Phosphaturic Mesenchymal Tumor Along the Hallux side Inducing a Chronic non-Healing Wound: A Case Report with Literature Review.

Phosphaturic mesenchymal tumor (PMT) is a rare paraneoplastic syndrome characterized by renal phosphate wasting, hypophosphatemia, and bone calcification disorders. Complete surgical resection of the tumor is believed to be the most effective treatment measure. However, the diagnosis of PMT is very difficult because of its insidious and small size, especially, when it appears in subcutaneous tissue with a chronic non-healing wound. We report a rare case of a 38-year-old man with a chronic non-healing wound on the left hallux for approximately eight months. Plain radiographic images and magnetic resonance imaging (MRI) revealed a cystic radiolucent shadow in the left distal phalanx. Bone scan observations also showed increased uptake in the same location. Histologically, this tumor was composed of numerous spindle cells with clusters of giant cells. The serum FGF23 level was significantly higher before surgery, with higher FGF23 levels closer to the tumor. Reverse transcription polymerase chain reaction and immunohistochemistry further confirmed the high expression of FGF23 in tumors. These data suggest that FGF23 may be a potential causative factor of PMT. The serum FGF23 levels might be useful for the diagnosis of PMT and localization of the tumor. The tumor was CD56- and D2 to 40-positive and CD31-negative. The non-healing wound caused by PMT might be attributed to the invasive growth of the tumor, destruction of intercellular junctions, and decrease in the number of endothelial cells.

Clinical, morphological and immunohistochemical analysis of 13 cases of phosphaturic mesenchymal tumor - A holistic diagnostic approach.

BACKGROUND: Phosphaturic mesenchymal tumor-mixed connective tissue (PMT-MCT) is a rare tumor characterized clinically by presence of tumor-induced osteomalacia (TIO), subsequent to elevated fibroblastic growth factor 23 (FGF23) levels. This study aims to analyse the morphological spectrum of PMT along with clinico-pathological correlation and immunophenotype profile of this rare tumor. MATERIALS AND METHODS: Detailed histological analysis of all tumors presenting with TIO over past 7 years was done retrospectively. Immunohistochemistry was performed in all cases for SATB2, STAT6, CD34, FGF23, ERG, S100 and smooth muscle actin (SMA). RESULTS: A total of 13 cases were analysed (8 female and 5 male) with mean age of 39.8 years. Five cases were arising from bone while 4 each from soft tissue and nasal cavity/paranasal sinus. All presented with hypophosphatemia, hyperphosphaturia, elevated serum FGF23 and features suggestive of osteomalacia. Histological examination revealed basophilic 'grungy' calcification seen in 7 (53.8%), osteoid formation in 8 (61.5%), chondroid matrix in 4 (30.8%), adipose tissue in 6 (46.2%), osteoclast-like giant cells in 9 (69.2%) and hemangiopericytomatous (HPC like) blood vessels in 7 cases (53.8%). HPC like vessels and adipose tissue were more common in nasal tumors while calcification was more common in tumors arising from bone. All cases showed immunoreactivity for SATB2 and clinical improvement following resection except one case with residual tumor. CONCLUSION: PMT shows varied histological pattern with various matrix components depending on the site of the tumor. Serum FGF-23 is a useful adjunctive marker for diagnosis.

Clinicopathologic and molecular features of six cases of phosphaturic mesenchymal tumor.

Phosphaturic mesenchymal tumors (PMT) are rare neoplasms characterized by secretion of FGF23, resulting in renal phosphate wasting and osteomalacia. This tumor-induced osteomalacia (TIO) is cured by complete resection; thus, diagnosis is important, particularly on biopsy. Although PMT have a classic histologic appearance of bland spindled cells with conspicuous vascular network and characteristic smudgy basophilic matrix, there is a broad histologic spectrum and variant histologic patterns can make recognition difficult. Recent studies have demonstrated FN1-FGFR1 and FN1-FGF1 gene fusions in PMT; however, approximately 50% of cases are negative for these fusions. We sought to characterize 6 cases of PMT in-depth, compare fusion detection methods, and determine whether alternative fusions could be uncovered by targeted RNA sequencing. Of the 6 cases of PMT in our institutional archive, 3 were not given diagnoses of PMT at the time of initial pathologic examination. We characterized the immunoprofile (SMA, D2-40, CD56, S100 protein, desmin, SATB2, and ERG) and gene fusion status (FN1 and FGFR1 rearrangements by fluorescent in situ hybridization (FISH) and two targeted RNA sequencing approaches) in these cases. Tumors were consistently positive for SATB2 and negative for desmin, with 5/6 cases expressing ERG and CD56. One specimen was acid-decalcified and failed FISH and RNA sequencing. We found FN1 gene rearrangements by FISH in 2/5 cases, and a FN1-FGFR1 fusion by targeted RNA sequencing. No alternative gene fusions were identified by RNA sequencing. Our findings suggest that IHC and molecular analysis can aid in the diagnosis of PMT, guiding excision of the tumor and resolution of osteomalacia.

Genetic profiling of a chondroblastoma-like osteosarcoma/malignant phosphaturic mesenchymal tumor of bone reveals a homozygous deletion of CDKN2A, intragenic deletion of DMD, and a targetable FN1-FGFR1 gene fusion.

Conventional osteosarcoma is the most common primary malignancy of bone. This group of neoplasms is subclassified according to specific histological features, but hitherto there has been no correlation between subtype, treatment, and prognosis. By in-depth genetic analyses of a chondroblastoma-like osteosarcoma, we detect a genetic profile that is distinct from those previously reported in benign and malignant bone tumors. The overall genomic copy number profile was less complex than that typically associated with conventional osteosarcoma, and there was no activating point mutation in any of H3F3A, H3F3B, IDH1, IDH2, BRAF, or GNAS. Instead, we found a homozygous CDKN2A deletion, a DMD microdeletion and an FN1-FGFR1 gene fusion. The latter alteration has been described in phosphaturic mesenchymal tumor. This tumor type shares some morphological features with chondroblastoma-like osteosarcoma and we cannot rule out that the present case actually represents an FN1-FGFR1 positive malignant phosphaturic mesenchymal tumor of bone without osteomalacia.

Integrative Modeling Reveals Annexin A2-mediated Epigenetic Control of Mesenchymal Glioblastoma.

Glioblastomas are characterized by transcriptionally distinct subtypes, but despite possible clinical relevance, their regulation remains poorly understood. The commonly used molecular classification systems for GBM all identify a subtype with high expression of mesenchymal marker transcripts, strongly associated with invasive growth. We used a comprehensive data-driven network modeling technique (augmented sparse inverse covariance selection, aSICS) to define separate genomic, epigenetic, and transcriptional regulators of glioblastoma subtypes. Our model identified Annexin A2 (ANXA2) as a novel methylation-controlled positive regulator of the mesenchymal subtype. Subsequent evaluation in two independent cohorts established ANXA2 expression as a prognostic factor that is dependent on ANXA2 promoter methylation. ANXA2 knockdown in primary glioblastoma stem cell-like cultures suppressed known mesenchymal master regulators, and abrogated cell proliferation and invasion. Our results place ANXA2 at the apex of a regulatory cascade that determines glioblastoma mesenchymal transformation and validate aSICS as a general methodology to uncover regulators of cancer subtypes.

STUMP un"stumped": anti-tumor response to anaplastic lymphoma kinase (ALK) inhibitor based targeted therapy in uterine inflammatory myofibroblastic tumor with myxoid features harboring DCTN1-ALK fusion.

BACKGROUND: Recurrent, metastatic mesenchymal myxoid tumors of the gynecologic tract present a management challenge as there is minimal evidence to guide systemic therapy. Such tumors also present a diagnostic dilemma, as myxoid features are observed in leiomyosarcomas, inflammatory myofibroblastic tumors (IMT), and mesenchymal myxoid tumors. Comprehensive genomic profiling was performed in the course of clinical care on a case of a recurrent, metastatic myxoid uterine malignancy (initially diagnosed as smooth muscle tumor of uncertain malignant potential (STUMP)), to guide identify targeted therapeutic options. To our knowledge, this case represents the first report of clinical response to targeted therapy in a tumor harboring a DCTN1-ALK fusion protein. METHODS: Hybridization capture of 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from this sample and sequenced to high, uniform coverage. Therapy was given in the context of a phase I clinical trial ClinicalTrials.gov Identifier: ( NCT01548144 ). RESULTS: Immunostains showed diffuse positivity for ALK1 expression and comprehensive genomic profiling identified an in frame DCTN1-ALK gene fusion. The diagnosis of STUMP was revised to that of an IMT with myxoid features. The patient was enrolled in a clinical trial and treated with an anaplastic lymphoma kinase (ALK) inhibitor (crizotinib/Xalkori®) and a multikinase VEGF inhibitor (pazopanib/Votrient®). The patient experienced an ongoing partial response (6+ months) by response evaluation criteria in solid tumors (RECIST) 1.1 criteria. CONCLUSIONS: For myxoid tumors of the gynecologic tract, comprehensive genomic profiling can identify clinical relevant genomic alterations that both direct treatment targeted therapy and help discriminate between similar diagnostic entities.

Phosphaturic mesenchymal tumors show positive staining for somatostatin receptor 2A (SSTR2A).

Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome associated with tumors that secrete phosphaturic hormones, most notably fibroblast growth factor 23 (FGF23). The majority of tumors associated with this syndrome show stereotypical histological features and are now known as phosphaturic mesenchymal tumors (PMTs). We postulated that immunohistochemistry for somatostatin receptor 2A (SSTR2A) could be used to definitively identify PMTs or other tumors that cause TIO. Immunohistochemistry for FGF23 and SSTR2A was performed on 15 tumors from 14 patients with a definite diagnosis of TIO. All showed positive staining for both markers. While FGF23 staining was quite focal in some tumors, SSTR2A showed diffuse strong expression. In 40 control tumors not known to be associated with the clinical or biochemical features of TIO, FGF23 expression was found in 2 cases (one aneurysmal bone cyst and one osteosarcoma). SSTR2A expression was found in 9 control tumors (4 synovial sarcomas, 2 hemangiomas, 2 aneurysmal bone cysts and one osteosarcoma). Only one tumor (an aneurysmal bone cyst) showed positive staining for both FGF23 and SSTR2A. SSTR2A also commonly stained neoplastic and non-neoplastic endothelial cells. We conclude that neither FGF23 nor SSTR2A expression are specific for the diagnosis of PMT. However both stains are highly sensitive. Because of its diffuse strong expression and widespread availability, immunohistochemistry for SSTR2A is useful to confirm the diagnosis of PMT in an appropriate setting particularly if material is limited. Negative staining can serve as an excellent rule out test for this diagnosis.

Phosphaturic mesenchymal tumor, nonphosphaturic variant, causing fatal pulmonary metastasis.

Phosphaturic mesenchymal tumors of the mixed connective tissue type (PMT-MCTs) are rare neoplasms, most of which are benign and cause tumor-induced osteomalacia because of overproduction of a phosphaturic hormone, fibroblast growth factor 23 (FGF23). This entity may have been unrecognized or misdiagnosed as other mesenchymal tumors, such as giant cell tumor, hemangiopericytoma, and osteosarcoma. Ten percent of these tumors, without phosphaturia, were diagnosed only by their histologic features. We report here the first case of malignant PMT-MCT, nonphosphaturic variant, resulting in fatal multiple lung metastases. Chondromyxoid matrix with "grungy" calcification, multinucleated giant cell proliferation, and expression of FGF23 mRNA (reverse transcription-polymerase chain reaction) and fibroblast growth factor 23 protein (immunohistochemistry) were seen in the primary and recurrent tumors of the right foot. The lung metastases showed flocculent calcification and FGF23 protein expression as well as giant cell proliferation. This unique case highlights the need for careful histologic assessment of PMT-MCTs, especially the nonphosphaturic variant, and the need for recognition of its rare malignant behavior.

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

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.

Primitive myxoid mesenchymal tumor of infancy: report of two cases and review of the literature.

Primitive myxoid mesenchymal tumor of infancy is a recently recognized soft tissue tumor with only a few cases reported. Here, we reported another two cases of the lesion, a 5-month-old boy presenting with a soft tissue mass in the neck region that recurred 2 months later and a 3-day-old girl with a congenital superficial dorsal lumbar mass that extended to the spinal canal 1 month later. They shared similar histological patterns, such as unusual diffuse myxoid background, delicate vascular network, small cystic spaces, low to moderate cellularity, and primitive mesenchymal tumor cells. Immunohistochemically, the tumor cells showed positive for vimentin, CD99, CD117 and nestin, negative for myoid, lipoblastic, histiocytic, and neural markers. In conclusion, primitive myxoid mesenchymal tumor of infancy is a distinctive entity with its own clinical pathological features. Expression of CD99, CD117 and nestin may be consistent with the primitive nature of the tumor and may serve as ancillary markers for differential diagnosis from the other infantile tumors.

Ectomesenchymal chondromyxoid tumor: histopathologic and immunohistochemical study of two cases without a chondroid component.

Ectomesenchymal chondromyxoid tumor (ECT) is a rare benign neoplasm usually affecting the anterior dorsum of the tongue. Histopathologically, it is formed by spindle, round and/or polygonal cells embedded in a chondromyxoid matrix. Immunohistochemical positivity for vimentin, S-100 protein, glial fibrillary acid protein and neuron-specific enolase are helpful to confirm the diagnosis. There are 42 cases of ECT of the tongue reported in the English language literature, three of them showing no chondroid matrix. We describe two additional cases of ECT lacking the chondroid component, exhibiting areas of reticulated myxoid and cellular pattern. Considering the microscopical features, ECT can be classified in classic and 'chondroid-free' variants, the latter including the reticulated myxoid and cellular patterns. It is important to consider that the cellular ECT usually exhibits predominance of an infiltrative atypical cellular component that may mimic a malignant tumor.

Malignant mesenchymoma of the heart base in a dog with infiltration of the pericardium and metastasis to the lung.

A 9-year-old male rottweiler was presented with abdominal distension, ascites and respiratory distress and marked bulging in the perineal region. At necropsy examination the animal had profuse ascites and hydropericardium and a multinodular mass in the right auricle of the heart infiltrating the epicardium and pericardium and metastasizing to the caudal lobe of the left lung. Microscopically and immunohistochemically the tumour was composed of neoplastic cells with muscular, cartilaginous and adipose differentiation. A diagnosis of malignant mesenchymoma with leiomyosarcomatous (≈ 50%), rhabdomyosarcomatous (≈ 30%), chondrosarcomatous (25%) and liposarcomatous (5%) components was made. Metastatic malignant mesenchymoma has not been reported previously at this site in the dog.

Ectomesenchymal chondromyxoid tumor of the anterior tongue: a rare case.

Ectomesenchymal chondromyxoid tumor is a rare tumor seen in the anterior dorsal aspect of the tongue. Diagnosis of this lesion without a prediagnosis clinically is made only with histopathological findings including the immunohistochemical examinations. However, diverse results are being reported in the literature with keratin staining. While glial fibrillary acid protein positiveness maintain being a fixed repeating feature, we emphasized for our case of a 28-year-old Caucasian woman having the findings of qualities supporting the ectomesenchymal origin of the mentioned tumor.

Phosphaturic mesenchymal tumour of the sinonasal area: case report and review of the literature.

BACKGROUND: Oncogenous osteomalacia (OOM), which is also known as tumour-induced osteomalacia, is a rare condition associated with a neoplasm and a related systemic bone demineralization caused by renal phosphate wasting. OOM usually occurs in association with a variety of different mesenchymal tumours, and they were categorized into four distinct morphological patterns which they termed "phosphaturic mesenchymal tumour". Of its 4 histopathological subtypes, the mixed connective tissue variant is most commonly observed. Only 10% of cases appear in the head and neck regions and moreover, only 5 previously published tumors were localized in the sinonasal area. The authors describe a case of a man with a PMT originating from the frontoethmoidal region. CASE PRESENTATION: A 53-year-old man was referred to our ORL clinic due to a presence of a mass at the nasal root having been growing asymptomatically for 1 year. CT scans demonstrated a large (25 × 20 × 35 mm) bilateral frontoethmoidal mass with destruction of nasal bones. The tumor did not appear to invade to the anterior skull base. A selective angiography revealed a moderate hypervascularization of the tumour during early and late arterial phases. The tumour was removed from the external approach and the definitive histopathological diagnosis was a phospaturic mesenchymal tumor. Dual energy X-ray absorptiometry revealed a slight osteopenia of the first and second lumbar vertebrae and neck of the thigh bone. The serum and urinary levels of both calcium and anorganic phosphate were within normal limits. The patient is doing well three years after the operation, and the serum and urine levels of calcium and phosphate remain well within normal limits. CONCLUSION: PMT is rare in the sinonasal region, it can be rarely observed without the signs of osteomalacia.

Ectomesenchymal chondromyxoid tumour of the tongue. A review of histological and immunohistochemical features.

BACKGROUND: Ectomesenchymal chondromyxoid tumour (ECT) is a rare, benign neoplasm of uncertain histogenesis, which appears to exclusively involve the oral cavity, particularly the tongue. CASE REPORT: We report the case of a 27-year-old woman with a 0.7 cm tumoral lesion of 3 months' duration on the dorsum of the tongue. Histologically, it comprised well-circumscribed, unencapsulated lobular proliferations of fusiform and polygonal cells, with varying degrees of cellularity, with neoplastic cells often set in a myxoid, chondroid or hyalinized background. Immunohistochemistry revealed positivity of the neoplastic cells for antibodies directed against S-100, glial fibrillary acidic protein and vimentin, plus negativity for CD-57(leu-7), epithelial membrane antigen, smooth muscle actin, desmin and cytokeratin AE1-AE3. The diagnosis was consistent with ECT. Total excision was performed and there has been no recurrence after 10 months' follow-up. CONCLUSION: This is the 37th case reported in the English language literature; ECT is characterized microscopically by a biphasic myxoid and chondroid pattern. Immunohistochemical expression of S100, glial fibrillary acidic protein and vimentin, very helpful in confirming diagnosis, suggest a probable mesenchymal and neural origin of this rare entity.

Tumor-induced osteomalacia associated with a maxillofacial tumor producing fibroblast growth factor 23: report of a case and review of the literature.

Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recently, it was reported that tumors associated with TIO produce fibroblast growth factor (FGF) 23, identified as the last member of the FGF family and of which excessive action causes several hypophosphatemic diseases whereas deficient FGF23 activity results in hyperphosphatemic tumoral calcinosis. In this case, although it was difficult to locate the associated tumor, an abnormal mass in the left maxilla was detected by imaging. The tumor was removed by partial resection of the left maxillary alveolar region. Thereafter, serum level of FGF23 rapidly decreased, hypophosphatemia improved, and the clinical symptoms greatly improved. Histopathologic diagnosis of the tumor was phosphaturic mesenchymal tumor, mixed connective tissue variant. Immunohistochemical findings confirmed that the removed tumor produced FGF23. These results indicate that development of osteomalacia in this patient was related to the maxillary tumor, which overexpressed FGF23.