Histopathological and genetic review of phosphaturic mesenchymal tumours, mixed connective tissue variant.

AIMS: Phosphaturic mesenchymal tumour, mixed connective tissue variant (PMT-MCT), is a tumour of uncertain differentiation, characterised by 'smudgy/grungy' calcification and vitamin D-resistant phosphaturic osteomalacia. Fibroblast growth factor (FGF)23 is recognised as a reliable marker of PMT-MCT, but quantitative evaluation has never been performed. We reviewed cases of tumour-associated osteomalacia or histologically definitive PMT-MCT without osteomalacia using histological, immunohistochemical and genetic methods and evaluated the diagnostic significance of these findings. METHODS AND RESULTS: A total of 19 tumours from 14 cases diagnosed previously as PMT-MCT were retrieved, on which immunohistochemical staining, reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in-situ hybridisation (FISH) analysis were performed. Histologically, fibrous capsule, calcification and giant cell reaction tended to be observed in soft-tissue PMT-MCT, while PMT-MCT of bone and multiple PMT-MCT showed an infiltrative growth pattern. The immunohistochemical results were as follows: the tumour cells were positive for FGF23 (nine of 12, 75%), FGFR1 (11 of 11, 100%), CD56 (12 of 14, 85.7%) and E26 oncogene homologue (ERG) (5 of 13, 38.4%). The sole malignant tumour was positive for p53. FGF23 mRNA was detected in seven of 14 formalin-fixed paraffin-embedded (FFPE) specimens and all five frozen specimens by RT-PCR. The level of FGF23 mRNA, which was determined by real-time PCR, varied among the phosphaturic cases. Two of 17 tumours were positive for FGFR1 gene rearrangement. CONCLUSIONS: It was considered that PMT-MCT is a histopathological entity with or without phosphaturia, with varying levels of FGF23 mRNA, and with or without fibronectin 1 (FN1)-FGFR1 fusion gene. The authors propose that the histology of PMT-MCT differs depending on its location, such as bone or soft tissue, which could complicate the differential diagnosis.

Tumor-induced osteomalacia: An overview.

Tumor-induced osteomalacia (TIO) is rare paraneoplastic syndrome of hypophosphatemic osteomalacia, caused by phosphaturic factors secreted by small mesenchymal origin tumors with distinct pathological features, called 'phosphaturic mesenchymal tumors'. FGF23 is the most well-characterized of the phosphaturic factors. Tumors are often small and located anywhere in the body from head to toe, which makes the localisation challenging. Functional imaging by somatostatin receptor-based PET imaging is the first line investigation, which should be followed with CT or MRI based anatomical imaging. Once localised, complete surgical excision is the treatment of choice, which brings dramatic resolution of symptoms. Medical management in the form of phosphate and active vitamin D supplements is given as a bridge to surgical management or in inoperable/non-localised patients. This review provides an overview of the epidemiology, pathophysiology, pathology, clinical features, diagnosis, and treatment of TIO, including the recent advances and directions for future research in this field.

Malignant transformation of phosphaturic mesenchymal tumor: a case report and literature review.

Phosphaturic mesenchymal tumor, mixed connective tissue variant (PMT-MCT) causes tumor-induced osteomalacia (TIO). Most cases follow a benign clinical course, with rare occurrences of malignant transformation. We report a case of malignant PMT-MCT and review previous malignant cases to identify predictive factors for transformation. A 13-yr-old female, who presented with hypophosphatemic rickets, elevated serum intact fibroblast growth factor 23 (FGF23) levels, and a nodule in the back, received a diagnosis of TIO because of the benign PMT histopathology. After resection of the primary tumor, regular imaging analyses did not indicate any relapse. At 17 years of age, a tumor developed in the left leg and increased in size. The resected tumor showed a histopathology of pleomorphic sarcoma positive for the TP53 mutation. Despite amputation of the affected leg, the patient died due to multiple metastases at 18 years of age. A literature review revealed that 14 out of 15 reported malignant PMT-MCT tumors occurred in adults, and found no predictive factors for malignant transformation and treatment outcome. Changes in size or number of the tumors along with intact FGF23 levels have been considered as the only sign of malignant transformation. This pediatric case report and literature review indicate the need for prolonged regular monitoring for PMT-MCT.

Phosphaturic mesenchymal tumor of the brain without tumor-induced osteomalacia in an 8-year-old girl: case report.

Phosphaturic mesenchymal tumor (mixed connective tissue variant) (PMT-MCT) are tumors that may cause tumor-induced osteomalacia and rarely appear intracranially. The authors describe the case of an 8-year-old girl who was found to have PMT-MCT with involvement of the cerebellar hemisphere and a small tumor pedicle breaching the dura mater and involving the skull. This was removed surgically in gross-total fashion without further complication. Histologically the tumor was confirmed to be a PMT-MCT. There was no evidence of tumor-induced osteomalacia. At the 42-month follow-up, the patient is doing well, has no abnormalities, and is free of recurrence. PMT-MCTs are rare tumors that may involve the brain parenchyma. A gross-total resection may be effective to cure these lesions.