Dual energy computed tomography cannot effectively differentiate between calcium pyrophosphate and basic calcium phosphate diseases in the clinical setting.

Background: Recent reports suggested that dual-energy CT (DECT) may help discriminate between different types of calcium phosphate crystals in vivo, which would have important implications for the characterization of crystal deposition occurring in osteoarthritis. Purpose: Our aim was to test the hypothesis that DECT can effectively differentiate basic calcium phosphate (BCP) from calcium pyrophosphate (CPP) deposition diseases. Methods: Discarded tissue after total knee replacement specimens in a 71 year-old patient with knee osteoarthritis and chondrocalcinosis was scanned using DECT at standard clinical parameters. Specimens were then examined on light microscopy which revealed CPP deposition in 4 specimens (medial femoral condyle, lateral tibial plateau and both menisci) without BCP deposition. Regions of interest were placed on post-processed CT images using Rho/Z maps (Syngo.via, Siemens Healthineers, VB10B) in different areas of CPP deposition, trabecular bone BCP (T-BCP) and subchondral bone plate BCP (C-BCP). Results: Dual Energy Index (DEI) of CPP was 0.12 (SD â€‹= â€‹0.02) for reader 1 and 0.09 (SD â€‹= â€‹0.03) for reader 2, The effective atomic number (Zeff) of CPP was 10.83 (SD â€‹= â€‹0.44) for reader 1 and 10.11 (SD â€‹= â€‹0.66) for reader 2. Nearly all DECT parameters of CPP were higher than those of T-BCP, lower than those of C-BCP, and largely overlapping with Aggregate-BCP (aggregate of T-BCP and C-BCP). Conclusion: Differentiation of different types of calcium crystals using DECT is not feasible in a clinical setting.

Metastatic Uterine Leiomyosarcoma With Rhabdomyosarcomatous Heterologous Differentiation.

Heterologous differentiation has only been previously reported twice in metastatic uterine leiomyosarcomas. We report herein the first case of metastatic uterine leiomyosarcoma with rhabdomyosarcomatous differentiation. A 67-yr-old woman presented with femur, abductor magnus, and lymph node metastases 9 yr after the primary diagnosis. The metastatic sites showed rhabdomyosarcomatous morphologic features, and immunohistochemical studies confirmed skeletal muscle differentiation. Molecular testing revealed the same loss-of-function TP53 mutation in the uterine leiomyosarcoma and metastatic sites supporting heterologous differentiation of the primary tumor. Our case highlights the morphologic shifts metastatic tumors may manifest and the potential diagnostic problems that may arise.

Tumor-induced osteomalacia treated with T12 tumor resection.

Summary: Tumor-induced osteomalacia (TIO) is a rare form of osteomalacia caused by fibroblast growth factor-23 (FGF23)-secreting tumors. Most of these tumors are phosphaturic mesenchymal tumors (PMTs) typically involving soft tissue in the extremities and bone of the appendicular skeleton and cranium. We report the case of a 60-year-old woman with about 3 years of persistent bone pain and multiple fractures, initially diagnosed as osteoporosis, who was found to have hypophosphatemia with low 1,25-dihydroxyvitamin D and elevated alkaline phosphatase and inappropriately normal FGF23 consistent with TIO. Her symptoms improved with phosphate supplementation, vitamin D and calcitriol. 68Ga-DOTATATE imaging revealed a T12 vertebral body lesion confirmed on biopsy to be a PMT. She underwent resection of the PMT with resolution of TIO and increased bone density. This rare case of TIO secondary to a PMT of the thoracic spine highlights some of the common features of PMT-associated TIO and draws attention to PMT-associated TIO as a possible cause of unexplained persistent bone pain, a disease entity that often goes undiagnosed and untreated for years. Learning points: Tumor-induced osteomalacia (TIO) is typically caused by phosphaturic mesenchymal tumors (PMTs) that are usually found in the soft tissue of the extremities and bone of the appendicular skeleton/cranium and rarely in the spine. TIO may be misdiagnosed as osteoporosis or spondyloarthritis, and the correct diagnosis is often delayed for years. However, osteoporosis, in the absence of fracture, is not associated with bone pain. The hallmark of TIO is hypophosphatemia with inappropriately normal or low 1,25-dihydroxyvitamin D and elevated or inappropriately normal fibroblast growth factor-23 (FGF23) levels. In patients with unexplained persistent bone pain, a serum phosphate should be measured. Consider PMT-associated TIO as a potential cause of unexplained persistent bone pain and hypophosphatemia. PMTs express somatostatin receptors and may be identified with 68Ga-DOTATATE imaging. Complete surgical resection is the preferred treatment for spinal PMTs associated with TIO.

Amyloid Arthropathy: A Review.

Amyloid arthropathy is a joint disease associated with systemic amyloidosis. Herein, we present a model case and review the clinicopathologic features and pathophysiology of this disorder. Amyloid arthropathy results from elevation of serum amyloidogenic proteins and their deposition as aggregates in synovial fluid and articular tissues. The most common proteins are beta-2-microglobulin in the context of long-term hemodialysis therapy and immunoglobulin light chains associated with plasma cell proliferations. We provide a comprehensive update on the pathogenesis, clinical manifestations, and pathologic features of amyloid arthropathy. We provide detailed insights on amyloid protein deposition and aggregation in joints and proper details for diagnosis.

A unique epithelioid vascular neoplasm of bone characterized by EWSR1/FUS-NFATC1/2 fusions.

An increasing number of epithelioid vascular lesions, in particular tumors from the benign and low-grade end of the spectrum, have been characterized by recurrent gene fusions. As a result, the detection of these molecular markers have improved the classification of diagnostically challenging cases. However, despite the significant progress, there are occasional lesions that do not fit in known histologic or molecular groups. Herein, we present five such unclassified epithelioid vascular lesions, which occurred in the bone and showed a distinct morphology composed of alternating vasoformative and solid growth and mild to moderate nuclear pleomorphism. The variegated morphologic appearance resembled that of composite hemangioendothelioma, being distinct from both epithelioid hemangioma and epithelioid hemangioendothelioma, and consistently showed cytologic atypia. Due to their unusual morphologic appearance and negative molecular work-up, targeted transcriptome sequencing was performed in two cases showing the presence of NFATC2 fusions with either EWSR1 or FUS genes. Three additional bone tumors with EWSR1 gene rearrangements were identified by FISH screening of a large cohort of 45 fusion-negative epithelioid vascular neoplasms, one fused to NFATC2 while two others to NFATC1. There were three females and two males, with a wide age range at presentation, mean of 44 years. The lesions occurred in the pelvis, maxillary sinus, and humerus. Two patients presented with polyostotic disease, both located in the pelvic bones. Two patients had available follow-up, one developed two local recurrences in the humerus over a 15-year period, while the other showed no recurrence 4 years subsequent to an en-bloc resection. Tumors were positive for CD31 and ERG, while negative for EMA, CK, synaptophysin, and chromogranin. FISH confirmed this abnormality in all cases, none of them being associated with gene amplifications. Further studies are needed to establish the pathogenetic relationship of this rare molecular subset with other epithelioid vascular tumors and to determine its clinical behavior.

Malignant peripheral nerve sheath tumors arising from schwannomas: case series and literature review.

A malignant peripheral nerve sheath tumor (MPNST) arising from a schwannoma is extremely rare, with limited literature on its clinicopathologic features. Here, we present a case series and literature review on patients with MPNSTs arising from schwannomas. We performed a retrospective review of patients from our institution's records to identify those with MPNSTs arising from schwannomas. We conducted a search for additional cases from the literature utilizing PubMed. 20 patients (including 2 at our institution and 18 from 16 prior publications) were identified. The patients aged 22-93 (mean 52) years, and 63% were females. Histologically, while most MPNSTs arising from schwannomas were of epithelioid-type, 7 tumors (including 2 at our institution) were of conventional spindle-cell type. All 20 patients underwent surgical excision, while a subset received additional radiotherapy and/or chemotherapy. In 17 patients with available follow-up, the overall survival was 2-72 (median 12) months. MPNSTs rarely arise from schwannomas and should be considered in patients with a clinical diagnosis of schwannoma, however, with atypical radiologic or clinical features. MPNSTs arising from schwannomas can show epithelioid or spindle-cell histology and harbor an aggressive course, even with surgical excision and adjuvant treatment.

Inflammatory myofibroblastic tumors associated with the placenta: a series of 9 cases.

Inflammatory myofibroblastic tumors (IMTs) of the uterus are often associated with pregnancy and are delivered with the placenta. We describe the clinical, pathologic, and molecular findings in nine cases of placenta-associated IMT (PaIMT). All the lesions were incidentally discovered at delivery or on placental pathological examination. The maternal age ranged from 21 to 41 (mean = 30.6) years. Eight patients had high-risk pregnancies, and when known, all patients were multigravida. Macroscopically, eight tumors were well defined, ranging in size from 2 to 6 cm present at the maternal surface of the placenta (n = 3) and membranes (n = 4) or separately delivered with the placenta (n = 2). All nine lesions revealed classical IMT morphology with spindle cells associated with a lymphoplasmacytic infiltrate and thin elongated vessels. Five showed decidualization, and five showed coagulative necrosis. All tumors expressed CD10. Of the seven tumors that were anaplastic lymphoma kinase (ALK) positive, six were confirmed to have an ALK rearrangement by fluorescence in situ hybridization (FISH), whereas one failed FISH testing. Fusions included TIMP3-ALK (n = 3), THBS1-ALK (n = 2), and a novel SYN3-ALK fusion (n = 1). Clinical follow-up was available in three patients, with no recurrence reported. There appears to be an increased frequency of uterine IMTs in pregnancy and associated with the placenta. No PaIMT has behaved aggressively, although follow-up has been quite limited. This may speak to a specific behavior of these tumors when associated with pregnancy.

Author Correction: Intragenic antagonistic roles of protein and circRNA in tumorigenesis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Novel and established EWSR1 gene fusions and associations identified by next-generation sequencing and fluorescence in-situ hybridization.

EWSR1 is a 'promiscuous' gene that can fuse with many different partner genes in phenotypically identical tumors or partner with the same genes in morphologically and behaviorally different neoplasms. Our study set out to examine the EWSR1 fusions identified at our institution over a 3-year period, using various methods, their association with specific entities and possible detection of novel partners and associations. Sixty-three consecutive cases investigated for EWSR1 gene fusions between 2015 and 2018 at our institution were included in this study. Fusions were identified by either break-apart fluorescence in-situ hybridization (FISH), our clinical RNA-based assay for fusion transcript detection or both. Twenty-eight cases were concurrently tested by FISH and NGS, 24 were tested by FISH alone and 11 by NGS alone. Of the 28 cases with dual testing, 24 were positive by both assays for an EWSR1 gene fusion, 3 cases were discordant with a positive FISH assay and a negative NGS assay, and 1 case was discordant with a negative FISH assay but a positive NGS assay. Three novel fusions were identified: a complex rearrangement involving three genes (EWSR1/RBFOX2/ERG) in Ewing sarcoma, a EWSR1/TCF7L2 fusion in a colon adenocarcinoma, and a EWSR1/TFEB fusion in a translocation-associated renal cell carcinoma. Both colonic adenocarcinoma and renal cell carcinoma had not been previously associated with EWSR1 rearrangements to our knowledge. In a subset of cases, detection of a specific partner had an impact on the histological diagnosis and patient management. In our experience, the use of a targeted NGS-based fusion assay is superior to EWSR1 break-apart FISH for the detection of known and novel EWSR1 rearrangements and fusion partners, particularly given the emerging understanding that distinct fusion partners result in different diseases with distinct prognostic and therapeutic implications.

Intragenic antagonistic roles of protein and circRNA in tumorigenesis.

circRNAs arise from back splicing events during mRNA processing, and when deregulated can play an active role in cancer. Here we characterize a new circRNA (circPOK) encoded by the Zbtb7a gene (also kown as POKEMON, LRF) in the context of mesenchymal tumor progression. circPOK functions as a non-coding proto-oncogenic RNA independently and antithetically to its linear transcript counterpart, which acts as a tumor suppressor by encoding the Pokemon transcription factor. We find that circPOK regulates pro-proliferative and pro-angiogenic factors by co-activation of the ILF2/3 complex. Importantly, the expression of Pokemon protein and circRNA is aberrantly uncoupled in cancer through differential post-transcriptional regulation. Thus, we identify a novel type of genetic unit, the iRegulon, that yields biochemically distinct RNA products, circular and linear, with diverse and antithetical functions. Our findings further expand the cellular repertoire towards the control of normal biological outputs, while aberrant expression of such components may underlie disease pathogenesis including cancer.

Prognostic Factors in Dedifferentiated Chondrosarcoma: A Retrospective Analysis of a Large Series Treated at a Single Institution.

BACKGROUND: Dedifferentiated chondrosarcomas (DDCSs) are highly malignant tumors with a dismal prognosis and present a significant challenge in clinical management. METHODS: In an IRB approved retrospective protocol, we identified 72 patients with DDCS treated at our institution between 1993 and 2017 and reviewed clinicopathological characteristics, treatment modalities, and outcomes to analyze prognostic factors. RESULTS: Femur (44.4%), pelvis (22.2%), and humerus (12.5%) were most commonly involved sites. Twenty-three patients (31.9%) presented with distant metastasis, and 3 (4.2%) of them also had regional lymph node involvement. The median overall survival (OS) was 13.9 months. On multivariate analysis, pathological fracture, larger tumor size, lymph node involvement, metastasis at diagnosis, extraosseous extension, and undifferentiated pleomorphic sarcoma component correlated with worse OS, whereas surgical resection and chemotherapy were associated with improved OS. For progression-free survival (PFS), pathological fracture and metastasis at diagnosis showed increased risk, while chemotherapy was associated with decreased risk. Among patients who received chemotherapy, doxorubicin and cisplatin were significantly associated with improved PFS but not OS. Among patients without metastasis at diagnosis, 17 (34.7%) developed local recurrence. Thirty-one (63.3%) developed distant metastases at a median interval of 18.1 months. On multivariate analysis, R1/R2 resection was related with local recurrence, while macroscopic dedifferentiated component was associated with distant metastasis. CONCLUSIONS: The prognosis of DDCS is poor. Complete resection remains a significant prognostic factor for local control. Chemotherapy with doxorubicin and cisplatin seems to have better PFS. More prognostic, multicenter trials are warranted to further explore the effectiveness of chemotherapy in selected DDCS patients.

tp53 deficiency causes a wide tumor spectrum and increases embryonal rhabdomyosarcoma metastasis in zebrafish.

The TP53 tumor-suppressor gene is mutated in >50% of human tumors and Li-Fraumeni patients with germ line inactivation are predisposed to developing cancer. Here, we generated tp53 deleted zebrafish that spontaneously develop malignant peripheral nerve-sheath tumors, angiosarcomas, germ cell tumors, and an aggressive Natural Killer cell-like leukemia for which no animal model has been developed. Because the tp53 deletion was generated in syngeneic zebrafish, engraftment of fluorescent-labeled tumors could be dynamically visualized over time. Importantly, engrafted tumors shared gene expression signatures with predicted cells of origin in human tissue. Finally, we showed that tp53del/del enhanced invasion and metastasis in kRASG12D-induced embryonal rhabdomyosarcoma (ERMS), but did not alter the overall frequency of cancer stem cells, suggesting novel pro-metastatic roles for TP53 loss-of-function in human muscle tumors. In summary, we have developed a Li-Fraumeni zebrafish model that is amenable to large-scale transplantation and direct visualization of tumor growth in live animals.

Primary thoracic giant cell tumor of bone sensitive to steroids.

Spinal giant cell tumor of bone (GCTB) is a rare benign, but locally aggressive, entity. We report the case of a 40-year-old man diagnosed with GCTB of the thoracic spine. The only symptom upon presentation was progressive back pain with pain radiating to the chest. Magnetic resonance imaging showed that the soft tissue mass extended posteriorly into the spinal canal, causing severe spinal cord compression. We initially treated this case with Decadron (Fresenius kabi, Bad Homburg vor der Hohe, Germany) for 1 week. This led to a reduction of tumor size and decompression of the spinal cord. To the best of our knowledge, there have been no prior reports of primary GCTB sensitive to steroid therapy within the existing literature.

Multiple giant cell tumors of bone arising from multiple fatty tumors.

We describe a patient with a history of giant cell tumor who over the course of 18 years developed multiple fat containing osseous lesions in the pelvis and spine. Two of these lesions subsequently evolved into biopsy proven giant cell tumor of bone. To our knowledge, this phenomenon of giant cell tumors evolving from fat containing lesions has not been described.

Adrenal Oncocytic Neoplasm with Paradoxical Loss of Important Mitochondrial Steroidogenic Protein: The 18 kDA Translocator Protein.

The adrenal glands produce a variety of hormones that play a key role in the regulation of blood pressure, electrolyte homeostasis, metabolism, immune system suppression, and the body's physiologic response to stress. Adrenal neoplasms can be asymptomatic or can overproduce certain hormones that lead to different clinical manifestations. Oncocytic adrenal neoplasms are infrequent tumors that arise from cells in the adrenal cortex and display a characteristic increase in the number of cytoplasmic mitochondria. Since the rate-limiting step in steroidogenesis includes the transport of cholesterol across the mitochondrial membranes, in part carried out by the 18-kDa translocator protein (TSPO), we assessed the expression of TSPO in a case of adrenal oncocytic neoplasm using residual adrenal gland of the patient as internal control. We observed a significant loss of TSPO immunofluorescence expression in the adrenal oncocytic tumor cells when compared to adjacent normal adrenal tissue. We further confirmed this finding by employing Western blot analysis to semiquantify TSPO expression in tumor and normal adrenal cells. Our findings could suggest a potential role of TSPO in the tumorigenesis of this case of adrenocortical oncocytic neoplasm.

BRAF mutation in 'sarcomas': a possible method to detect de-differentiated melanomas.

AIMS: BRAF is mutated in 50-60% of melanomas, but BRAF mutation in sarcomas has not been systematically evaluated. Some melanomas are spindled and may show no immunohistochemical evidence of melanocytic differentiation. Similarly, many sarcomas are undifferentiated, i.e. undifferentiated pleomorphic sarcomas (UPS). Diagnosing melanoma versus sarcoma in an undifferentiated spindle cell malignancy can be challenging. Our aim was to evaluate the prevalence of BRAF mutation in sarcomas and the use of BRAF mutational status in the diagnosis of spindle cell malignancies. METHODS AND RESULTS: BRAF mutational analysis was performed on tissue from 104 patients: 90 with sarcoma only (50 UPS) and 14 with sarcoma and melanoma (seven UPS). In the sarcoma-only group, BRAF mutation was absent. In the sarcoma-melanoma group, three sarcomas showed BRAF mutation; all were UPS, occurred after the melanomas and did not stain for melanocytic markers. One melanoma-sarcoma pair showed identical BRAF V600E mutations. CONCLUSIONS: The presence of BRAF mutation in these tumours raises the possibility that poorly differentiated spindle cell malignancies with BRAF mutation may represent melanomas, and BRAF mutational analysis should be considered in a patient with a spindle cell malignancy and a history of melanoma, as a positive result may indicate de-differentiated melanoma.

Dedifferentiation in gastrointestinal stromal tumor to an anaplastic KIT-negative phenotype: a diagnostic pitfall: morphologic and molecular characterization of 8 cases occurring either de novo or after imatinib therapy.

Most gastrointestinal stromal tumors (GISTs) can be recognized by their monotonous cytologic features and overexpression of KIT oncoprotein. Altered morphology and loss of CD117 reactivity has been described previously after chronic imatinib treatment; however, this phenomenon has not been reported in imatinib-naive tumors. Eight patients with abrupt transition from a classic CD117-positive spindle cell GIST to an anaplastic CD117-negative tumor were investigated for underlying molecular mechanisms of tumor progression. Pathologic and molecular analysis was performed on each of the 2 components. Genomic DNA polymerase chain reaction for KIT, PDGFRA, BRAF, and KRAS hot spot mutations and fluorescence in situ hybridization for detecting KIT gene copy number alterations were performed. TP53 mutational analysis was performed in 5 cases. There were 7 men and 1 woman, with an age range of 23 to 65 years. Five of the primary tumors were located in the stomach, and 1 case each originated in the small bowel, colon, and rectum. In 3 patients, the dedifferentiated component occurred in the setting of imatinib resistance, whereas the remaining 5 occurred de novo. The dedifferentiated component had an anaplastic appearance, including 1 angiosarcomatous phenotype, with high mitotic activity and necrosis, and showed complete loss of CD117 (8/8) and CD34 (5/8) expression and de novo expression of either cytokeratin (4/8) or desmin (1/8). There was no difference in the KIT genotype between the 2 components. However, 2 imatinib-resistant tumors showed coexistence of KIT exon 11 and exon 13 mutations. Fluorescence in situ hybridization showed loss of 1 KIT gene in 3 cases and low-level amplification of KIT in 2 other cases in the CD117-negative component, compared with the CD117-positive area. TP53 mutation was identified in 1/5 cases tested, being present in both components. In summary, dedifferentiation in GIST may occur either de novo or after chronic imatinib exposure and can represent a diagnostic pitfall. This phenomenon is not related to additional KIT mutations, but might be secondary to genetic instability, either represented by loss of heterozygosity or low level of KIT amplification.

Intraosseous benign notochord cell tumors (BNCT): further evidence supporting a relationship to chordoma.

BACKGROUND: Previous studies have documented the existence of intraosseous benign notochordal cell tumors (BNCTs) within the axial skeleton. Evidence suggests that they may be associated with the development of chordomas. To further investigate the relationship between BNCT and classic chordoma, we reviewed a large series of resected sacral/coccygeal chordomas in an attempt to identify the presence of coexisting BNCTs. DESIGN: Eighty-two sacrectomy/coccygectomy specimens performed for chordoma were identified. Available hematoxylin and eosin slides were reviewed to identify BNCTs and assess their relationship with the coexisting chordoma. BNCTs were defined, in accordance with prior descriptions, as cohesive aggregates of large cells that appeared adipocyte-like because of their vacuolated cytoplasm. The cells exhibited only minimal nuclear atypia and lacked lobulation and myxoid stroma. RESULTS: We identified 6 BNCTs, each was adjacent to but separate from the sacral chordoma. There were 5 females and 1 male, and the mean age was 58 years. Five lesions arose in the sacrum. One lesion arose in the coccyx, and involved 2 contiguous vertebral levels. The BNCTs ranged in size from 1 to 20 mm with a mean size of 6.1 mm. The lesions were exclusively composed of adipocyte-like nuclei without significant nuclear atypia or myxoid stroma. Three lesions contained sclerotic bony trabeculae and intralesional hematopoietic elements were identified in 1 case. In all cases the chordoma was of the conventional type and were morphologically different from the BNCT. CONCLUSIONS: BNCTs were identified in 7.3% of sacral/coccygeal resections performed for primary chordoma. We speculate that this finding provides further evidence that BNCT is the precursor lesion for chordoma. Additional investigations are needed to further understand this relationship.

Ductulo-insular pancreatic endocrine neoplasms: clinicopathologic analysis of a unique subtype of pancreatic endocrine neoplasms.

Pancreatic neoplasms with mixed ductal and endocrine components are a heterogeneous group of tumors. The least recognized of these are pancreatic endocrine tumors (PETs) displaying benign-appearing tumor-associated ductules. To characterize these ductulo-insular pancreatic endocrine tumors (DI-PETs), we reviewed a series of 92 resected PETs. To be considered as a DI-PET we required the presence and tight intermingling of ductules with the dominant endocrine component (including the presence of ductulo-insular units). A total of 15 PETs fulfilled our criteria (16.3%). The average age of the DI-PET patients was similar to typical PETs (54 years vs 56 years). These tumors were smaller and more often insulin positive than typical PETs (p <0.05). Diffuse stromal fibrosis was more frequent in DI-PETs (11 of 15; 73.3.7%) compared with PETs (8 of 72; 11.1%) (p <0.05). The tumor-associated ductules were composed of cuboidal cells with dense eosinophilic cytoplasm and round nuclei without atypia or mitoses. They were positive for cytokeratin 7 and cytokeratin 19 and lacked any neuroendocrine markers. Reversibly, the endocrine component was negative for cytokeratin 7 and cytokeratin 19 and positive for neuroendocrine markers. Ultrastructural examination of ductulo-insular units confirmed a dual ductal and endocrine differentiation with amphicrine differentiation in one case. Follow-up was available in 12 cases with an average follow-up of 70.1 months (range 25-203 months). Ten patients are currently alive, and two patients died 81 and 158 months after surgery. We conclude that DI-PETs are not uncommon and that they are biologically similar to other PETs. We also hypothesize that the ductal cells develop by transdifferentiation of the endocrine cells.