A 42-year-old female was reportedly well until 9 years previously when she developed back and flank pain during pregnancy. Routine clinical laboratory assays performed at that time revealed hypophosphatemia in the setting of normal calcium and parathyroid hormone levels (). Urine phosphate was in the low-normal range for a small individual, which was attributed to a low dietary phosphorus intake and her very low serum phosphate levels.16
An elevated alkaline phosphatase was also noted. DEXA scans were ordered and revealed low bone mineral density. A diagnosis of hypophosphatemic osteomalacia of unclear etiology was made and treatment with phosphorus (750mg four times daily) and vitamin D (ergocalciferol, 50,000 units twice weekly) was initiated.
Laboratory values of current case
Further questioning revealed a negative family history of the heritable forms of osteomalacia. As TIO was considered a probable diagnosis, numerous exploratory investigations were undertaken over the following years in search for a causative tumor. During this time, she continued pharmacologic treatment with phosphorus and vitamin D with excellent clinical and biochemical response, including improvement of her bone mineral density by 35.3% at the hip, 31.5% at the 1/3 radius site, and 10.0% at the lumbar spine. Her evaluations included x-rays; bone scans; CT scans of the chest, abdomen, and pelvis; and whole body technetium-99M sestamibi scans, all of which were negative for tumors. An octreotide scan was also performed and showed a promising focus of increased uptake in the midline abdomen. A follow-up MRI suggested an area of arterial phase enhancement in the pancreatic head and an endoscopic ultrasound revealed a bilobar 11.0 × 6.0 mm hypoechoic lesion at the bifurcation of the celiac axis. The patient subsequently underwent open laparotomy and 2 small lymph nodes were excised. Microscopic examination of the nodes showed evidence of lipogranulomata, which have not been previously implicated in TIO. Furthermore, no change in her clinical status was observed post-operatively.
During the course of these evaluations, the patient revealed that a dental exam performed by her previous oral and maxillofacial surgeon had revealed a lesion in her right mandible. Radiographs retrieved from this assessment, performed 9 years prior, showed an entirely radiolucent lesion with distinct interradicular scalloping between the roots of #28-31 (). According to the clinician’s records, the patient’s dentition was otherwise intact and the associated teeth were determined to be vital. The records indicated that the clinical and radiographic impression was that of a traumatic bone cyst and that a biopsy was performed which supported this diagnosis histologically. The patient reported that her mandibular lesion remained asymptomatic over the following years and that additional radiographs were not ordered.
Panoramic radiograph taken 9 years prior to presentation showing a radiolucent lesion with interradicular scalloping.
Upon learning of the mandibular lesion, the patient’s endocrinologist immediately referred her to the Department of Oral and Maxillofacial Surgery at our institution for reevaluation. A new panoramic radiograph was obtained and demonstrated a multilocular lesion with predominantly corticated borders corresponding in the area of interest (). The lesion remained confined to the #28-31 region but was now characterized by internal opacities and increased radiodensity towards the posterior aspect. The lamina dura of teeth #29 and 30 were effaced and the corresponding periodontal ligament spaces were irregularly widened. Scalloping of the inferior mandibular cortex was noted. Examination of a cone-beam computerized tomography (CBCT) scan (i-CAT Classic CBCT [Imaging Sciences, Hatfield, PA]) revealed a lesion of mixed density with well-demarcated borders anteriorly and less distinct borders posteriorly (). Significant expansion with associated cortical thinning was also detected. Internally, coarse opacities and variably-sized loculations were seen. A contrast-enhanced CT scan confirmed a lytic lesion with a focus of high density, but no abnormal enhancement, alleviating concerns of a high-flow lesion. The radiographic differential consisted of a calcifying epithelial odontogenic tumor, calcifying odontogenic cyst and its variants, ossifying fibroma, osteosarcoma, chondromyxoid fibroma, and chondrosarcoma. Given the clinical history of hypophosphatemia and hyperphosphaturia, a low-flow vascular lesion, central giant cell granuloma, and PMTMCT were also considered, all of which have been documented causes of TIO.
Panoramic radiograph taken at presentation showing a multilocular lesion with internal opacities.
A mandibular cone-beam computerized tomography scan. Bucco-lingual expansion is evident. A, axial. B, coronal.
After a negative aspiration, the area was surgically explored and histologic examination of the biopsy specimen revealed a hypercellular tumor composed of a dense population of spindle-shaped cells. The cells had dark but uniform nuclei and were present in a fascicular pattern in focal areas (). Frequent deposits of acellular, “grungy”-type calcifications and ovoid fragments of viable bone were noted; scattered osteoclast-type multinucleated giant cells were also noted (). An immunohistochemical panel consisting of vimentin, pancytokeratin, desmin, S-100 and CD34 was performed. The tumor cells were strongly and diffusely positive with vimentin but exhibited no reactivity with the remaining markers. The microscopic features in concert with the patient’s clinical history supported a diagnosis of PMTMCT. Serum FGF23 concentrations were measured using an ELISA that detects only full length FGF23 (Intact FGF23 ELISA, Kainos Laboratories Tokyo, Japan). 17
Pre-operative FGF23 concentrations were 192 pg/ml (normal = 0–71 pg/ml), consistent with an FGF23-mediated cause of osteomalacia.
Figure 4 Microscopic images of lesion. A, A cellular spindle cell proliferation exhibiting a fascicular pattern (hematoxylin-eosin, original magnification X100). B, “Grungy”-type calcifications and osteoclast-like giant cells (arrows) (hematoxylin-eosin, (more ...)
Although a complete surgical excision of the lesion was planned, the tumor was found to be in direct contact with the inferior alveolar nerve intraoperatively. After great consideration, conservative curettage was performed to avoid sacrifice of the nerve although this limited the ability to completely resect the lesion. The histology of the curettage specimen was identical to that of the biopsy. Moreover, analysis of the excised tissue via reverse transcriptase polymerase chain reaction (RT-PCR) confirmed FGF23 expression (data not shown).
Following surgery, the patient experienced rapid normalization of her serum phosphate levels (). Notably, there was a significant reduction of her plasma FGF23 level to 98 pg/ml 11 days after the surgery. A follow-up FGF23 measurement 4½ months post-surgery remained slightly elevated at 92 pg/ml. Although she was able to discontinue her medications for several months, she has since resumed supplementation with phosphorus and ergocalciferol, though at lower doses than her pre-surgical treatment. The patient continues to do well clinically but maintains a vigilant follow-up regimen due to the conservative nature of her surgery.