Immunohistochemistry for YAP1 N-terminus and C-terminus highlights metaplastic thymoma and high-grade thymic epithelial tumors by different staining patterns.

Metaplastic thymoma (MT), a rare subtype of thymic epithelial tumors (TETs), harbors YAP1::MAML2 fusions. Poroma, a skin tumor, also carries these fusions and exhibits a unique staining pattern for YAP1 immunohistochemistry (IHC), namely, a YAP1 N-terminus (YAP1[N])-positive but YAP1 C-terminus (YAP1[C])-negative pattern. In this context, MT was recently reported to lack YAP1(C) expression exclusively among TET subtypes. However, a lack of information about YAP1(N) expression in that study and another report that wild-type YAP1 expression was diminished in type B3 thymoma and thymic carcinoma warrants further studies for YAP1 expression in TETs. Thus, we immunohistochemically examined YAP1(N) and YAP1(C) staining patterns in our TET samples, including 14 cases of MT. In addition, 11 of the 14 MT cases were genetically analyzed with the formalin-fixed paraffin-embedded tissues if they harbored YAP1::MAML2 fusions. MT consistently exhibited YAP1(N)-positive and YAP(C)-negative staining, whereas type B3 thymoma and thymic carcinoma showed relatively heterogeneous staining patterns for YAP1(N) and YAP1(C) and were sometimes negative for both antibodies. Furthermore, a lower expression of YAP1 was found in type B3 compared to B2 thymomas. Among genetically analyzed 11 MT cases, 6 cases showed YAP1::MAML2 fusions, whereas the analysis failed in 5 very old cases due to poor RNA quality. These results indicate that IHC of both YAP1(N) and YAP1(C) is recommended to obtain staining patterns almost unique to MT. The biological significance of YAP1 in high-grade TETs warrants further investigation.

Polymorphic lymphoproliferative disorder arising in a rheumatoid arthritis patient, presenting as fibrin-associated large B-cell lymphoma-like lesions in aortic and mitral valves.

We herein report a case of methotrexate-associated lymphoproliferative disorder (MTX-LPD) showing fibrin-associated large B-cell lymphoma-like heart valve lesions, and Epstein-Barr virus (EBV)-positive mucocutaneous ulcer-like cutaneous and oral mucosal lesions. MTX-LPD is a critical complication that can occur in RA patients who are treated with MTX. EBV also plays a defining or important role in LPDs. Among the sites of MTX-LPD, 40-50% occur in extranodal sites, including the gastrointestinal tract, skin, liver, lung, and kidney. There are few reports of MTX-LPDs involving the heart valves, and to the best of our knowledge, this is the first case to be reported in the English literature. The possibility of EBV-positive LPD should be considered in RA patients, even in patients with an atypical site, as in this case.

Insulin-like Growth Factor II mRNA-binding Protein 3 is a Highly Sensitive Marker for Intravascular Large B-cell Lymphoma: Immunohistochemical Analysis of 152 Pathology Specimens From 88 Patients.

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of aggressive extranodal large B-cell lymphoma characterized by the selective growth of lymphoma cells within the lumina of blood vessels, particularly capillaries. IVLBCL lacks mass formation, and its diagnosis can be challenging. We analyzed the utility of insulin-like growth factor II mRNA-binding protein 3 (IMP3) immunohistochemistry for IVLBCL diagnosis in various organs. Double staining with paired box 5 (PAX5) was performed for validation. Overall, 152 pathological specimens (111 positive and 41 negative for IVLBCL) obtained from 88 patients with a diagnosis of IVLBCL were stained for IMP3 and IMP3/PAX5. As negative controls, 40 pathology specimens from 38 patients with no history of IVLBCL or other B-cell lymphomas were stained for IMP3, which comprised 31 benign pathological specimens from 29 patients in whom malignancy was suspected, 7 cases of appendicitis with intravascular and/or intralymphatic lymphoid proliferations, and 2 cases of intravascular natural killer/T-cell lymphoma. All mononuclear cells with cytoplasmic staining were considered positive for IMP3 expression, but expression restricted to germinal center B cells was excluded from evaluation. All 111 IVLBCL pathological specimens were positive for IMP3 and IMP3/PAX5. In addition, 11 of the 41 specimens originally diagnosed as IVLBCL-negative showed IMP3/PAX5 double-positive cells, raising the suspicion of IVLBCL. However, of the 40 negative control samples, IMP3-positive non-germinal center B cells were detected in only 2 samples ( P = 0.0131) and no intravascular IMP3-positive B cells suspicious for IVLBCL were identified. Altogether, IMP3 immunohistochemistry is a highly sensitive marker of IVLBCL and can be a helpful adjunct for IVLBCL diagnosis.

Successful treatment of systemic AL amyloidosis with autologous hematopoietic stem cell transplantation combined with cell-free and concentrated ascites reinfusion therapy.

Key Clinical Message: AL patients develop the unique toxicities of fluid retention and non-cardiogenic pulmonary edema during the course of stem cell mobilization. We propose mobilization with CART as effective and safe treatment for AL patients with refractory anasarca. Abstract: We describe a 63-year-old male with systemic immunoglobulin light chain (AL) amyloidosis with cardiac, renal, and liver involvement. After four courses of CyBorD, mobilization with G-CSF at 10 µg/kg was initiated and CART was simultaneously performed for fluid retention. No adverse events were observed during collection or reinfusion. Anasarca gradually disappeared and he underwent autologous hematopoietic stem cell transplantation. The complete remission of AL amyloidosis has been maintained, and the condition of the patient has remained stable for 7 years. We propose mobilization with CART as an effective and safe treatment option for AL patients with refractory anasarca.

Pheochromocytoma Multisystem Crisis Complicated by Severe Acute Pancreatitis.

A 43-year-old man developed headache, dizziness, abdominal pain, and vomiting. His blood pressure was 203/121 mmHg, heart rate 122 beats/min, body temperature 39.1°C, and respiratory rate 24/min. He had elevated levels of creatinine at 2.95 mg/dL and lipase at 1,364 U/L as well as an extremely low calcium level at 5.2 mg/dL. Hypertriglyceridemia and hyperglycemia were seen. Chest and abdominal computed tomography showed interstitial pneumonia, severe pancreatitis, and a right adrenal tumor. The patient also developed vertebral artery dissection and medullary infarction. After right adrenalectomy, the patient was diagnosed with pheochromocytoma multisystem crisis (PMC). Acute pancreatitis might augment numerous life-threatening manifestations of PMC.

An extremely rare case of anterior mediastinal leiomyosarcoma: a case report.

We herein report an extremely rare case of leiomyosarcoma found in the anterior mediastinum. A 79-year-old man presented to our hospital with an anterior mediastinal mass incidentally found by chest computed tomography (CT) scan. Percutaneous needle biopsy revealed the presence of an undifferentiated sarcoma. Transsternal resection of the tumor with adjacent left mediastinal pleura was performed, and pathological analysis revealed a leiomyosarcoma, which was 11 cm in diameter, with bare margins. He was followed up on an outpatient basis with no adjuvant therapy. Although mediastinal lymph node recurrence was suspected on chest CT scan 18 months after surgery, the patient remained asymptomatic and rejected any additional antitumor treatments. He died of respiratory failure after incidental traumatic spinal injury about 30 months after tumor resection.

Primary Hepatic Neuroendocrine Carcinoma with Thrombocytopenia Due to Diffuse Bone Marrow and Splenic Infiltration: An Autopsy Case.

An 82-year-old man with fever and back pain was referred to our hospital and was thus found to be thrombocytopenic. A bone marrow biopsy revealed the diffuse infiltration of poorly differentiated neuroendocrine carcinoma (NEC). Computed tomography revealed a large hepatic mass. Considering the risk of bleeding due to thrombocytopenia, a needle biopsy was not performed. The patient rapidly deteriorated and died 10 days after presentation. An autopsy confirmed the diagnosis of primary hepatic NEC, with diffuse metastasis to the spleen, bone marrow, and systemic lymph nodes. This is an extremely rare case of NEC presenting with thrombocytopenia due to extensive bone marrow and splenic infiltration.

Immunohistochemistry of the oncofetal protein IMP3 is helpful in the diagnosis of intravascular large B-cell lymphoma using skin biopsy.

BACKGROUND: The oncofetal protein insulin-like growth factor 2 mRNA binding protein-3 (IMP3) is expressed in various cancers. In this study, we examined the diagnostic utility of IMP3 immunohistochemistry in the context of intravascular large B-cell lymphoma (IVL). METHODS: We obtained 25 skin biopsy (SB) specimens diagnosed as IVL and nine IVL-negative SB specimens from 27 IVL patients. Additionally, 27 negative SB specimens from 26 non-IVL patients were obtained from our pathology archives. We performed IMP3 immunohistochemistry on these 61 SB specimens, considering IMP3 expression in any mononuclear cell as positive. In selected cases, triple immunostaining for IMP3, PAX5, and CD34 was performed to analyze the origin and location of IMP3-positive cells. RESULTS: IMP3 was expressed in most intravascular lymphoma cells in all the 25 SB specimens diagnosed as IVL. Furthermore, our evaluation revealed the presence of intravascular IMP3-positive B-cells in five of the nine negative SB specimens from IVL patients; however, this was not observed in the 27 SB specimens from non-IVL patients. CONCLUSION: IMP3 was expressed in most IVL cells, and IMP3 immunohistochemistry could serve as a sensitive diagnostic aid for detecting IVL cells in SB.

The Expression of Insulin-Like Growth Factor 2 Messenger RNA-Binding Protein 3 in Langerhans Cell Histiocytosis and Langerhans Cell Sarcoma.

Langerhans cell neoplasms, which include Langerhans cell histiocytosis and Langerhans cell sarcoma, are tumors that originate from dendritic cells. Langerhans cell sarcoma is defined as a high-grade neoplasm with overtly malignant cytological features and the Langerhans cell-like phenotype, and generally has a poorer prognosis and more aggressive phenotype than Langerhans cell histiocytosis. Insulin-like growth factor 2 messenger RNA-binding protein 3 (IGF2BP3 or IMP3) is an oncofetal protein that is expressed in various cancer types; its expression is often associated with a poor prognosis and aggressive phenotype. Here, we used immunohistochemistry to evaluate IGF2BP3 expression in Langerhans cell neoplasms. IGF2BP3 expression was scored as negative (< 1%) or positive (≥ 1%) by immunohistochemistry. All 4 patients with Langerhans cell sarcoma (100%) and 6 of 22 pediatric (age < 18 years) patients with Langerhans cell histiocytosis (27.3%) had positive results for IGF2BP3; however, 16 of 22 pediatric patients with Langerhans cell histiocytosis (72.7%) and all 15 adult (age ≥ 18 years) patients with Langerhans cell histiocytosis (100%) had a negative result. Among patients with Langerhans cell histiocytosis, IGF2BP3 expression was independent of sex, location, prognosis, and BRAF V600E staining results. Taken together, these results indicate that IGF2BP3 expression may be a helpful marker for distinguishing Langerhans cell sarcoma from Langerhans cell histiocytosis in adult patients.

Successful ixazomib treatment for relapsed and refractory acute myeloid leukemia transformed from myelodysplastic syndrome.

Elevated NF-kB levels have been identified in primitive bone marrow cells from patients with MDS/AML, suggesting NF-kB as a therapeutic target in MDS/AML. We herein describe an MDS patient ineligible for SCT who, following treatment with azacitidine and bortezomib, transformed to leukemia, but maintained complete remission after monotherapy with ixazomib.

Successful Treatment of Incidental Histiocytic Sarcoma Concomitant with Laryngeal Carcinoma.

Histiocytic sarcoma (HS) is an extremely rare non-Langerhans cell disorder with an aggressive course and limited treatment options. HS most often presents at an advanced clinical stage, with a limited response to chemotherapy and high mortality. No standard treatment has been established for HS. We herein describe the first case of HS concomitant with laryngeal carcinoma that was promptly diagnosed and successfully treated; the condition of the patient has remained stable for 4 years with no recurrence.

Neonatal Fc receptor induces intravenous immunoglobulin growth suppression in Langerhans cell histiocytosis.

The neonatal Fc receptor (FcRn) plays a role in trafficking IgG and albumin and is thought to mediate intravenous immunoglobulin (IVIG) therapy for certain diseases. IVIG can be used for the treatment of human Langerhans cell histiocytosis (LCH); however, the mechanism remains unclear. The expression and function of FcRn protein have not been studied in LCH, though the expression of FcRn messenger RNA (mRNA) have been reported. In this report, we confirmed the expression of FcRn in 26 of 30 pathological cases (86.7%) diagnosed immunohistochemically as LCH. The expression was independent of age, gender, location, multi- or single-system, and the status of BRAFV600E immunostaining. We also confirmed the expression of FcRn mRNA and protein in the human LCH-like cell line, ELD-1. FcRn suppressed albumin consumption and growth of IVIG preparation-treated ELD-1 cells, but not of IVIG preparation-untreated or FcRn-knockdown ELD-1 cells. In addition, FITC-conjugated albumin was taken into Rab11-positive recycle vesicles in mock ELD-1 cells but not in FcRn-knockdown ELD-1 cells. IVIG preparation prolonged this status in mock ELD-1 cells. Therefore, ELD-1 recycled albumin via FcRn and albumin was not used for metabolism. Our results increase our understanding of the molecular mechanism of IVIG treatment of LCH.

Invasive solid papillary carcinoma with neuroendocrine differentiation of the breast: a case report and literature review.

BACKGROUND: Solid papillary carcinoma (SPC) of the breast is a rare breast cancer that accounts for less than 1% of all breast cancers. The optimal clinical management of SPC remains controversial. Here, we report a case of invasive SPC with neuroendocrine differentiation in addition to review of the current literature. CASE PRESENTATION: A premenopausal 46-year-old female presented with a mass in her left breast that tended to increase in size over a 10-month period. Mammography and ultrasonography revealed a mass in the left upper-inner quadrant. The resulting images suggested a category 3 breast tumor according to the Breast Imaging Reporting and Data System (BI-RADS). A core needle biopsy (CNB) was performed, and the pathological findings showed a solid papillary pattern and atypical cells suggestive of noninvasive SPC. After a left partial mastectomy and sentinel lymph node biopsy (SLNB), the specimens were sent for histopathological analysis for further investigation. Postoperative pathological findings suggested invasive SPC. Whole-breast radiation therapy and adjuvant hormonal therapy were performed as postoperative treatments. Three years after surgery, multiple lung metastases were detected, and the patient was treated with a gonadotropin-releasing hormone agonist and an aromatase inhibitor. Five months later, multiple liver metastases and bone metastases appeared, and oral 5-fluorouracil was chosen for the subsequent treatment. The patient has been treated for 5 years to date, and she is continuing to take oral 5-fluorouracil and is alive without any further disease progression. CONCLUSIONS: We report a rare case of premenopausal invasive SPC with multiple metastases. Further study is needed to clarify the molecular characteristics and clinical behaviors of SPC and to explore the optimal treatment strategy.

The acquisition of trisomy 8 associated with Behçet's-like disease in myelodysplastic syndrome.

A relationship has been reported between myelodysplastic syndrome (MDS) and autoimmune disease. Behçet's disease is a multisystem inflammatory disorder with mucocutaneous, articular, gastrointestinal, neurological, and vascular manifestations. The co-occurrence of MDS with trisomy 8 and Behçet's-like disease was recently demonstrated. We herein describe a case that shows the relationship between the acquisition of trisomy 8 and occurrence of Behçet's-like disease. Immune dysregulation and altered T-cell hemostasis play an important role in the pathogenesis of Behçet's-like disease and MDS with trisomy 8.

Prediction of response to first-line therapy with ITP by flow cytometric analysis of bone marrow lymphocyte phenotypes.

In the present study, we analyzed phenotypes of cells in the lymphocyte region of bone marrow in 68 patients with primary immune thrombocytopenia (ITP) to determine whether cellular phenotype predicts response to first-line therapy (corticosteroids or corticosteroids plus intravenous immunoglobulin). In 52 newly diagnosed ITP patients, an abnormal CD4:CD8 ratio (CD4/CD8 ratio < 0.4 and 2.3 < CD4/CD8 ratio) was noted in 22 patients in the responder group, whereas all non-responder and control individuals showed normal CD4:CD8 ratio (p < 0.001). The absolute number of CD19+ cells in patients with 0.4 ≤ CD4/CD8 ratio ≤ 2.3 or 2.3 < CD4/CD8 ratio was higher than that in other groups. (p = 0.016). In 16 chronic ITP patients, the absolute number of NK cells in the responder group was lower than those in the non-responder and control groups (p = 0.032). An abnormal CD4:CD8 ratio was noted in all patients in the responder group, whereas all patients in non-responder and control groups showed normal CD4:CD8 ratio (p < 0.001). The present results indicate that CD4:CD8 ratio, B cells, and NK cells contribute to the prediction of therapeutic outcomes of ITP patients.