The first autopsy case of Epstein-Barr virus-positive marginal zone lymphoma that deteriorated after COVID-19 vaccination.

This is the first autopsy case of Epstein-Barr virus-positive marginal zone lymphoma (EBV + MZL) with an other iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPD) (methotrexate [MTX]-associated LPD) that deteriorated after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. This case had a unique immunophenotype. A 71-year-old female patient with rheumatoid arthritis receiving MTX presented with fatigue 1 week after the SARS-CoV-2 vaccination. She was hospitalized due to hepatorenal dysfunction and pancytopenia. Computed tomography revealed systemic lymphadenopathy. Her physical condition deteriorated, and the patient died. The autopsy revealed systemic lymphadenopathy comprising medium-sized atypical lymphocytes and scattered Hodgkin/Reed-Sternberg (H/RS)-like cells. An immunohistochemical examination showed that atypical lymphocytes were positive for CD79a and MUM-1 and some were positive for CD20 and IRTA-1. H/RS-like cells were immunoreactive for CD30 and CD15 and ringed by T cells. Both cell types were positive for EBV-encoded small RNA. The majority of H/RS-like cells were positive for CD20, whereas a small number of CD3-positive cells were admixed. We herein presented the first autopsy case of EBV + MZL that deteriorated after the SARS-CoV-2 vaccination.

Recent Advances in the Diagnosis, Pathogenesis, and Management of Myxoinflammatory Fibroblastic Sarcoma.

Myxoinflammatory fibroblastic sarcoma (MIFS) is an infiltrative, locally aggressive fibroblastic neoplasm of intermediate malignancy that typically arises in the distal extremities of middle-aged adults. It can histologically be confused with a number of benign and malignant conditions. Recently, high-grade examples of MIFS have been described. Immunohistochemistry plays a very limited role in the diagnosis of MIFS. Several genetic alterations have been identified in MIFS, including a t(1;10)(p22;q24) translocation with TGFBR3 and/or OGA rearrangements, BRAF rearrangement, and VGLL3 amplification. Although it appears that VGLL3 amplification is the most consistent alteration, the molecular pathogenesis of MIFS remains poorly understood. A wide resection is considered the standard treatment for MIFS. Radiotherapy may be a viable option in cases with inadequate surgical margins or cases where surgery is likely to cause significant functional impairment. The systemic treatment options for advanced or metastatic disease are very limited. This review provides an updated overview of the clinicoradiological features, pathogenesis, histopathology, and treatment of MIFS.

Bortezomib Increased Vascular Permeability by Decreasing Cell-Cell Junction Molecules in Human Pulmonary Microvascular Endothelial Cells.

Bortezomib (BTZ), a chemotherapeutic drug used to treat multiple myeloma, induces life-threatening side effects, including severe pulmonary toxicity. However, the mechanisms underlying these effects remain unclear. The objectives of this study were to (1) investigate whether BTZ influences vascular permeability and (2) clarify the effect of BTZ on the expression of molecules associated with cell-cell junctions using human pulmonary microvascular endothelial cells in vitro. Clinically relevant concentrations of BTZ induced limited cytotoxicity and increased the permeability of human pulmonary microvascular endothelial cell monolayers. BTZ decreased the protein expression of claudin-5, occludin, and VE-cadherin but not that of ZO-1 and ß-catenin. Additionally, BTZ decreased the mRNA expression of claudin-5, occludin, ZO-1, VE-cadherin, and ß-catenin. Our results suggest that BTZ increases the vascular permeability of the pulmonary microvascular endothelium by downregulating cell-cell junction molecules, particularly claudin-5, occludin, and VE-cadherin.

A case of pituitary adenoma with infiltration into the sphenoid sinus accompanied by melanocyte proliferation.

A 71-year-old woman presenting with headache and nausea was admitted to hospital. Magnetic resonance imaging revealed a tumorous lesion that surrounded the sella turcica and infiltrated the sphenoid sinus with bone destruction. The tumor was removed by nasal endoscopy. The histology was consistent with pituitary adenoma; immunohistochemistry indicated silent corticotroph adenoma with melanocyte proliferation. The possibility that melanocytes were incorporated into the tumor mass in the sphenoid sinus and underwent proliferation was evaluated by investigating the mechanisms of melanocyte proliferation associated with basic fibroblast growth factor (bFGF) and α melanocyte-stimulating hormone (αMSH). In the normal tissue, the pars intermedia and adrenocorticotropic hormone (ACTH)-producing cells were positive for αMSH. None of the control adenoma tissues were positive for bFGF or αMSH by immunostaining. In the present case, bFGF-positive cells and αMSHpositive cells were observed, suggesting that both may have been involved in melanocyte proliferation. The expression of bFGF has been linked to aggressive disease. Pituitary adenoma with melanocyte proliferation has not been previously reported. Careful follow-up is deemed necessary in the future.

Eicosapentaenoic acid ameliorates pulmonary hypertension via inhibition of tyrosine kinase Fyn.

Pulmonary arterial hypertension (PAH) is a multifactorial disease characterized by pulmonary arterial vasoconstriction and remodeling. Src family tyrosine kinases, including Fyn, play critical roles in vascular remodeling via the inhibition of STAT3 signaling. EPA is known to inhibit Fyn kinase activity. This study investigated the therapeutic potential and underlying mechanisms of EPA and its metabolite, resolvin E1 (RvE1), to treat PAH using monocrotaline-induced PAH model rats (MCT-PAH), human pulmonary artery endothelial cells (HPAECs), and human pulmonary artery smooth muscle cells (HPASMCs). Administration of EPA 1 and 2 weeks after MCT injection both ameliorated right ventricular hypertrophy, remodeling and dysfunction, and medial wall thickening of the pulmonary arteries and prolonged survival in MCT-PAH rats. EPA attenuated the enhanced contractile response to 5-hydroxytryptamine in isolated pulmonary arteries of MCT-PAH rats. Mechanistically, the treatment with EPA and RvE1 or the introduction of dominant-negative Fyn prevented TGF-ß2-induced endothelial-to-mesenchymal transition and IL-6-induced phosphorylation of STAT3 in cultured HPAECs. EPA and RvE1 suppressed Src family kinases' activity as evaluated by their phosphorylation status in cultured HPAECs and HPASMCs. EPA and RvE1 suppressed vasocontraction of rat and human PA. Furthermore, EPA and RvE1 inhibited the enhanced proliferation and activity of Src family kinases in HPASMCs derived from patients with idiopathic PAH. EPA ameliorated PAH's pathophysiology by mitigating vascular remodeling and vasoconstriction, probably inhibiting Src family kinases, especially Fyn. Thus, EPA is considered a potent therapeutic agent for the treatment of PAH.

Highly expressed tumoral emmprin and stromal CD73 predict a poor prognosis for external auditory canal carcinoma.

Squamous cell carcinoma of the external auditory canal (SCC-EAC) is rare and has a poor prognosis. The SCC-EAC cases with high-grade tumor budding (TB) or poorly differentiated clusters (PDCs) are associated with shorter survival than those with low-grade TB or PDCs. Extracellular matrix metalloproteinase inducer (emmprin) is a protein expressed in tumor cells that stimulates the production of MMP-2 by stromal fibroblasts to facilitate tumor invasion. Recently, we reported that emmprin forms a complex with CD73 to regulate MMP-2 production from fibroblasts in vitro. Here, we examined the association of emmprin and CD73 expression with TB or PDCs as well as with survival in 34 biopsy specimens of SCC-EAC patients. High tumoral emmprin expression was associated with high-grade TB, whereas high stromal CD73 expression was associated with high-grade PDCs. Furthermore, concurrent elevated expression of tumoral emmprin and stromal CD73 was determined to be an independent poor prognostic factor. In immunoprecipitation analyses, complex formation between emmprin and CD73 was demonstrated in vitro. Production of MMP-2 from fibroblasts was more abundant when cocultured with tumor cells than from fibroblasts cultured alone. Furthermore, MMP-2 production was reduced by the transfection of CD73 siRNA in fibroblasts cocultured with tumor cells. The colocalization of emmprin and CD73 was enhanced in not only the peripheral cells of the tumor cell clusters that interact with fibroblasts but also in the cells of intratumor clusters. Overall, this study provides novel insights into the roles of emmprin, CD73, and MMP-2 in tumor invasiveness.

[A Case of Meningeal Solitary Fibrous Tumour/Haemangiopericytoma WHO Grade III Metastasized to the Spleen Shortly After Tumor Resection].

Revision of WHO guidelines in 2016 led to the classification of solitary fibrous tumours(SFTs)and haemangiopericytomas(HPCs)as a single tumor entity characterized by NAB2-STAT6 fusion. Standard-of-care treatment involves surgery, but local recurrence and distant metastasis sometimes occur. The average latency to metastasis after surgery is 99 months. A 38-year-old female patient presented with a complaint of headache. An 8×5×2cm lesion showing Gd-T1 enhancement was detected near the superior sagittal sinus. Pathological assessment following resection revealed proliferating, polymorphic, atypical tumor cells with distinct nucleoli in a "patternless pattern." Cellularity was moderate to high, and mitotic figures were observed in 15/10 high power fields. Immunohistochemically, tumor cells tested positive for STAT6, and RT-PCR revealed a NAB2-STAT6 fusion gene(exons 6 and 17, respectively), supporting a diagnosis of SFT/HPC WHO grade III. Despite postoperative radiotherapy, multiple metastases to the spleen were detected 8 months after surgery, and distal pancreatectomy with splenectomy was performed. The pathology of the splenic tumor was similar to that of the intracranial tumor. Recurrent disease in a lymph node was detected 1 month later, and local radiation therapy was administered. The patient died of cancerous peritonitis 5 months later. In this case, exceedingly rapid metastasis to the spleen occurred, despite the administration of vigorous treatment. Here, we review SFT/HPC incidence, treatment, and outcomes to better understand this rare malignancy.

Multiple Thrombi in the Heart in Trousseau Syndrome Caused by Pancreatic Carcinoma.

A 65-year-old woman presented to our emergency room because of sudden onset of right hemiparesis with severe fatigue. Neurological examination revealed right hemiparesis with right facial numbness and an extensor planter response on the right side.Magnetic resonance imaging with diffusion-weighted imaging revealed multiple highintensity areas in both cerebral hemispheres and the right cerebellum. A diagnosis of acute stage of multiple brain infarctions caused by emboli was made. An abdominal computed tomography showed a pancreatic tumor with multiple liver metastases. High D-dimer and serum carbohydrate antigen 19-9 concentration strongly suggested Trousseau syndrome associated with pancreatic cancer. The patient had another large embolic stroke and died on day 47. Autopsy was performed. There were large thrombi in the left ventricular apex and in the left atrial appendage There was also a papillary-shaped vegetation on the aortic valve that consisted mainly of fibrin without any inflammatory cells or destruction of the valve, these findings being characteristic of NBTE. This case is remarkable in that the patient had 3 different types of cardiac thrombi in her heart associated with Trousseau syndrome.

Prolactin-producing pituitary adenoma with atypical spindle cell morphology: a case report.

Reported herein is a 25-year-old woman who was treated for a large and highly atypical prolactin-producing pituitary adenoma. On presentation, she exhibited right hemiparesis and left-sided visual loss, associated with amenorrhea. A massive (>5 cm) intra- and suprasellar lesion was seen on imaging, and her serum prolactin level was 4408 ng/ml. The patient received dopamine agonist treatment preoperatively for 4 weeks. To resect the tumor, a two-stage excision was required. Histologically, the specimen was composed of polygonal or spindle cells showing marked nuclear pleomorphism and/or multinucleation. Fibrosis was also focally conspicuous. Differential diagnoses included pituitary adenoma, pituitary carcinoma, pituicytoma, paraganglioma, spindle cell oncocytoma, and meningioma. Immunohistochemically, the tumor cells were positive for prolactin, chromogranin-A, and synaptophysin, but were negative for glial fibrillary acidic protein, S-100 protein, epithelial membrane antigen, and vimentin. No apparent cerebrospinal or systemic metastases are found. Ultimately, prolactin-producing pituitary adenoma was diagnosed. Our case highlights the difficulty in definitively diagnosing an unusual prolactin-producing adenoma based on histopathology alone and the importance of referring to clinical information and immunohistochemical findings when deriving the diagnosis.

[A case of ganglioglioma extended to the lateral ventricle and associated with neurofibromatosis type 1].

We encountered a rare case of intraventricular ganglioglioma associated with neurofibromatosis type 1. A 42-year-old woman presented with a feeling of heaviness of the head and dizziness. She was diagnosed with neurofibromatosis type 1 because she had multiple subcutaneous neurofibromas and café au lait spots. On admission, she deteriorated slightly(Japan Coma Scale 1)and suffered from cognitive dysfunction and right hemiparesis. A computed tomography(CT)scan showed that she had an obstructed hydrocephalus with a long and circular mass lesion, 2cm in diameter, in the anterior horn of the left lateral ventricle. The mass showed low signal intensity(SI)on the T1-weighted image(WI), heterogeneous high SI on the T2-WI, and dense enhancement on a Gd-DTPA contrast MRI, extending from the head of the left caudate nucleus to the lateral ventricle. The patient underwent an urgent operation via an anterior transcallosal approach because of an obstructed hydrocephalus. The tumor was removed in its entirety, including its origin at the caudate head. The pathological diagnosis was a ganglioglioma grade 1 according with the classification of the World Health Organization. Here we describe this case and discuss the rare association between gangliogliomas and neurofibromatosis type 1.

Tumor budding in colorectal carcinoma assessed by cytokeratin immunostaining and budding areas: possible involvement of c-Met.

Tumor budding/sprouting has been shown to be an independent adverse prognostic factor in T1 and T3N0 colorectal carcinomas, however, its assessment could be improved by more accurate identification of budding carcinoma cells and consideration of budding areas. Moreover, tumor budding mechanisms are yet to be defined. In this study, we evaluated the identification of budding tumor cells by either H&E staining alone or H&E with immunohistochemistry and developed a scoring system based on budding grades and areas. We examined whether the budding score correlated with clinicopathologic features and prognosis and the association between tumor budding/sprouting and c-Met protein expression and phosphorylation and MET gene copy numbers because c-Met is known to play an important role in colorectal carcinoma tumorigenesis. Cytokeratin immunohistochemistry could identify tumors with shorter disease-free survival (DFS) from the low-grade budding group assessed with H&E alone. High budding scores based on budding grade and area were more significantly correlated with DFS than scores obtained using the budding grade alone. In tumors with a high budding score, c-Met expression and phosphorylation levels and MET gene copy numbers were significantly increased at the invasive front compared with those in superficial tumor portions. This study showed for the first time that high levels of phospho-c-Met at the invasive front were significantly associated with a high budding score and shorter DFS. In conclusion, a budding score assessed by budding grades and budding-positive areas correlates highly with clinicopathologic aggressive features of colorectal carcinoma.

Keratin-Positive Giant Cell-Rich Tumor: A Review and Update.

Keratin-positive giant cell-rich tumor (KPGCT) is an extremely rare and recently described mesenchymal neoplasm that occurs in both soft tissue and bone, frequently found in young women. It has locally recurrent potential if incompletely excised but low risk for metastasis. KPGCT is histologically similar to conventional giant cell tumors of soft tissue but shows the presence of keratin-positive mononuclear cells. Interestingly, KPGCT also shares some morphological features with xanthogranulomatous epithelial tumors. These two tumors have recently been shown to harbor an HMGA2-NCOR2 fusion, arguing in favor of a single entity. Surgery is the treatment of choice for localized KPGCT. Therapeutic options for advanced or metastatic disease are unknown. This review provides an overview of the current knowledge on the clinical presentation, pathogenesis, histopathology, and treatment of KPGCT. In addition, we will discuss the differential diagnosis of this emerging entity.

Giant Cell Tumor of Soft Tissue: An Updated Review.

Giant cell tumor of soft tissue (GCTST) is a locally aggressive mesenchymal neoplasm of intermediate malignancy that predominantly occurs in the superficial soft tissue of the extremities. It is histologically similar to a giant cell tumor of bone (GCTB) and shows a mixture of round to oval mononuclear cells and osteoclast-like multinucleated giant cells. Currently, immunohistochemistry plays a very limited role in the diagnosis of GCTST. Primary or secondary malignant GCTST has recently been described and tumors exhibiting high-grade histological features demonstrate higher rates of distant metastasis. GCTST lacks the H3-3A gene mutations that are identified in the vast majority of GCTBs, suggesting a different pathogenesis. Surgery is the standard treatment for localized GCTST. Incomplete surgical resection is usually followed by local recurrence. Radiation therapy may be considered when the close proximity of critical structures prevents microscopically negative surgical margins. The systemic treatment options for advanced or metastatic disease are very limited. This review provides an updated overview of the clinicoradiological features, pathogenesis, histopathology, and treatment for GCTST. In addition, we will discuss the differential diagnosis of this peculiar neoplasm.

A case of giant nipple adenoma.

BACKGROUND: Nipple adenoma is a relatively rare benign disease. Clinically, it often presents with nipple erosions, and it should be differentiated from Paget's disease. CASE PRESENTATION: The patient was a 63-year-old woman who complained of a lump in her left nipple for more than 30 years. Computed tomography performed for screening congestive heart failure suggested a left nipple mass of 40 mm in size. Needle biopsy revealed nipple adenoma, and skin biopsy was also performed to confirm the diagnosis. Nipple tumor resection was performed under local anesthesia, and we confirmed that the final diagnosis was nipple adenoma with negative margins. The patient has been free from recurrence for 2 years since the surgery. CONCLUSIONS: We have reported our experience of a case of giant nipple adenoma.

Atypical Spindle Cell/Pleomorphic Lipomatous Tumor: A Review and Update.

Atypical spindle cell/pleomorphic lipomatous tumor (ASCPLT) is a rare and recently described adipocytic neoplasm that primarily occurs in the subcutis of the limbs and limb girdles, particularly of middle-aged adults. It has locally recurrent potential if incompletely excised but no risk for distant metastasis. ASCPLT is histologically similar to spindle cell/pleomorphic lipoma and atypical lipomatous tumor and shows a mixture of atypical spindle cells, adipocytes, lipoblasts, floret-like multinucleated giant cells, and/or pleomorphic cells. It has been recently recognized that ASCPLT can undergo sarcomatous transformation. However, the biological significance of morphological sarcomatous transformation in ASCPLT remains uncertain. Immunohistochemically, the tumor cells show variable expression of CD34, S-100 protein, and desmin. Loss of nuclear Rb expression is observed in the majority of cases. ASCPLT lacks MDM2 gene amplification but can show RB1 gene deletion in a significant subset of cases. Complete surgical excision is the treatment of choice. This review provides an overview of the current knowledge on the clinicoradiological features, pathogenesis, histopathology, and treatment of ASCPLT. In addition, we will discuss the differential diagnosis of this new entity.

Stromal CD73 Expression in Breast Cancer: Subtype-specific Expression and its Prognostic Significance.

BACKGROUND/AIM: Invasive ductal carcinoma (IDC) is classified into distinct subtypes with varying prognoses and treatment sensitivities. For instance, triple-negative breast cancer (TNBC) is associated with poorer outcomes than other subtypes. We have previously reported the role of interstitial CD73 in tumor invasion and its correlation with prognosis in other cancers. This study aimed to investigate the expression of stromal CD73 (sCD73) in IDC and its potential prognostic significance. PATIENTS AND METHODS: We analyzed 61 cases of human epidermal growth factor receptor 2-negative IDC, including TNBC and hormone receptor-positive (luminal-type) cases, treated surgically at our institution from 2005 to 2010. Cases that received preoperative drug therapy were excluded. CD73 expression was evaluated by immunostaining of the tumor stroma. RESULTS: sCD73 expression was observed in 70% of all cases, with a significantly higher rate in TNBC (93%) compared with luminal breast cancer (48%). High sCD73 expression was associated with poor prognosis in terms of overall survival (OS) and disease-free survival (DFS) across all cases. In patients with luminal breast cancer, high sCD73 expression was also indicative of poor prognosis with respect to both OS and DFS. CONCLUSION: High expression of sCD73 is associated with poor prognosis in IDC, particularly in luminal breast cancer. Further research is needed to establish sCD73 as an independent prognostic factor.

Inhibitory Effect of Pyra-Metho-Carnil on the Differentiation and Maturation of Macrophages in Normal and Cancer Microenvironments.

BACKGROUND/AIM: In a previous study, we have demonstrated heightened Pyra-Metho-Carnil (PMC) efficacy in nude mice with intact innate immunity that lack T and B cells. This has prompted hypothesizing that PMC may target macrophages that promote cancer growth. In this study, we conducted co-culture experiments with macrophages derived from THP-1 human monocyte cell lines and spheroids representing normal and cancer microenvironments. We then performed RNA sequencing and flow cytometry analysis to elucidate the mechanisms by which PMC affects macrophage differentiation and maturation. MATERIALS AND METHODS: THP-1 cells were differentiated by phorbol 12-myristate 13-acetate (PMA) and matured by PMA and lipopolysaccharide (LPS) either with or without PMC. Co-cultures were performed using stimulated THP-1 cells and HKe3-wild-type KRAS or HKe3-mutant (mt) KRAS spheroids. We then performed RNA-seq analysis of THP-1 cells stimulated by PMA (either with or without PMC) and flow cytometry analysis of mice peripheral blood obtained after PMC administration. RESULTS: THP-1 cells matured by PMA and LPS specifically increased the area of HKe3-mtKRAS cancer spheroids and the addition of PMC to THP-1 cells was found to inhibit cancer spheroid growth. RNA-seq data suggested that PMC treatment of THP-1 cells stimulated with PMA suppressed cell motility regulatory functions via down-regulation of the NF[Formula: see text]B pathway. Furthermore, flow cytometry results showed that PMC treatment suppressed monocyte maturation in B6 mice. CONCLUSION: The high level of in vivo tumor suppression caused by PMC may be due to inhibition of the differentiation and maturation of tumor-associated macrophages via the NF[Formula: see text]B signaling pathway.

Imatinib mesylate inhibits cell growth of malignant peripheral nerve sheath tumors in vitro and in vivo through suppression of PDGFR-ß.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive and associated with poor prognosis. Basic research to develop new treatment regimens is critically needed. METHODS: The effects of imatinib mesylate on MPNSTs were examined in six human MPNST cell lines and in a xenograft mouse model. RESULTS: The results showed expression of platelet-derived growth factor receptor-ß and suppression of its phosphorylation by imatinib mesylate in all six cell lines. Imatinib mesylate effectively suppressed MPNST cell growth in vitro at concentrations similar to those used clinically (1.46 - 4.6 µM) in three of six cell lines. Knockdown of PDGFR-ß by transfection with a specific siRNA also caused significant reduction in cell proliferation in the sensitive cell lines, but not in the resistant cell lines. Furthermore, imatinib mesylate also significantly suppressed colony formation within soft agar and tumor growth in xenograft models using two of the three sensitive MPNST cell lines. There was excellent agreement between in vitro and in vivo sensitivity to imatinib mesylate, suggesting possible selection of imatinib-sensitive tumors by in vitro analysis. CONCLUSIONS: The results suggest that imatinib mesylate may be useful in the treatment of MPNST patients and in vitro studies may help select cells that are sensitive to imatinib mesylate in vivo.

Biology and Management of Deep-seated Atypical Lipomatous Tumor of the Extremities.

Adipocytic neoplasms are frequently encountered in clinical practice. Atypical lipomatous tumor (ALT) is a locally aggressive but non-metastasizing adipocytic neoplasm that primarily occurs in the proximal extremities of middle-aged to older adults. Histologically, ALT is divided into adipocytic (lipoma-like), sclerosing and inflammatory subtypes. The sclerosing subtype is an unfavorable prognostic factor for local recurrence. ALT is characterized by supernumerary ring and/or giant rod chromosomes. These rings and giant markers invariably contain amplified sequences originating from the long arm of chromosome 12, including the MDM2 proto-oncogene (MDM2) and cyclin-dependent kinase 4 (CDK4) gene. MDM2 and/or CDK4 nuclear immunopositivity is present in most cases. Confidently differentiating deep-seated ALT from deep-seated ordinary lipoma is often difficult on imaging. Moreover, the sclerosing subtype may mimic a higher grade liposarcoma. Detection of MDM2 amplification by fluorescence in situ hybridization would be helpful diagnostically for ALT in more difficult cases. The standard treatment for deep-seated ALT is surgery. Although there is no consensus on the best surgical approach for deep-seated ALT of the extremities, the use of marginal resection is acceptable to preserve musculoskeletal function. This review provides an overview of the current knowledge on the clinical and imaging characteristics, pathogenesis, histopathology, and management of deep-seated ALT of the extremities.