| Part I The clinical study of tumor induced osteomalaciaObjectTumor induced osteomalacia (TIO) is a rare paraneoplastic syndrome induced by tumor produced phosphaturic factors, i. e. phosphatonins. The disorder is characterized by renal tubular phosphate loss, secondary to this process hypophosphatemia and defective production of active form of vitamin D. Clinical manifestations include bone pain, pathological fractures, muscle weakness and general fatigue. Osteomalacia-associated tumors are mesenchymal tumors that are usually benign. They are usually situated in the bones and in soft tissue. Most of them are small, slow-growing and difficult to locate. Their insignificant size and various locations coupled with rare occurrence of the disease and non-specificity of clinical symptoms lead to difficulties in reaching a diagnosis. The aim of this study is to discuss the pathophysiology of disease symptoms, diagnostic methods and treatment of oncogenic osteomalacia.MethodWe analyzed the clinical data of eighty nine patients who had been diagnosed as tumor induced osteomalacia from2004to2013in Peking Union Medical College Hospital. After taking their medical history, Physical examination was performed. Their bone turnover markers were measured and technetium-99m octreotide scintigraphy (99Tcm-OCT) was performed on every patient. If a tumor was suspected, BUS, CT or MRI was preceded on the patient. If99Tcm-OCT was negative but the patient was highly suspicious of TIO, the patient would get PET scan. After the tumor was located, it was resected in our hospital.ResultThere were forty three men (43/89,48.3%) and forty six (46/89,51.7%) women in our study. Their mean age was42.9±12.3years, the youngest was eighteen years old and the oldest was seventy one years old. The median value of their disease duration was four year long, the longest one was twenty seven year and the shortest one is about one year. All of these patients were presented with bone pain and fatigue. Fifty seven patients (57/89,77.0%) were shorter than before and fifty six patients(56/89,63.0%) had at least one fragile fracture. Thirty six patients (36/89,40.4%) had rib fracture, twenty seven (27/89,24.7%) had femur fracture, ten (10/89,11.2%) had pelvis fracture and eight (8/89,9.0%) had vertebrate fracture. Fifty three patients (53/89,59.6%) had biconcave or wedged vertebrate. Twenty two patients (22/89,24.7%) have pseudo-fracture.The mean level of serum phosphate was0.45±0.13mmol/L, ALP was282±158U/L, PTH was70.1±56.3pg/ml,24h Up was580.27±346.38mg, TmP/GFR was0.38±0.15mmol/L,25(OH)D:3was20.10±23.13ng/ml,1,25(OH)2D:3was14.0±9.78pg/ml and β-CTX was0.80±0.83ng/ml。Seventy three (73/89,82.0%) of all these patients had high99Tcm-OCT uptake. Fifty four of all these suspicious lesions were located in soft tissue while nineteen were in bone. Once the suspicious lesion was located by99Tcm-OCT, we proceeded to anatomic imaging such as BUS、CT and MRI to confirm the location of the tumor. The detection rate was one hundred percent (41/41,100%) for BUS, ninty two percent (33/36,91.7%) for CT and ninty five percent (41/43,95.3%) for MRI. Sixteen patients (16/89,18.0%) were99Tcm-OCT negative. Ten of these patients received68Ga-DOTA PET scan. ALL of them had found their suspicious lesions with68Ga-DOTA PET and they were proved to be the tumor location.Sixty seven (67/89,75.3%) of these tumors occurred in soft tissue, twenty two (22/89,24.7%) occurred in bone. They were located form head to toe, but the most common place was lower limb (48/89,53.9%). Twenty six tumors (26/89,29.3%) were locatd in the head region, six (6/89,6.7%) in the upper limb, five (5/89,5.6%) in the thorax and abdominal region and four (4/89,4.5%) in the pelvis and groin region. Tumors associated with TIO had included a wide range of histopathological diagnoses, with seventy eight phosphaturic mesenchymal tumors and a few other tumors. While most of these tumors (81/89,91.0%) were benign, eight (8/89,9.0%) were malignant. Tumor resection was almost always curative, and following complete resection of the tumor, phosphate level returned to normal in senventy six patients (76/89,85.4%) by post-operative day five. Of these patients, twenty five recoverd in three days, twenty three recoverd in three to five days, seventeen recoverd in five to seven days, six recoverd in one to two weeks and five patients took more than two weeks to recover. While phosphate level was not recovered in thirteen patients (13/89,14.6%). During the followup, the symptoms relapsed in six patients. For the patiets who were cured completely, bone pain disappeared gradually in six months post operation and their bone mineral density increased gradually.Conclusion1.99Tcm-OCT was a very helpful method in our hospital for locating TIO tumors. The detection rate of99Tcm-PCT in our patients was82.0%. Once the suspicious lesion was located by99cm-OCT, we proceeded to BUS、CT and MRI to confirm the location of the tumor.2.68Ga-DOTA PET was more specific than99Tcm-OCT in locating TIO tumors.3. Tumors associated with TIO had included a wide range of histopathological diagnoses, including phosphaturic mesenchymal tumor, odontogenic fibroma, hemangioma, giant cell tumor of tendon sheath, neurofibroma. A few other tumor or carcinoma could also lead to osteomalacia, for example renal clear cell carcinoma, thymus carcinoid.4. The treatment of choice for TIO was resection of the tumor with a wide margin to insure complete resection. The majority of patients demonstrated surgical cure, as evidenced by the return of serum phosphate to normal, by post-operative day5.5. Although most of the tumors were benign, malignant presentation and metastases could occur.6. Recurrences of these tumors could happen. All the patients should be followed up for as long as possible since recurrence could happen at any time. Part II The histopathological study of tumor induced osteomalaciaObjectTumor induced osteomalacia (TIO) is a rare paraneoplastic syndrome induced by tumor produced phosphaturic factors, i. e. phosphatonins. There is at least four phosphatonins, FGF23, MEPE, FGF7and sFRP4. FGF23is the widely recognized phosphaturic hormone that results in urine phosphate wasting and low levels of1,25(OH)2D3. FGF23is mainly secreted by osteocyte and osteoblast in bone tissue, with a little expression by pericyte like cells in bone marrow, hypothalamus. So we speculate that the tumor cells in TIO that secrete FGF23are osteogenic cells.The aim of this study is to discuss the histopathology of tumor induced osteomalacia and whether osteogenic cells are present in tumors associated with TIO.MethodUtilizing immunohistochemical techniques, positive detection of protein that are sequencially expressed during different stages of osteoblast differentiation has been demonstrated for Cbfal, ALP, OC, DMP1, MEPE, FGF23.ResultsThe phosphaturic mesenchymal tumor (PMT) contained neoplastic cells that were spindled in shape. Bone like structure was a frequent finding and steoclast-like giant cells could be seen. A prominent feature of these tumors was an elaborate intrinsic microvasculature with an admixture of vessel size and vascular pattern. The nuclear grade was low, and mitotic activity was usually absent or very low. But the tumors were poorly circumscribed and infiltration of surrounding tissues was common.FGF23was positive in all of the46tumors associated with TIO. FGF23is primarily secreted by osteoblast and osteocyte. This may suggest that the tumor cells that secret FGF23are osteogenic cells.MEPE was positive in97.6%of tumors associated with TIO. It is recognized that MEPE is secreted by osteocyte located in bone matrix. It is likely that the cells that express MEPE are osteocyte.As a very important transcription factor in regulating the differentiation of mesenchymal stem cell to osteoblast, Cbfal was expressed in97.6%of tumors associated with TIO.The expression of Cbfal may indicate that the cells that are expressed are immature osteoblasts.ALP was positive in97.6%of the tumors associated with TIO. ALP is mainly produced by osteoblast. Its expression could be recognized as a marker of osteoblast.As the only and very specific marker of mature osteoblast, OC was positive in93.5%of the tumors. It is likely that there are mature osteoblasts in these tumor tissues.DMP1was positive in58.7%of tumors associated with TIO. Secreted by osteocyte located in bone matrix, the expression of DMP1may indicate that the cells that it is secreted are osteocytes.Cbfal, ALP, OC, MEPE, DMP1, FGF23are factors that are sequentially expressed during different stages of osteoblast differentiation. Tumors associated with TIO expressd almost all of this factors. This may indicate that osteogenic cells are present in these tumors.In Our study we also found that ALP, OC and FGF23were also expressed by malformed endothelial cells in these tumors, while they were not expressed by normal endothelial cells.ConclusionTumors associated with TIO expressd the phosphaturic factors FGF23and MEPE. These two factors are related to hypophosphatemia and osteomalacia.A series of molecules that are sequentially expressed in different stages of osteoblast differentiation were also expressed in tumors associated with TIO. This may indicated that osteogenic cells are present in these tumors.The malformaed endothelial cells are multipotential cells in tumors associated with TIO and they may have the potential of transdifferentiation to become osteogenic cells. |
PDF Full Text Request