A 35-year-old man came to the Department of Neurology with the main complaint of gradually aggravating muscle weakness and lower back pain for 1 year. He presented no headache, vomiting, and dystaxia and had a family history of similar diseases. Physical examination showed symmetrically impaired limb muscle strength with normal muscle tone. No dysphonia, dysphagia, paraesthesia, diplopia, and altered consciousness were found. His electromyogram report was normal. Magnetic resonance imaging (MRI) of the lower and upper extremities revealed fat deposition in the lower extremity muscles and a tumor in the axilla. No nerve compression or obvious inflammation was found in the lumbar spine. Therapy to relieve the pain was suggested for a temporary period. Due to continuous hypophosphatemia ranging from 0.28 to 0.49 mmol/L (normal range, 0.81–1.45 mmol/L), the patient was transferred to the Department of Endocrinology. His urine phosphate level was as high as 27 mmol/day, whereas his serum phosphate level was only 0.49 mmol/L. Furthermore, the patient’s ALP level was 171 U/L (normal range, 40–130 U/L). The serum calcium and urine calcium concentrations were normal. His parathyroid hormone (PTH) level was 66.72 pg/ml (normal range, 15–65 pg/ml), and his vitamin D3 level was 22.4 ng/ml. Dual-energy X-ray absorptiometry revealed z-scores of −3.0, −2.0, and −1.8 for the left femoral neck, left hip, and lumbar region, respectively. Bone scintigraphy showed suspicious bone metastasis due to multiple bilateral uptakes in the ribs, hip joint, knee, proximal femur, and ankle ( Figure 1 ). However, hypophosphatemia osteomalacia was suspected as the first diagnosis. The 18-Fluoride-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) showed a tumor in the axilla (47 × 37 mm) and a tumor in the sphenoid sinus (30 × 26 mm) with a maximum standard uptake value (SUV_max) of 3.0 ( Figures 2 , 3 ). Only the tumor in the sphenoid sinus showed prominent somatostatin receptor (SSTR) gene expression as shown by the 68-gallium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid octreotate (Ga-68-DOTATATE) PET/CT (SUV_max = 30.2). TIO was diagnosed with a culprit tumor in the sphenoid sinus. The patient underwent a resection of the sphenoid sinus tumor. His serum phosphate concentration increased to 1.13 mmol/L in the first follow-up after the surgery. Pathology diagnosis showed a PMT with the negative immunohistochemistry of S-100. A month later, the patient underwent a resection of the axillary tumor. Histological analyses revealed a neurilemmoma with the positive immunohistochemistry of S-100.

Sinonasal TIOs include TIOs that occur in the nasal cavity, ethmoid sinus, frontal sinus, maxillary sinus, and sphenoid sinus. Relevant studies were collected using the PubMed database to review the sphenoid and sinonasal TIOs reported in the literature. The following keywords were used: “mesenchymal tumor,” “hypophosphataemic osteomalacia,” “phosphaturic mesenchymal tumor,” “mesenchymal phosphaturic tumor,” “oncogenic osteomalacia,” “tumor-associated hypophosphataemic osteomalacia,” and “tumor-induced osteomalacia” in combination with “nasal, sinonasal, or paranasal sinuses” or “nasal, sphenoid, sinus or ethmoid sinus,” or “nasopharyngeal, craniofacial, or head.” In addition, the end-list references in the case studies and reviews were also checked to include all relevant cases. We tried to find all the original papers to check the information in similar reviews, although several case reports failed to locate the original papers. The last literature search was performed on April 5, 2022.

We collected information on the age, gender, clinical features, duration of disease, tumor site, multiple sinonasal invasion, the levels of serum phosphate, serum ALP, PTH, 1,25-dihydroxy vitamin D, and FGF23, the biopsy of the tumor, functional scintigraphy, immunostaining, recurrence, and the outcomes. The clinical features included muscle symptoms such as weakness; osteomalacia-associated symptoms such as bone pain, fracture, difficulty in walking, and shortening of height, among others; and symptoms caused by the tumor location such as nasal obstruction, headache, and epistaxis. The course of the disease was calculated from the date of symptom onset to the first operation. A local invasion was defined as tumors extending to the adjacent sinonasal sinus, intracranial fossa, and orbit; adjacent soft tissues such as the nasopharynx; and adjacent fossa such as the pterygopalatine fossa and infratemporal fossa. If multiple preoperative serum phosphates were recorded, the average value was adopted. Since the normal ranges for ALP, PTH, and FGF23 varied between the different reports, we converted these values as times for the upper limit of normal (ULN). If no reference range was given in the paper, the value in each column was substituted as normal, high, or low.

Data were analyzed using GraphPad software. The Shapiro–Wilk test was used to determine whether the data were normally distributed. Continuous variables were expressed as the mean ± SD for data with normal distribution, while the median and interquartile range (IQR) were used for data with non-normal distribution. Normally distributed data were subjected to Student’s t-test; otherwise, the Mann–Whitney U test was used. Fisher’s exact test was performed for categorical variables. A p-value <0.05 was considered statistically significant.

Only 17 cases (including our study) of TIOs in the sphenoid sinus were obtained. The detailed clinical features of these patients are presented in Table 1 (5–16). The ratio of male cases to female cases for sphenoid sinus TIOs was 1.83:1. The average age of these patients was 43.3 ± 13.7 years. The majority (16/17) of these cases had muscle symptoms or osteomalacia, while at least six cases showed local symptoms such as nasal obstruction, headache, and epistaxis. Case 4 showed no muscle or osteomalacia-associated symptoms and had normal ALP and PTH levels; however, the preoperative serum phosphate level was absent. Only three cases (including our case) showed sphenoid sinuses without invasion in the nasal cavity, other paranasal sinuses, intracranial fossa, orbit, and adjacent fossa, which could be identified as isolated sphenoid sinus diseases. Case 16 reported a recurrence that occurred 32 months after the first surgery. TIO was cured in the majority (16/17) of these cases, while the remaining case did not report the outcome.

To summarize, 153 cases of sinonasal TIOs were reported, including our case ( Supplementary Material ). Among them, 74 were male cases and 78 were female cases. The gender of one case was not reported. The ratio of male cases to female cases was 1:1.05, and the average age at diagnosis was 45.2 ± 11.2 years. Most of the sinonasal TIOs (124/153, 81.0%) were diagnosed in patients aged from 30 to 60 years. A total of 16 patients (10.5%) were aged 60 years or older, nine patients (5.9%) were in their 20s, and two patients (1.3%) were diagnosed in their teenage years. Age was not reported in two cases (1.3%). TIOs in the sinonasal sinus have often been reported as occupying adjacent sinuses, bones, or soft tissues. Ethmoid sinus was the predominant site (64.7%), followed by the nasal cavity (50.3%), maxillary sinus (19.0%), frontal sinus (16.4%), sphenoid sinus (11.8%), intracranial fossa (5.9%), orbit (2.6%), nasopharynx (2.6%), and adjacent fossa (1.3%). A total of 66 patients (43.1%) showed tumors invading more than one sinus. Among the 86 TIOs that were present in only one sinus, 45.3% occurred in the ethmoid sinus, followed by the nasal cavity (30.2%), maxillary sinus (14.0%), frontal sinus (7.0%), and sphenoid sinus (3.5%).

We compared the clinical features of sphenoid TIOs with those of non-sphenoid sinonasal TIOs ( Table 2 ). The differences in the age, gender distribution, duration of disease, serum phosphate, and the ALP, PTH, and FGF23 levels between the two groups were not significant. However, the concentration of 1,25-dihydroxy vitamin D in the sphenoid TIO group was much higher than that in the non-sphenoid sinonasal TIO group. Most papers reported the clinical symptoms associated with hypophosphatemia, except for one paper. In addition, two case series did not show the clinical symptoms linked with hypophosphatemia for each patient. Although these patients in the two case series were likely to have clinical symptoms linked with hypophosphatemia, we could not confirm. It is interesting to note that five cases reported no symptoms associated with hypophosphatemia. A total of 16 patients were cured in the sphenoid group, but the outcome of one patient was unknown. In the non-sphenoid sinonasal group, 118 cased were cured.

The results of the biopsy of the tumor were reported in 22 cases. The pathological results of the biopsy in 11 patients were consistent with the final pathological results of the resected tumor. However, 50% of the biopsy specimens were insufficient for diagnosis or led to a different diagnosis. After the prevalence of functional scintigraphy, the diagnosis of TIOs became much easier. There were 53 cases that reported positive scanning of octreotide scintigraphy, while 39 cases reported positive results in ¹⁸F-FDG PET/CT or the somatostatin receptor PET/CT.

Most of the cases reported in the literature were cured by surgery, embolism, medication, radiotherapy, or a combination of these therapies ( Table 3 ). A total of 21 patients received more than one surgery due to recurrence or incomplete surgery. One patient underwent two surgeries for two culprit tumors. Most patients showed good outcomes, with 111 cases reported to have normalized phosphate levels 1 day to 1 month after surgery. Five patients died of cerebral hernia, bronchopneumonia, cerebral hemorrhage before surgery, epistaxis, and metastasis of colon cancer. Nine cases reported intracranial invasion, two cases died, and five cases were alive with no evidence of disease. One case was diagnosed as malignant PMT without a long-term outcome, while the outcome of one case was unavailable.

Although PMTs are the mainstream pathological diagnosis in patients with TIO, almost 30.7% of tumors are still diagnosed as other tumors, including hemangiopericytoma, glomangiopericytoma, and glomangioma ( Table 4 ), among others. Four cases with other pathology diagnoses were revised as PMT according to an updated diagnosis or a suggested diagnosis by Folpe et al. (9, 12, 17). Histopathological results are not specific in PMTs; however, some of the immunostaining results may help in the differential diagnosis. We summarized the immunohistochemical results in the review, including our case, in Table 5 . All the reported cases had positive immunostaining of SSTR, CD56, vimentin, and special AT-rich sequence-binding protein 2 (SATB2). Furthermore, all the reported cases had negative immunostaining of synaptophysin (Syn), chromogranin, AE1/AE3, and epithelial membrane antigen (EMA). The majority of the immunostaining results for desmin, S-100, and CD34 were negative. The immunostaining results for smooth muscle actin (SMA), CD99, neuron-specific enolase (NSE), and CD68 were not consistent. The expression of FGF23 in tumors is a strong indicator of TIOs. Only 12 cases reported the expression of FGF23 through immunostaining, mRNA expression, chromogenic in-situ hybridization, or Northern hybridization of FGF23 in tumors or tumor-derived cell lines.

TIO is rarely caused by more than one tumor. However, Peterson et al. reported a case with a second PMT in the maxillary sinus 2 years after the first surgery of PMT in the tibia ( Supplementary Material ) (18). Both Arai et al. (19) and Higley et al. (20) also reported more than one culprit tumor in two different sites. Furthermore, PMT also rarely coexists with another type of tumor. However, Ha et al. reported a PMT case with concurrent lymphoma, wherein Ga-68-DOTATATE PET/CT played a crucial role in distinguishing the culprit tumor (21).