Varied presentation of sinonasal phosphaturic mesenchymal tumour: report of a case series with follow-up.

PURPOSE: Phosphaturic mesenchymal tumour (PMT) of the paranasal sinuses is a rare tumour that is associated with oncogenous osteomalacia causing predominant musculoskeletal symptoms. We present a series of eight patients diagnosed to have PMT of the paranasal sinuses with varied presentation and highlight the appropriate evaluation required to arrive at the diagnosis. METHODS: Retrospective review of eight patients diagnosed to have PMT-causing tumour-induced osteomalacia with follow-up data. RESULTS: Eight patients, 4 males and 4 females, aged 36-67 years (mean = 44 years) presented with vague musculoskeletal symptoms (6 patients) or epistaxis (3 patients). Six patients were found to have hypophosphatemia, phosphaturia and raised FGF-23 levels preoperatively. All eight patients were found to have a tumour in the nose and/ paranasal sinuses with one patient having intracranial extension. All patients were treated with endoscopic excision of these tumours which resulted in resolution of symptoms and normalisation of biochemical abnormalities. In addition, one patient required a craniofacial resection. Histopathological features were consistent with PMT mixed connective tissue variant. Two atypical patients were seen. The longest follow-up was for 5 years and there was no evidence of recurrence during the follow-up period in any patient. CONCLUSION: Diagnosis of PMT of the paranasal sinuses causing oncogenous osteomalacia requires a high index of suspicion when there are no ENT symptoms. Appropriate biochemical tests and histopathology lead to the correct diagnosis. Total endoscopic surgical excision leads to a good outcome.

Phosphaturic mesenchymal tumor and related wound problem.

INTRODUCTION: Phosphaturic mesenchymal tumor mixed connective tissue type (PMT/MCT) is the most common type (up to 90%) of phosphaturic mesenchymal tumor (PMT), a rare clinicopathologic entity. Besides overproduction of fibroblast growth factor 23 (FGF23), there is a big variation of immunohistochemical characteristic across types of PMT, which makes it difficult to obtain an early diagnosis of PMT/MCT. As a benign tumor, PMT/MCT usually happens in subcutaneous tissues and leads to nonhealing of wound. A complete excision of PMT/MCT facilitates wound healing. CONCLUSIONS: Review of the existing evidence indicates that early diagnosis of PMT/MCT is critically important when treating PMT/MCT wound. Hence standardization of early diagnosis for PMT/MCT is mandated.

[Clinical and immunohistopathologic study of phosphaturic mesenchymal tumor].

Objective: To study the clinicopathological characteristics and immunohistochemical phenotype of phosphaturic mesenchymal tumor (PMT) . Methods: The clinicopathological data and immunohistochemical profiles were obtained retrospectively from 206 patients diagnosed with PMT at Peking Union Medical College Hospital (PUMCH) during July 2008 to September 2017, with a review of literature. Results: The mean age of PMT patients was 42 years (range 13 to 70 years), with a male to female ratio of 1.1∶1.0. All patients presented with different degree of bone pain, muscle weakness, shorten of stature, thoracic deformity and pathological fractures, with hypophosphatemia and high serum ALP. Phosphatemia returned to normal within 1 week after operation in all cases underwent complete tumor resection. The duration of osteomalacia before resection (documented in 197 cases) ranged from 20 days to 40 years (average 5.7 years). The average blood phosphorus concentration raised from 0.49 mmol/L to 0.92 mmol/L before and after tumor resection (P<0.01), with 147 cases (84.0%, 147/175) returned to normal range within 2 weeks. The rate or blood phosphorus concentration recovery in 15 days after operation was 79.6% in average, displayed significant differences between patients with complete resection and those with partial resection (85.4% vs. 21.1%, P<0.01). PMT lesions mainly involved lower extremities (55.8%), followed by head and neck (29.1%). In immunohistochemical study, all cases were positive for vimentin (100.0%), while most cases were positive for NSE (96.3%), CD56 (94.2%), FGF23(88.4%), CD68 (88.3%), D2-40 (70.9%), CD34 (23.1%), SMA (55.5%), bcl-2 (59.8%) and CD99 (47.1%). The Ki-67 positive index of tumor varied from less than 2% (51.4%), 3% to 10% (41.3%) to >10% (7.2%). Conclusions: PMT mainly occurs in lower limbs or head and neck, with unique clinical characteristics and blood biochemical indexes. The tumor expresses a variety of immunohistochemical markers, indicating the potential of multi-directional differentiation. Clinical profile, blood biochemistry testing and immunohistochemical phenotype is helpful for diagnosis of PMT.

The phosphaturic mesenchymal tumor: why is definitive diagnosis and curative surgery often delayed?

BACKGROUND: Tumor-induced osteomalacia is a paraneoplastic syndrome resulting in renal phosphate wasting and decreased bone mineralization. Phosphaturic mesenchymal tumors represent a rare etiology of tumor-induced osteomalacia. Nonspecific symptoms of fatigue, bone pain, and musculoskeletal weakness make the diagnosis elusive and lead to a delay in surgical treatment. QUESTIONS/PURPOSES: In this case series, the following three questions were asked: (1) How do the clinical presentation and features of phosphaturic mesenchymal tumors delay the diagnosis? (2) What is the clinical course after surgical treatment of phosphaturic mesenchymal tumors? (3) How frequently do phosphaturic mesenchymal tumors recur and are there factors associated with recurrence? METHODS: This study retrospectively reviewed the cases of five adults diagnosed and treated for phosphaturic mesenchymal tumors. Patients were identified through an internal orthopaedic oncology database with clinical, surgical, and histologic data obtained through a systematic chart review. RESULTS: Five patients presented with a long-standing history of osteomalacia, generalized fatigue, pain, and weakness before the diagnosis was reached at an average of 7.2 years (range, 2-12 years) after initial symptom onset. The diagnosis appeared to be delayed owing to the cryptic medical presentation, difficulty in locating tumor by imaging, and confirming histologic appearance. Two patients treated with wide surgical resection did not experience recurrence compared with three patients who did show recurrent signs and symptoms after marginal excision. A postoperative increase in fibroblast-derived growth factor-23 was associated with recurrent disease. CONCLUSIONS: Although uncommon, the diagnosis of phosphaturic mesenchymal tumor should be considered in any patient who presents with hypophosphaturic osteomalacia and no other physiologic cause. Definitive treatment is early, wide surgical resection.

Tumor-induced osteomalacia with elevated fibroblast growth factor 23: a case of phosphaturic mesenchymal tumor mixed with connective tissue variants and review of the literature.

Tumor-induced osteomalacia (TIO), or oncogenic osteomalacia (OOM), is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recent evidence shows that tumor-overexpressed fibroblast growth factor 23 (FGF23) is responsible for the hypophosphatemia and osteomalacia. The tumors associated with TIO are usually phosphaturic mesenchymal tumor mixed connective tissue variants (PMTMCT). Surgical removal of the responsible tumors is clinically essential for the treatment of TIO. However, identifying the responsible tumors is often difficult. Here, we report a case of a TIO patient with elevated serum FGF23 levels suffering from bone pain and hypophosphatemia for more than three years. A tumor was finally located in first metacarpal bone by octreotide scintigraphy and she was cured by surgery. After complete excision of the tumor, serum FGF23 levels rapidly decreased, dropping to 54.7% of the preoperative level one hour after surgery and eventually to a little below normal. The patient's serum phosphate level rapidly improved and returned to normal level in four days. Accordingly, her clinical symptoms were greatly improved within one month after surgery. There was no sign of tumor recurrence during an 18-month period of follow-up. According to pathology, the tumor was originally diagnosed as "lomangioma" based upon a biopsy sample, "proliferative giant cell tumor of tendon sheath" based upon sections of tumor, and finally diagnosed as PMTMCT by consultation one year after surgery. In conclusion, although an extremely rare disease, clinicians and pathologists should be aware of the existence of TIO and PMTMCT, respectively.

Phosphaturic mesenchymal tumor (mixed connective tissue variant): a case report with spectral analysis.

We present a further case of a rare mesenchymal neoplasm termed phosphaturic mesenchymal tumor (mixed connective tissue variant). The patient was a 42-year-old man with a long history of osteomalacia of unknown etiology with pathological bone fracture, abnormality of parathyroid glands, kyphosis, scoliosis, and spondylosis. Laboratory investigation disclosed hypophosphatemia, elevated serum alkaline phosphatase activity, and normal serum calcium level. The patient had a soft tissue mass in the right inguinal area, measuring 11 x 6 x 5 cm, which was previously interpreted as a calcified hematoma on sonography. The tumor was surgically removed. Grossly, the tumor was well circumscribed, unencapsulated, and had soft to dense consistency. The cut surface had a variegated appearance due to the presence of large hemorrhagic areas admixed with foci of grey-yellow tissue. Histologically, the tumor was composed of primitive mesenchymal cells, osteoclast-like cells, and cells showing myofibroblastic features without cytologic atypia. There were a well developed vascular network, microcystic areas, and poorly formed cartilaginous foci. Unusual and hitherto unpublished prominent features were flower-like, slate-gray crystals, widespread hemosiderin deposits and large areas of hemorrhages, with the latter comprising approximately 60% of the tumor. A spectral analysis indicated that chemically, the crystals mainly consisted of calcium phosphate and sodium nitrate.

Persistent tumor-induced osteomalacia confirmed by elevated postoperative levels of serum fibroblast growth factor-23 and 5-year follow-up of bone density changes.

OBJECTIVE: To describe a case of persistent tumor-induced osteomalacia, determine whether serum fibroblast growth factor-23 (FGF-23) levels postoperatively indicate incomplete tumor resection, and report lumbar spine and forearm bone mineral density (BMD) changes during 5 years of follow-up. METHODS: We present clinical, radiologic, histologic, and bone densitometry data as well as serum FGF-23 levels (determined with use of a novel C-terminal enzyme-linked immunosorbent assay) from the study patient and discuss these findings in the context of previous literature. RESULTS: A 52-year-old man, who presented with muscle weakness and multiple fractures, was found to have low values for serum phosphorus, serum 1,25-dihydroxyvitamin D, and maximal tubular reabsorption of phosphate per glomerular filtration rate, a high level of serum alkaline phosphatase, and a normal serum concentration of parathyroid hormone, characteristic of tumor-induced osteomalacia. Magnetic resonance imaging to evaluate an abnormality of the left foot revealed a soft tissue mass, biopsy of which confirmed the presence of a benign, phosphaturic, mesenchymal tumor. The baseline serum FGF-23 level (2,050 RU/mL) was more than 17 times the upper limit of normal for adults (23 to 118 RU/mL) and decreased substantially within 1 day after partial resection of the tumor but remained above normal postoperatively. BMD changes indicated rapid substantial recovery of vertebral BMD but ongoing loss of forearm bone density. CONCLUSION: The serum FGF-23 level is high in a substantial proportion of patients with tumor-induced osteomalacia. The postoperative above normal levels of serum FGF-23 correlated with known persistence of tumor in our study patient. In a patient with normal renal function, such as our study patient, levels of serum FGF-23 studied with use of the C-terminal enzyme-linked immunosorbent assay reached their nadir within 24 hours postoperatively. This result suggests that this assay can provide clinicians with rapid prognostic information in patients with known or suspected residual tumor. BMD should be assessed at both appendicular and axial sites in patients with persistent tumor-induced osteomalacia.

Malignant hypoglycemia associated with a large mesenchymal tumor: case report and review of the literature.

PURPOSE: To examine hypoglycemia associated with a non-islet-cell tumor caused by the secretion of abnormal insulinlike growth factors. PATIENT AND METHODS: We describe a 54-year-old woman with a massive solitary fibrous tumor who experienced worsening hypoglycemia with suppressed levels of insulin and insulinlike growth factor I but abnormally "normal" levels of insulinlike growth factor II. RESULTS: Efforts to control her symptoms with frequent meals, prednisone, and intravenous dextrose infusions were only partially successful. Attempts at reducing the tumor size by embolizing its arterial supply and percutaneous alcohol injections were unsuccessful, and the patient died 24 hours after surgical debulking. DISCUSSION: Patients with non-islet-cell tumor hypoglycemia usually have abnormally high levels of an incompletely processed precursor of insulinlike growth factor II, which is more bioavailable than the normal molecule. In some patients, treatment with corticosteroids and growth hormone increases blood sugar levels, but the most effective therapeutic approach is to resect or debulk the tumor.

Plasma neuropeptide Y in healthy children: influence of age, anaesthesia and the establishment of an age-adjusted reference interval.

Plasma concentrations of neuropeptide Y, analysed in 112 healthy children, decreased significantly with age, while sex, discomfort induced by the sampling procedure or induction of general anaesthesia did not have a significant influence. An age-adjusted upper reference limit was established and proved to be useful when tested prospectively in 56 children with tumours. Two of 18 children with preliminary diagnosis of rhabdomyosarcoma had elevated plasma neuropeptide Y; both showed malignant ectomesenchymoma (p < 0.01), a mixed tumour with neural crest features. Among 38 children with neural crest derived tumours, all 7 with benign ganglioneuromas had plasma neuropeptide Y concentrations below the reference limit, while 13 of 31 with neuroblastoma had elevated concentrations (p < 0.05). Only neuroblastoma patients with elevated plasma neuropeptide Y had a poor outcome; 10 of 13 died, whereas all with normal concentrations are alive after 3-74 months of follow-up (p < 0.001).

Hypercalcemic hyperparathyroidism complicating oncogenic osteomalacia. Effect of successful tumor resection on mineral homeostasis.

Described herein is a case of oncogenic osteomalacia that ran a course of at least 16 years before curative resection of a mixed mesenchymal tumor. Hypercalcemic hyperparathyroidism developed in the patient, and review of the literature indicated that this occurs in about 10 percent of reported cases. Changes in serum parathyroid hormone levels with and without phosphate supplement therapy and before and after tumor resection suggested that both the high intake of phosphate and the effect of the neoplasm on vitamin D bioactivation engendered the parathyroid overactivity. Despite marked hyperparathyroidism, serum 1,25-dihydroxyvitamin D levels were subnormal preoperatively but showed a sevenfold increase within 48 hours of tumor resection. Thereafter, a gradual increase in the maximal tubular reabsorption of phosphate occurred during several months. Biopsy of the iliac crest confirmed that tumor removal was followed by resolution of osteomalacia, but there was no accompanying increase in vertebral mineral density as assessed by quantitative computed tomography or in total-body bone mineral as measured with dual-photon absorptiometry. The findings presented are consistent with secretion by the tumor of a factor with a short half-life that is potent enough to inhibit renal 25-hydroxyvitamin D-1 alpha-hydroxylase despite hyperparathyroidism. The resulting subnormal circulating 1,25-dihydroxyvitamin D levels may have secondarily contributed to decreased renal tubular reabsorption of phosphate.

Tumor-induced osteomalacia. Kinetics of calcium, phosphorus, and vitamin D metabolism and characteristics of bone histomorphometry.

A patient with a mesenchymal tumor and hypophosphatemic osteomalacia was studied before and after tumor excision. Initial laboratory values included normal serum calcium, decreased serum phosphorus and tubular reabsorption of phosphate, undetectable 1,25-dihydroxyvitamin D, and normal parathyroid hormone. Histomorphometry of a bone biopsy specimen showed evidence of increased osteoclastic bone resorption. By 16 hours after tumor removal, 1,25-dihydroxyvitamin D level had normalized, but serum phosphorus level was unchanged; at 28 hours, both serum phosphorus value and tubular reabsorption of phosphate were within normal limits. It is concluded that tumor removal is associated with rapid correction both of 1,25-dihydroxyvitamin D production and of renal phosphate wasting. Increased bone resorption suggests the production of an osteoclast activator by the tumor and may explain the typically normal serum calcium value in this disorder.

[Mesenchymal tumor associated with hypoglycemia and an elevated NSILP (author's transl)]. / Tumeur mésenchymateuse hypoglycémiante de la cuisse avec NSILP élevé.

An unusually located mesenchymal tumor with hypoglycemia is observed. Insulin, cortisol, growth hormone, glucagon levels are within the normals. The glucogenic aminoacids have also been measured, as well as the NSILP which was three times as high as the upper limit of normal values. The various processes which might have brought about the patient's hypoglycemia are discussed.

Effect of ovariectomy on x-ray carcinogenesis in rats.

Tumor induction by fractionated whole-body X-irradiation (400 rad) was studied in spayed Sprague-Dawley rats. Ovariectomy was chosen as an intensifying factor for radiation leukemogenesis. Ovariectomized rats gained more body weight and responded more quickly (but transiently) in the recovery of WBC levels after the last (3rd or 4th) X-irradiation. A total of 26 tumors developed in 21 out of 47 ovariectomized rats, 11 tumors in 6 out of 13 ovariectomized and ovary-grafted rats, and 44 tumors in 25 out of 29 sham-ovariectomized rats during the observation period up to 64 weeks after starting X-irradiation. Eighty per cent of tumors were of mammary gland origin in the latter two groups with intact or grafted ovaries. By contrast, 61.1% of tumors in the spayed rats were derived from the subcutaneous mesenchymal tissue and the hematopoietic tissue. This may imply that some forms of mesenchymal tumors including leukemia are under the suppressive influence of female sex hormones.