopathology
ProcedureComplete resectionSurgeryRTPRRT
1Infrastructure maxillectomyYes48CuredOdontogenic fibroma
2Retromastoid craniotomy with left petrosectomyNoYesYes96CuredHemangiopericytoma
3FESSNoYesFESS 2 timesIMRT 54 Gy in 30 fractions36CuredPMTMCT
4Frontal craniotomy and excisionNoYesEndoscopic endonasal tumor excision29CuredPMTMCT
5Retromastoid craniotomy with tumor excisionNoYesYesYes13PersistencePMTMCT
6Right maxillectomyYesNo12CuredPMT OF like
7Endoscopic endonasal tumor excisionYes2CuredPMTMCT

F, fractures; FESS, functional endoscopic sinus surgery; IMRT, intensity-modulated radiation therapy; MW, muscle weakness; NA, not available; OF, ossifying fibroma like; P, pain; PE, physical examination; PMTMCT, phosphaturic mesenchymal tumor mixed connective tissue type; PRRT, peptide receptor radionuclide therapy; RT, radiation therapy.

Cohort 2

This cohort consists of 163 index patients from 109 publications. Pertinent data relevant to index patients is provided in Table 2. Details of clinically relevant parameters are summarized in Table 3. Tests done using two different methods have been tabulated separately in Table 3. Due to heterogeneity in reporting of various parameters, the number of cases included (as denominator) have been specified for each parameter. The mean age was 46 ± 14 years with equal male:female ratio. The reported frequency of tumor sites, in descending order, are paranasal sinuses, mandible, intracranial, maxilla, oral cavity and others. Approximately half the patients (44.1%) had evident local symptoms. Bone pain and muscle weakness were most commonly reported. Late complications of hypophosphatemia such as fractures (61%) and bony deformities including kyphosis/scoliosis with resultant height loss (25.7%) were seen in a significant number of patients. Most patients were diagnosed late in their disease course, despite early access to health care, with median duration from symptom onset being almost 4 years. Out of 163 patients, median elevation of FGF-23 up to 3.6 times ULN has been reported in 55 patients with the interquartile range (IQR) being 1.8–6.8 × ULN. The primary treatment modality was surgery in most patients (97.5%). Two patients with intracranial tumors, who declined surgery, were treated with primary EBRT. Also, two patients received immediate post-operative EBRT for prevention of recurrence due to fear of incomplete tumor removal.

Table 2

Review of published literature on head and neck TIO cases: list of index cases with relevant data.

Case no.AuthorAge/sexLocation of tumor

Duration of symptomsLocalizing imagingFGF-23Persistence/recurrence

Secondary modalityHPR
Pre-surgeryPost-surgery
1Renton (5)53FLeft ethmoid60X-rayNANANAHemangiopericytoma
2Sweet (6)25FLeft middle turbinate12CTNANANoHemangiopericytoma
3Nitzan (7)26MLeft mandibular molar legion24X-rayNANANoGiant cell tumor
4Nomura (8)29MMandible24X-rayNANAPersistenceRT, chemotherapy, 2nd surgery, chemotherapyPMT ossifying fibroma like
5Linsey (9)54FRight nasopharynx30CTNANANAPMTMCT
6Shenker (10)55MNeckNANANANANoPMTMCT
7Sheshadri (11)40FEthmoid sinusNACTNANANAHemangiopericytoma
8Jefferies (12)27FLeft maxillary sinus24CTNANANAPMT
9Weidner (13)39FRight maxillary sinus24CTNANARecurrenceRepeat surgery

Primitive mesenchymal tumor
10Papotti (10)38FNasal cavityNANANANANoPMTMCT
11Harvey (10)32FThyroid144PENANAPersistenceRepeat surgery: partial f/b total laryngectomy f/b RT and continued on medical managementMalignant PMTMCT
12Lee (14)66FLeft nasal cavity36CTNANANoHemangiopericytoma
13Catalano (15)66FRight maxillary and ethmoidal sinusmany yearsCTNANANoHemangiopericytoma
14Wilkins (16)55MLeft infratemporal mass24CTNANANoSinonasal hemangiopericytoma like
15David (17)60FRight subfrontal mass18CTNANARecurrenceMedical managementHemangiopericytoma
16Kim (18)41MRight upper premolar48PENANANoGiant cell tumor
17Kim (18)32FLeft mandibular molar area96PENANANoOssifying fibroma
18Avila (19)48MMandible60MRINANANoChronic inflammatory tissue with fibrosis and epithelial rests
19Yang (20)31FLeft mandible96CTNANANAPMT-MCT
20Gonzalez-Compta (21)69FRight ethmoido-frontal mass216CTNANAPatient died of tumorPMT
21Ohashi (22)43MLeft maxillary sinus14CTNANANAHemangiopericytoma
22Clunie (23)60FEthmoid sinuses60CTNANARecurrenceMedical managementHemangiopericytoma
23Sandhu (24)46MRight ethmoid sinus18CTNANANoHemangiopericytoma
24Reyes-Mugica (25)9FLeft mandible1.5MRINANANoPMT-MCT
26John (27)54FRight frontal, ethmoidal, sphenoid sinusesNAPENANANAPatient received Immediate RT following surgeryMalignant Schwannoma
27Reis-Filho (28)47FCavernous sinus84CTNANANoPMTMCT
28Fuentealba (29)63FMaxillary sinus60CTNANAPersistenceSurgery, RT, embolizationHemangiopericytoma
29Ungari (30)24MEthmoidNACTNANANAHemangiopericytoma
30Folpe (10)29MEthmoid/

sphenoid sinus
24NANANANoHemangiopericytoma
31Folpe (10)46MEthmoid sinus36NANANARecurrenceRepeat surgeryHemangiopericytoma
32Dupond (31)71MLower mandible12FDG-PET199 Ru/mL (N <100)22 Ru/mL (POD 8)NAPMTMCT
33Kaylie (32)46FTemporal bone120CTNANANAPMTMCT
34Inokuchi (33)24FRight nasal cavity and paranasal sinuses4CT484 Ru/mL (N: 32–84)58 Ru/mL (POD 3)NoHemangiopericytoma
35Yoshioka (34)45MClivus10MRINA49 pg/mLRecurrenceAfter first surgery received RT followed by medical management. Octreotide was not effective.Hemangiopericytoma
36Koriyama (35)41FRight maxillary sinus36CT309 pg/mL (N: 10–50)50 (2 h post surgery)NoPMTMCT
37Elston (36)69FSkull84Octreoscan67 RU/mL (N: 3–45)32 RU/mL (3–45) (POD 0)NoPMTMCT
38Beech (37)42MRight ethmoid sinus84MRINANANoHemangiopericytoma
39Ahn (38)61MLeft lower buccal vestibule17PENANANoHemangiopericytoma
40Uramoto (39)48MTongue24CTNANARecurrenceSecond surgery, RT

Malignant PMTMCT
41Lewiecki (40)46MMandible24Octreoscan262 RU/mL (N <180)UD (POD 10)NoPMT
42Kenealy (41)79FLeft ethmoid sinusNACT355 U/mL (N: 3–45)NANAPMTMCT
43Kenealy (41)40FLeft ethmoid sinus60Octreoscan484 U/mL (N: 3–45)NANAHemangiopericytoma
44Kyoung-In Yun (42)71FMandible108PENANANoHemangiopericytoma
45Woo (43)42FMandible108PE192 pg/mL (N: 1–71)98 pg/mL (POD 11)PersistencePatient on oral phosphate solution with close follow-up last FGF-23 92 pg/mLPMTMCT
46Savage (44)73FLeft maxillary sinus84111In-pentetreotideNANANoHemangiopericytoma
47Kurien (45)55MRight sphenoid, ethmoid sinus24CTNANANoHemangiopericytoma
48Gupta (46)51MNasal cavity108FDG-PETNANANoPMTMCT
49Gore (47)52FNasal cavity48Octreoscan573 Ru/mL (N <230)Normal (45 min post surgery)NoPMTMCT
50Kobayashi (48)53FTemporal bone48SVS558.8 pg/mL (N: 4–54.3)Normal (POD 4)NoPMTMCT
51Shelekhova (49)70FMaxillary sinusNAMRINANANAPMTMCT
52Shelekhova (49)53MFrontal sinusNACTNANANAPMTMCT
53Pedrazzoli (50)37FRight maxillary sinus32CTNANANoHemangiopericytoma
54Mori (51)42MLeft maxillary alveolus36MRI241 pg/mL (N: 10–50)Normal (1 h post surgery)NoPMTMCT
55Parshwanath (52)42FLeft nasal cavity and ethmoid sinus42CTNANANoPMT
56Battoo (53)34FLeft nasal cavity60PENANANAGiant cell tumor
57Peterson (54)33FMaxillary sinusNANANANANAPMT
58Peters (55)22MRight temporal lobe mass96PENANAPersistenceThree craniotomies with angioembolization, RT, PRRT, octreotide, dasatinibHemangiopericytoma
59Akhter (56)52MC5 vertebraeNAFDG-PETNANANoPMTMCT
60Xian-Ling (57)43FRight petrous apex48MRINANAPersistenceOctreotide therapy

PMTMCT
61Xian-Ling (57)42FLeft ethmoid sinus24OctreoscanNANANoPMTMCT
62Guglielmi (58)22MLeft ethmoid sinus24OctreoscanNANAPersistenceRepeat surgery

Hemangiopericytoma
63Uno (59)53FRight temporal bone48CT>200 (N: 10–50 pg/mL)<50 (POD-2)NAPMT-MCT
64Uno (59)61MLeft basi frontalis60CT400 (N: 10–50 pg/mL)<3 pg/mL (immediately)PersistenceRepeat surgery

PMT-MCT
65Andreupoulou (60)63MLeft frontal lobeNASVS156 pg/mL101 pg/mL (6 months post RT)At 6 months, patient had declining FGF-23PMTMCT
66Bergwitz (61)56MMandible228PE870 Ru/ml (N <180)NAPersistenceMultiple surgeries, cinacalcet

Ameloblastic fibrosarcoma
67Monappa (62)35MRight mandible36PENANANoPMTMCT
68Chokyu (63)57MMiddle cranial fossa24MRI84 pg/mL (N: 10–50)14 pg/mL (POD 7)NoPMT
69Chiam (64)55MRight nasal cavity18MRI232 RU/mL (N <180)18RU/mL (<180) day 5NoPMTMCT
70Cho (65)47FNasal cavity, ethmoidal sinus36CTNANANoHemangiopericytoma
72Brandwein-Gensler (67)66FNasal cavity, maxillaNAPENANANoGlomangiopericytoma
73Munoz (68)60MPosterior neck24FDG-PET575 RU/mL (N <180)NormalNoPMTMCT
74Chang (69)37mLeft nasal cavity60PENANANoHemangiopericytoma
75Jiang (70)38FMandible24OctreoscanNANANoPMT-MCT
76Jiang (70)69FMandible240Octreoscan393 pg/mL (N: 10–50)8NoPMT-MCT
77Jiang

(70)
28MMandible48OctreoscanNANANoOdontogenic fibroma
78Jiang (70)56FMandible120OctreoscanNANANoPMT-MCT
79Jiang (70)55FLower gingiva204OctreoscanNANANoPMT-MCT
80Jiang (70)45FMandible132OctreoscanNANANoOdontogenic fibroma
81Jiang (70)50FMandible36OctreoscanNANANoPMT-MCT
82Jiang (70)27MMaxilla72OctreoscanNANANoOdontogenic fibroma
83Jiang (70)49FNasal sinus72OctreoscanNANARecurrenceObservationPMT-MCT
84Jiang (70)24MNasal sinus48OctreoscanNANANoPMT-MCT
85Jiang (70)45FNasal sinus120OctreoscanNANANoPMT-MCT
86Jiang (70)57FNasal sinus102OctreoscanNANANoPMT-MCT
87Fatani (71)58MFloor of mouth, mandible240CTNANARecurrenceMultiple surgeries, wedge lung resectionMalignant PMTMCT
88Mathis (72)28FCribriform plate36MRINANANoPMTMCT
89Mathis (72)32MAnterior cranial fossa, ethmoid sinus12CTNANAPersistenceMultiple surgeries

PMTMCT
90Tarasova (73)60FLeft frontal mass48SVS132 pg/mL (N: 10–50)134 Ru/mL (N <180) (3 years after RT)NoNA
91Papierska (74)40NARight maxillary sinusNAOctreoscan260.4 Ru/ml (N: 5-105)NANAGlomangiopericytoma
92Lee (75)60FRight maxillary sinus72CTNANANoGlomangiopericytoma
93Allevi (76)FRight maxillary sinusOctreoscanNANANoPMT hemangiopericytoma
94Annamalai (77)49MLeft nasal cavity180FDG-PET/DOTA224.5 RU/mL (N <150)64.6 RU/mL (POD 2)NoPMTMCT
95Okamiya (78)35FLeft ethmoid sinus8FDG-PET147 pg/mL (N: 14–40)16 pg/mLNoPMTMCT
96Arnaoutakis (54)50FRight ethmoid sinus6PENANANAPMT
97Mok (79)48MRight maxillary sinus12MRINANANoPMT
98Fernández-Cooke (80)3MMaxilla and mandible6PE395.1 pg/mL (N <40) 1267.2 RU/ML (N <60)NormalPersistenceRFA, Local steroid infiltration, calcitonin, bisphosphonates, propranolol, cinacalcetCentral giant cell granuloma
99Fathalla (81)49FRight frontal lobe36Octreoscan609 RU/mL (N: 0–180)NANoPMTMCT
100Ray (82)35MLeft nasal cavity24CT5 X NNANoHemangiopericytoma
101Qari (83)60MGingiva of mandibular teeth72PENANANoPMT
102Wasserman (84)50MC3 vertebrae24NANANANoPMTMCT
103Wasserman (84)33FNose, lips, tongue120NANANAPersistenceNAMalignant PMTMCT
104Mani (85)56MOccipital bone36PENANANoPMTMCT
105Yu (86)37MMaxilla36PE129.97 pg/mL (N: 33.9–51.6)64.9 pg/mLNoPMTMCT
106Yu (86)50MMandible6PE312.84 pg/mL (N: 33.9–51.6)NANoSpindle cell tumor with PMT features
107Yu (86)50MLeft nasal cavity72Octreoscan272.71 pg/mL (N: 33.9–51.6)5.93 pg/mLNoPMTMCT
108Yu (86)38FLeft nasal cavity and ethmoid sinus12Octreoscan350.9 pg/mL (N: 33.9–51.6)NANoPMTMCT
109Takashi (87)77MLeft parotid gland96FDG-PET186.9 pg/mL6.5 pg/mLNoPMTMCT
110Gresham (88)42MEthmoid mass36MRINANANoGlomangioma
111Agaimy (89)48MNasal cavityNANANANACellular, nondescript
112Lee (90)33MRight mandible156Ga-DOTANOC86.7 pg/mL (N: 10–50)NANoGiant cell granuloma
113Lee (90)52MLeft ethmoid sinus6Ga-DOTANOC492.3 pg/mL (N: 10–50)NAPersistenceRTPMT
114Schober (91)59FRight fronto-basal region22SVS1600 Ru/mL (N: 26–110)74 Ru/mL RecurrenceRepeat surgery

Meningioma
115Zuo (92)NAMLeft nasal cavity36OctreoscanNANANoPMT
116Zuo (92)NAFLeft maxillary bone36FDG-PETNANANoPMT
117Hana (93)38MBilateral ethmoid sinus84MRI120 pg/mL (N: 10–50)ND (POD-1)PersistenceRepeat surgeryPMTMCT
118Chanukya (94)31MLeft nasal cavity24Ga-DOTANOC1310 Ru/mL (N: 0–150)109 Ru/mL (1 month post surgery)NoHemangiopericytoma
119Gonzalez (95)42MNasofrontal sinus72PE75.9 pg/mL (N: 8–54)8.4 pg/mLNoPMTMCT
120Singh (96)67MPosterior wall of mastoid antrum204Ga-DOTANOC237 Ru/mL (N: 0–150)NANAPMT
121Singh (96)45MLeft side of body of mandible12Ga-DOTANOC1553 Ru/mL (N: 0–150)NANAPMT
122Pelletier (97)37MMandibleNASVS f/b MRI310 Ru/mL (N: 19–114)NANANA
123Pelletier (97)49FMandibleOctreoscan of growing lesion on MRI with FDG-avidity and gradient on SVS1194 Ru/mL (N: 19–114)200 Ru/mLPersistenceNANA
125Villepelet (99)41FRight ethmoid sinusNACTNA48 pg/mL (POD-5)NoPMT
126Pelo (100)62FLeft TMJ60PENANANoPMT
127He (101)54FRight parotid24Ga-DOTANOCNANANASalivary basal cell adenoma
128Wu (102)49FRight mandible216NANANAPersistenceMultiple surgeriesOdontogenic fibroma
129Wu (102)20FLeft maxilla48NANANANoOdontogenic fibroma
130Wu (102)30FRight maxilla60NANANANoPMT of mixed epithelial & connective tissue type
131Wu (102)36MLeft mandible60NANANANoPMT of mixed epithelial & connective tissue type
132Wu (102)25MRight maxilla72NANANANoPMT of mixed epithelial and connective tissue type
133Wu (102)15FRight mandible24NANANANoPMT of mixed epithelial and connective tissue type
134Wu (102)41MRight mandible60NANANANAPMT of mixed epithelial and connective tissue type
135Wu (102)34MLeft maxilla72NANANANoPMT of mixed epithelial and connective tissue type
136Wu (102)50MRight mandible18NANANANoPMT of mixed epithelial and connective tissue type
137Wu (102)66MRight maxilla108NANANANoPMT of mixed epithelial and connective tissue type
138Wu (102)26MLeft maxilla36NANANANoPMT of mixed epithelial and connective tissue type
139Wu (102)32MRight maxilla36NANANANoPMT of mixed epithelial and connective tissue type
140Wu (102)41MRight mandible60NANANANoPMT of mixed epithelial and connective tissue type
141Wu (102)22MRight mandible24NANANANoPMT of mixed epithelial and connective tissue type
142Wu (102)31MRight maxilla36NANANANoPMT of mixed epithelial and connective tissue type
143Wu (102)51MLeft mandible132NANANANoPMT of mixed epithelial and connective tissue type
144Wu (102)75MRight mandible72NANANANoPMT of mixed epithelial and connective tissue type
145Ding (103)66FRight nasal cavity48Ga-DOTATATENANANANA
146Ding (103)41MRight mandible108Ga-DOTATATENANANANA
147Mishra (104)46MRight temporal lobe mass60Ga-DOTANOC1028 Ru/mL (N <180)NANAPMTMCT
148Mishra (104)52FLeft skull base tumor24Ga-DOTANOC725 Ru/mL (N <180)150 Ru/mL (3 months post-surgery)NoPMTMCT
149Li (105)40FLeft nasal cavity12HistoryNANARecurrenceRepeat surgery twiceHemangiopericytoma
150Acharya (106)42MRight mandible12FDG-PET332 Ru/mL (N <180)53 Ru/mL (POD 54)NoPMTMCT
151Kurien (107)39FRight nasal cavity24NA260 Ru/mL (N <180)40 Ru/mLNoPMTMCT
152Kurien (107)36FLeft ethmoid sinus24NANA126 Ru/mLNoPMTMCT
153Kurien (107)51MMiddle turbinate36NA604 Ru/mL (N <180)<5 Ru/mLNoPMTMCT
154Kurien (107)44MMiddle turbinate48NA145 Ru/mL (N <180)94.7 Ru/mLNoPMTMCT
155Kurien (107)55MPosterior ethmoid, sphenoid24NANANANoPMTMCT
156Kurien (107)37FAnterior ethmoid with intracranial extension36NA695 Ru/mL (N <180)38 Ru/mLPersistenceRTMalignant PMTMCT
157Kurien (107)62FNasal cavity, all PNS48NANA899 Ru/mLPersistenceObservationPMTMCT
158Paul (108)54FLeft mandible24Ga-DOTATATE1094 Ru/mL (N <180)369 Ru/mL (POD-5) 44 Ru/mL (4 months post-surgery)NoPMTMCT
159Pal (109)28MMandibleNAGa-DOTATATE201 Ru/mL (N <180)307 Ru/mLPersistentMedical managementHemangiopericytoma
160Pal (109)52FRight nasal cavityNAGa-DOTATATE814 Ru/mL (N <180)NANoArteriovenous hemangioma
161Pal (109)36FLeft maxillary sinusNAGa-DOTATATE1239 Ru/mL (N <180)NANoPMTMCT
162Pal (109)58MLeft nasal cavityNAGa-DOTATATE513 Ru/mL (N <180)NANoHemangiopericytoma
163Pal (109)36FLeft nasal cavityNAFDG-PET2467 Ru/mL (N <180)NANoHemangiopericytoma

F, female; M, male; N, normal value; NA, not available; OF, ossifying fibroma like; PE, physical examination; PMTMCT, phosphaturic mesenchymal tumor mixed connective tissue type; POD, post-op day; PRRT, peptide receptor radionuclide therapy; RT, radiation therapy; SVS, selective venous sampling of FGF-23; UD, undetectable.

Table 3

Summary of literature review.

ParameterValueNo. of patients with available data
Age (years) (mean ± s.d.)46 ± 14160
Sex81:81162
Location of tumor % (no.)163
 Paranasal sinuses43.7 (76)
 Mandible21.5 (34)
 Intracranial11.8 (19)
 Maxilla9 (13)
 Oral cavity6.2 (10)
 Skull1.2 (2)
 Parotid1.3 (2)
 Posterior neck1.3 (2)
 Cervical vertebra1.3 (2)
 Infratemporal fossa0.7 (1)
 Mastoid antrum0.7 (1)
 Thyroid0.7 (1)
Local symptoms % (no.)44.1 (49)111
Hypophosphatemic symptoms
 Muscle weakness % (no.)77.9 (106)136
 Fractures % (no.)61.2 (68)111
 Bone pains % (no.)100 (142)142
 Bony deformities % (no.)25.7 (27)105
Duration of symptoms (months), median (IQR)36 (24–72)139
Biochemical profile
 S. Calcium (mg %) (mean ± s.d.)8.9 ± 0.587
 S. Phosphorus (mg %) (mean ± s.d.)
  Pre-op1.4 ± 0.4119
  Post-op3 ± 0.762
 S. Alkaline phosphatase (U/L) (median (IQR))313 (200–420)95
 TMP/GFR (median (IQR))0.9 (0.6–1.3)39
 TRP (median (IQR))61 (46.2–72.2)21
 PTH (pg/mL) (median (IQR))55.9 (39.3–83.7)73
 1,25 (OH)2 vitamin D3 (pg/mL) (median (IQR))18 (8.2–26.2)46
FGF-23 (Pre-op) (median (IQR))
 X ULN3.6 (1.8–6.8)55
 C-terminal (Ru/mL)573 (234–1058)33
 Intact (pg/mL)256 (131–393)22
FGF-23 (Post-op)
 C-terminal (Ru/mL)69.3 (36.5–138)18
 Intact (pg/mL)14 (5.9–50)15
Tumor size (cm) (median (IQR))2.5 (1.8–3.2)70
Localization imaging % (no.)131
 History and PE16.7 (22)
 X-ray2.3 (3)
 CT scan25.9 (34)
 MRI10.6 (14)
 Octreotide scintigraphy20.6 (27)
 FDG-PET/CT8.4 (11)
 Ga-DOTA-based PET/CT11.4 (15)
 Selective venous sampling of FGF-233.8 (5)
Primary modality of treatment % (no.)160
 Surgery97.5 (156)
 Radiation therapy1.2 (2)
 Combined surgery + radiation therapy1.2 (2)
 Complete response to primary treatment % (no.)80.4 (119)148
 Persistent disease % (no.)13.5 (20)148
 Follow-up (months)13 (5.2–36)108
 Recurrence % (no.)7 (9)128
 Time to recurrence (months) (range)2–204
Site wise persistence/recurrence % (no./no.)
 Paranasal sinuses14.4 (7/4)76
 Mandible17.6 (6/0)34
 Intracranial36.8 (4/3)19
 Maxilla7.6 (1/0)13
 Oral cavity33.3 (1/2)10
 Thyroid100 (1)1
Secondary modality of treatment % (no.)26
 Surgery65.4 (17)
 RT30.8 (8)
 Chemotherapy7.7 (2)
 Cinacalcet7.7 (2)
 Octreotide7.7 (2)
 Radiofrequency ablation3.8 (1)
 PRRT3.8 (1)
 Others3.8 (1)
 Metastasis % (no.)2.7 (4)148
Histopathology % (no.)158
 PMTMCT48.7 (77)
 PMT ossifying fibroma like1.3 (2)
 PMT mixed epithelial and connective tissue type9.5 (15)
 Malignant PMTMCT3.2 (5)
 Hemangiopericytoma22.8 (36)
 Giant cell tumor3.2 (5)
 Odontogenic fibroma3.2 (5)
 Glomangiopericytoma2.5 (4)
 Malignant schwannoma0.6 (1)
 Meningioma0.6 (1)
 Salivary basal cell adenoma0.6 (1)
 Ameloblastic fibrosarcoma0.6 (1)
 Primitive mesenchymal tumor0.6 (1)
 Arteriovenous hemangioma0.6 (1)
 Spindle cell tumor with PMT features0.6 (1)
 Cellular non-descript0.6 (1)
 Chronic inflammatory tissue with fibrosis and epithelial cell rests0.6 (1)

Out of 148 patients for whom outcome data were available; 119 patients had complete initial response to surgery, 20 patients had persistent disease and 9 patients had recurrence as defined by worsening of post-operatively documented normal biochemistry over a variable period of 2–204 months. Patients with persistent/recurrent disease (n = 29) were predominantly managed with surgery (65.3%) and/or radiotherapy (30.7%). Among these patients 11 were reported to be alive with no evidence of disease (ANED) and remaining patients were managed with phosphorus supplements with/without other treatment modalities. Four patients had metastatic disease with lymph node and/or lung metastasis. Histopathologically, PMTMCT (48.7%) remains the most commonly reported tumor type followed by hemangiopericytoma (22.7%), PMT of mixed epithelial and connective tissue type (9.4%), giant cell tumor (3.1%) and odontogenic fibroma (3.1%). Other rare types of tumor have been shown in Table 3.

Discussion

TIO is a rare and underreported condition due to unawareness about the characteristic clinical and biochemical profile among treating clinicians. Through this study, we aim to highlight our experience with TIO cases involving head and neck region and provide a review of published literature analyzed on a per-patient basis. This will increase awareness and provide valuable insight on critical management issues for this rare diagnosis.

Cohort 1

A significant time gap between initial presentation till diagnosis persists even in the presence of local symptoms (1). For any atypical head and neck mass, clinician should enquire into history relevant to osteomalacia, and for a symptomatic patient appropriate biochemistry (S. calcium, S. phosphorus and alkaline phosphatase) should be requested. Vice versa, in a patient with non-localized TIO, a clinician should examine oral and nasal cavities for palpable swellings and enquire about relevant local symptoms.

At our center we carry out a complete biochemical evaluation for TIO which includes calcium studies (S. calcium, S. phosphorus, ALP), TMP/GFR, 1,25 (OH) vitamin D3 and FGF-23 levels. FGF-23 serves as a diagnostic marker as well as an indicator of residual disease or recurrence during long-term follow-up. Thereafter, functional imaging with Ga-DOTANOC PET/CT for localization is done. Its superiority compared to FDG-PET/CT is well established (110, 111, 112). Functional imaging is followed by appropriate anatomic imaging to determine tumor extent and plan for surgical management. Alternatively, in a TIO patient presenting with local symptoms or a mass in head and neck region, anatomic imaging (CT/MRI) followed by biopsy can also be used.

Complete surgical removal with wide margin of excision remains the cornerstone of management in these cases (3). This is particularly difficult in intracranial tumors resulting in persistent disease as noted in both our patients with intracranial tumors.

S. Phosphorus and FGF-23 levels are used for post-operative surveillance. Half-life of FGF-23 is very short and one can document it immediately post-operatively (93). Persistent elevation of FGF-23 was noted post-operatively in two patients (cases 1 and 6), which normalized on re-evaluation after 3 months. This observation has been previously reported particularly with C-terminal FGF-23 assay (108, 109). Phosphate supplements are discontinued post-operatively to allow for surveillance. Reimaging is performed in patients with persistent symptoms and biochemically active disease.

In recurrent or persistent cases, complete tumor removal resulted in cure in two patients, hence, this remains the preferred approach at our institute. In inoperable cases, two patients received external beam radiotherapy (EBRT) and one patient received peptide receptor radiotherapy (PRRT). In one patient (Case 2) EBRT was given after first surgery due to difficult tumor location at petrous apex. He had a gradual and complete response to RT over next 4 years. In another scenario (case 3), the patient had persistent disease after functional endoscopic sinus surgery (FESS) for left ethmoid sinus tumor. Following two repeat FESS, patient was considered for EBRT for persistent disease. Patient received IMRT 54 Gy in 30 fractions. S. Phosphorus and FGF-23 normalized gradually over one and half years and this patient who was previously bedbound is now walking without any support.

One patient (case 5) in our cohort has received PRRT for persistent disease after two surgeries for base of skull tumor (113). As tumor was Ga-DOTATATE avid having Krenning score IV, patient was considered for PRRT after a thorough discussion in a multidisciplinary meeting. This patient has stable disease after two cycles of PRRT with 150–200 uCi 177Lu-DOTATATE.

PMTMCT remains the commonest histopathologic entity in these patients. We also reported one patient for each of the following: PMT-OF like, odontogenic fibroma and hemangiopericytoma in our cohort. Detailed histopathological findings for cases three, four and six have been published previously (114).

Although the sample size of cohort 1 was small, the epidemiological data are similar to cohort 2. There is an increased prevalence of local symptoms at presentation and higher rate of persistence following primary surgery at our center. This could be attributed to referral bias to a tertiary care center.

Cohort 2

Here we present a detailed review of published English literature for TIO cases involving head and neck region (n = 163) (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109). This is the largest series of its kind published to date.

Epidemiology

As is the case with overall TIO literature, almost equal male:female ratio is reported in head and neck TIO patients (3). Middle age is the most common age at presentation and three pediatric cases are reported so far. TIO is a difficult diagnosis in pediatric patients as heritable hypophosphatemic rickets is a more likely diagnosis unless the tumor is evident. Fernández-Cooke et al. have reported a 3-year-old child with rickets and a jaw tumor. Two years went by before a link was established between the two and a diagnosis of TIO was made (80). In the case described by Reyes-Mugica et al. the heightened awareness of pediatric endocrinologist for this condition led to early screening with imaging and subsequent surgical removal resulting in cure within 6 weeks of onset of symptoms (25). In the third case reported by Wu et al. also the duration of hypophosphatemic symptoms was 2 years (102).

The time from symptom onset to final diagnosis remains dreadfully long. In this series of cases of TIO involving head and neck region, only 10% (n = 14) were diagnosed in the first year of disease onset with majority of them having local symptoms at presentation. Feng et al. observed a misdiagnosis rate of 95.1% with 240 case-times of misdiagnoses among 144 cases of TIO even in the presence of evident hypophosphatemia in 43.1% cases (115). Reasons cited for misdiagnosis were disease rarity, insidious onset, nonspecific clinical manifestations and poor recognition by the clinician. Presence of local compressive symptoms and/or swelling in approximately 50% patients in this review highlights the problem of delayed or missed diagnosis as musculoskeletal symptoms are ignored until presentation with advanced local symptoms.

Biochemical profile

The typical biochemical profile in TIO is straightforward: hypophosphatemia with normocalcemia, moderately elevated ALP, normal PTH, inappropriately normal-to-high urinary phosphate excretion, low serum 1,25 (OH)2 vitamin D3 and elevated FGF-23 levels (3).

FGF-23 is useful as a tumor marker. Based on two case reports, half-life of FGF-23 is between 20–50 min (116, 117). More recently, Hana et al. reported half-life of FGF-23 to be 18.5 min in a patient with intracranial PMTMCT using intact FGF-23 assay (93). This allows FGF-23 to be used for intraoperative monitoring to determine the extent of tumor removal. Immediate post-op decline in FGF-23 levels within normal range is reported by other investigators (36, 47, 51, 59) as well. Elston et al. reported discordant increase in C-terminal FGF-23 post-op which has not been confirmed by other studies (36). As previously stated, persistent elevation in C-terminal FGF-23 in immediate post-operative period has been documented despite complete tumor removal (108, 109). With no reports on levels of other postulated phosphotonins like matrix extracellular phosphoglycoprotein (MEPE) and secreted frizzled-related protein 4 (SFRP4) in patients with TIO, their role still remains unclear (118).

Location of tumor

Most common site for TIO in head and neck region is paranasal sinuses. Among them, ethmoid sinuses are the most common site followed by maxillary, sphenoid and frontal sinuses. Most common tumors are PMTMCT, hemangiopericytoma and glomangiopericytoma, in descending order. The second most common site is bony tumors arising from the mandible and maxilla with odontogenic fibroma and, PMT of mixed connective tissue and epithelial components as special tumor types. Third position is for intracranial tumors involving anterior cranial fossa, middle cranial fossa, and posterior cranial fossa, in descending order of prevalence. Reported tumors include PMTMCT, hemangiopericytoma and meningioma. Tumors of oral cavity include gingival tumors (molar/premolar), tongue and buccal vestibule in that order of occurrence. Apart from PMTMCT (including malignant) and hemangiopericytoma, tumors from this region also include giant cell tumor and ossifying fibroma. Rarely tumors have been reported from skull, parotid glands, posterior neck, infratemporal fossa, mastoid antrum, thyroid and vertebra.

Localization imaging

Classically, history of local compressive symptoms and/or visible mass on physical examination is instrumental in diagnosing TIO even in this current era of sensitive imaging modalities. Earlier clinicians were dependent on physical examination and x-rays for diagnosing TIO. Renton et al., Nitzan et al., and Nomura et al. have localized head and neck TIO through x-rays alone (5, 7, 8). With the introduction of CT scans (1980–2000), 60% tumors in the head and neck region were localized with this modality. The first localization of head and neck TIO on MRI was reported by Avila et al. in 1996 using MR skeletal survey (19).

Following in vitro demonstration of somatostatin receptors (SSTRs) by Reubi et al. (119), scintigraphic studies using 111In-pentetreotide for tumor localization was published by De Beur et al. in 2002 (120). Subsequently, localization with 99mTc-MIBI and FDG-PET scans was reported (121, 122). Use of FDG-PET was limited due to poor specificity of non-receptor-based imaging, and slow-growing nature of these tumors resulting in false-negative results (96). With improved spatial resolution, lower radiation dose and more rapid whole-body tomographic imaging of PET/CT studies in comparison to scintigraphy, 68Ga-DOTA-based PET/CT scans became the investigation modality of choice in TIO patients (112, 123). Various studies have shown superiority of 68Ga-DOTATATE PET/CT and 68Ga-DOTANOC PET/CT over FDG-PET/CT and Octreoscan for tumor localization in TIO (110, 111, 112). The largest such study is that of 54 patients by Zhang et al. using 68Ga-DOTATATE PET/CT reported 100% sensitivity and 90.9% specificity in lesion detection (124). Use of positron emitter radiotracer 68Ga enabling PET-based imaging along with higher affinity SSTR ligands like DOTATATE (SSTR 2>5) and DOTANOC (SSTR 2,3,5) are postulated to be responsible for enhanced sensitivity of 68Ga-DOTA-based PET/CT over Octreoscan (112). Thereafter, Singh et al. highlighted the issue of multiple low-grade benign uptakes using 68Ga-DOTANOC PET/CT especially at fracture sites and described the use of SUVmax and anatomical imaging showing soft tissue component in the lesion to pinpoint the causal lesion (96). In summary, Ga-DOTA-based PET/CT is superior to other functional studies like FDG-PET and Octreoscan, but its utilization will depend on local availability and expertise (119).

Selective venous sampling of FGF-23 has been studied for accurate localization of TIO. Kobayashi et al. used selective venous sampling as an initial guiding modality localizing the tumor to right head and neck region, although on retrospect distortion of right external ear canal was noted and no prior functional imaging was done to localize the tumor (48). Andreopoulou et al. reported sensitivity of 87% and specificity of 71% at FGF-23 concentration ratio of 1.6 between the venous drainage of the tumor bed and general circulation after sampling 17 major veins and their branches (60). They concluded that selective venous sampling is not useful in the absence of suspicious lesion on imaging studies and its use should be limited to cases with multiple suspicious sites or before resection in anatomically challenging cases. In 2017, Lee et al. reported contrasting results. In their cohort, five patients negative on both 111Indium-octreotide scintigraphy and FDG-PET/CT were subjected to selective blood sampling from 10 to 14 sites (90). They identified the culprit lesion on follow-up with targeted MRI or whole-body Ga-DOTATOC in four patients. Tarasova et al. and Shober et al. have used selective venous FGF-23 sampling to confirm the SSTR expressing meningioma to be the FGF-23 secreting culprit lesion as many meningiomas are avid on SSTR-based imaging but may not be the source of FGF-23 (73). In summary, in the current era of SSTR-based imaging, the role of this modality seems to be limited to cases with multiple suspicious uptake sites, intracranial lesions consistent with meningioma, and lastly in imaging negative cases to identify a target for focused follow-up imaging.

Treatment

Primary modality

Complete surgical resection with adequate wide margin remains the treatment of choice in these tumors (3). This is supported in head and neck TIO cases where anatomical sites less amenable for this approach have higher persistence or recurrence rate for example intracranial tumors. Hana et al. also reiterated this principle in their report on recurrent anterior skull base tumor with enbloc tumor removal followed by filling of the large skull base defect with pedicle subgaleal flap resulting in absence of recurrence over 25-month follow-up (93).

Stereotactic radiotherapy has been described in two cases as primary modality. Both patients had frontal lobe tumors and both refused surgery. One patient had lower plasma FGF-23 and oral phosphorous requirement at 6-month follow-up. The details of RT are not described in this case report (60). The second patient received 60 Gy of fractionated stereotactic radiotherapy over 5 weeks (73). On follow-up, patient was off phosphorus supplement and had normal FGF-23 concentration after 4 years. The tumor was stable with areas of multiple small hemorrhages. BMD improved by approximately 50% with no evident new fracture. As the tumors are slow growing, radiotherapy is deemed to be less effective (3).

Surgery combined with adjuvant post-op radiotherapy was used by John et al. in a case of invasive ‘malignant schwannoma’ (27). Over 2.5 years of follow-up, serum phosphorus normalized but 1,25(OH) vitamin D3 was persistently low. MRI showed no evidence of residual/recurrent tumor. Similarly, Lee et al. described a case where the patient received post-operative radiotherapy following incomplete removal of an ethmoid tumor, which resulted in normal serum phosphorus with no residual tumor on MRI after completion of RT (90).

In summary, although complete surgical excision remains the treatment modality of choice, in rare cases radiation therapy can be used with an expectant slow response.

Persistent/recurrent disease

Persistent/recurrent disease signifies failure of complete resection of the tumor after primary excision. This occurs more commonly in intracranial disease and oral cavity lesions where enbloc tumor removal is challenging and leads to higher surgical morbidity and complications. Serial biochemical follow-up is essential as true recurrences after complete biochemical resolution are known, but usually it is the recurrence of symptoms which brings the disease to surface.

After anatomic imaging to confirm the site of tumor recurrence, re-exploration of the surgical site along with attempted enbloc removal remains the preferred approach. Out of eleven patients with persistent/recurrent disease who have ANED on follow-up, eight have been treated with re-surgery alone.

In persistent cases multiple re-surgeries, radiotherapy, cinacalcet and octeotride have been used with limited success. Seufert et al. reported a patient with left thigh TIO localized on octreotide scinitigraphy having complete resolution of phosphaturia and normalization of serum phosphorus with 50–100 µg of octreotide thrice a day in preoperative setting (125). However, this initial success has not been replicated in subsequent studies (34, 126). Extrapolating from patients with hypoparathyroidism with elevated FGF-23 and serum phosphorus levels, Gellers et al. advocated for the use of cinacalcet in the treatment of TIO (127). But development of hypercalciuria and hypocalcemia limits the use of cinacalcet in this cohort. Disease stability with dasatinib has been reported (55). As these tumors also express SSTR, PRRT remains a potentially useful option in tumors showing Krenning III/IV uptake on 68Ga-DOTATATE PET/CT (113). It has been more than a decade of successful utilization of two radiopeptides 90Y-DOTATOC and 177Lu-DOTATATE for treatment of advanced neuroendocrine tumors (NETs) (128). After binding to SSTR these peptides are internalized in tumor cells and the released breakdown products in lysosomes mediate radioactivity-induced local damage (128). Apart from our case, we could not find any other experience with PRRT in TIO literature. In patients with persistent disease, treatment with oral phosphate supplements and calcitriol is continued for symptomatic improvement.

Metastases

Four cases of malignant TIO in head and neck region are reported so far. Three of them originated from oral cavity and one from mandible. Uramoto et al. described a case of malignant PMTMCT involving tongue with lymph node metastases treated with two surgeries followed by radiation therapy with persistent disease on last follow-up (39). Bergwitz et al. reported a patient with ameloblastic fibrosarcoma of mandible with pulmonary and lymph node metastases (61). Patient had multiple recurrences and was managed with repeated surgeries, and lastly cinacalcet with persistent hypophosphatemia. Fatani et al. reported an interesting case of malignant PMTMCT arising from oral cavity who after 17 years of follow-up developed lung metastases which were resected in addition to multiple surgeries for primary disease (71). Patient was normophosphatemic on follow-up. The fourth case of malignant PMTMCT was reported by Wasserman et al. (84). The tumor involved nose, lip and mouth. No further follow-up/management details have been reported.

Histopathology

Weidner et al. initially proposed the term phosphaturic mesenchymal tumors (PMT) and their classification into four distinct subtypes: (I) mixed connective tissue variant (MCT), (II) osteoblastoma like, (III) Non-ossifying fibroma type, (IV) ossifying fibroma like (129). In 2004, Folpe et al. reviewed all previously published cases and found that they all belong to PMTMCT category (10). In this review we have reported the revised diagnosis as mentioned by Folpe et al. In 2018, Wu et al. described a new entity called “PMT mixed epithelial and connective tissue type” which is found exclusively in alveolar bone of maxilla and mandible (102). They found this tumor to be common in males and in patients <40 years of age. They have proposed a revised diagnosis of previously published six cases to this new entity, but we have reported them according to the original report. Apart from PMTs, other reported tumors in head and neck region causing TIO include meningioma, salivary basal cell adenoma, malignant schwannoma, ameloblastic fibrosarcoma, and spindle cell tumor with PMT features.

Study limitations

To our knowledge this is the largest review of TIO due to tumors located in head and neck region till date. The per-patient analysis method used in this study with minute detailing of all clinically relevant published aspects is the major strength of this study. There are several limitations in this study. As the review is a retrospective analysis of published case reports, all the limitations pertaining to retrospective studies apply to it. Additionally, many case reports lacked important clinical details as majority of them focused on pathology or imaging. A meticulous attempt was made to include all published literature regarding the subject but a few studies may not have been included.

Summary

TIO in the head and neck region is a rare disorder that warrants management by a multidisciplinary team including an endocrinologist, head and neck surgeon, radiologist, nuclear physicist and pathologist. Low phosphorus with elevated FGF-23 levels in a patient with clinical features of osteomalacia and/or mass in the head and neck region should be evaluated with Ga-DOTA-based PET/CT imaging. An alternative approach would be anatomical imaging followed by biopsy in a patient with local symptoms and clinically apparent swelling. Complete surgical excision with wide margin is of utmost importance in these cases resulting in dramatic clinical and biochemical normalcy. Clinical and biochemical follow-up is necessary even after documented cure as true recurrences have been reported. Whenever complete excision is not achieved, repeat surgical excision is recommended for accessible disease burden. In inoperable cases, radiotherapy, PRRT and medical management are suitable alternatives which should be decided by a multidisciplinary team on an individual basis. Although the tumor remains benign in most cases, one must remain vigilant in case of long-standing disease due to the reported risk of metastasis. Histopathological examination in most cases reveals PMTMCT, but other types are also seen.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research has been supported by Department of Endocrinology, Seth GS Medical College & KEM Hospital, Mumbai, India and Diamond Jubilee Society Trust (DJST), KEM Hospital, Mumbai, India.

References

  • 1

    DreznerMK. Tumor-induced osteomalacia. In Primer on Metabolic Bone Diseases and Disorders of Mineral Metabolism 4th ed. ch 74 pp 331337. Ed. FavusMJ. Philadelphia, PA, USA: Lippincott-Raven1999.

    • Search Google Scholar
    • Export Citation
  • 2

    McCanceR. Osteomalacia with Loosers nodes (Milkman’s syndrome) due a raised resistance to vitamin D acquired about the age of 15 years. Quarterly Journal of Medicine 1947 3346.

    • Search Google Scholar
    • Export Citation
  • 3

    ChongWHMolinoloAAChenCCCollinsMT. Tumor-induced osteomalacia. Endocrine-Related Cancer 2011 R53R77. (https://doi.org/10.1530/ERC-11-0006)

  • 4

    JiangYXiaWBXingXPSilvaBCLiMWangOZhangHBLiFJingHLZhongDR Tumor‐induced osteomalacia: an important cause of adult‐onset hypophosphatemic osteomalacia in China: report of 39 cases and review of the literature. Journal of Bone and Mineral Research 2012 19671975. (https://doi.org/10.1002/jbmr.1642)

    • Search Google Scholar
    • Export Citation
  • 5

    RentonPShawDG. Hypophosphatemic osteomalacia secondary to vascular tumous of bone and soft tissue. Skeletal Radiology 1976 2124. (https://doi.org/10.1007/BF00347723)

    • Search Google Scholar
    • Export Citation
  • 6

    SweetRAMalesJLHamstraAJDeLucaHF. Vitamin D metabolite levels in oncogenic osteomalacia. Annals of Internal Medicine 1980 279280. (https://doi.org/10.7326/0003-4819-93-2-279)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    NitzanDWMarmaryYAzazB. Mandibular tumor-induced muscular weakness and osteomalacia. Oral Surgery Oral Medicine and Oral Pathology 1981 253256. (https://doi.org/10.1016/0030-4220(81)90257-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    NomuraGKoshinoYMorimotoHKidaHNomuraSTamaiK. Vitamin D resistant hypophosphatemic osteomalacia associated with osteosarcoma of the mandible: report of a case. Japanese Journal of Medicine 1982 3539. (https://doi.org/10.2169/internalmedicine1962.21.35)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    LinseyMSmithWYamauchiHBernsteinL. Nasopharyngeal angiofibroma presenting as adult osteomalacia: case report and review of the literature. Laryngoscope 1983 13281331. (https://doi.org/10.1002/lary.1983.93.10.1328)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    FolpeALFanburg-SmithJCBillingsSDBiscegliaMBertoniFChoJYEconsMJInwardsCYJan de BeurSMMentzelT Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature. American Journal of Surgical Pathology 2004 130. (https://doi.org/10.1097/00000478-200401000-00001)

    • Search Google Scholar
    • Export Citation
  • 11

    SeshadriMSCornishCJMasonRSPosenS. Parathyroid hormone like bioactivity in tumours from patients with oncogenic osteomalacia. Clinical Endocrinology 1985 689697. (https://doi.org/10.1111/j.1365-2265.1985.tb01130.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    JefferisAFTaylorPCAWalsh-WaringGP. Tumour associated hypophosphatemic osteomalacia occurring in a patient with an odontogenic tumour of the maxilla. Journal of Laryngology and Otology 1985 10111017. (https://doi.org/10.1017/s0022215100098091)

    • Search Google Scholar
    • Export Citation
  • 13

    WeidnerNbarRSWeissDStrottmannMP. Neoplastic pathology of oncogenic osteomalacia/rickets. Cancer 1985 16911705. (https://doi.org/10.1002/1097-0142(19850415)55:8<1691::aid-cncr2820550814>3.0.co;2-s)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    LeeHKSungWWSolodnikPShimshiM. Bone scan in tumour-induced osteomalacia. Journal of Nuclear Medicine 1995 247249.

  • 15

    CatalanoPJBrandweinMShahDKUrkenMLLawsonWBillerHF. Sinonasal hemangiopericytomas: a clinicopathologic and immunohistochemical study of seven cases. Head and Neck 1996 4253. (https://doi.org/10.1002/(SICI)1097-0347(199601/02)18:1<42::AID-HED6>3.0.CO;2-Z)

    • Search Google Scholar
    • Export Citation
  • 16

    WilkinsGEGranleeseSHegeleRGHoldenJAndersonDWBondyGP. Oncogenic osteomalacia: evidence for a humoral phosphaturic factor. Journal of Clinical Endocrinology and Metabolism 1995 16281634. (https://doi.org/10.1210/jcem.80.5.7745010)

    • Search Google Scholar
    • Export Citation
  • 17

    DavidKReveszTKratimenosGKrauszTCrockardHA. Oncogenic osteomalacia associated with a meningeal phosphaturic mesenchymal tumour. Journal of Neurologicalsurgery 1996 288292.

    • Search Google Scholar
    • Export Citation
  • 18

    KimYGChoiYSLeeSCRyuDM. Tumour-induced osteomalacia associated with lesions in the oral and maxillofacial region: report of two cases. Journal of Oral and Maxillofacial Surgery 1996 13521357. (https://doi.org/10.1016/s0278-2391(96)90497-8)

    • Search Google Scholar
    • Export Citation
  • 19

    AvilaNASkarulisMRubinoDMDoppmanJL. Oncogenic osteomalacia: lesion detection by MR skeletal survey. American Journal of Roentgenology 1996 343345. (https://doi.org/10.2214/ajr.167.2.8686600)

    • Search Google Scholar
    • Export Citation
  • 20

    YangIMParkYKHyunYJKimDYWooJTKimSWKimJWKimYSChoiYK. Oncogenic osteomalacia caused by a phosphaturic mesenchymal tumour of the oral cavity: a case report. Korean Journal of Internal Medicine 1997 8995. (https://doi.org/10.3904/kjim.1997.12.1.89)

    • Search Google Scholar
    • Export Citation
  • 21

    Gonzalez-ComptaXManos-PujolMFoglia-FernandezMPeralECondomEClavegueraTDicenta-SousaM. Oncogenic osteomalacia: case report and review of head and neck associated tumours. Journal of Laryngology and Otology 1998 389392. (https://doi.org/10.1017/s0022215100140551)

    • Search Google Scholar
    • Export Citation
  • 22

    OhashiKOhnishiTIshikawaTTaniHUesugiKTakagiM. Oncogenic osteomalacia presenting as bilateral stress fractures of the tibia. Skeletal Radiology 1999 4648. (https://doi.org/10.1007/s002560050471)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    ClunieGPRFoxPEStampTCB. Four cases of acquired hypophosphatemic (oncogenic) osteomalacia. Problems of diagnosis, treatment and long-term management. Rheumatology 2000 14151421. (https://doi.org/10.1093/rheumatology/39.12.1415)

    • Search Google Scholar
    • Export Citation
  • 24

    SandhuFAMartuzaRL. Craniofacial hemangiopericytoma associated with oncogenic osteomalacia: case report. Journal of Neuro-Oncology 2000 241247. (https://doi.org/10.1023/a:1006352106762)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Reyes-MugicaMArnsmeierSLBackeljauwPFPersingJEllisBCarpenterTO. Phosphaturic mesenchymal tumour-induced rickets. Pediatric and Developmental Pathology 2000 6169. (https://doi.org/10.1007/s100240050008)

    • Search Google Scholar
    • Export Citation
  • 26

    KawaiYMorimotoSSakaguchiKYoshinoHYotsuiTHirotaSInoharaHNakagawaTHattoriKKuboT Oncogenic osteomalacia secondary to nasal tumour with decreased urinary excretion of cAMP. Journal of Bone and Mineral Metabolism 2001 6164. (https://doi.org/10.1007/s007740170062)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    JohnMRWickertHZaarKJonssonKBGrauerARuppersbergerPSchmidt-GaykHMurerHZieglerRBlindE. A case of neuroendocrine oncogenic osteomalacia associated with a PHEX and fibroblast growth factor-23 expressing sinusoidal malignant schwannoma. Bone 2001 393402. (https://doi.org/10.1016/s8756-3282(01)00586-5)

    • Search Google Scholar
    • Export Citation
  • 28

    Reis-FilhoJSPaivaMELopesJM. August 2003: 47-year-old female with a 7-year history of osteomalacia and hypophosphatemia. Brain Pathology 2004 111112 115. (https://doi.org/10.1111/j.1750-3639.2004.tb00505.x)

    • Search Google Scholar
    • Export Citation
  • 29

    FuentealbaCPintoDBallesterosFPachecoDBoettigerOSotoNFernandezWGablerFGonzalesGReginatoAJ. Oncogenic hypophosphatemic osteomalacia associated with a nasal hemangiopericytoma. Journal of Clinical Rheumatology 2003 373379. (https://doi.org/10.1097/01.rhu.0000101906.15276.ed)

    • Search Google Scholar
    • Export Citation
  • 30

    UngariCRocchiGRinnaCAgrilloALattanziAPagnoniM. Hypophosphaturic mesenchymal tumour of the ethmoid associated with oncogenic osteomalacia. Journal of Craniofacial Surgery 2004 523527.

    • Search Google Scholar
    • Export Citation
  • 31

    DupondJLMahammediHMagyNBlagosklonovOMeaux-RuaultNKantelipB. Detection of a mesenchymal tumor responsible for hypophosphatemic osteomalacia using FDG-PET. European Journal of Internal Medicine 2005 445446. (https://doi.org/10.1016/j.ejim.2005.07.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    KaylieDMJacksonCGGardnerEK. Oncogenic osteomalacia caused by phosphaturic mesenchymal tumor of the temporal bone. Otolaryngology–Head and Neck Surgery 2006 653654. (https://doi.org/10.1016/j.otohns.2005.03.086)

    • Search Google Scholar
    • Export Citation
  • 33

    InokuchiGTanimotoHIshidaHSugimotoTYamauchiMMiyauchiANibuK. A paranasal tumor associated with tumor-induced osteomalacia. Laryngoscope 2006 19301933. (https://doi.org/10.1097/01.mlg.0000231295.67060.89)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    YoshiokaKNagataRUedaMYamaguchiTKonishiYHosoiMInoueTYamanakaKIwaiYSatoT. Phosphaturic mesenchymal tumor with symptoms related to osteomalacia that appeared one year after tumorectomy. Internal Medicine 2006 11571160. (https://doi.org/10.2169/internalmedicine.45.1797)

    • Search Google Scholar
    • Export Citation
  • 35

    KoriyamaNNishimotoKKodamaTNakazakiMKuronoYYoshidaHTeiC. Oncogenic osteomalacia in a case with a maxillary sinus mesenchymal tumor. American Journal of the Medical Sciences 2006 142147. (https://doi.org/10.1097/00000441-200609000-00010)

    • Search Google Scholar
    • Export Citation
  • 36

    ElstonMSStewartIJClifton-BlighRConaglenJV. A case of oncogenic osteomalacia with preoperative secondary hyperparathyroidism: description of the biochemical response of FGF23 to octreotide therapy and surgery. Bone 2007 236241. (https://doi.org/10.1016/j.bone.2006.07.027)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    BeechTJRokadeAGittoesNJohnsonAP. A hemangiopericytoma of the ethmoid sinus causing oncogenic osteomalacia: a case report and review of the literature. International Journal of Oral and Maxillofacial Surgery 2007 956958. (https://doi.org/10.1016/j.ijom.2007.03.005)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    AhnJMKimHJChaCMKimJYimSGKimHJ. Oncogenic osteomalacia: induced by tumour, cured by surgery. Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontics 2007 636641. (https://doi.org/10.1016/j.tripleo.2005.12.027)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    UramotoNFurukawaMYoshizakiT. Malignant phosphaturic mesenchymal tumor, mixed connective tissue variant of the tongue. Auris Nasus Larynx 2009 104105. (https://doi.org/10.1016/j.anl.2008.01.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    LewieckiEMUrigEJWilliamsRC. Tumor-induced osteomalacia: lessons learned. Arthritis and Rheumatism 2008 773777. (https://doi.org/10.1002/art.23278)

  • 41

    KenealyHHoldawayIGreyA. Occult nasal sinus tumours causing oncogenic osteomalacia. European Journal of Internal Medicine 2008 516519. (https://doi.org/10.1016/j.ejim.2008.01.011)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    YunKIKimDHPyoSW. A phosphaturic mesenchymal tumor of the floor of the mouth with oncogenic osteomalacia: report of a case. Journal of Oral and Maxillofacial Surgery 2009 402405. (https://doi.org/10.1016/j.joms.2008.01.007)

    • Search Google Scholar
    • Export Citation
  • 43

    WooVLLandesbergRImelEASingerSRFolpeALEconsMJKimTHarikLRJacobsTP. Phosphaturic mesenchymal tumor, mixed connective tissue variant, of the mandible: report of a case and review of the literature. Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontics 2009 925932. (https://doi.org/10.1016/j.tripleo.2009.07.005)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    SavageCRZimmerLA. Oncogenic osteomalacia from pterygopalatine fossa mass. Journal of Laryngology and Otology 2009 10521054. (https://doi.org/10.1017/S0022215109004927)

    • Search Google Scholar
    • Export Citation
  • 45

    KurienRManipadamMTRupaV. Oncogenic osteomalacia in a patient with an ethmoid sinus tumour. Journal of Laryngology and Otology 2010 799803. (https://doi.org/10.1017/S0022215109992313)

    • Search Google Scholar
    • Export Citation
  • 46

    GuptaRSharmaAKshAKhadgawatRDindaAK. Phosphaturic mesenchymal tumour of the sinonasal tract. Acta Endocrinologica (Bucharest) 2009 5 537541. (https://doi.org/10.4183/aeb.2009.537)

    • Search Google Scholar
    • Export Citation
  • 47

    GoreMOWelchBJGengWKabbaniWMaaloufNMZerweknJEMoeOWSakhaeeK. Renal phosphate wasting due to tumor-induced osteomalacia: a frequently delayed diagnosis. Kidney International 2009 342347. (https://doi.org/10.1038/ki.2008.355)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    KobayashiKNakaoKKawaiKItoKHukumotoSAsakageTOotaSMotoiR. Tumor-induced osteomalacia originating from the temporal bone: a case report. Head and Neck 2011 10721075. (https://doi.org/10.1002/hed.21355)

    • Search Google Scholar
    • Export Citation
  • 49

    ShelekhovaKVKazakovDVMichalM. Sinonasal phosphaturic mesenchymal tumor (mixed connective tissue variant): report of 2 cases. American Journal of Surgical Pathology 2010 596597. (https://doi.org/10.1097/PAS.0b013e3181d594fa)

    • Search Google Scholar
    • Export Citation
  • 50

    PedrazzoliMCollettiGFerrariMRossettiGMoneghiniLAutelitanoL. Mesenchymal phosphaturic neoplasm in the maxillary sinus: a case report. International Journal of Oral and Maxillofacial Surgery 2010 10271032. (https://doi.org/10.1016/j.ijom.2010.04.039)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51

    MoriYOgasawaraTMotoiTShimizuYChikazuDTamuraKFukumotoSTakatoT. Tumor-induced osteomalacia associated with a maxillofacial tumor producing fibroblast growth factor 23: report of a case and review of the literature. Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontics 2010 e57e63. (https://doi.org/10.1016/j.tripleo.2009.10.052)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 52

    ParshwanathHAKulkarniPRRaoRJoshiSKPatilP. Phosphaturic mesenchymal tumor of ethmoid sinus. Indian Journal of Pathology and Microbiology 2010 384385. (https://doi.org/10.4103/0377-4929.64317)

    • Search Google Scholar
    • Export Citation
  • 53

    BattooAJSalihSUnnikrishAGJojoABahadurSIyerSKuriakoseMA. Oncogenic osteomalacia from nasal cavity giant cell tumor. Head and Neck 2012 454457. (https://doi.org/10.1002/hed.21562)

    • Search Google Scholar
    • Export Citation
  • 54

    ArnaoutakisDNaseriI. Sinonasal phosphaturic mesenchymal tumor: a rare and misinterpreted entity. Journal of Neurological Surgery Reports 2015 e233e238. (https://doi.org/10.1055/s-0035-1562852)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 55

    PetersKBMcLendonRMorseMAVredenburghJJ. Treatment of recurrent intracranial hemangiopericytoma with SRC-related tyrosine kinase targeted therapy: a case report. Case Reports in Oncology 2010 9397. (https://doi.org/10.1159/000307468)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56

    AkhterMSugruePABainsRKhavkinYA. Oncogenic osteomalacia of the cervical spine: a rare case of curative resection and reconstruction. Journal of Neurosurgery. Spine 2011 453456. (https://doi.org/10.3171/2010.11.SPINE09750)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57

    Xian-LingWJian-MingBWen-wenZZhao-HuiLJing-TaoDJu-MingLYi-MingM. Osteomalacia caused by tumors in facies cranii mimicking rheumatoid arthritis. Rheumatology International 2012 25732576. (https://doi.org/10.1007/s00296-011-2018-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58

    GuglielmiGBiscegliaMScillitaniAFolpeAL. Oncogenic osteomalacia due to phosphaturic mesenchymal tumor of the craniofacial sinuses. Clinical Cases in Mineral and Bone Metabolism 2011 4549.

    • Search Google Scholar
    • Export Citation
  • 59

    UnoTKawaiKKuniiNFukumotoSShibaharaJMotoiTSaitoN. Osteomalacia caused by skull base tumors: report of 2 cases. Neurosurgery 2011 E239E244; discussion E244. (https://doi.org/10.1227/NEU.0b013e31821867f7)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 60

    AndreupoulouPDumitrescuCEKellyMHBrillanteBAPeckCMCWodajoFMChangRCollinsMT. Selective venous catheterization for the localization of phosphaturic mesenchymal tumors. Journal of Bone and Mineral Research 2011 12951302.

    • Search Google Scholar
    • Export Citation
  • 61

    BergwitzCCollinsMTKamathRSRosenbergAE. Case 33–2011: a 56-year-old man with hypophosphatemia. New England Journal of Medicine 2011 16251635. (https://doi.org/10.1056/NEJMcpc1104567)

    • Search Google Scholar
    • Export Citation
  • 62

    MonappaVNaikAMMathewMRaoLRaoSKRamachandraLPadmapriyaJ. Phosphaturic mesenchymal tumour of the mandible – the useful criteria for a diagnosis on fine needle aspiration cytology. Cytopathology 2014 5456. (https://doi.org/10.1111/cyt.12030)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63

    ChokyuIIshibashiKGotoTOhataK. Oncogenic osteomalacia associated with mesenchymal tumor in the middle cranial fossa: a case report. Journal of Medical Case Reports 2012 181. (https://doi.org/10.1186/1752-1947-6-181)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 64

    ChiamPTanHCBeeYMChandranM. Oncogenic osteomalacia – hypophosphatemic spectrum from benignancy to malignancy. Bone 2013 182187. (https://doi.org/10.1016/j.bone.2012.11.040)

    • Search Google Scholar
    • Export Citation
  • 65

    ChoSDoNYYuSWChoiJY. Nasal hemangiopericytoma causing oncogenic osteomalacia. Clinical and Experimental Otolaryngology 2012 173176.

  • 66

    BurnandHSamuelsAHaganISawantNMutimerJ. Bilateral subtrochanteric fractures in tumor-induced osteomalacia caused by a nasal hemangiopericytoma. Hip International 2012 227229. (https://doi.org/10.5301/HIP.2012.9235)

    • Search Google Scholar
    • Export Citation
  • 67

    Brandwein-GenslerMSiegalGP. Striking pathology gold: a singular experience with daily reverberations: sinonasal hemangiopericytoma (glomangiopericytoma) and oncogenic osteomalacia. Head and Neck Pathology 2012 6474. (https://doi.org/10.1007/s12105-012-0337-8)

    • Search Google Scholar
    • Export Citation
  • 68

    MunozJOrtegaRMCelzoFDonthireddyV. Tumour-induced osteomalacia. BMJ Case Reports 2012 2012 bcr0320125975. (https://doi.org/10.1136/bcr.03.2012.5975)

    • Search Google Scholar
    • Export Citation
  • 69

    ChangCVCondeSJLuvizottoRAMNunesVSBonatesMCFelicioACLindseySCMoraesFHTagliariniJVMazetoGMFS Oncogenic osteomalacia: loss of hypophosphatemia might be the key to avoid misdiagnosis. Arquivos Brasileiros de Endocrinologia e Metabologia 2012 570573. (https://doi.org/10.1590/S0004-27302012000800018)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 70

    JiangYXiaWBXingXPSilvaBCLiMWangOZhangHBLiFJingHLZhongDR Tumor-induced osteomalacia: an important cause of adult-onset hypophosphatemic osteomalacia in China: report of 39 cases and review of the literature. Journal of Bone and Mineral Research 2012 19671975. (https://doi.org/10.1002/jbmr.1642)

    • Search Google Scholar
    • Export Citation
  • 71

    FataniHASunbuliMLaiSYBellD. Phosphaturic mesenchymal tumor: a report of 6 patients treated at a single institution and comparison with reported series. Annals of Diagnostic Pathology 2013 319321. (https://doi.org/10.1016/j.anndiagpath.2012.06.005)

    • Search Google Scholar
    • Export Citation
  • 72

    MathisDAStehelEJBeshayJEMickeyBEFolpeALRaisanenJ. Intracranial phosphaturic mesenchymal tumors: report of 2 cases. Journal of Neurosurgery 2013 903907. (https://doi.org/10.3171/2012.12.JNS12598)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 73

    TarasovaVDTrepp-CarrascoAGThompsonRReckerRRChongWHCollinsMTArmasLA. Successful treatment of tumor-induced osteomalacia due to an intracranial tumor by fractionated stereotactic radiotherapy. Journal of Clinical Endocrinology and Metabolism 2013 42674272. (https://doi.org/10.1210/jc.2013-2528)

    • Search Google Scholar
    • Export Citation
  • 74

    PapierskaLĆwikłaJBMisiorowskiWRabijewskiMSikoraKWanyuraH. Unusual case of phosphaturic mesenchymal tumor. Polskie Archiwum Medycyny Wewnetrznej 2013 255256. (https://doi.org/10.20452/pamw.1738)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 75

    LeeGGDhongHJParkYSKoYH. Sinonasal glomangiopericytoma causing oncogenic osteomalacia. Clinical and Experimental Otorhinolaryngology 2014 145148. (https://doi.org/10.3342/ceo.2014.7.2.145)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 76

    AlleviFRabbiosiDMandalaMCollettiG. Mesenchymal phosphaturic tumour: early detection of recurrence. BMJ Case Reports 2014 2014 bcr2013202827. (https://doi.org/10.1136/bcr-2013-202827)

    • Search Google Scholar
    • Export Citation
  • 77

    AnnamalaiAKSampathkumarKKaneSShettyNSKulkarniSRangarajanVPurandareNPaiPSMahuvakarADShanthiR Needles in the haystack – synchronous multifocal tumor-induced osteomalacia. Journal of Clinical Endocrinology and Metabolism 2016 390393. (https://doi.org/10.1210/jc.2015-3854)

    • Search Google Scholar
    • Export Citation
  • 78

    OkamiyaTTakahashiKKamadaHHiratoJMotoiTFukumotoSChikamatsuK. Oncogenic osteomalacia caused by an occult paranasal sinus tumor. Auris Nasus Larynx 2015 167169. (https://doi.org/10.1016/j.anl.2014.10.001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 79

    MokYLeeJCLumJHYPeterssonF. From epistaxis to bone pain – report of two cases illustrating the clinicopathological spectrum of phosphaturic mesenchymal tumor with fibroblast growth factor receptor 1 immunohistochemical and cytogenetic analyses. Histopathology 2016 925930. (https://doi.org/10.1111/his.12872)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 80

    Fernandez-CookeECruz-RojoJGallegoCRomanceAIMosqueda-PenaRAlmadenYdel PozoJS. Tumor-induced rickets in a child with a central giant cell granuloma: a case report. Pediatrics 2015 e1518e1523. (https://doi.org/10.1542/peds.2014-2218)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 81

    FathallaHCusimanoMDi levaAKaramchandaniJFungRKovacsK. Osteomalacia-inducing tumors of the brain: a case report, review and a hypothesis. World Neurosurgery 2015 189.e1189.e5. (https://doi.org/10.1016/j.wneu.2015.02.030)

    • Search Google Scholar
    • Export Citation
  • 82

    RaySChakrabortyPPBiswasKGhoshSMukhopadhyaySChowdhuryS. A case of oncogenic osteomalacia due to occult nasal sinus tumor. Clinical Cases in Mineral and Bone Metabolism 2015 6568. (https://doi.org/10.11138/ccmbm/2015.12.1.065)

    • Search Google Scholar
    • Export Citation
  • 83

    QariHHamao-SakamotoAFuselierCChengYSLKesslerHWrightJ. Phosphaturic mesenchymal tumor: 2 new oral cases and review of 53 cases in the head and neck. Head and Neck Pathology 2016 192200. (https://doi.org/10.1007/s12105-015-0668-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 84

    WassermanJKPurginaBLaiCKGravelDMahaffeyABellDChioseaSI. Phosphaturic mesenchymal tumor involving the head and neck: a report of five cases with FGFR1 fluorescence in situ hybridization analysis. Head and Neck Pathology 2016 279285. (https://doi.org/10.1007/s12105-015-0678-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 85

    ManiMKPanigrahiMK. Unusual calvarial tumour-oncogenic osteomalacia. British Journal of Neurosurgery 2017 495496. (https://doi.org/10.3109/02688697.2016.1161165)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 86

    YuWJHeJWFuWZWangCZhangZL. Reports of 17 Chinese patients with tumor-induced osteomalacia. Journal of Bone and Mineral Metabolism 2017 298307. (https://doi.org/10.1007/s00774-016-0756-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 87

    TakashiYKinoshitaYItoNTaguchiMTakahashiMEgamiNTajimaSNangakuMFukumotoS. Tumor-induced osteomalacia caused by a parotid tumor. Internal Medicine 2017 535539. (https://doi.org/10.2169/internalmedicine.56.7565)

    • Search Google Scholar
    • Export Citation
  • 88

    GreshamMSShenSZhangYJGallagherK. Anterior skull base glomangioma-induced osteomalacia. Journal of Neurological Surgery Reports 2017 e9e11. (https://doi.org/10.1055/s-0036-1597599)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 89

    AgaimyAMichalMChioseaSPeterssonFHadravskyLKristiansenGHorchRESchmoldersJHartmannAHallerF Phosphaturic mesenchymal tumors: clinicopathologic, immunohistochemical and molecular analysis of 22 cases expanding their morphologic and immunophenotypic spectrum. American Journal of Surgical Pathology 2017 13711380. (https://doi.org/10.1097/PAS.0000000000000890)

    • Search Google Scholar
    • Export Citation
  • 90

    LeeJYParkHSHanSLimJKHongNParkSIRheeY. Localization of oncogenic osteomalacia by systemic venous sampling of fibroblast growth factor 23. Yonsei Medical Journal 2017 981987. (https://doi.org/10.3349/ymj.2017.58.5.981)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 91

    SchoberHCKneitzCFieberFHesseKSchroederH. Selective blood sampling for FGF-23 in tumor-induced osteomalacia. Endocrinology Diabetes and Metabolism Case Reports 2017 1. (https://doi.org/10.1530/EDM-17-0006)

    • Search Google Scholar
    • Export Citation
  • 92

    ZuoQYWangHLiWNiuXHHuangYHChenJYouYHLiuBYCuiAMDengW. Treatment and outcomes of tumor-induced osteomalacia associated with phosphaturic mesenchymal tumors: retrospective review of 12 patients. BMC Musculoskeletal Disorders 2017 403. (https://doi.org/10.1186/s12891-017-1756-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 93

    HanaTTanakaSNakatomiHShojimaMFukumotoSIkemuraMSaitoN. Definitive surgical treatment of osteomalacia induced by skull base tumor and determination of the half-life of serum fibroblast growth factor 23. Endocrine Journal 2017 10331039. (https://doi.org/10.1507/endocrj.EJ17-0177)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 94

    ChanukyaGVMengadeMGoudJRaoISJainA. Tumor-induced osteomalacia: a Sherlock Holmes approach to diagnosis and management. Annals of Maxillofacial Surgery 2017 143147. (https://doi.org/10.4103/ams.ams_123_16)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 95

    GonzalezGBaudrandRSepulvedaMFVucetichNGuardaFJVillanuevaPContrerasOVillaASalechFToroL Tumor-induced osteomalacia: experience from a South American academic centre. Osteoporosis International 2017 21872193. (https://doi.org/10.1007/s00198-017-4007-2)

    • Search Google Scholar
    • Export Citation
  • 96

    SinghDChopraARavinaMKongaraSBhatiaEKumarNGuptaSYadavSDabadghaoPYadavR Oncogenic osteomalacia: role of Ga-68 DOTANOC PET/CT scan in identifying the culprit lesion and its management. British Journal of Radiology 2017 20160811. (https://doi.org/10.1259/bjr.20160811)

    • Search Google Scholar
    • Export Citation
  • 97

    PelletierKTroyanovSGuiteJFSainte-MarieLGRobergeDLessardM. Localization of ectopic fibroblast growth factor 23 production in tumor-induced osteomalacia using selective venous samplings. Clinical Nephrology 2017 107110. (https://doi.org/10.5414/CN108981)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 98

    MumfordEMarksJWagnerTGallimoreAGaneSWalshSB. Oncogenic osteomalacia: diagnosis, localisation, and cure. Lancet Oncology 2018 e365. (https://doi.org/10.1016/S1470-2045(18)30276-6)

    • Search Google Scholar
    • Export Citation
  • 99

    VillepeletACasiraghiOTemamSMoya-PlanaA. Ethmoid tumor and oncogenic osteomalacia: case report and review of the literature. European Annals of Otorhinolaryngology Head and Neck Diseases 2018 365369. (https://doi.org/10.1016/j.anorl.2018.07.001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 100

    PeloSGaspariniGGaragiolaUD’AmatoGSaponaroGDonedduPTodaroMMoroA. Phosphaturic mesenchymal tumor, an unusual localization in head and neck. Journal of Surgical Case Reports 2018 rjy091. (https://doi.org/10.1093/jscr/rjy091)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 101

    HeQXuZZhangBHuWZhangX. Tumor-induced osteomalacia caused by a parotid basal cell adenoma detected by 68Ga-DOTANOC PET/CT. Clinical Nuclear Medicine 2018 e198e199. (https://doi.org/10.1097/RLU.0000000000002076)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 102

    WuHBuiMMZhouLLiDZhangHZhongD. Phosphaturic mesenchymal tumor with an admixture of epithelial and mesenchymal elements in the jaws: clinicopathological and immunohistochemical analysis of 22 cases with literature review. Modern Pathology 2019 189204. (https://doi.org/10.1038/s41379-018-0100-0)

    • Search Google Scholar
    • Export Citation
  • 103

    DingJHuGWangLLiFHuoL. Increased activity due to fractures does not significantly affect the accuracy of 68Ga-DOTATATE PET/CT in the detection of culprit tumor in the evaluation of tumor-induced osteomalacia. Clinical Nuclear Medicine 2018 880886. (https://doi.org/10.1097/RLU.0000000000002290)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 104

    MishraTDesouzaMAPatelKMazumdarGA. Phosphaturic mesenchymal tumors involving skull bones: report of two rare cases. Asian Journal of Neurosurgery 2019 253255. (https://doi.org/10.4103/ajns.AJNS_176_17)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 105

    LiJHuangYYangFZhangQChenDWangQ. Sinonasal hemangiopericytoma caused hypophosphatemic osteomalacia: a case report. Medicine 2018 e13849. (https://doi.org/10.1097/MD.0000000000013849)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 106

    AcharyaRPWonAMMoonBSFlintJHRoubaudMSWilliamsMDHesselACMurphyJr WAChambersMSGagelRF. Tumor‐induced hypophosphatemic osteomalacia caused by a mesenchymal tumor of the mandible managed by a segmental mandibulectomy and microvascular reconstruction with a free fibula flap. Head and Neck 2019 E93E98. (https://doi.org/10.1002/hed.25657)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 107

    KurienRRupaVThomasM. Varied presentation of sinonasal phosphaturic mesenchymal tumour: report of a case series with follow-up. European Archives of Oto-Rhino-Laryngology 2019 16771684. (https://doi.org/10.1007/s00405-019-05341-8)

    • Search Google Scholar
    • Export Citation
  • 108

    PaulJCherianKEKapoorNPaulTV. Treating osteoporosis: a near miss in an unusual case of FGF-23 mediated bone loss. BMJ Case Reports 2019 e228375. (https://doi.org/10.1136/bcr-2018-228375)

    • Search Google Scholar
    • Export Citation
  • 109

    PalRBhadadaSKSinghareABhansaliAKamalanathanSChadhaMChauhanPSoodADhimanVSharmaDC Tumor-induced osteomalacia: experience from three tertiary care centers in India. Endocrine Connections 2019 266276. (https://doi.org/10.1530/EC-18-0552)

    • Search Google Scholar
    • Export Citation
  • 110

    JadhavSKasaliwalRLeleVRangarajanVChandraPShahHMalhotraGJagtapVSBudyalSLilaAR Functional imaging in primary tumour-induced osteomalacia: relative performance of FDG PET/CT vs somatostatin receptor-based functional scans: a series of nine patients. Clinical Endocrinology 2014 3137. (https://doi.org/10.1111/cen.12426)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 111

    AgrawalKBhadadaSMittalBRShuklaJSoodABhattacharyaABhansaliA. Comparison of 18F-FDG and 68Ga DOTATATE PET/CT in localization of tumor causing oncogenic osteomalacia. Clinical Nuclear Medicine 2015 e6e10. (https://doi.org/10.1097/RLU.0000000000000460)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 112

    El-MaoucheDSadowskiSMPapadakisGZGuthrieLCottle-DelisleCMerkelRMilloCChenCCKebebewECollinsMT. 68Ga-DOTATATE for tumor localization in tumor-induced osteomalacia. Journal of Clinical Endocrinology and Metabolism 2016 35753581. (https://doi.org/10.1210/jc.2016-2052)

    • Search Google Scholar
    • Export Citation
  • 113

    BasuSFargoseP. 177Lu-DOTATATE PRRT in recurrent skull-base phosphaturic mesenchymal tumor causing osteomalacia: a potential application of PRRT beyond neuroendocrine tumors. Journal of Nuclear Medicine Technology 2016 248250. (https://doi.org/10.2967/jnmt.116.177873)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 114

    KaneSVKakkarAOzaNSridharEPaiPS. Phosphaturic mesenchymal tumor of the nasal cavity and paranasal sinuses: a clinical curiosity presenting a diagnostic challenge. Auris Nasus Larynx 2018 377383. (https://doi.org/10.1016/j.anl.2017.05.006)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 115

    FengJJiangYWangOLiMXingXHuoLLiFYuWZhongDRJinJ The diagnostic dilemma of tumor induced osteomalacia: a retrospective analysis of 144 cases. Endocrine Journal 2017 675683. (https://doi.org/10.1507/endocrj.EJ16-0587)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 116

    KhosraviACutlerCMKellyMHChangRRoyalRESherryRMWodajoFMFedarkoNSCollinsMT. Determination of the elimination half-life of fibroblast growth factor-23. Journal of Clinical Endocrinology and Metabolism 2007 23742377. (https://doi.org/10.1210/jc.2006-2865)

    • Search Google Scholar
    • Export Citation
  • 117

    TakeuchiYSuzukiHOguraSImaiRYamazakiYYamashitaTMiyamotoYOkazakiHNakamuraKNakaharaK Venous sampling for fibroblast growth factor-23 confirms preoperative diagnosis of tumor-induced osteomalacia. Journal of Clinical Endocrinology and Metabolism 2004 39793982. (https://doi.org/10.1210/jc.2004-0406)

    • Search Google Scholar
    • Export Citation
  • 118

    MinisolaSPeacockMFukumotoSCiprianiCPepeJTellaSHCollinsMT. Tumour-induced osteomalacia. Nature Reviews Disease Primers 2017 17044. (https://doi.org/10.1038/nrdp.2017.44)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 119

    ReubiJCWaserBSchaerJCLaissueJA. Somatostatin receptor sst1–sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. European Journal of Nuclear Medicine 2001 836846. (https://doi.org/10.1007/s002590100541)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 120

    de BeurSMJStreetenEACivelekACMcCarthyEFUribeLMarxSJOnobrakpeyaORaiszLGWattsNBSharonM Localisation of mesenchymal tumours by somatostatin receptor imaging. Lancet 2002 761763. (https://doi.org/10.1016/S0140-6736(02)07846-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 121

    KimizukaTOzakiYSumiY. Usefulness of 201 Tl and 99m Tc MIBI scintigraphy in a case of oncogenic osteomalacia. Annals of Nuclear Medicine 2004 6367. (https://doi.org/10.1007/BF02985616)

    • Search Google Scholar
    • Export Citation
  • 122

    DupondJLMahammediHPrieDCollinFGilHBlagosklonovORicbourgBMeaux-RuaultNKantelipB. 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 375378. (https://doi.org/10.1016/j.bone.2005.01.001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 123

    BreerSBrunkhorstTBeilFTPeldschusKHeilandMKlutmannSBarvencikFZustinJGratzKFAmlingM. 68Ga DOTATATE PET/CT allows tumor localization in patients with tumor-induced osteomalacia but negative 111In-octreotide SPECT/CT. Bone 2014 222227. (https://doi.org/10.1016/j.bone.2014.04.016)

    • Search Google Scholar
    • Export Citation
  • 124

    ZhangJZhuZZhongDDangYXingHDuYJingHQiaoZXingXZhuangH 68Ga DOTATATE PET/CT is an accurate imaging modality in the detection of culprit tumors causing osteomalacia. Clinical Nuclear Medicine 2015 642646. (https://doi.org/10.1097/RLU.0000000000000854)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 125

    SeufertJEbertKMüllerJEulertJHendrichCWernerESchützeNSchulzGKennWRichtmannH Octreotide therapy for tumor-induced osteomalacia. New England Journal of Medicine 2001 18831888. (https://doi.org/10.1056/NEJMoa010839)

    • Search Google Scholar
    • Export Citation
  • 126

    OvejeroDEl‐MaoucheDBrillanteBAKhosraviAGafniRICollinsMT. Octreotide is ineffective in treating tumor‐induced osteomalacia: results of a short‐term therapy. Journal of Bone and Mineral Research 2017 16671671. (https://doi.org/10.1002/jbmr.3162)

    • Search Google Scholar
    • Export Citation
  • 127

    GellerJLKhosraviAKellyMHRiminucciMAdamsJSCollinsMT. Cinacalcet in the management of tumor‐induced osteomalacia. Journal of Bone and Mineral Research 2007 931937. (https://doi.org/10.1359/jbmr.070304)

    • Search Google Scholar
    • Export Citation
  • 128

    CivesMStrosbergJ. Radionuclide therapy for neuroendocrine tumors. Current Oncology Reports 2017 9. (https://doi.org/10.1007/s11912-017-0567-8)

  • 129

    WeidnerN. Review and update: oncogenic osteomalacia-rickets. Ultrastructural Pathology 1991 317333. (https://doi.org/10.3109/01913129109016242)

If the inline PDF is not rendering correctly, you can download the PDF file here.

 

     European Society of Endocrinology

     Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 424 424 54
PDF Downloads 209 209 86
  • View in gallery

    Flowchart of search strategy and selection of studies for inclusion in systematic review.

  • View in gallery

    (Case 1): A 32-year-old female presented with bone pains and multiple fractures for 7 years. On examination, approximately 2 cm-sized round swelling in right upper alveolus was seen (A). Preoperative chest radiograph (image contrast adjusted) showing Looser’s zone along lateral border of scapula (arrows) suggestive of osteomalacia (B). Axial contrast-enhanced CT image soft tissue window showing small enhancing lesion in right upper alveolus (arrow) extending from canine to 1st molar tooth causing erosion of right upper alveolus (C). Ga-DOTATATE PET scan showing increased uptake at the level of right maxillary alveolus (arrow) (D). After excision histopathological examination showing tumor comprising of spindle cells with scattered osteoclastic giant cells bearing histologic semblance to giant cell granuloma (odontogenic fibroma) (E) (H&E, 400×).

  • View in gallery

    (Case 5): A 53-year-old female presenting with pain in bilateral groins and difficulty in walking for 3-year duration. As investigations confirmed the diagnosis of FGF-23-dependent hypophosphatemic osteomalacia, 68Ga-DOTATATE PET scan was done to locate the tumor which showed increased uptake in base of skull in left side (dashed arrows) (A). Corresponding axial CT images (B) showing soft tissue density lesion involving occipital bone on left side with erosion of the mastoid and petrous part of adjacent temporal bone. Retromastoid craniotomy with tumor excision was done. Histopathological examination showed hypercellular tumor composed of prominent small blood vessels with areas of hemorrhage (H&E, 200×) (D). Post first surgery repeat 68Ga-DOTATATE scan and corresponding CT images showing residual uptake in base of skull in left side (dashed arrows) in the soft tissue density lesion involving occipital bone on left side with erosion of the mastoid and petrous part of adjacent temporal bone (E). After failed second surgery, patient is now having stable disease after two cycles of PRRT.

  • View in gallery

    (Case 6): A 33-year-old female presenting with pain in bilateral groins, difficulty in walking and multiple fractures for 3-year duration. There was past history of dental surgery for some ‘gum swelling’. On examination, there was swelling in right upper alveolar region (A). X-ray right forearm AP view (image contrast adjusted) showing ulnar shaft fracture (B). MRI hip showing bilateral femoral neck insufficiency fractures which was reported as ‘bilateral avascular necrosis’ (C). Ga-DOTANOC scan showing uptake in the right maxillary tumor (D). CECT PNS axial view showing 3 cm tumor in right maxillary region (E). Patient was cured with right maxillectomy and osseous reconstruction. Histopathology showed tumor composed of cellular connective tissue intermixed with woven bone displaying osteoblastic rimming (i.e. ossifying fibroma-like histology) (H&E, 100×).

  • 1

    DreznerMK. Tumor-induced osteomalacia. In Primer on Metabolic Bone Diseases and Disorders of Mineral Metabolism 4th ed. ch 74 pp 331337. Ed. FavusMJ. Philadelphia, PA, USA: Lippincott-Raven1999.

    • Search Google Scholar
    • Export Citation
  • 2

    McCanceR. Osteomalacia with Loosers nodes (Milkman’s syndrome) due a raised resistance to vitamin D acquired about the age of 15 years. Quarterly Journal of Medicine 1947 3346.

    • Search Google Scholar
    • Export Citation
  • 3

    ChongWHMolinoloAAChenCCCollinsMT. Tumor-induced osteomalacia. Endocrine-Related Cancer 2011 R53R77. (https://doi.org/10.1530/ERC-11-0006)

  • 4

    JiangYXiaWBXingXPSilvaBCLiMWangOZhangHBLiFJingHLZhongDR Tumor‐induced osteomalacia: an important cause of adult‐onset hypophosphatemic osteomalacia in China: report of 39 cases and review of the literature. Journal of Bone and Mineral Research 2012 19671975. (https://doi.org/10.1002/jbmr.1642)

    • Search Google Scholar
    • Export Citation
  • 5

    RentonPShawDG. Hypophosphatemic osteomalacia secondary to vascular tumous of bone and soft tissue. Skeletal Radiology 1976 2124. (https://doi.org/10.1007/BF00347723)

    • Search Google Scholar
    • Export Citation
  • 6

    SweetRAMalesJLHamstraAJDeLucaHF. Vitamin D metabolite levels in oncogenic osteomalacia. Annals of Internal Medicine 1980 279280. (https://doi.org/10.7326/0003-4819-93-2-279)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    NitzanDWMarmaryYAzazB. Mandibular tumor-induced muscular weakness and osteomalacia. Oral Surgery Oral Medicine and Oral Pathology 1981 253256. (https://doi.org/10.1016/0030-4220(81)90257-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    NomuraGKoshinoYMorimotoHKidaHNomuraSTamaiK. Vitamin D resistant hypophosphatemic osteomalacia associated with osteosarcoma of the mandible: report of a case. Japanese Journal of Medicine 1982 3539. (https://doi.org/10.2169/internalmedicine1962.21.35)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    LinseyMSmithWYamauchiHBernsteinL. Nasopharyngeal angiofibroma presenting as adult osteomalacia: case report and review of the literature. Laryngoscope 1983 13281331. (https://doi.org/10.1002/lary.1983.93.10.1328)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    FolpeALFanburg-SmithJCBillingsSDBiscegliaMBertoniFChoJYEconsMJInwardsCYJan de BeurSMMentzelT Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature. American Journal of Surgical Pathology 2004 130. (https://doi.org/10.1097/00000478-200401000-00001)

    • Search Google Scholar
    • Export Citation
  • 11

    SeshadriMSCornishCJMasonRSPosenS. Parathyroid hormone like bioactivity in tumours from patients with oncogenic osteomalacia. Clinical Endocrinology 1985 689697. (https://doi.org/10.1111/j.1365-2265.1985.tb01130.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    JefferisAFTaylorPCAWalsh-WaringGP. Tumour associated hypophosphatemic osteomalacia occurring in a patient with an odontogenic tumour of the maxilla. Journal of Laryngology and Otology 1985 10111017. (https://doi.org/10.1017/s0022215100098091)

    • Search Google Scholar
    • Export Citation
  • 13

    WeidnerNbarRSWeissDStrottmannMP. Neoplastic pathology of oncogenic osteomalacia/rickets. Cancer 1985 16911705. (https://doi.org/10.1002/1097-0142(19850415)55:8<1691::aid-cncr2820550814>3.0.co;2-s)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    LeeHKSungWWSolodnikPShimshiM. Bone scan in tumour-induced osteomalacia. Journal of Nuclear Medicine 1995 247249.

  • 15

    CatalanoPJBrandweinMShahDKUrkenMLLawsonWBillerHF. Sinonasal hemangiopericytomas: a clinicopathologic and immunohistochemical study of seven cases. Head and Neck 1996 4253. (https://doi.org/10.1002/(SICI)1097-0347(199601/02)18:1<42::AID-HED6>3.0.CO;2-Z)

    • Search Google Scholar
    • Export Citation
  • 16

    WilkinsGEGranleeseSHegeleRGHoldenJAndersonDWBondyGP. Oncogenic osteomalacia: evidence for a humoral phosphaturic factor. Journal of Clinical Endocrinology and Metabolism 1995 16281634. (https://doi.org/10.1210/jcem.80.5.7745010)

    • Search Google Scholar
    • Export Citation
  • 17

    DavidKReveszTKratimenosGKrauszTCrockardHA. Oncogenic osteomalacia associated with a meningeal phosphaturic mesenchymal tumour. Journal of Neurologicalsurgery 1996 288292.

    • Search Google Scholar
    • Export Citation
  • 18

    KimYGChoiYSLeeSCRyuDM. Tumour-induced osteomalacia associated with lesions in the oral and maxillofacial region: report of two cases. Journal of Oral and Maxillofacial Surgery 1996 13521357. (https://doi.org/10.1016/s0278-2391(96)90497-8)

    • Search Google Scholar
    • Export Citation
  • 19

    AvilaNASkarulisMRubinoDMDoppmanJL. Oncogenic osteomalacia: lesion detection by MR skeletal survey. American Journal of Roentgenology 1996 343345. (https://doi.org/10.2214/ajr.167.2.8686600)

    • Search Google Scholar
    • Export Citation
  • 20

    YangIMParkYKHyunYJKimDYWooJTKimSWKimJWKimYSChoiYK. Oncogenic osteomalacia caused by a phosphaturic mesenchymal tumour of the oral cavity: a case report. Korean Journal of Internal Medicine 1997 8995. (https://doi.org/10.3904/kjim.1997.12.1.89)

    • Search Google Scholar
    • Export Citation
  • 21

    Gonzalez-ComptaXManos-PujolMFoglia-FernandezMPeralECondomEClavegueraTDicenta-SousaM. Oncogenic osteomalacia: case report and review of head and neck associated tumours. Journal of Laryngology and Otology 1998 389392. (https://doi.org/10.1017/s0022215100140551)

    • Search Google Scholar