Key-words:
Fibroblast growth factor-23 - intracranial - oncogenic osteomalacia - phosphaturic
mesenchymal tumor - temporal–occipital bone
Introduction
Phosphaturic mesenchymal tumor (PMT) is a rare and distinctive tumor frequently associated
with oncogenic osteomalacia (OO). PMT usually occurs in the soft tissue or bones of
the extremities and occasionally in the craniofacial area in the mouth, nasopharynx,
or one of the paranasal sinuses.[[1]] Occurrence in intracranial and craniovertebral region is very rare, and only a
few cases have been reported.[[2]],[[3]],[[4]],[[5]],[[6]] We hereby report two rare cases of PMT, the first case being intracranial involving
the temporal bone and the second a skull base tumor originating from the occipital–temporal
bone.
Case Report
Case 1
A 46-year-old male came to the outpatient department of our hospital with the complaints
of progressive difficulty in walking for the past 5 years. Two years back, he had
suffered from a bilateral femoral fracture. His serum phosphorus was 1.6 mg/dl (normal
range 2.4–4.5 mg/dl), 1,25-dihydroxy vitamin D was 24 ng/mL (normal range 30–100 ng/mL),
and alkaline phosphatase was 942.6U/L (normal range 53–128U/L). A diagnosis of hypophosphatemic
osteomalacia was made clinically. Serum fibroblast growth factor (FGF)-23 was 1023
RU/mL (normal <180 RU/mL). Based on the above clinical and biochemical findings, a
diagnosis of OO was suspected. A whole-body positron emission tomography (PET) scan
revealed multiple osteolytic lesions in the axial skeleton with no evidence of abnormal
FDG uptake. With this clinical history, a somatostatin receptor PET scintigraphy was
advised which revealed a somatostatin receptor-positive extra-axial disease in the
right temporal lobe with the involvement of adjacent petrous temporal bone, suggestive
of malignant meningioma. Subsequent magnetic resonance imaging (MRI) revealed a well-demarcated
lobulated dumbbell-shaped heterogeneously enhancing mass lesion in the right temporal
region measuring 1.9 cm × 1.7 cm × 2.6 cm, involving the mastoid bone, epitympanum
with erosions of the bone, especially the tegmen tympanum, and an intracranial epidural
component. The mass was hypointense on T1-weighted images and heterogeneously enhancing
on T2-weighted and fluid-attenuated inversion recovery images [[Figure 1]]. The patient underwent right temporal craniotomy and stereotactic gross total excision
of the lesion. The postoperative period was uneventful.
Figure 1: Case 1 (a) Axial Tl-weighted, (b) Axial T2-weighted, and (c) coronal fluid-attenuated
inversion recovery reveal a well-demarcated lobulated mass in the right temporal region
causing bone erosion. It has an intracranial component and is hypointense on T1 and
heterogeneously hyperintense on T2 and fluid-attenuated inversion recovery images
Histopathology revealed a cellular tumor composed of sheets of oval-to-short fusiform
cells possessing scanty cytoplasm and relatively uniform-appearing nuclei [[Figure 2]]a. Scattered osteoclastic giant cells were focally identified. Foci of “grungy”
calcification were also detected [[Figure 2]]a. Ectatic thin-walled vascular spaces, hemorrhage with hemosiderin pigment deposits,
and areas of fibrosis with hyalinization were evident. Few mitoses were noted. No
sarcomatous features were detected. On immunohistochemistry, the tumor cells were
diffusely positive for vimentin and focally positive for smooth muscle actin, whereas
they were negative for S100 and CD34 [[Figure 2]]b, [[Figure 2]]c, [[Figure 2]]d. A diagnosis of PMT, mixed connective tissue type (PMTMCT), was confirmed on the
basis of the above clinical, biochemical, histopathological, and immunohistochemical
features.
Figure 2: Photomicrograph of Case 1 shows the following: (a) tumor composed of relatively uniform
short spindly cells embedded in hyalinized stroma with foci of "grungy" calcification
(H and E, x400); (b-d) tumor cells are diffusely positive for vimentin (x400), focally
positive for smooth muscle actin (x400), and negative for CD34 (x200)
Case 2
A 52-year-old woman came with the complaints of pain in bilateral hips and thighs
and progressive difficulty in walking for the past 2 years. The patient had been investigated
outside and was diagnosed as hypophosphatemic osteomalacia and treated with phosphate
supplements. Her serum calcium was normal (9.2 mg/dl), phosphorus was low (1.6 mg/dl),
parathyroid hormone levels were normal (39.65 pg/ml), 24-h urinary phosphorus was
elevated (1005 mg/day), and FGF-23 was elevated (725 RU/mL). With the above clinical
and biochemical details, a defect in renal tubular function due to OO was suspected.
A whole-body somatostatin receptor PET scan was advised, which revealed a large expansile
lesion, involving the left occipital bone including the clivus, and occipital condyle
with erosion of mastoid and petrous part of the adjacent temporal bone. Brain MRI
revealed a contrast-enhancing left skull base tumor involving the occipital condyle,
suggestive of a meningioma or glomus tumor. The patient underwent a left retromastoid
craniotomy and complete resection of the tumor.
Histopathology revealed fragments of neoplasm composed of oval-to-short fusiform cells
arranged in sheets and fascicles within a vascularized stroma, containing thin-walled
vessels and numerous scattered osteoclastic giant cells [[Figure 3]]a. Areas showing basophilic extracellular matrix were also identified [[Figure 3]]b. There were no sarcomatous changes. A diagnosis of PMTMCT was given.
Figure 3: Photomicrograph of Case 2 shows the following: (a) numerous osteoclastic giant cells
and a richly vascularized stroma (H and E, x400); (b) extracellular basophilic matrix
(H and E, x400)
On follow-up after 3 months of surgery, the patient's serum phosphorus level (2.3
mg/dL) and FGF-23 (150 RU/mL) levels had normalized, and her strength was improving.
Discussion
Impaired mineralization of osteoid matrix in mature bone leads to osteomalacia. FGF-23-secreting
mesenchymal tumors and Fanconi's syndrome are acquired causes of osteomalacia; the
former is referred as OO.[[7]] The tumor that secretes FGF-23 inhibits the renal reabsorption of phosphorus and
downregulates 25-hydroxyvitamin D-1a-hydroxylase.[[1]],[[8]] Patients with OO have hypophosphatemia, normocalcemia, hyperphosphaturia, and increased
alkaline phosphatase.[[9]] It is a paraneoplastic syndrome of renal phosphate wasting, leading to weakness,
progressive muscle and bone pain, and recurrent fractures in adults.
PMT is usually located in the soft tissue, but the intra-osseous location is also
known.[[1]] Occurrence in the extremities or appendicular skeleton is more common than in the
trunk or axial skeleton.[[1]],[[2]] Craniofacial sinuses can be involved in 5% of the cases;[[1]] however, the involvement of the intracranial compartment and temporal–occipital
bone is very rare. To the best of our knowledge, <10 cases of intracranial PMT and
<5 cases of PMT arising in the temporal–occipital bone have been reported in the English
literature.[[2]],[[3]],[[4]],[[5]],[[6]],[[10]]
Histologically, it corresponds to a polymorphous group of neoplastic entities, the
most common of which is the so-called “mixed connective tissue type.”[[1]],[[9]] Other histological types of PMTs are the osteoblastoma-like tumor, the nonossifying
fibroma-like tumor, and the ossifying fibroblastoma-like tumor. Histological features
of malignancy are observed in some cases.[[1]],[[9]]
The best treatment for OO is complete removal of the tumor, but because of its unusual
location and occult nature, correct diagnosis and resection are delayed for years.[[8]],[[11]],[[12]] This was indeed true for our patients, for whom it took 5 and 3 years, respectively,
to find a primary lesion. In such cases, medical management becomes necessary. Medical
management comprises phosphorus supplementation to replace the ongoing renal phosphorus
loss and calcitriol to supplement insufficient renal production of 1,25-dihydroxy
vitamin D. The dosing should be adjusted to improve symptoms, maintain fasting phosphorus
in the low normal range, and maintain PTH in the normal range without inducing hypercalcemia
or hypercalciuria. Close monitoring of serum calcium and phosphorus, urine calcium,
renal function, serum alkaline phosphatase, and PTH is recommended to assess the safety
and efficacy of therapy.
Some PMTs express somatostatin receptors that bind octreotide; this has provided the
rationale for therapeutic trial of octreotide in patients with TIO and residual tumor.
However, due to limited experience with octreotide treatment, it should be reserved
for cases refractory to conventional medical treatment.
Thus, PMT should be suspected in older children or adults with hypophosphatemia and
osteomalacia who lack a personal or family history of metabolic, renal, or malabsorptive
diseases. A thorough workup including a history, physical examination, and biochemical
evaluation, followed by radiological search for tumor in the extremities and head,
should be done.[[10]] As these tumors are often small, slow-growing, and located in unexpected anatomical
regions, imaging techniques such as MRI, computed tomography, or PET scan with particular
attention to the brain are recommended.[[2]],[[12]] Somatostatin receptor imaging has been recently proved to improve the detection
of such tumors, based on the postulate that these tumors express somatostatin receptors.[[10]] Both meningioma and PMT should be considered as differentials if an extra-axial,
well-circumscribed, contrast-enhancing tumor is encountered in such patients. Knowledge
of this rare entity at uncommon sites is important to proactively identify, treat,
and prevent associated bony morbidities in affected patients.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
In the form the patient(s) has/have given his/her/their consent for his/her/their
images and other clinical information to be reported in the journal. The patients
understand that their names and initials will not be published and due efforts will
be made to conceal their identity, but anonymity cannot be guaranteed.
