Osteomalacia oncogénica secundaria a tumor mesenquimal fosfatúrico del pie / Oncogenic osteomalacia secondary to phosphaturic mesenchymal tumour of the foot

RESUMEN La osteomalacia oncogénica es un síndrome metabólico paraneoplásico caracterizado por hipofosfatemia debida a la pérdida renal de fosfato, con nivel bajo de vitamina D. Este trastorno está asociado con la liberación de factores fosfatúricos por células tumorales, especialmente el factor de crecimiento fibrolástico 23 (FGF23). Las neoplasias relacionadas con la osteomalacia oncogénica suelen ser tumores pequeños de linaje mesenquimatoso y pueden ser difíciles de localizar en algunos casos debido a su tamaño y ubicación poco accesible al examen físico. Presentamos a un paciente que desarrolló fracturas vertebrales y de cadera debido a osteomalacia oncogénica asociada con un tumor mesenquimatoso fosfatúrico del tejido graso profundo de la planta del pie, que finalmente se diagnosticó después de 3 años del inicio de los síntomas, cuando el tumor pudo ser localizado por el rastreo gammagráfico óseo con pentatreótido marcado con indio-111 y por las imágenes de resonancia magnética nuclear.

ABSTRACT Oncogenic osteomalacia is a paraneoplastic metabolic syndrome characterised by a low phosphates in the blood due to renal phosphate losses with inadequately normal or low vitamin D levels. This disorder is associated with the release of tumour cell-secreted phosphaturic factor, most notably fibroblast growth factor 23 (FGF-23). The neoplasms related to oncogenic osteomalacia are usually small tumours of mesenchymal lineage, and they may be difficult to locate in the physical examination in some cases, due to their size and inaccessible location. The case is presented of a patient who developed vertebral and hip fractures due to oncogenic osteomalacia associated with a phosphaturic mesenchymal tumour of the deep fat tissue in the sole of the foot. This was finally diagnosed after 3 years of the onset of symptoms after being located by bone scintigraphy with Indium-111 labelled pentetreotide and magnetic resonance imaging.

Tumor-Induced Osteomalacia: A Case Study Of A Nasal Tumor

Oncogenous osteomalacia, which is also known as tumor-induced osteomalacia, is a condition where a neoplasm isassociated with systemic bone demineralization and renal phosphaturia. We report a case who presented with a bleedingnasal mass, generalized fatigue, and cramps in her leg. Excision was done, and histopathologically, it was diagnosed tobe a phosphaturic mesenchymal tumor. The cramps disappeared soon after surgery and she is on regular follow-up forthe past 2 years.

Tumor-induced osteomalacia

Tumor-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic syndrome characterized by hypophosphatemia resulting from decreased tubular phosphate reabsorption, with a low or inappropriately normal level of active vitamin D. The culprit tumors of TIO could produce fibroblast growth factor 23 which plays a role in regulating renal Pi handling and 25-hydroxyvitamin D 1α-hydroxylase activity. Chronic hypophosphatemia could eventually lead to inadequate bone mineralization, presenting as osteomalacia. The diagnosis should be considered when patients manifest as hypophosphatemia and osteomalacia, or rickets and needs to be differentiated from other disorders of phosphate metabolism, such as the inhereditary diseases like X-linked hypophosphataemic rickets, autosomal dominant hypophosphataemic rickets, autosomal recessive hypophosphataemic rickets and acquired diseases like vitamin D deficiency. Localization of responsible tumors could be rather difficult since the vast majority are very small and could be everywhere in the body. A combination of thorough physical examination, laboratory tests and imaging techniques should be applied and sometimes a venous sampling may come into handy. The technology of somatostatin-receptor functional scintigraphy markedly facilitates the localization of TIO tumor. Patients undergoing complete removal of the causative neoplasm generally have favorable prognoses while a few have been reported to suffer from recurrence and metastasis. For those undetectable or unresectable cases, phosphate supplements and active vitamin D should be administrated and curative intended radiotherapy or ablation is optional.

Clinical characteristics and treatment strategy of five phosphaturic mesenchymal tumors in hips / 中华骨科杂志

Objective To analyze the clinical characteristics and treatment strategy of phosphaturic mesenchymal tumors in hips.Methods From May 2017 to November 2017,five patients with phosphaturic mesenchymal tumors in hips,who treated in our hospital were retrospectively reviewed.The clinical manifestations,laboratory inspection,radiological examination,pathological examination and treatment were analyzed.Results Two male cases (40％) and 3 female (60％) were included.The overall age was 49～63 years old (average 54.40±5.37 years old).The course was 19～101 months (average 51.20±32.41months).Four cases of tumor were located in femoral head and 1 case was in femur intertrochanteric region.The maximum tumor diameter was 0.76～1.83 cm (average 1.28±0.39 cm).The early clinical manifestations of the patients were mainly non-specific bone pain or fatigue.The symptoms of the hip were not obvious.All patients had been misdiagnosed.After pathological frac-ture of the hip,the patient suffered from hip pain,thigh pain,fatigue,etc.,or limited hip function.The severe patients had a systemic multiple pathologic fractures.The serum phosphorus was lower than normal in preoperative period and recovered to normal level in 3-8 days after surgery.The postoperative ALP decreased significantly than preoperative in 4 patients and 1 case was slightly higher than preoperative.Preoperative 1,25-(OH)2-D3 and PTH were in normal range.99Tcm-octreotide (OCT) scan or 68Ga DOTA-TATE PET/CT can detect the disease.X-ray,CT and MRI can identify the lesions.The lesions of femoral head were basically under the joint surface,with a nodular change.Part of the tumor was infiltrating and close to the cortex.The pathology was mainly manifested as a large number of thin-walled vessels in the bone trabeculae.There were dense spindle cells or astrocytes between the blood vessels and the atypia is not obvious.Three patients were treated with total hip arthroplasty and two with segmental resection and bone graft.After surgical removal of the tumor,the patient's systemic pain or anemic symptoms were gradually relieved and the joint function was restored.Meanwhile,the bone density was increased.Conclusion The clinical features of the phosphaturic mesenchymal tumors in hips were not obvious.Comprehensive diagnosis should be carried out in combination with the clinical manifestations,laboratory examination,radiological examination and pathological examination.Total hip arthroplasty or segmental resection with bone graft can effectively remove the tumor and achieve good prognosis.

Successful Localization Using ⁶⁸Ga-DOTATOC PET/CT of a Phosphaturic Mesenchymal Tumor Causing Osteomalacia in a Patient with Concurrent Follicular Lymphoma / 대한핵의학회잡지

Diagnosing tumor-induced osteomalacia is often challenging because conventional imaging modalities may fail to locate the responsible tumor. This report describes the ability of ⁶⁸Ga-DOTATOC PET/CT to successfully distinguish between the responsible phosphaturic mesenchymal tumor and concurrent lymphoma lesions. A 52-year-old man with bone pain for several years was diagnosed with a vitamin D-resistant hypophosphatemic osteomalacia. Whole body ¹⁸F-FDG PET/CT revealed multiple enlarged hypermetabolic lymph nodes in his bilateral cervical, axillary, mediastinal, abdominal, pelvic, and inguinal regions. Core needle biopsy of the right cervical lymph node confirmed the diagnosis of follicular lymphoma. However, lymphoma was not considered the cause of osteomalacia. ⁶⁸Ga-DOTATOC PET/CT before chemotherapy showed a small nodule with intensely increased uptake in the right inguinal region, which was distinguished from the other enlarged lymph nodes. The nodule was surgically removed and histopathologically consistent with phosphaturic mesenchymal tumor. After surgery, the patient's serum phosphorus and alkaline phosphatase levels normalized without nutritional supplement.

Phosphaturic mesenchymal tumor (PMT): exceptionally rare disease, yet crucial not to miss

Phosphaturic mesenchymal tumors (PMTs) are very rare tumors which are frequently associated with Tumor Induced Osteomalacia (TIO), a paraneoplastic syndrome that manifests as renal phosphate wasting. The tumor cells produce a peptide hormone-like substance known as fibroblast growth factor 23 (FGF23), a physiologic regulator of phosphate levels. FGF23 decreases proximal tubule reabsorption of phosphates and inhibits 1-α-hydroxylase, which reduces levels of 1-α, 25-dihydroxyvitamine D3. Thus, overexpression of FGF23 by the tumor cells leads to increased excretion of phosphate in the urine, mobilization of calcium and phosphate from bones, and the reduction of osteoblastic activity, ultimately resulting in widespread osteomalacia. Patients typically present with gradual muscular weakness and diffuse bone pain from pathologic fractures. The diagnosis is often delayed due to the non-specific nature of the symptoms and lack of clinical suspicion. While serum phosphorus and FGF23 testing can assist in making a clinical diagnosis of PMT, the responsible tumor is often difficult to locate. The pathologic diagnosis is often missed due to the rarity of PMTs and histologic overlap with other mesenchymal neoplasms. While patients can experience severe disabilities without treatment, excision is typically curative and results in a dramatic reversal of symptoms. Histologically, PMT has a variable appearance and can resemble other low grade mesenchymal tumors. Even though very few cases of PMT have been reported in the world literature, it is very important to consider this diagnosis in all patients with hypophosphatemic osteomalacia. Here we present a patient who suffered for almost 5 years without a diagnosis. Ultimately, the PMT was located on a 68Ga-DOTA TATE PET/CT scan and subsequently confirmed by histologic and immunohistologic study. Interestingly, strong positivity for FGFR1 by IHC might be related to the recently described FN1-FGFR1 fusion. Upon surgical removal, the patient's phosphate and FGF23 levels returned to normal and the patient's symptoms resolved.

Oncogenic Osteomalacia with Multiple Insufficiency Fractures: A Case Report

Oncogenic osteomalacia is a rare paraneoplastic syndrome, characterized by hypophosphatemia, renal phosphate wasting, osteomalacia, and multiple insufficiency fractures, as a result of the tumor. A wide excision of the causative tumor is considered as the treatment of choice, following which, a dramatic recovery is expected. Authors report a case in which the symptoms and bone mineral density were dramatically recovered after an excision of the causative tumor around the tibialis posterior muscle in oncogenic osteomalacia.

Osteomalacia oncogénica: Presentación de dos casos

La osteomalacia oncogénica es una enfermedad rara. Existen descriptos alrededor de 337 casos. Es ocasionada por un tumor productor del factor de crecimiento fibroblástico 23 (FGF-23), hormona que disminuye la reabsorción tubular de fosfatos y altera la hidroxilación renal de la vitamina D, con hipofosfatemia, hiperfosfaturia y niveles bajos de calcitriol. Se presentan dos pacientes de 44 y 70 años, que consultaron por dolores óseos generalizados de aproximadamente un año de evolución en los que se hallaron alteraciones bioquímicas compatibles con osteomalacia hipofosfatémica. En el primer caso se realizó la resección de una tumoración en tejido celular subcutáneo del pie derecho, un año después del diagnóstico clínico. Luego de la exéresis, se disminuyó el aporte de fosfatos que recibía el paciente, pero reaparecieron los dolores al intentar suspenderlos. Ocho años más tarde, hubo recidiva local de la tumoración por lo que se efectuó resección completa. Después de la misma, se logró suspender el aporte de fosfatos. En el segundo caso, el paciente se estudió con tomografía por emisión de positrones con 18F-fluorodesoxiglucosa, hallando formación nodular hipermetabólica en partes blandas de antepie derecho, de 2.26 cm de diámetro. Luego de su escisión se pudo suspender el aporte de fosfatos. Ambos pacientes se encuentran asintomáticos con indicadores de metabolismo fosfocálcico normales. El diagnóstico anatomopatológico en ambos fue un tumor mesenquimático fosfatúrico, variante mixta del tejido conectivo, la entidad más frecuentemente asociada a la osteomalacia oncogénica.

Oncogenic osteomalacia is a rare disease. It is caused by a tumor that produces fibroblast growth factor 23, a hormone that decreases the tubular phosphate reabsorption and impairs renal hydroxylation of vitamin D. This leads to hyperphosphaturia with hypophosphatemia and low calcitriol levels. About 337 cases have been reported and we studied two cases; 44 and 70 year-old men who sought medical attention complaining of suffering diffuse bone pain over a period of approximately one year. In both cases, a laboratory test showed biochemical alterations compatible with a hypophosphatemic osteomalacia. In the first case, a soft tissue tumor of the right foot was removed, one year after the diagnosis. The patient was allowed to diminish the phosphate intake, but symptoms reappeared at this time. Eight years later, a local recurrence of the tumor was noted. A complete excision was now performed. The patient was able to finally interrupt the phosphate intake. In the second case, an F-18 fluorodeoxyglucose positron emission tomography, with computed tomography revealed a 2.26 cm diameter hypermetabolic nodule in the soft tissue of the right forefoot. After its removal, the patient discontinued the phosphate intake. Both patients are asymptomatic and show a regular phosphocalcic laboratory evaluation. The histopathological diagnosis was, in both cases, a phosphaturic mesenchymal tumor, a mixed connective tissue variant. This is the prototypical variant of these tumors.

Hyperphosphaturic Mesenchymal Tumor induced Osteomalacia– A Case Report.

Hyperphosphaturic Mesenchymal Tumor (HMT) is a very rare benign tumor of the soft tissue or bone which produces tumor induced osteomalacia, also called as oncogenic osteomalacia. This activity can only be stopped by the surgical removal of the tumor. We present a 23 years old man who presented with long standing bony pains without any relief by a variety of medications. The clue to the diagnosis was taken from pelvis skiagram, Magnetic Resonance Imaging (MRI) of the body, PET scan and the blood chemistry.

Tumor mesenquimatoso fosfatúrico de fosa nasal con compromiso intracraneano: reporte de un caso y revisión de la literatura / Nasal fossa phosphaturic mesenchymal tumor with intracraneal compromise: case report and review of the literature

El tumor mesenquimatoso fosfatúrico (TMF) es una enfermedad extremadamente rara. Según evidencia reciente es causado por la sobreexpresión del factor de crecimiento fibroblástico 23 (FGF23), el cual genera hipofosfemia y osteomalacia. A continuación presentamos el caso de un paciente de 42 años con un tumor mesenquimatoso fosfatúrico de fosa nasal izquierda con extenso compromiso intracraneano. Cabe destacar que hasta la fecha hay 142 casos reportados de TMF en la literatura de los cuales solo 11 se ubican en fosa nasaly cavidades sinusales, y sólo dos de ellos ubicados en fosa nasal¹. El paciente tuvo una exitosa resolución quirúrgica con la consecuente normalización de parámetros analíticos (incluido el FGF23), mejoría sintomática y ausenia de recidiva hasta la fecha.

The phosphaturic mesenchymal tumor (PMT) is an extremely rare disease. According to recent evidence is caused by overexpression of fibroblast growth factor 23 (FGF23) which generates hypophosphatemia and osteomalacia. We report the case of a 42 year old patient with a left nasal fossa phosphaturic mesenchymal tumor with intracranial involvement. Should be noted that to date there are 142 reported cases of PMT in the literature of which only 11 are located in nasal fossa and sinus cavities, two of them located in nasal fossa¹. The patient had a successful surgical resolution with consequent normalization of analytical parameters (including FGF23), absence of symptoms and no recurrence to date.

Osteomalacia inducida por tumor: hemangiopericitoma rinosinusal / Tumor-induced osteomalacia: rhinosinusal hemangiopericytoma

La osteomalacia inducida por tumor es una rara enfermedad del metabolismo óseo caracterizada por el aumento en la excreción de fosfato a nivel renal seguido de hipofosfatemia. Es causada por agentes fosfatúricos producidos por determinados tumores. La resección total del tumor resulta en la completa reversión de las anormalidades bioquímicas, la desaparición de las manifestaciones clínicas y los hallazgos en los estudios por imágenes. Presentamos el caso de un varón de 61 años con cuadro clínico y laboratorio compatibles con osteomalacia oncogénica inducida por tumor mesenquimático de localización rinosinusal. En nuestro caso el diagnóstico histológico correspondió a una neoplasia de tipo vascular: hemangiopericitoma.

Tumor-induced osteomalacia is a rare disease of bone metabolism. The characteristic of this disease is an increase in phosphate excretion followed by hypophosphatemia, due to phosphaturic agents produced by different types of tumors. Tumor resection results in complete resolution of clinical, biochemical and radiological abnormalities. We present the case of a 61 year old man with signs, symptoms and laboratory findings consistent with oncogenic osteomalacia due to a rhino-sinusal mesenchymal tumor. The histological diagnosis showed a vascular neoplasm: hemangiopericytoma.

Osteomalacia por tumor secretor de FGF-23 / Ostemalacia due to a tumor secreting FGF-23

Se presenta un caso de osteomalacia oncogénica en un varón de 50 años, con fuertes dolores óseos y gran debilidad muscular durante 4 años. Tenía varias deformidades vertebrales dorsales en cuña, fracturas en ambas ramas iliopubianas y en una rama isquiopubiana, y una zona de Looser en la meseta tibial derecha. Se localizó un tumor de 2 cm de diámetro en el hueco poplíteo derecho mediante centellograma con octreótido marcado con tecnecio. El tumor fue extirpado quirúrgicamente. La microscopía mostró un tumor mesenquimático fosfatúrico, de tejido conectivo mixto. La inmunotinción demostró FGF-23. Hubo rápida mejoría, con consolidación de las fracturas pelvianas y de la pseudofractura tibial y normalización de las alteraciones bioquímicas.

A case of oncogenic osteomalacia in a 50-year-old male is here presented. He suffered severe bone pain and marked muscular weakness of 4 years' duration. There were several vertebral deformities in the thoracic spine, bilateral fractures of the iliopubic branches, another fracture in the left ischiopubic branch, and a Looser's zone in the right proximal tibia. An octreotide-Tc scan allowed to identify a small tumor in the posterior aspect of the right knee. It was surgically removed. Microscopically, it was a phosphaturic mesenchymal tumor-mixed connective tissue (PMT-MCT). Expression of FGF-23 was documented by immune-peroxidase staining. There was rapid improvement, with consolidation of the pelvic fractures and the tibial pseudo-fracture. The laboratory values returned to normal.

Oncogenic osteomalacia, you say? better start looking then - a case report

Tumour-induced or oncogenic osteomalacia (OOM) is a rare paraneoplastic syndrome characterized by bone pain and muscle weakness. A biochemical profile consisting of normocalcaemia, hypophosphataemia, phosphaturia, increased serum alkaline phosphatase and inappropriately low serum levels of 1, 25-dihydroxyvitamin-D is diagnostic. OOM is usually caused by an osseous or soft-tissue tumour of mesenchymal origin that secretes phosphaturic substances leading to increased urinary phosphate wasting. These tumours are small and slow growing. The diagnosis continues to be easily missed and when eventually made, localization of the tumour can be difficult. We describe the case of a young man who presented with severe generalized pain associated with muscle weakness. He was extensively investigated and eventually diagnosed to have OOM 3 years after initial presentation. Specialized investigations were necessary to localize the offending tumour.

Osteomalácia oncogênica: cintilografia com sestamibi-99mTc na localização do tumor / Oncogenic osteomalacia: localization of underlying peripheral tumor with99mTc-sestamibi scintigraphy

A osteomalácia oncogênica hipofosfatêmica (OOH) é uma síndrome paraneoplásica induzida por tumor, de tecidos mole ou ósseo. Apresenta-se com dor e fraturas, acompanhada de hipofosfatemia, hiperfosfatúria e concentrações plasmáticas de 1,25(OH)2D3 inapropriadamente normais/diminuídas. Após a remoção do tumor, a completa resolução das anormalidades clínicas e bioquímicas é sua maior característica. Uma mulher de 44 anos de idade é descrita no caso com dificuldade para caminhar por causa de dores nos membros inferiores, fraqueza muscular generalizada e hipofosfatemia com relativa hiperfosfatúria. A cintilografia de corpo total com sestamibi-99mTc mostrou acúmulo do radiofármaco no terço superior de coxa esquerda onde pequeno tumor foi detectado no exame pelo ultra-som. Com a retirada do tumor, um lipoma, os sintomas melhoraram após um mês, com recuperação completa ao redor do quarto mês. Neste caso, a cintilografia de corpo inteiro com sestamibi-99mTc foi decisiva na localização do tumor causador da osteomalácia oncogênica.

Oncogenic osteomalacia is a paraneoplastic syndrome usually induced by bone or soft tissue tumors. It is presented by the development of pain and fractures with hypophosphatemia, hyperphosphaturia, and inappropriate normal/low plasma 1,25(OH)2D3 concentration. After the removal of the tumor the complete resolution of all biochemical and clinical abnormalities is the main characteristic. A case of a 44-year-old female with difficulty in walking due to leg pain and generalized muscle weakness and hypophosphatemia, with relative hyperphosphaturia, is described. A whole-body 99mTc-sestamibi scintigraphy showed accumulation in the left thigh region, and a small tumor was detected by ultrasound examination. By removal of the tumor, a lipoma, the symptoms improved significantly after a month, with complete recovery by the fourth month. In this case, 99mTc-sestamibi scintigraphy was useful in identifying the location of the tumor, which caused oncogenic osteomalacia.

A Case of Sporadic Nonfamilial Hypophosphatemic Osteomalacia / 대한내분비학회지

Acquired hypophosphatemic rickets, or osteomalacia, requires the recognition of the typical clinical and radiological features of osteomalacia in association with hypophosphatemia, which is caused by the decrease in intestinal absorption or impaired renal tubular phosphate reabsorption. The latter form may either be hereditary or acquired. Acquired hypophosphatemic osteomalacia includes oncogenic osteomalacia, neurofibromatosis, fibrous dysplasia, renal tubular acidosis and sporadic nonfamilial hypophosphatemic osteomalacia. A 33-year-old man presented with bone pain, progressive severe muscle weakness and a height loss of more than 10 cm over a 5 year period. The familiy history was negative for bone disease or other renal tubular defects. He was found to have hypophosphatemia, impaired phosphate reabsorption, normocalcemia, normal vitamin D metabolite levels, normal PTH and elevated alkaline phophatase. A bone biopsy showed thickened unmineralized osteoid compared to pelvic bone in control cases. Clinical symptoms, such as bone pain and muscle weakness, were improved after supplementation of oral phosphorus and calcitriol, although the serum phosphorus level did not normalize.

A Case of Oncogenic Osteomalacia Caused by Chondromyxoid Fibroma / 대한내분비학회지

Oncogenic osteomalacia is a rare clinicopathological condition. The syndrome is characterized by hypophosphataemic osteomalacia with hyperphosphaturia, low plasma 1,25-dihydroxyvitamin D and normal plasma calcaemia and parathyroid hormone, associated with a tumor, generally of mesenchymal origin. Complete excision of the tumour results in cure of the whole syndrome. Recently we experienced 56-year-old woman with oncogenic osteomalacia caused by a chondromyxoid fibroma of the left foot. We report this case with the review of literatures.

A Case of Osteosarcoma induced Oncogenic Osteomalacia Detected by MRI / 대한내분비학회지

Oncogenic osteomalacia is a syndrome characterized by phosphaturia, hypophosphatemia, decreased 1,25-dihydroxyvitamin D level and specific signs and symptoms of osteomalacia. It is associated with the presence of neoplasm originated from mesenchyme. Until now, less than 100 cases of oncogenic osteomalacia have been reported. The pathophysiology of oncogenic osteomalacia has not been fully understood, but it has been suggested that a certain substance released by tumor may inhibit not only la-hydroxylase activity and reduce 1,25-dihydroxyvitamin D level in part, but directly inhibit reabsorption of phosphate. And then, reduced phosphaturia, hypophosphatemia and eventually osteomalacia develop. We report a case of osteosarcoma induced oncogenic osteomalacia detected by MRI in 59 year old woman.