Malignant Epithelioid Mesenchymal Neoplasm with FUS::CREM Gene Fusion Arising in the Tongue: A Case Report Detailing Clinicopathological, Imaging, and Molecular Features.

FUS::CREM fusion is a distinct primary driver in rare neoplasms of the head and neck and other anatomic sites. Herein, we describe the clinicopathological, imaging, and molecular features of a malignant epithelioid mesenchymal neoplasm harboring FUS::CREM fusion, arising in the tongue of a 46-year-old male. Clinically, the patient presented with a left upper neck mass. Imaging revealed a 4.0 cm mass at the left base of tongue. Histologically, the tumor consisted of sheets of loosely cohesive, small round to ovoid cells with moderate cytoplasm, small nuclei with coarse chromatin, frequent nuclear pseudoinclusions, and dense peripheral lymphoplasmacytic and histiocytic infiltrates. Malignant features, including tumor necrosis, perineural invasion, and increased mitotic activity were observed; however, lymphovascular invasion was absent with no evidence metastatic disease in the examined lymph nodes. A comprehensive panel of immunohistochemical stains showed positivity for synaptophysin and ALK, with negative results for all other markers. RNA-based next-generation sequencing using anchored multiplex polymerase chain reaction (PCR) was performed and detected FUS::CREM fusion gene. The patient was treated by excision and postsurgical chemoradiation with no evidence of recurrence after four months. Additional cases supported by comprehensive clinical data collected over an extended period are necessary to precisely characterize epithelioid mesenchymal neoplasms harboring FUS::CREM fusion in the head and neck.

A 50-Year-Old Man Presenting with Multiple Bone Lesions and a Diagnosis of Phosphaturic Mesenchymal Tumor of the Femur.

BACKGROUND Phosphaturic mesenchymal tumor (PMT) is an extremely rare mesenchymal neoplasm that is commonly seen in bone and soft tissue. It is associated with a paraneoplastic syndrome, oncogenic osteomalacia, due to tumor-induced urinary phosphate wasting. It is demonstrated to be predominantly mediated by fibroblast growth factor 23 (FGF23)/fibroblast growth factor receptor 1 (FGFR1) axis. Clinically, PMT usually presents as a solitary lesion in the bone. The diagnosis of PMT is challenging due to its non-specific clinical manifestation, radiologic findings, and morphological features. CASE REPORT We report the case of a 50-year-old man presenting with multiple lytic bone lesions and associated pathologic fracture of the right femur, clinically suspicious for multiple myeloma or other metastatic malignant process. Resection from the right femur showed a hypercellular lesion composed of oval-to-spindled cells infiltrating the native trabecular bone with admixed multinucleated giant cells. Immunohistochemical (IHC) staining and in situ hybridization (ISH) demonstrated the tumor cells were positive for SATB2, ERG, FGFR1, and FGF23 ISH. DNA and RNA next-generation sequencing showed marked increases in mRNA levels of FGF23 and FGFR1. The constellation of clinicoradiologic, histomorphologic, IHC, and molecular findings supported a diagnosis of primary benign PMT. CONCLUSIONS This case report discusses a patient with PMT presenting with multifocal lesions due to tumor-induced osteomalacia at initial presentation. We hope that this report will increase the awareness of clinician and pathologists of PMT as a differential diagnosis in patients presenting with multifocal lytic bone lesions. In turn, this will prevent misdiagnosis and overtreatment of a typically benign process.

Klotho Overexpression Is Frequently Associated With Upstream Rearrangements in Fusion-Negative Phosphaturic Mesenchymal Tumors of Bone and Sinonasal Tract.

Phosphaturic mesenchymal tumors (PMT) are uncommon neoplasms that cause hypophosphatemia/osteomalacia mainly by secreting fibroblast growth factor 23. We previously identified FN1::FGFR1/FGF1 fusions in nearly half of the PMTs and frequent KL (Klotho or α-Klotho) overexpression in only those with no known fusion. Here, we studied a larger cohort of PMTs for KL expression and alterations. By FN1 break-apart fluorescence in situ hybridization (FISH) and reappraisal of previous RNA sequencing data, 6 tumors previously considered "fusion-negative" (defined by negative results of FISH for FN1::FGFR1 fusion and FGF1 break-apart and/or of RNA sequencing) were reclassified as fusion-positive PMTs, including 1 containing a novel FN1::ZACN fusion. The final cohort of fusion-negative PMTs included 33 tumors from 32 patients, which occurred in the bone (n = 18), soft tissue (n = 10), sinonasal tract (n = 4), and brain (n = 1). In combination with previous work, RNA sequencing, RNA in situ hybridization, and immunohistochemistry showed largely concordant results and demonstrated KL/α-Klotho overexpression in 17 of the 28 fusion-negative and none of the 10 fusion-positive PMTs studied. Prompted by a patient in this cohort harboring germline KL upstream translocation with systemic α-Klotho overexpression and multifocal PMTs, FISH was performed and revealed KL rearrangement in 16 of the 33 fusion-negative PMTs (one also with amplification), including 14 of the 17 cases with KL/α-Klotho overexpression and none of the 11 KL/α-Klotho-low fusion-negative and 11 fusion-positive cases studied. Whole genomic sequencing confirmed translocation and inversion in 2 FISH-positive cases involving the KL upstream region, warranting further investigation into the mechanism whereby these rearrangements may lead to KL upregulation. Methylated DNA immunoprecipitation and sequencing suggested no major role of promoter methylation in KL regulation in PMT. Interestingly, KL-high/-rearranged cases seemed to form a clinicopathologically homogeneous group, showing a predilection for skeletal/sinonasal locations and typically matrix-poor, cellular solitary fibrous tumor-like morphology. Importantly, FGFR1 signaling pathways were upregulated in fusion-negative PMTs regardless of the KL status compared with non-PMT mesenchymal tumors by gene set enrichment analysis, perhaps justifying FGFR1 inhibition in treating this subset of PMTs.

Superficial GLI1-amplified mesenchymal neoplasms: Expanding the spectrum of an emerging entity which reaches the realm of dermatopathology.

Mesenchymal neoplasms with GLI1 alterations (rearrangements and/or amplification) have been reported recently in several anatomic locations, which include head and neck, soft tissue, and gastrointestinal tract. Herein, to the best of our knowledge, we describe the first three cases of superficial/subcutaneous mesenchymal neoplasm with GLI1 amplification. The neoplasms exhibited low-grade cytologic features with predominant round cell morphology, glomangioma-like areas and a rich background capillary network. There were two to three mitotic figures per 10 HPF and focal necrosis in one case. The tumors exhibited variable expression of CDK4, MDM2, STAT6, D2-40, CD56 and cyclin D1. p16 had strong and diffuse nuclear and cytoplasmic expression in two cases. Numerous other stains were negative. Fluorescence in situ hybridization detected GLI1, DDIT3, and CDK4 coamplification in all cases, while next generation sequencing did not detect a GLI1 gene fusion. The overall features were compatible with a GLI1-amplified mesenchymal neoplasm. In Case 1 a new distant skin lesion appeared 1 month after the surgery exhibiting similar morphology albeit with a higher mitotic index. In Cases 2 and 3, there is no evidence of local recurrence or systemic disease after 8 years and 1 month of follow-up, respectively. These new cases of superficial GLI1-amplified neoplasm expand its clinical spectrum and enter the realm of dermatopathology. The combination of CDK4, cyclin D1, D2-40, and p16 expression with variable MDM2, STAT6, CD56, and S100 immunoreactivity in a low-grade neoplasm with round/ovoid cytomorphology resembling a vascular or adnexal neoplasm may suggest the possibility of GLI1-amplified neoplasm.

Primary uterine ectomesenchymoma harboring a DICER1 mutation: case report with molecular analysis.

Ectomesenchymoma is an exceedingly rare biphasic malignant tumor characterized by the presence of mesenchymal and neuroectodermal elements. The majority of patients are infants or children. We describe the first case of this entity diagnosed as a primary uterine tumor. A 72-year-old female presented with post-menopausal bleeding. Dilatation and curettage showed irregular mesenchymal proliferation of uncertain nature. In the hysterectomy specimen, a myxoid spindle cell tumor with areas of skeletal muscle and neural differentiation was found in the uterus, with direct invasion of the small intestine, and biphasic differentiation into rhabdomyosarcoma and ganglioneuroblastoma was unequivocally seen in a lymph node metastasis. The morphological findings were validated by immunohistochemistry. Massive parallel sequencing identified TP53, PTEN, and DICER1 mutations in the tumor. This report describes the presence of ectomesenchymoma in an unusual primary organ and in an uncharacteristic age and presents novel data regarding the genetic characteristics of this tumor.

Primary myxoid and epithelioid mesenchymal tumor of the kidney with a novel GLI1-FOXO4 fusion.

To our knowledge, we describe the first mesenchymal tumor with a novel GLI1-FOXO4 fusion gene. This well-circumscribed kidney tumor displayed variably myxoid and epithelioid histologic features with a focally nodular growth pattern. The tumor cells showed bland, round to ovoid nuclei, with no overt high-grade features. The tumor showed focal immunopositivity for smooth muscle actin and Melan-A, which raised the possibility of a relationship with a perivascular epithelioid cell tumor. The clinical and morphologic features appear distinct from other reported neoplasms harboring GLI1 or FOXO4 gene rearrangements. The patient underwent radical nephrectomy and is without evidence of disease during a relatively short clinical follow-up period. However, the features of this tumor likely warrant long-term follow-up to monitor for the possibility of a late recurrence or metastasis. In addition to reporting this novel fusion-positive tumor, we also provide a brief review of GLI1 and FOXO4 gene functions in both normal and neoplastic contexts.

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.

Spindle-cell (Sarcomatoid) Variant of Cutaneous Anaplastic Large-cell Lymphoma (C-ALCL): An Unusual Mimicker of Cutaneous Malignant Mesenchymal Tumors-A Series of 11 Cases.

Cutaneous anaplastic large-cell lymphoma (C-ALCL) represents one of the entities within the group of CD30-positive lymphoproliferative disorders of the skin. Most cases are ALK-negative, though isolated cases of ALK-positive C-ALCL have also been reported. By definition, the diagnosis of C-ALCL requires the expression of CD30 in >75% of the cells. Histopathologically, C-ALCL shows a dermal-based nodular and circumscribed proliferation of large pleomorphic cells with vesicular nuclei, prominent nucleoli, and eosinophilic cytoplasm, including hallmark cells. Since 1990, isolated case reports of a so-called "sarcomatoid" variant have been published in the literature. Herein, we present a series of 11 cases of spindle (sarcomatoid) C-ALCL, with comprehensive histopathologic, immunophenotypic, and molecular data. Spindle C-ALCL represents a potential mimicker of malignant mesenchymal or hematopoietic tumors in the skin and should always be considered in the differential diagnosis when assessing cutaneous pleomorphic spindle cell neoplasms.

TRPA1 Expression in Synovial Sarcoma May Support Neural Origin.

Synovial sarcoma (SS) is a malignant mesenchymal soft tissue neoplasm. Despite its name, the cells of origin are not synovial cells, but rather neural, myogenic, or multipotent mesenchymal stem cells have been proposed as possible cells originators. Unlike other sarcomas, an unusual presentation of long-term pain at the tumor site has been documented, but the exact mechanisms have not been fully clarified yet. The transient receptor potential ankyrin 1 (TRPA1) is a nonselective cation channel mainly expressed in primary sensory neurons, where it functions as a pain sensor. TRPA1 have also been described in multiple non-excitable cells, including those derived from neural crest stem cells such as glial cells and, in particular, Schwann cell oligodendrocytes and astrocytes. We evaluated TRPA1 expression in SS. We selected a cohort of 41 SSs, and by immunohistochemistry, we studied TRPA1 expression. TRPA1 was found in 92.6% of cases. Triple TRPA1/pS100/SOX10 and TRPA1/SLUG/SNAIL staining strongly supports a neural origin of SS. TRPA1 positivity was also observed in a subset of cases negative with pS100, SOX10 and/or SLUG/SNAIL, and these divergent phenotypes may reflect a process of tumor plasticity and dedifferentiation of neural-derived SSs. Given the functional diversity of TRPA1 and its expression in neuronal and non-neuronal multipotent neural crest stem cells, it remains to be determined whether TRPA1 expression in SSs neoplastic cells plays a role in the molecular mechanism associated with premonitory pain symptoms and tumor progression.

[Hereditary cancer predisposition syndromes associated with sarcomas]. / Felnottkori szarkómához asszociált örökletes daganatszindrómák.

Based on our current knowledge, 5-10% of all malignancies are part of hereditary cancer syndromes. Although the increasing diagnostic role of molecular genetic testing makes us able to recognize more hereditary cancer patients, the careful exploration of family and clinical history by physicians is still the most important step for the diagnosis. In our review we deal with mesenchymal tumours associated with hereditary syndromes. Sarcomas comprise only 1% of all malignancies, but they often associate with familiar diseases so they can serve as an indicator of these syndromes. The diagnosis of hereditary cancer predisposition syndromes is essential to ensure appropriate therapy and follow-up for our patients.

Mesenchymal tumours with RREB1-MRTFB fusion involving the mediastinum: extra-glossal ectomesenchymal chondromyxoid tumours?

AIMS: Ectomesenchymal chondromyxoid tumour (ECT) is a rare benign intraoral tumour which almost exclusively presents as a small mass of the anterior dorsal tongue. Recently, the RREB1-MRTFB (previously known as MKL2) fusion gene has been identified in 90% of ECTs, all located in the tongue, emphasising its genetic distinctiveness. Here, we report two mesenchymal tumours involving the superior mediastinum of adult women with RREB1-MRTFB fusions. METHODS AND RESULTS: Both tumours presented as well-circumscribed paravertebral masses that were clinically suspected to be schwannoma. After fragmented resection, recurrence was not observed at 27 and 18 months. Although tumours were originally unclassifiable, next-generation sequencing detected identical RREB1 (exon 8)-MRTFB (exon 11) fusion transcripts, which were validated by reverse transcriptase-polymerase chain reaction, Sanger sequencing, and fluorescence in-situ hybridisation. Both tumours shared hyalinised areas with round cells embedded in a cord or reticular manner. The tumour cells showed mild nuclear atypia of possible degenerative type with very low mitotic activity, and were at least focally positive for S100, glial fibrillary acidic protein, smooth muscle actin and epithelial membrane antigen. Overall, these findings suggest that they may represent previously undescribed extra-glossal ECT involving the mediastinum. However, the histology was not classic for ECT, because that in case 2 was predominated by storiform growth of spindle cells, whereas the tumour in case 1 lacked myxoid change. CONCLUSIONS: We have provided the first evidence that RREB1-MRTFB fusion is not limited to tumours in the head region, and whether such tumours represent extra-glossal ECTs requires further research.

Phosphaturic mesenchymal tumors: A review and update.

Perhaps the rarest cause of osteomalacia is that caused by a neoplasm, so-called "tumor-induced osteomalacia" (TIO). Although very rare cases of TIO have been associated with carcinomas and syndromes such as neurofibromatosis type-1 and McCune-Albright syndrome, the overwhelming majority of TIO is caused by tumors of mesenchymal origin. Although it was historically felt that almost any mesenchymal tumor type could occasionally result in TIO, it has become increasingly clear over the past several decades that almost all cases of mesenchymal tumor-associated TIO are caused by a single entity, known as "phosphaturic mesenchymal tumor" (PMT). This article will review historical aspects of this tumor, as well as its clinical, morphological, immunohistochemical and molecular genetic features. The distinction of PMT from its many potential morphological mimics is discussed in detail.

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.

Mesenchymal Tumors with EWSR1 Gene Rearrangements.

Among the various genes that can be rearranged in soft tissue neoplasms associated with nonrandom chromosomal translocations, EWSR1 is the most frequent one to partner with other genes to generate recurrent fusion genes. This leads to a spectrum of clinically and pathologically diverse mesenchymal and nonmesenchymal neoplasms, variably manifesting as small round cell, spindle cell, clear cell or adipocytic tumors, or tumors with distinctive myxoid stroma. This review summarizes the growing list of mesenchymal neoplasms that are associated with EWSR1 gene rearrangements.

Prognostication in Mesenchymal Tumors: Can We Improve?

Prognostication in mesenchymal tumors can be challenging. They exhibit diverse, and sometimes overlapping, histologic features that are not always predictive of their true behavior. This article highlights examples of both traditional and emerging sarcoma biomarkers.

New advances in the molecular classification of pediatric mesenchymal tumors.

Pediatric soft tissue tumors are relatively rare and show significant overlap in morphology and immunoprofile, often posing diagnostic and management challenges. Thus, their classification remains often subjective or lumped under "unclassified categories," as a number of lesions lack objective and reproducible criteria in diagnosis. Although in a subset of cases immunohistochemistry has been proved useful to identify a specific line of differentiation, most tumors lack a readily defined histogenesis, being characterized by a rather non-specific immunoprofile. Furthermore, tumors with an ambiguous diagnosis are difficult to grade and their risk of malignancy or clinical management remains uncertain. Advances in molecular genetics, including the more wide application of next generation sequencing in routine clinical practice, have improved diagnosis and refined classification based on objective molecular markers. Importantly, some soft tissue tumors in children are characterized by recurrent gene fusions involving either growth factors (eg, PDGFB) or protein kinases (eg, ALK, ROS, NTRK, BRAF), which have paved the way for new targeted treatments that block the respective upregulated downstream pathways. However, the majority of gene fusions or mutations detected in soft tissue tumors result in an abnormal function of transcription factors or chromatin remodeling. The present review focuses on the latest genetic discoveries in the spectrum of both benign and malignant pediatric soft tissue neoplasia. These genetic abnormalities promise to provide relevant insight for their proper classification, prognosis, and treatment. The entities discussed herein are grouped either based on their shared genetic mechanism or based on their presumed line of differentiation.

Mesenchymal Neoplasms of the Genitourinary System: A Selected Review with Recent Advances in Clinical, Diagnostic, and Molecular Findings.

Mesenchymal neoplasms of the genitourinary (GU) tract often pose considerable diagnostic challenges due to their wide morphologic spectrum, relative rarity, and unexpected incidence at GU sites. Soft tissue tumors arise throughout the GU tract, whether from adventitia surrounding or connective tissues within the kidneys, urinary bladder, and male and female genital organs. This selected article focuses on a subset of these lesions, ranging from benign to malignant and encompassing a range of patterns of mesenchymal differentiation, where recent scholarship has lent greater insight into their clinical, molecular, or diagnostic features.

Histopathological and genetic review of phosphaturic mesenchymal tumours, mixed connective tissue variant.

AIMS: Phosphaturic mesenchymal tumour, mixed connective tissue variant (PMT-MCT), is a tumour of uncertain differentiation, characterised by 'smudgy/grungy' calcification and vitamin D-resistant phosphaturic osteomalacia. Fibroblast growth factor (FGF)23 is recognised as a reliable marker of PMT-MCT, but quantitative evaluation has never been performed. We reviewed cases of tumour-associated osteomalacia or histologically definitive PMT-MCT without osteomalacia using histological, immunohistochemical and genetic methods and evaluated the diagnostic significance of these findings. METHODS AND RESULTS: A total of 19 tumours from 14 cases diagnosed previously as PMT-MCT were retrieved, on which immunohistochemical staining, reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in-situ hybridisation (FISH) analysis were performed. Histologically, fibrous capsule, calcification and giant cell reaction tended to be observed in soft-tissue PMT-MCT, while PMT-MCT of bone and multiple PMT-MCT showed an infiltrative growth pattern. The immunohistochemical results were as follows: the tumour cells were positive for FGF23 (nine of 12, 75%), FGFR1 (11 of 11, 100%), CD56 (12 of 14, 85.7%) and E26 oncogene homologue (ERG) (5 of 13, 38.4%). The sole malignant tumour was positive for p53. FGF23 mRNA was detected in seven of 14 formalin-fixed paraffin-embedded (FFPE) specimens and all five frozen specimens by RT-PCR. The level of FGF23 mRNA, which was determined by real-time PCR, varied among the phosphaturic cases. Two of 17 tumours were positive for FGFR1 gene rearrangement. CONCLUSIONS: It was considered that PMT-MCT is a histopathological entity with or without phosphaturia, with varying levels of FGF23 mRNA, and with or without fibronectin 1 (FN1)-FGFR1 fusion gene. The authors propose that the histology of PMT-MCT differs depending on its location, such as bone or soft tissue, which could complicate the differential diagnosis.

Programmed Death Ligand 1 (PD-L1) Expression in Malignant Mesenchymal Tumors.

OBJECTIVE: Programmed death ligand 1 (PD-L1) found on tumor cells has recently been reported to have a key role in the development and dissemination of many tumors, such as lung and breast carcinomas. In this study, we retrospectively analyzed PD-L1 expression among different types of sarcomas. MATERIAL AND METHOD: Tissue microarrays of 3-4 mm diameter were composed from paraffin blocks of 222 various sarcomas. Slides prepared from microarrays were stained for PD-L1 antibody (Cell Signaling, E1L3N®) using Leica Bond Autostainer. Any membranous staining over 5% of the cells was regarded as positive. Quantitative real-time PCR with TaqMan gene expression assays for PDL1 was performed using whole sections from FFPE tissue of PD-L1 positive cases, by normalizing absolute values to ß-actin. Relative expression level of mRNA of PDL1 was calculated and scored using Log102(threshold cycle of b-actin - threshold cycle of PDL1). RESULTS: Immunohistochemically, PD-L1 expression was present in 34 of 222 (15%) sarcomas. 5/13 (39%) undifferentiated pleomorphic sarcomas, 6/18 (33%) malignant peripheral nerve sheath tumors, 5/16 (31%) dedifferentiated liposarcomas, 4/19 (21%) rhabdomyosarcomas, 2/16 (13%) epithelioid sarcomas, 2/15 (13%) leiomyosarcomas, 3/26 (12%) synovial sarcomas, 1/18 (6%) myxoid liposarcoma, 1/2 (50%) extraskeletal myxoid chondrosarcoma, 1/3 (33%) alveolar soft part sarcoma, 1/3 (33%) parachordoma/myoepithelioma, 1/5 (20%) pleomorphic liposarcoma, 1/7 (14%) angiosarcoma, 1/8 (13%) Ewing sarcoma showed PD-L1 expression. Cases of solitary fibrous tumor/hemangiopericytoma (18), desmoplastic round cell tumor (14), Ewing-like sarcoma (6), epithelioid hemangioendothelioma (5), clear cell sarcoma (4), myxofibrosarcoma (4), low grade fibromyxoid sarcoma (2) were all negative. Tumor-infiltrating hematopoietic cells were positive for PD-L1 in 32 cases (15%) with only 2 cases overlapping with PD-L1 staining in tumoral cells. Sixteen of 34 (47%) immunohistochemically PD-L1 positive cases showed significant but low-level PD-L1 mRNA overexpression. CONCLUSION: We have shown PD-L1 expression in a subset of sarcomas, both at the protein and mRNA level. High-grade pleomorphic sarcomas tend to show more frequent PD-L1 expression. Clinical trials are necessary to further assess the effect of anti PD-L1 drugs on sarcomas showing PD-L1 expression.

Phosphaturic Mesenchymal Tumors: Clinicopathologic, Immunohistochemical and Molecular Analysis of 22 Cases Expanding their Morphologic and Immunophenotypic Spectrum.

Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm of uncertain histogenesis that has been linked to tumor-induced osteomalacia (TIO) since 1959. The neoplastic cells produce increased amount of FGF23 which results in TIO via uncontrolled renal loss of phosphate (phosphaturia), and consequently diminished bone mineralization. To date, ∼300 cases have been reported. Although there is increasing evidence that PMT can be diagnosed by reproducible histopathologic features, firm diagnosis has been often restricted to cases associated with TIO and, hence, diagnosis of "nonphosphaturic variants" remained challenging. Recently, FGFR1/FN1 gene fusions were detected in roughly half of cases. We herein reviewed the clinicopathologic features of 22 PMTs (15 cases not published before), stained them with an extended immunohistochemical marker panel and examined them by fluorescence in situ hybridization for FGFR1 gene fusions. Patients were 12 males and 9 females (one of unknown sex) aged 33 to 83 years (median: 52 y). Lesions affected the soft tissues (n=11), bones (n=6), sinonasal tract (n=4), and unspecified site (n=1). Most lesions originated in the extremities (9 in the lower and 4 in the upper extremities). Acral sites were involved in 10 patients (6 foot/heel, 3 fingers/hands, and 1 in unspecified digit). Phosphaturia and TIO were recorded in 10/11 and 9/14 patients with detailed clinical data, respectively. Limited follow-up (5 mo to 14 y; median: 16 mo) was available for 14 patients. Local recurrence was noted in one patient and metastasis in another patient. Histologically, 11 tumors were purely of conventional mixed connective tissue type, 3 were chondromyxoid fibroma-like, 2 were hemangio-/glomangiopericytoma-like with giant cells, and 1 case each angiomyolipoma-like and reparative giant cell granuloma-like. Four tumors contained admixture of patterns (predominantly cellular with variable conventional component). Immunohistochemistry showed consistent expression of CD56 (11/11; 100%), ERG (19/21; 90%), SATB2 (19/21; 90%), and somatostatin receptor 2A (15/19; 79%), while other markers tested negative: DOG1 (0/17), beta-catenin (0/14), S100 protein (0/14), and STAT6 (0/7). FGFR1 fluorescence in situ hybridization was positive in 8/17 (47%) evaluable cases. These results add to the phenotypic delineation of PMT reporting for the first time consistent expression of SATB2 and excluding any phenotypic overlap with solitary fibrous tumor or sinonasal glomangiopericytoma. The unifying immunophenotype of the neoplastic cells irrespective of the histologic pattern suggests a specific disease entity with diverse morphotypes/variants rather than different neoplasms unified by TIO.