Tumor induced osteomalacia: A single center experience on 17 patients.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome due to a phosphaturic tumor, which overproduces Fibroblast Growth Factor 23 (FGF-23), causing hyperphosphaturia, hypophosphatemia, low 1,25(OH)2D and osteomalacia. Tumor localization is critical, diagnostic delay ranges from 2.5 to 28 years and to date surgical removal is considered effective treatment. We retrospectively evaluated patients with definite diagnosis of TIO referred to a tertiary Rheumatology Center between September 2000 and May 2020, investigating clinical management and disease outcome. We included 17 patients: 10 (58.8%) were females, mean age at diagnosis was 55.3 ± 13.9 years (mean ± standard deviation), with a diagnostic delay from symptoms onset to tumor detection of 6.6 ± 6.25 years. Biochemical data were: serum phosphorus 1.3 ± 0.4 mg/dL (Reference Range: 2.5-4.6), serum 1,25(OH)2D 31.8 ± 22.9 ng/mL (RR: 25-86), intact FGF-23, 358.9 ± 677 pg/mL (RR: 25-45); 24 h-Urine Phosphorus was increased in only 2 patients, while tubular reabsorption of phosphate (TRP) was decreased in all patients confirming a renal phosphate wasting. In 2013 68Ga- DOTA-based PET/CT was introduced in routinely practice and diagnostic delay was consistently reduced (from 8.6 ± 7.9 to 4.3 ± 2.4 years). Thirteen patients underwent surgery, one patient underwent radiofrequency ablation; 3 patients, not eligible for surgery, were treated only with supplements of phosphorus and calcitriol. One was started on Burosumab after several unsuccessful surgical attempts. After surgery or ablation, 8 patients had complete remission, 3 TIO persistence, and 3 had overtime relapse. Relapses were observed only in patients who previously underwent closed biopsy. To our knowledge, this is the widest European cohort of TIO patients in the last two decades. We confirm a usual diagnostic delay and recommend a stepwise diagnostic approach. Tumor biopsy is not recommended due to the potential cell spilling. Surgery is generally considered a definitive treatment, even though other approaches have been successful in curing TIO. Active surveillance on possible recurrence is always needed. Burosumab appears a promising therapy.

Accuracy of CT and MRI to assess resection margins in primary malignant bone tumours having histology as the reference standard.

AIM: To evaluate the accuracy of magnetic resonance imaging (MRI) and computed tomography (CT) in assessing the resection margins of primary malignant bone tumours. MATERIALS AND METHODS: Resected primary malignant bone tumour specimens removed from 46 patients (27 male; mean age: 48±22 years) were imaged using MRI (fat-saturated proton density-weighted and three-dimensional fat-suppressed T1-weighted gradient-recalled-echo) and CT immediately after surgery. A radiologist and an orthopaedist evaluated bone and soft-tissue margins of the specimens on both examinations. Histological evaluation was performed by a senior orthopaedic oncology pathologist. Margins were classified as R0 (safe margins), R1 (residuals between 0 and 1 mm), and R2 (macroscopic residuals). Cohen's k, chi-square, and McNemar's statistics were used. RESULTS: Having histology as the reference standard, reproducibility of the radiologist ranged from moderate (k=0.544) to substantial (k=0.741) for bone and soft-tissue margins on CT, respectively, while that of the orthopaedist ranged from fair (k=0.316) to moderate (k=0.548). When comparing R2 and R0+R1 scores, reproducibility of readers' evaluation of bone margins increased ranging from substantial (k=0.655) to perfect (k=1.000). Inter-reader agreement ranged from fair (k=0.308) to substantial (k=0.633). Accuracy of the radiologist and orthopaedist ranged from 76% to 83% and from 68% to 72%, respectively. When comparing R2 and R0+R1 scores, the accuracy of both readers ranged from 83% to 100%. There was no association between local recurrence and margin scores of histology, MRI, and CT (p≥0.058). CONCLUSIONS: MRI and CT may be useful for extemporaneous analysis of resection margins of primary malignant bone tumours, although wide accuracy variability between the different imaging methods was observed.

Malignant peripheral nerve sheath tumor of the bladder A case report.

Malignant peripheral nerve sheath tumor (MPNST) is an uncommon malignant tumor often associated with Neurofibromatosis type 1 (NF1). Although different soft tissue mesenchymal tumors may arise in the bladder, MPNST is a very rare occurrence. Here, we present a case of MPNST of the bladder in a 50 year old patient with NF1 with involvement of the entire wall of the organ leading to a functional exclusion. The principal differential diagnoses and a short review of the literature are presented.

Osteoporosis with vertebral fractures in young males, due to bone marrow mastocytosis: a report of two cases.

Male osteoporosis in young patients is an unusual condition, always worth investigating as a possible manifestation of secondary osteoporosis. Mastocytosis is a clonal disorder of mast cells with heterogeneous presentations; when pathologic cells accumulate only in the bone marrow, vertebral fractures and systemic osteoporosis may represent the sole clinical presentation at the onset of the disease. We report on two young male patients who came to our attention because of multiple dorsal and lumbar vertebral fractures, with no other signs of systemic mastocytosis (SM). Lumbar and femoral dual x-ray absorptiometry showed reduced bone mineral density values; biochemical investigations did not report significant anomalies, suggestive of secondary osteoporosis. One of the patients underwent iliac crest bone biopsy, which was not diagnostic. A vertebral intralesional CT-guided bone biopsy was performed in both patients, which allowed the diagnosis of SM. Our experience pointed out that bone biopsy still remains the gold standard for the diagnosis of SM. However, iliac crest biopsy can be not significant because of circumscribed bone marrow involvement: in these cases only intralesional bone biopsy could be diagnostic.

Lymphoid neogenesis in juvenile idiopathic arthritis correlates with ANA positivity and plasma cells infiltration.

OBJECTIVE: The aim of the study was to evaluate the pattern of the lymphoid organization in the synovial tissue of patients affected with juvenile idiopathic arthritis (JIA). METHODS: A total of 40 JIA patients who underwent synoviectomy or synovial biopsies were enrolled. The mean age at surgery was 15.1 yrs (range 6-30 yrs) and the mean disease duration was 6.7 yrs (range 3 months to 22.2 yrs). Tissue specimens were grouped according to the following criteria: (i) diffuse perivascular infiltrate without lymphoid organization, (ii) T cell-B cell aggregates with or without germinal centre reaction. RESULTS: Synovial tissues from 12 JIA patients did not show any sign of lymphoid organization, whereas 28 patients displayed a variable number of T-B cell aggregates. Typical features consistent with a germinal centre reaction were present in two JIA patients only. Lymphoid organization in JIA patients did not correlate with the duration and severity of the disease or with the degree of synovial inflammation, but did positively correlate with the presence of anti-nuclear antibodies. Moreover, a diffuse lymphocyte infiltration was significantly related to the presence of an acute phase of inflammation and the presence of lymphoid aggregates correlated with the degree of plasma cells infiltration. CONCLUSIONS: Lymphoid neogenesis in JIA represents a phase in the immunopathological process that characterize the development of inflammatory synovitis. It is not related to disease activity or severity, but appears to be more frequent in patients with circulating anti-nuclear antibodies.

Synovial expression of osteopontin correlates with angiogenesis in juvenile idiopathic arthritis.

OBJECTIVE: To evaluate the synovial expression of osteopontin (OPN) and its possible correlation with the degree of synovial angiogenesis in human chronic idiopathic arthritis. METHODS: Forty-five patients with active juvenile idiopathic arthritis (JIA) were studied. All patients underwent SF aspiration before steroid injection. A paired plasma sample was collected from 22 JIA patients. Plasma from 15 age-matched healthy subjects was used as control. Plasma and SF were tested by ELISA for OPN and vascular endothelial growth factor (VEGF). Synovial tissue was obtained at synovectomy from 10 JIA patients. Immunohistochemistry was performed according to a standard technique with anti-OPN, anti-CD68, anti-CD31 anti-VEGF and anti-alpha(v)beta(3) antibodies. RESULTS: OPN levels were significantly higher in SF than in paired plasma samples (P<0.001). The same pattern was observed for VEGF (P<0.001). A positive correlation between OPN and VEGF concentrations was found in SF (r = 0.6, P = 0.001). In synovial tissue, OPN was expressed at the level of the lining and sublining layers with a distribution similar to that observed for VEGF. OPN expression in the lining layer correlated with the number of vessels present in the areas underlying the sublining layer. CONCLUSIONS: Synovial expression of OPN correlates with parameters of angiogenesis in JIA. These data support, in human disease, the possible role of OPN in the vascularization of inflamed synovial tissue, as previously shown in OPN-deficient animal models of arthritis.

A case of oncogenic osteomalacia detected by 111In-pentetreotide total body scan.

A case of tumor-induced osteomalacia in a 35-year-old woman suffering from severe bone pain and muscle weakness is described. This uncommon disease is characterized by a reduced serum phosphorus level with elevated urinary phosphate excretion, normocalcemia, high serum bone alkaline phosphatase and a deficiency of 1,25 dihydroxyvitamin D3. The tumors responsible for oncogenic osteomalacia are usually small, benign and commonly located in bone or soft tissues of the head and the limbs, so the diagnosis can often be difficult. In this case a 111In-pentetreotide scintigraphy was able to detect a hemangiopericytoma located in the right mascellar sinus. Removal of the tumor resulted in the reversal of clinical and biochemical abnormalities.

Duodenal expression of a putative stimulator of Fe transport and transferrin receptor in anemia and hemochromatosis.

BACKGROUND & AIMS: Stimulator of Fe Transport (SFT) and transferrin receptor (TfR) are proteins involved in iron transport. This study evaluated iron metabolism protein expression in duodenal biopsy specimens from controls and patients with abnormal iron metabolism. METHODS: Twelve controls, 8 patients with iron deficiency anemia, 7 with HFE-related hemochromatosis, and 6 with non-HFE-related iron overload were studied. Immunohistochemistry was performed on duodenal biopsy specimens with anti-TfR and anti-SFT antibodies which recognize a putative stimulator of Fe transport of ~80 kilodaltons. RESULTS: In controls, the putative stimulator of Fe transport was expressed in the middle and distal part of the villi in the subapical cytoplasmatic region. Its expression increased in anemics and, to a lesser degree, in HFE-related hemochromatotics, whereas it was reduced in patients with non-HFE-related iron overload. TfR expression showed a crypt-to-tip gradient in controls, but not in anemics, in whom it was uniformly overexpressed. TfR expression was intermediate in HFE-related hemochromatotics and similar to controls in non-HFE-related iron overload. CONCLUSIONS: Expression of the putative stimulator of Fe transport and TfR increases in iron deficiency. Increased expression of both proteins is present only in HFE-related hemochromatotics suggesting that other factors may be involved in determining non-HFE-related iron overload phenotype.

Experimental study of a sleeve microanastomotic technique.

Sleeve anastomosis is an end-to-end variant (i.e., end in end) that makes it possible to suture two vessels quickly and with few stitches. Various methods have been described in the literature concerning experimental surgery (microsurgery and transplantation) and clinical microsurgery. The authors tested for a method that would eliminate narrowing of the inserted vessel segment and that would improve efficiency and feasibility of the technique. The experimental study was performed in 60 rats weighing 200 to 400 g. Telescoping microanastomosis consists of hemi-invagination of a 2-mm-caliber artery at high pressure (subrenal aorta), sidecut of the distal wall of the external arterial segment, and suture with three endoluminal stitches. A total of 61 anastomoses were subdivided in three groups: (1) one-sleeve anastomosis, (2) double-sleeve anastomosis with interposition of an arterial graft, and (3) a control series of conventional end-to-end anastomoses. Patency rates of 95% to 100% at 1 week and 1 month demonstrated no differences among groups.

Multifocal osteosarcoma as second tumor after childhood retinoblastoma.

We present a case of multifocal osteosarcoma (MFOS) arising 11.5 years after successful treatment of bilateral retinoblastoma. The clinical, imaging and pathological findings at onset, after therapy, and during follow-up are described. Fluorescent in situ hybridization did not reveal a deletion of the RB-1 retinoblastoma gene, although the presence of an inactivating mutation invisible to this method cannot be ruled out. The MFOS may have been a second multifocal tumor associated with the original retinoblastoma or a post-irradiation sarcoma with extensive metastases.

Retrospective analysis of ploidy in primary osseous and extraosseous Ewing family tumors in children.

AIMS: To retrospectively study the DNA content in a series of childhood Ewing Family Tumors (EFT), and to investigate its prognostic value. METHODS: The study was performed on a series of 27 EFTs (osseous Ewing's sarcoma, 18 cases; extraosseous Ewing's sarcoma, 2; peripheral neuroepithelioma, 4; Askin Rosai tumors, 3). Ploidy was investigated using both flow cytometry (FCM) and image cytometry (ICM) on tumor cell suspensions from formalin-fixed paraffin-embedded specimens or fresh frozen tissue obtained from the primary tumor at diagnosis. RESULTS: Ploidy was evaluable by FCM in all cases, and by ICM in 23/27. When fresh frozen tissue and paraffin-embedded samples from the same tumor were available for analysis, they yielded equal results. The rate of agreement between FCM and ICM was 82%. The majority of cases were diploid, and in the present series aneuploidy seemed to be associated with a poor outcome. CONCLUSIONS: These results suggest that aneuploidy could be an indicator of a bad prognosis in EFT; however, the small number of cases precludes any conclusion of statistical value. Larger retrospective studies on ploidy using archival material could be performed and their reliability is supported by the concordance of results from fresh and formalin-fixed tissue.

Glomus tumour: the immunohistochemical characteristics of twenty-three cases.

Twenty-three cases of glomus tumour were investigated with the antibodies keratin, vimentin, neurofilaments, desmin, actin, S100, Factor VIII-related antigen, substance P and KP1/CD68. It will be shown that the glomus cells were vimentin-positive in 11 out of 23 cases (48%), actin-positive in 16 out of 23 cases (70%) and desmin-positive in 9 out of 23 cases (39%). The KP1 monoclonal antibody demonstrated the presence of numerous mast cells in some cases. The substance P was only occasionally positive in six cases (26%). No positive staining was seen with keratin, neurofilaments, S100 and Factor VIII-related antigen. It is confirmed that glomus cells can be considered as elements of smooth muscle origin. Our study suggests a possible explanation of the mechanism which induces paroxysmal attacks in patients with glomus tumours.

Malignant proliferating onycholemmal cyst.

A slowly growing malignant tumor of the nail unit in a 74-year-old female is reported. At light microscopy, the tumor was composed of small keratinous cysts with abrupt central keratinization, and of solid nests and strands of atypical keratinocytes filling the dermis and penetrating the phalangeal bone. In our view, this can be regarded as the malignant analog of the keratin cysts arising from the nail bed epithelium, as first reported by Samman in 1959. Since, according to several authors, the nail bed epithelium is comparable to the outer root sheath of the follicle and since the reported tumor showed some analogies with malignant proliferative trichilemmal cyst, it is suggested that this new entity be designated as malignant proliferating onycholemmal cyst.

Mixed germ cell tumour of the mediastinum (seminoma, embryonal carcinoma, choriocarcinoma and teratoma). Light and electron microscopic cytology and histological investigation.

A mixed germ cell tumour of the mediastinum was found in a 27-year-old subject. It had four components: seminoma, embryonal carcinoma, choriocarcinoma and teratoma. Material for light microscopy (L.M.) and ultrastructural studies were obtained with computerized tomography (CT) guided fine needle aspiration. Three histotypes were identified with ultrastructural studies while only seminoma was identified with L.M. The slides prepared for L.M. were reexamined in the light of findings with electron microscopy (E.M.) and previously unidentified cellular elements were found to be characteristic of choriocarcinoma and teratoma. Histological examination of surgical and autopsy material confirmed the cytological findings. Because of the singularity of this case, the rarity of this type of neoplasm and the difficulty in arriving at a differential diagnosis from other neoplastic and non neoplastic lesions, only the ultrastructural cytological examination allowed us to identify the mixed nature of the tumour. Such an identification is not always possible with L.M. but it is a determining factor in the prognosis and therapy.