Ovoid Cells Research Articles

Novel fusion sarcomas including targetable NTRK and ALK

BackgroundChallenging emerging entities with distinctive molecular signatures may benefit from algorithms for diagnostic work-up. MethodsFusion sarcomas (2020–2021, during pandemic) were diagnosed by clinicoradiology, morphology, phenotype, and next-generation sequencing (NGS). ResultsSix fusion sarcomas in two males and four females involved the chest-wall, neck, or extremities; ages ranged 2-73, median 18 years. Sizes ranged 5.3-25.0, median 9.1 cm. These include high grade 1) TPR-NTRK1 of proximal femur with a larger rounded soft tissue mass, previously considered osteosarcoma yet without convincing tumor matrix. A pathologic fracture necessitated emergency hemipelvectomy (NED) and 2) novel KANK1-NTRK2 sarcoma of bone and soft tissue with spindled pleomorphic to epithelioid features (AWD metastases). 3) Novel ERC1-ALK unaligned fusion, a low grade infiltrative deep soft tissue hand sarcoma with prominent-vascularity, myopericytoid/lipofibromatosis-like ovoid cells, and collagenized stroma, was successfully treated with ALK-inhibitor (Crizotinib), avoiding amputation. These NTRK and ALK tumors variably express S100 and CD34 and were negative for SOX10. 4) and 5) CIC-DUX4 round cell tumors (rapid metastases/demise), one with COVID superinfection, were previously treated as Ewing sarcoma. These demonstrated mild pleomorphism and necrosis, variable myxoid change and CD99 reactivity, and a distinctive dot-like-Golgi WT1 immunostaining pattern. 6) A chest wall/thoracic round cell sarcoma, focal CD34/ keratins/CK7, revealed nuclear-STAT6, STAT6-NAB2 by NGS, confirming malignant solitary fibrous tumor, intermediate-risk-stratification (AWD metastases). ConclusionsRecent fusion sarcomas include new KANK1-NTRK2 and ERC1-ALK, the latter successfully treated by targeted-therapy. ALK/NTRK fusion partners TPR and KANK1 suggest unusual high-grade morphology/behavior. Clinicoradiologic, morphologic, and phenotypic algorithms can prompt molecular-targeted immunostains or NGS for final classification and promising inhibitor therapy.

Angiomatoid Fibrous Histiocytoma: Case Presentation with Review of Literature

Angiomatoid fibrous histiocytoma is a rare neoplasm with an intermediate malignant potential, that mostly occurs in the subcutis and features varying proportions of epithelioid, ovoid and spindle cells in a nodular and syncytial growth pattern, with hemorrhagic pseudovascular spaces. Here, we report the clinical case of a 68-year-old man who presented with AFH on the right arm; the disease relapsed a few years after surgical excision. We also conduct a brief review of the literature, focusing on the biological and genetic characteristics and the differential diagnosis from other more or less similar entities.

Telocytes and their structural relationships with surrounding cell types in the skin of silky fowl by immunohistochemistrical, transmission electron microscopical and morphometric analysis

Telocytes (TCs), a novel type of interstitial cells, were identified in various animals. Since TCs have not observed in avian skin, hence, we carried out immunohistochemistrical and transmission electron microscopical studies in the skin of the silky fowl to investigate the TCs. TCs appear as CD34, c-Kit, and PDGFRα immunopositive. The elongated TCs with 2 long and thin telopodes (Tps) are located in the dermis. Generally, a TC possesses a fusiform, ovoid and polygonal cell body with 2 Tps (lengths = 5.27–21.85 μm), which are uneven in thickness including thick sections – podoms (diameters = 0.40–0.47 μm) and thin sections – podomers (diameters = 0.03–0.04 μm). TCs/Tps are observed frequently in close proximity to neighboring cell types/structures, such as adipocytes, collagen fibers, and capillaries. Under a magnified field, homocellular TCs/Tps contacts are observed through gap junctions (distances = 0.01–0.05 μm), whereas some of TCs/Tps have heterocellular close contacts by point contacts with surrounding cells, including stem cells and melanocytes. The multivisicular bodies, especially exosomes (diameters = 0.09–0.23 μm) releasing from TCs/Tps are observed in close proximity to TCs/Tps. Our results illustrated that the novel type of interstitial cells – TCs are present in the dermis of the silky fowl, and they have special structural relationships with surrounding cell types. The study provides histological evidence for TCs involvement in intercellular communication, skin regeneration, and pigmentogenesis in avian skin.

Detection of BCOR gene rearrangement in Ewing-like sarcoma: an important diagnostic tool

BackgroundBCOR-CCNB3 sarcoma (BCS) is a group of undifferentiated small round cell sarcomas harboring the BCOR gene rearrangement which shares morphology with the Ewing sarcoma family as well as other malignant round blue cell tumors, thus making them difficult to diagnose. The aim of this study was to explore the role of molecular techniques in the diagnosis of BCS.MethodsTwenty-three cases of EWSR1 rearrangement-negative undifferentiated small round cell sarcomas (Ewing-like sarcoma) were analyzed for the presence of BCOR gene rearrangement by Fluorescence in situ hybridization (FISH) and Reverse Transcription -Polymerase Chain Reaction (RT-PCR). The clinicopathological features of the positive cases were also reviewed. Fifteen additional cases were used as negative controls.ResultsEight cases were found with BCOR gene rearrangement by FISH and reappraised as BCS. The patients ranged in age from 8 to 20 years old, with a male predominance (M:F = 6:2). All tumors were located in the lower extremities. The tumor locations were more common in bone (n = 6) than deep soft tissue (n = 2). Histologically, 7 of 8 tumors were predominately composed of spindle or ovoid cells. The tumor cells were usually arranged in solid hypercellular sheets without a distinct architectural pattern. IHC showed expression of TLE1 (100%), CCNB3 (88%), BCOR (71%). RT-PCR for BCOR-CCNB3 fusion transcript was positive in 7 of 8 cases. Pre-operative chemotherapy resulted in eradication of tumors in 5 patients after a follow-up of 7 to 42 months.ConclusionsEfficient diagnosis of BCOR rearranged sarcomas is achieved by the using a combination of FISH and RT-PCR assays.

Superficial ALK-rearranged myxoid spindle cell neoplasm: a cutaneous soft tissue tumor with distinctive morphology and immunophenotypic profile.

Gene rearrangements involving the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase gene have been identified in various neoplasms, including inflammatory myofibroblastic tumor and epithelioid fibrous histiocytoma. We present an ALK-rearranged cutaneous soft tissue tumor with unique morphologic and immunophenotypic features that are not shared by other entities with ALK rearrangements. The six cases involved two females and four males, aged 18-84 (mean 51) years old. Three tumors were on the back and three on the lower extremities (thigh, knee, shin); ranging from 0.5 to 5.6 (mean 2.1) cm. Four were confined to the dermis; two involved the subcutis. All six cases were characterized by the presence of spindled to ovoid cells arranged in concentric whorls and cords against a myxoid to myxohyaline stroma and relatively cellular aggregates of plump ovoid to epithelioid cells. Four cases showed distinct hyalinized blood vessels. Both cases that involved the subcutis showed peripheral lipofibromatosis-like areas. Tumor-infiltrating lymphocytes were absent to moderate. Severe cytologic atypia or conspicuous mitotic activity was not identified. Immunohistochemically, all tumors diffusely expressed ALK (D5F3) and CD34. All but one tumor was diffusely positive for S100 protein. All tumors were negative for EMA, AE1/AE3, SMA, and SOX10. Next-generation sequencing revealed ALK fusions with FLNA (3 cases), MYH10 (2 cases), and HMBOX1 (1 case) as the partner genes. In all six cases, the breakpoints involved exon 20 of ALK, which preserves the receptor tyrosine kinase domains of ALK in the fusion product. Of the four cases with limited follow-up information (2-18 months), none recurred. In conclusion, we report an ALK-rearranged cutaneous soft tissue tumor characterized by the presence of myxoid spindle cell whorls and cords, and co-expression of ALK, CD34, and frequently S100 protein, we term "superficial ALK-rearranged myxoid spindle cell neoplasm".

Pseudoendocrine Sarcoma: Clinicopathologic Analysis of 23 Cases of a Distinctive Soft Tissue Neoplasm With Metastatic Potential, Recurrent CTNNB1 Mutations, and a Predilection for Truncal Locations.

The number of recognized epithelioid soft tissue neoplasms continues to increase and includes epithelioid schwannoma, sclerosing epithelioid fibrosarcoma, and emerging entities such as sarcomas with GLI1 alterations. Here, we describe 23 cases of a previously unrecognized entity, provisionally termed "pseudoendocrine sarcoma." Pseudoendocrine sarcoma is a rare, distinctive tumor of uncertain lineage with a predilection for paravertebral soft tissue in older adults. Fifteen patients (65%) were male and 8 were female. Age at presentation ranged from 29 to 78 years (median: 62 y). Nineteen tumors (83%) occurred in truncal locations, including 15 tumors (65%) in paravertebral soft tissue; other locations included the posterior head (2 tumors), thigh (1), and orbit (1). Tumor size ranged from 2 to 19 cm (median: 6.35 cm). Pseudoendocrine sarcoma is composed of sheets, trabeculae, and nests of epithelioid or ovoid cells with indistinct borders, palely eosinophilic cytoplasm, and highly monomorphic, round nuclei with speckled chromatin. Pseudoglandular architecture was at least focally present in 16 tumors (70%), large extracellular hyaline globules were identified in 12 tumors (52%), and psammomatous calcifications were present in 8 (35%). Metaplastic ossification was identified in 2 tumors, and myxoid stroma was present in 1. Lymphovascular invasion was present in 5 of 18 tumors (28%). Immunohistochemistry demonstrated that most tumors showed nuclear positivity for β-catenin (20/21 tumors; 95%), and some showed at least focal positivity for S-100 (9/22; 41%), desmin (3/8; 38%), or CD34 (2/8; 25%). All tumors were negative for neuroendocrine and epithelial markers, including synaptophysin (21 tumors), chromogranin (19), INSM1 (4), pan-K (16), CAM5.2 (13), AE1/AE3 (6), epithelial membrane antigen (20), and E-cadherin (13). DNA sequencing detected CTNNB1 point mutations in all 6 sequenced tumors: D32H, S33C, S33F, S37A, S37C, and S37F. RNA sequencing was negative for gene fusions in all 6 sequenced tumors. Clinical follow-up was available for 17 patients (74%; range: 4 mo to 20 y; median: 3.5 y), including 14 patients with >1 year of follow-up. Six of 14 patients with long-term follow-up experienced local recurrence (43%, at intervals of 3 to 6 y). One tumor showed a local lymph node metastasis within the primary excision specimen, and 3 patients developed distant lung metastases (21%). No patient died of the disease as yet. Despite its bland morphology and resemblance to the well-differentiated neuroendocrine tumor, pseudoendocrine sarcoma is best considered an intermediate-grade sarcoma, given its pathologic characteristics and clinical behavior.

RARE-21. A RARE CASE OF PEDIATRIC SPINDLE CELL ONCOCYTOMA WITH EML4-ALK FUSION

A 12 year-old male presented with a 2-month history of intermittent headaches, nausea, and vomiting. Magnetic resonance imaging (MRI) of the brain revealed a 2.2 x 3.5 x 2.6 cm lobulated, sellar/suprasellar mass, mildly T1/T2 hyperintense, with mild homogeneous enhancement and diffusion restriction. He underwent transsphenoidal and right craniotomies for gross total resection of the mass. Pathology demonstrated a hypercellular neoplasm with spindled to ovoid tumor cells arranged in fascicles and tight whirls, consistent with a spindle cell oncocytoma. OncoKids, a DNA- and RNA-based next generation sequencing panel, demonstrated an in-frame EML4 exon 2-ALK exon 19 fusion with a total of 179,872 supporting reads. The EML4-ALK fusion gene is predicted to encode a chimeric tyrosine kinase that facilitates multimerization and autophosphorylation of ALK, and activates its downstream targets, such as RAS/ERK, PI3K/AKT, and JAK/STAT pathways. This fusion is found in approximately 5% of patients with non-small cell lung cancer, a subset of inflammatory myofibroblastic tumors, as well as single cases of pulmonary atypical carcinoid, cholangiocarcinoma, and high-grade glioma. However, it has not been previously described in oncocytoma. Chromosomal microarray analysis demonstrated two interstitial non-contiguous deletions in 2p, and an interstitial deletion in 18q that does not include any known cancer-related genes. The deleted segment in 2p23.3p23.2 includes DNMT3A, which mediates DNA methylation and functions in modification of gene expression. DNMT3A mutations are frequent in hematological malignancies, however their role in oncocytoma is currently unknown. The proximal breakpoint of the deletion in 2p23.3p23.2 is in close proximity to but does not reside within ALK. Spindle cell oncocytoma is rarely reported in the pediatric population, with only one case described in the literature. This is the first case report of an oncocytoma with an EML4-ALK fusion. Additional studies are warranted to confirm its functional effect.

Plexiform fibromyxoma: Review of rare mesenchymal gastric neoplasm and its differential diagnosis.

Plexiform fibromyxoma (PF) is a very rare mesenchymal neoplasm of the stomach that was first described in 2007 and was officially recognized as a subtype of gastric mesenchymal neoplasm by World Health Organization (WHO) in 2010. Histologically, PF is characterized by a plexiform growth of bland spindle to ovoid cells embedded in a myxoid stroma that is rich in small vessels. The lesion is usually paucicellular. While mucosal and vascular invasion have been documented, no metastasis or malignant transformation has been reported. Its pathogenesis is largely unknown and defining molecular alterations are not currently available. There are other mesenchymal tumors arising in the gastrointestinal tract that need to be differentiated from PF given their differing biologic behaviors and malignant potential. Histologic mimics with spindle cells include gastrointestinal stromal tumor, smooth muscle tumor, and nerve sheath tumor. Histologic mimics with myxoid stroma include myxoma and aggressive angiomyxoma. Molecular alterations that have been described in a subset of PF may be seen in gastroblastoma and malignant epithelioid tumor with glioma-associated oncogene homologue 1 (GLI1) rearrangement. The recent increase in publications on PF reflects growing recognition of this entity with expansion of clinical and pathologic findings in these cases. Herein we provide a review of PF in comparison to other mesenchymal tumors with histologic and molecular resemblance to raise the awareness of this enigmatic neoplasm. Also, we highlight the challenges pathologists face when the sample is small, or such rare entity is encountered intraoperatively.

Nanoscale dynamics of peptidoglycan assembly during the cell cycle of Streptococcus pneumoniae

Dynamics of cell elongation and septation are key determinants of bacterial morphogenesis. These processes are intimately linked to peptidoglycan synthesis performed by macromolecular complexes called the elongasome and the divisome. In rod-shaped bacteria, cell elongation and septation, which are dissociated in time and space, have been well described. By contrast, in ovoid-shaped bacteria, the dynamics and relationships between these processes remain poorly understood because they are concomitant and confined to a nanometer-scale annular region at midcell. Here, we set up a metabolic peptidoglycan labeling approach using click chemistry to image peptidoglycan synthesis by single-molecule localization microscopy in the ovoid bacterium Streptococcus pneumoniae. Our nanoscale-resolution data reveal spatiotemporal features of peptidoglycan assembly and fate along the cell cycle and provide geometrical parameters that we used to construct a morphogenesis model of the ovoid cell. These analyses show that septal and peripheral peptidoglycan syntheses first occur within a single annular region that later separates in two concentric regions and that elongation persists after septation is completed. In addition, our data reveal that freshly synthesized peptidoglycan is remodeled all along the cell cycle. Altogether, our work provides evidence that septal peptidoglycan is synthesized from the beginning of the cell cycle and is constantly remodeled through cleavage and insertion of material at its periphery. The ovoid-cell morphogenesis would thus rely on the relative dynamics between peptidoglycan synthesis and cleavage rather than on the existence of two distinct successive phases of peripheral and septal synthesis.

Primary high-grade myoepithelial carcinoma of the lung: A study of three cases illustrating frequent SMARCB1-deficiency and review of the literature

Primary myoepithelial carcinoma of the lung is exceptionally rare and, hence, remained poorly characterized. We present 3 tumors affecting 2 males and 1 female aged 60 to 84 years. Tumor size ranged from 4 to 10 cm. All presented as well circumscribed non-encapsulated peripheral solitary masses. One patient died postoperatively. The other two were lost to follow-up. Histologically, all tumors were high-grade with predominance of myxoid/chordoid (2) and rhabdoid (1) pattern. Immunohistochemistry (IHC) showed reactivity with vimentin, pankeratin, EMA and smooth muscle actin. Two tumors were SMARCB1-deficient (one with additional loss of SMARCA2 and PBRM1). RNA sequencing revealed no gene fusions. Review of reported cases (total: 16) showed that pulmonary myoepithelial carcinoma affects both sexes equally at a median age of 60 years (24–84), presents predominantly as peripheral masses (69%) in the lower lobes (66%) of smokers (70%) with a median size of 6 cm (1.5–13), and originates as high-grade de novo carcinoma. Forty percent of patients died of disease at a median of 12.5 months (0 to 62). Only 40% of patients were disease free at last follow-up (median, 9.5 months). Prominent lobulation and myxoid stroma were frequent histological features. Most tumors displayed variable combinations of epithelioid, spindle, plasmacytoid, clear, ovoid or round cells. Three of 6 tumors subjected to different RNA panels showed EWSR1 rearrangements (fused to PBX1, ZNF444 or to unknown partner). Two of 3 tumors lacking gene fusions were SMARCB1-deficient (both showed secondary EWSR1 FISH abnormalities due to 22q deletion). Primary pulmonary myoepithelial carcinoma is a rare aggressive malignancy that recapitulates its soft tissue and salivary counterpart. Exclusion of metastasis from other primaries is mandatory and can only be achieved by detailed clinical history and imaging.

Ossifying low grade endometrial stromal sarcoma with PHF1-BRD8 fusion

Low-grade endometrial stromal sarcoma and ossifying fibromyxoid tumors are two types of mesenchymal tumors that share no similarities in terms of site, sex, and morphological characteristics. They are rare, low grade tumors of uncertain lineage, with no definite immunological markers. Interestingly, a common PHF1 gene- related rearrangement was observed in these two tumors. Here, we report a case of endometrial stromal sarcoma with distinct ossification. Microscopically, the tumor is composed of bland-looking ovoid cells with low cellularity in the fibromyxoid stroma. Foci of metaplastic bone formation were noted. Using a combination of FISH, transcriptome sequencing, and molecular techniques, we identified a new PHF1-BRD8 fusion transcript, which was previously described, but in its reciprocal fusion form. This case expands the current understanding of low-grade endometrial stromal sarcoma and emphasizes the importance of molecular characterization of unique fusion, which may be related to its distinct morphological features and the possibly chemosensitive target.

Morphology and phylogenetic relationships of two new Antarctic species in phylogroup Chloromonadinia (Volvocales, Chlorophyceae)

ABSTRACT The phylogroup Chloromonadinia (Volvocales, Chlorophyceae) comprises green microalgae that inhabit a variety of environments, including freshwater, soil, and snow. Two strains were isolated from two sites in the South Shetland Islands in maritime Antarctica, and their morphological and molecular characteristics were studied. Light microscopy of the strain KSF0090 revealed ellipsoidal or broad ellipsoidal, sometimes almost spherical cells with a chloroplast without a pyrenoid, a prominent eyespot, and a hemispherical papilla. The vegetative cells of KSF0208 were ellipsoidal to ovoid cells with a chloroplast with a central pyrenoid, a linear eyespot, and a papilla. The two strains differed from other closely related species based on size and the aforementioned morphological characteristics. Nuclear small subunit rDNA sequence data indicated that each strain formed a distinct well-supported lineage within the phylogroup Chloromonadinia. In addition, comparative analyses of the secondary structures of internal transcribed spacer 2 and compensatory base changes were used to identify and characterize the two strains. Based on their morphological and molecular characteristics, we propose KSF0090 and KSF0208 as two new species, Chloromonas deceptionensis sp. nov. and Ostravamonas greenwichensis sp. nov., respectively.

Recurrent MEIS1-NCOA2/1 fusions in a subset of low-grade spindle cell sarcomas frequently involving the genitourinary and gynecologic tracts.

Sarcomas with MEIS1-NCOA2 fusions have been so far reported in 2 cases each of primitive renal sarcomas and intraosseous pelvic rhabdomyosarcomas. Their histologic spectrum, anatomic distribution, and clinical behavior remain poorly defined. In this study, we report 6 additional spindle cell sarcomas with MEIS1-NCOA2 or NCOA1 fusions that fall into the same disease spectrum with the previously reported renal sarcomas. The patients' age range was wide (20-76 years, mean 46) and all except one were female. The tumors arose in the kidney (n = 2), and one each in the uterine corpus, vagina, scrotum, and para-rectal region. The consistent morphology was that of monomorphic spindle to ovoid cells in a storiform, whorling, or solid pattern. Alternating cellularity, myxoid stroma, and microcystic changes were seen in some cases. Mitotic activity varied greatly (<1-33/10 high power fields). The immunophenotype was nonspecific, with most cases expressing variable degrees of TLE1, WT1, cyclin D1, CD56, and CD10. Using various platforms of RNA-based targeted sequencing, MEIS1-NCOA2 fusions were recurrently identified in 5 cases, and a novel MEIS1-NCOA1 fusion was found in one renal tumor. The gene fusions were validated by fluorescence in situ hybridization using custom BAC probes. Of the 5 patients with available follow-up (5 months to 8 years), all experienced local recurrences, but no distant spread or death from disease. Our results expand the clinicopathologic spectrum of sarcomas with MEIS1-NCOA2/1 fusions, providing evidence of an undifferentiated spindle cell phenotype with nonspecific immunoprofile and low-grade clinical behavior.

Salivary Duct Carcinoma With Rhabdoid Features-No or Aberrant Expression of E-cadherin and Genetic Changes in CDH1: Immunohistochemical and Genetic Analyses of 17 Cases.

Salivary duct carcinoma is a relatively uncommon malignancy of the salivary glands; however, it frequently occurs as a carcinomatous component of carcinoma ex pleomorphic adenoma. We previously reported salivary duct carcinoma with rhabdoid features (SDCRF) as an extremely rare subtype of salivary duct carcinoma, and that it occurred as a salivary counterpart of pleomorphic lobular carcinoma of the breast (PLCB). We collected new cases of SDCRF for this study, in which we examined a total of 17 cases immunohistochemically and genetically. As it is known that PLCB exhibits loss of or aberrant E-cadherin expression and carries nonsense/missense mutations in or deletion of the CDH1 gene, we examined the CDH1 gene status of our SDCRF cases. All of the examined SDCRF cases involved the diffuse proliferation of large ovoid cells with eosinophilic cytoplasm and eccentric nuclei, which displayed reduced cell-cell adhesion. Most cases were positive for pan-cytokeratin, androgen receptor, gross cystic disease fluid protein-15, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1, and WI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4, whereas they were negative for vimentin. No and decreased/cytoplasmic E-cadherin expression was observed in 11 and 4 of 17 cases, respectively, whereas no and decreased/cytoplasmic β-catenin expression were observed in 10 and 5 of 17 cases, respectively. Among the 11 cases that could be genetically analyzed, a nonsense mutation (1 case), missense mutations (6 cases), and insertions (1 case) were detected in the CDH1 gene. In conclusion, we propose that SDCRF is the salivary counterpart of PLCB due to its morphology and immunophenotype, and the genetic status of CDH1.

Gene Expression in Solitary Fibrous Tumors (SFTs) Correlates with Anatomic Localization and NAB2-STAT6 Gene Fusion Variants

Solitary fibrous tumors (SFTs) harbor recurrent NAB2-STAT6 gene fusions, promoting constitutional up-regulation of oncogenic early growth response 1 (EGR1)-dependent gene expression. SFTs with the most common canonical NAB2 exon 4-STAT6 exon 2 fusion variant are often located in the thorax (pleuropulmonary) and are less cellular with abundant collagen. In contrast, SFTs with NAB2 exon 6-STAT6 exon 16/17 fusion variants typically display a cellular round to ovoid cell morphology and are often located in the deep soft tissue of the retroperitoneum and intra-abdominal pelvic region or in the meninges. Here, we employed next-generation sequencing-based gene expression profiling to identify significant differences in gene expression associated with anatomic localization and NAB2-STAT6 gene fusion variants. SFTs with the NAB2 exon 4-STAT6 exon 2 fusion variant showed a transcriptional signature enriched for genes involved in DNA binding, gene transcription, and nuclear localization, whereas SFTs with the NAB2 exon 6-STAT6 exon 16/17 fusion variants were enriched for genes involved in tyrosine kinase signaling, cell proliferation, and cytoplasmic localization. Specific transcription factor binding motifs were enriched among differentially expressed genes in SFTs with different fusion variants, implicating co-transcription factors in the modification of chimeric NGFI-A binding protein 2 (NAB2)-STAT6-dependent deregulation of EGR1-dependent gene expression. In summary, this study establishes a potential molecular biologic basis for clinicopathologic differences in SFTs with distinct NAB2-STAT6 gene fusion variants.

Co-expression of CD34 and h-caldesmon in a benign meningioma-like dermal neoplasm, a case report

Meningioma-like dermal tumor with diffuse coexpression of CD34 and hcaldesmon is rarely reported. Herein, we report a case of a 58-years-old woman who complained of a solitary dome-shaped papule on the left hand. An ellipse of skin measuring 1 x 0.5 x 0.5 cm was excised and sent for histopathological evaluation. Upon sectioning, the specimen showed a whitish firm dermal nodule measuring 3 mm in its greatest dimension. Microscopic examination revealed a well-circumscribed barely encapsulated dermal lesion showing compact round whorled sheets formed of round to ovoid uniform cells with abundant pink cytoplasm. Occasional intranuclear vacuoles were seen. A minor capillary-sized vascular component was seen in the background. Immunohistochemical (IHC) study revealed a diffuse positivity of tumor cells to CD34 and h-caldesmon along with faint reaction to Smooth Muscle Actin (SMA) and ER. However, Desmin, S100, HMB45, EMA, Pan Cytokeratin, and Chromogranin were all negative. Ki67 was very low (1%). The main differential diagnoses of the current lesion are meningioma and glomus family tumors. While the current lesion is morphologically reminiscent of cutaneous meningioma; neither the location nor the IHC stains support that diagnosis. The glomus family is highly suggestive. However, the location, the compact nature of the proliferation, and the positivity of CD34, all are unusual in such entities.

Decreased Colonic Guanylin/Uroguanylin Expression and Dried Stool Property in Mice With Social Defeat Stress.

Psychological stress is deeply involved in the pathophysiology of not only mental illness but also functional gastrointestinal disorders. In the present study, we examined the relationship between psychological stress and abnormality of stool properties, focusing on the alteration of plasma glucocorticoid and guanylin (GN)/uroguanylin (UGN) expression in the colon. A murine model of chronic social defeat stress (CSDS) was established by exposing a C57BL/6N intruder mouse to a CD-1 aggressor mouse for 3–5 min. Thereafter the mice were kept in the same cage but separated by a divider for the remainder of the day. This procedure was repeated for 10 consecutive days, and then a social interaction test was performed to evaluate social avoidance. Fresh fecal and blood samples were collected for stool property analysis and measurement of the plasma glucocorticoid level by ELISA. The expression of GN, UGN, and guanylate cyclase 2C in the colonic tissues was examined by real-time RT-PCR and immunohistochemistry. Moreover, Lovo cells were stimulated with dexamethasone, and the expression of GN/UGN mRNA was examined. In the CSDS group, the time spent in the social interaction zone was significantly shorter when the CD-1 aggressor mouse was present than when it was absent. The social interaction ratio was also significantly lower in the CSDS group relative to the controls. The mean Bristol scale score was significantly lower in the CSDS group, but the fecal sodium concentration did not differ between CSDS mice and controls. The level of plasma corticosterone was significantly higher in the CSDS group than in the controls immediately after the 10th day of CSDS. The expression of both GN and UGN was significantly decreased in the CSDS mice. GN was expressed in all colonic epithelial cells, and UGN was expressed in ovoid or pyramidal epithelial cells in the colonic mucosa. The expression of both GN and UGN was significantly decreased in the CSDS mice relative to controls. The expression of both GN and UGN was significantly suppressed in Lovo cells upon stimulation with dexamethasone. Psychological stress-induced glucocorticoid may suppress colonic GN/UGN expression, resulting in a change in stool properties leading to constipation.

PATH-17. NOVEL DUAL HISTONE 3 K27M AND G34R POINT MUTATIONS IN A MIDLINE GLIOMA

Abstract BACKGROUND Histone H3 alterations due to mutations on H3F3A and HIST1H3B genes, have in recent years been associated with distinct entities and tumor locations within the context of infiltrative gliomas. H3K27M is associated with a midline location and is included in the WHO 2016 as the diffuse midline glioma H3K27M-mutant, a specific diagnostic entity. H3G34R, thought to be a mutually exclusive alteration, is less common but has been associated with a cerebral hemispheric location. We report the first case to our knowledge with both of these alterations in the same tumor. METHODS Clinical and pathologic records of the patient were reviewed and presented. RESULTS A 39-year-old man presented with acute right face, arm, and leg numbness and mild weakness; examination was notable for right lower motor neuron facial nerve palsy and numbness, along with numbness and subtle slowing of rapid alternating movements in the left arm and leg. A non-enhancing left thalamic mass was identified and stereotactically biopsied. Infiltrative glial neoplasm with moderately-increased cellularity was seen, with ovoid cells, enlarged nuclei, apoptotic bodies, and mitotic figures. No necrosis or microvascular proliferation seen. Immunostain was positive for H3K27M. O6-methylguanine-methyltransferase (MGMT) promoter was not methylated. Next-generation sequencing showed dual in cis H3 point mutations in K27M (HIST1H3B c.83A &amp;gt;T) and G34R (HIST1H3B c.103G &amp;gt;C). Additional alterations were noted in NF1, PIK3CA, ATRX, FGFR3, and NSD1. Isocitrate dehydrogenase (IDH1/2) mutations were not identified. CONCLUSION This case of a young man with a midline glioma is novel for carrying both H3K27M and H3G34R alterations and indicates these alterations are not mutually exclusive. The interaction seen here suggests H3K27M dominance for a midline phenotype.

The First Case Of The Myopericytomatosis Of The Foot With RAF1 Rearrangement Involving Intron 7 (ATG7-RAF- 1)

Abstract Introduction/Objective Myopericytomatosis, recently described by Yin P. Hung et al [1], is an extremely rare myopericytic proliferation with only less than 15 reported cases in the English literature. This neoplasm has been described as dermal or subcutaneous well-circumscribed nodules composed of ovoid to spindled cells in a perivascular distribution, with no significant necrosis, atypia or mitosis. It usually involves the lower extremities with the ankle being the most common location. Next-generation DNA sequencing (NGS) in all the previously reported cases exhibited PDGFRB alterations with no BRAF, NOTCH, and/or GLI1 alterations [1]. Methods We report a 47-year-old man who presented multiple well-encapsulated nodules on his right foot that were localized to the fascia/subcutaneous fat by MRI; fibromas were the main radiologic differential diagnosis. Results The biopsy and subsequent excisional specimens showed diffuse involvement by numerous discrete myopericytomatous nodules composed of bland spindled to ovoid cells. Immunohistochemical staining demonstrated that the myopericytic cells are strongly positive for SMA, focally positive for caldesmon with a patchy cytoplasmic CD99 staining. Ki-67 showed a low proliferation rate of 1–2%. Desmin, CD31, CD34, HHV8, STAT6, S100, HMB45, and Melan-A immunostains were negative. The diagnosis of myopericytomatosis was made. The NGS revealed that the tumor cells are positive for RAF1 rearrangement involving intron 7 (ATG7-RAF-1) with no other findings, including PDGFRB alterations. Conclusion Myopericytomatosis is an exceedingly rare entity with most of the previously reported cases involving the lower extremities and only two cases involving the foot. In all the prior cases, the PDGFRB mutation N666K was noted [1]. We report the first case of RAF1 rearrangement in myopericytomatosis of the foot with no other genetic alterations.

Cribriform Adenocarcinoma of the Minor Salivary Gland (CAMSG); A Separate and Malignant Entity

Abstract Introduction/Objective Cribriform adenocarcinoma of the minor salivary gland (CAMSG) is a recently described salivary gland neoplasm (SGN) that WHO includes under the polymorphous adenocarcinoma (PAC) subheading. CAMSG is reported to occur mostly in the base of the tongue and lingual tonsils. Methods We present a case of CAMSG of buccal mucosa in a 48-year old woman who presented with pain and swelling on the left side of the face that started after tooth extraction. Imaging revealed a large expansile mass (5.8 x 4.3 x 6.1 cm) originating in the left mandibular angle extending into masticator space, maxillary sinus, pterygopalatine fossa, sphenoid, middle cranial fossa, orbit and skull base. Ameloblastoma, primary intraosseous carcinoma, and squamous cell carcinoma were considered. Incisional biopsy revealed a tumor comprised of round to ovoid cells with clear to vesicular nuclei (ground-glass appearance) and occasional mitosis present in irregular solid, cribriform, and microcystic patterns in a hyalinized stroma with the presence of abundant mucin within lobules and stroma. Results Differential diagnosis of secretory carcinoma, hyalinizing clear cell carcinoma, and less likely PAC and mucoepidermoid carcinoma were considered, all inconsistent with the imaging findings. The tumor cells were positive for S100 and negative for CD117, ki67, p63, CD117, and TTF-1. Based on a prominent cribriform pattern, vesicular nuclei, and S-100 expression, a diagnosis of cribriform adenocarcinoma of minor salivary gland origin was rendered. The patient subsequently underwent left partial maxillectomy, left partial mandibulectomy, and resection of the skull base and left neck dissection and was staged as pT4bN0, with negative margins and vascular invasion. The patient underwent radiation therapy and at 6- month follow up was alive and healthy. Clinically and histologically CAMSG overlaps with tumors of both salivary and non-salivary gland origin. Conclusion Recognition of CAMSG as a distinct entity will help in accurate diagnosis and categorization in the WHO classification of SGNs.