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.

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.

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.

The association of lymphocyte phenotypes and outcomes after discontinuing eltrombopag in immune thrombocytopenia.

AIM: Eltrombopag is a highly effective treatment for immune thrombocytopenia (ITP). Cases of durable remission after the discontinuation of eltrombopag in adult ITP have recently been reported; however, the frequency and mechanisms responsible for this phenomenon remain unknown. In the present study, we examined the phenotypes of lymphocytes in ITP to clarify whether they predict outcomes after the discontinuation of eltrombopag. METHODS: We analysed 56 adult ITP patients treated with eltrombopag at our hospital between January 2008 and January 2020. Patients' characteristics at the initiation and discontinuation of eltrombopag, the prognostic significance of lymphocytes and other factors were evaluated. RESULTS: A total of 38 patients showed complete response (CR). Eltrombopag was discontinued in 28 of 38 patients who achieved CR. Among the 28 patients, 12 (42.8%) had an immediate relapse after discontinuing eltrombopag and 16 (57.2%) showed sustained response without additional ITP therapy, despite discontinuing eltrombopag, with a median follow-up of 42 months. No significant differences were observed in platelets, the median duration of eltrombopag, the absolute number of T, B and NK cells at the initiation of eltrombopag between patients who sustained response and those who relapsed after discontinuing eltrombopag. However, the number of B and NK cells at the discontinuation of eltrombopag was higher in patients who sustained response than in those who relapsed (P = .022 and P = .012 respectively). CONCLUSIONS: The present results indicate that the absolute number of B (≥0.20 × 109 /L) and NK (≥0.30 × 109 /L) cells at the discontinuation of eltrombopag contributes to the prediction of outcomes.

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.

Effective upfront treatment with low-dose ibrutinib for a patient with B cell prolymphocytic leukemia.

B cell prolymphocytic leukemia (B-PLL) is a rare and aggressive disease that is associated with poor survival. Although initially asymptomatic patients do not require therapy, most patients will progress and inevitably require treatment. More than 50% of patients with B-PLL carry abnormalities in the TP53 tumor suppressor gene and/or complex karyotype and show resistance to conventional chemotherapy. The efficacy of ibrutinib, a B cell receptor inhibitor, for B-PLL with the TP53 abnormality as second-line therapy was recently demonstrated. We herein report that low-dose ibrutinib as upfront therapy induced a complete response in a B-PLL patient with the TP53 abnormality, whose condition has since remained stable with no recurrence for 12 months. Effective treatments for B-PLL are lacking and given its rarity, prospective comparative therapies are not yet available. This case suggests that upfront therapy with ibrutinib improves the outcome of B-PLL.

Successful treatment with brentuximab vedotin for relapsed and refractory adult T cell leukemia.

Although treatments for adult T-cell leukemia/lymphoma in the past two decades have advanced, the current standard treatment for aggressive adult T-cell leukemia/lymphoma, particularly in patients who are not eligible for stem cell transplantation, remains inadequate; therefore, treatments to prolong the duration of remission and provide relevant benefits in terms of survival and quality of life are needed. Adult T-cell leukemia/lymphoma tumor cells express CD30 in some cases and the increased expression of CD30 is considered to be one of the causes of constitutive NF-κB activation in adult T-cell leukemia/lymphoma cells. Brentuximab vedotin represents a major breakthrough in the treatment of CD30-positive lymphomas. Elderly patients treated with chemotherapy generally have higher rates of grade 3 or 4 adverse events; however a retrospective analysis demonstrated the safety and efficacy of brentuximab vedotin in adults ≥60 years with relapsed and refractory CD30-positive lymphomas. We herein report the clinical effects of brentuximab vedotin and the significance of CD30 expression in an elderly refractory/relapse adult T-cell leukemia/lymphoma patient. CD30 expression is associated with disease progression in adult T-cell leukemia/lymphoma patients and brentuximab vedotin may be a new and promising treatment option for these patients. Further investigations on the use of brentuximab vedotin for adult T-cell leukemia/lymphoma are needed.

Clinical effects of CD45 on the prognosis of extramedullary myeloma relapse.

WHAT IS KNOWN AND OBJECTIVES: The incidence of extramedullary relapse (EMR) arising during the clinical course of multiple myeloma (MM) has increased in recent years. Therefore, we herein investigated the effects of immunophenotyping on the prognosis of MM patients with EMR. METHODS: We conducted a retrospective review on data collected from MM patients with EMR between January 2007 and December 2018 at the Japanese Red Cross Society Wakayama Medical Center. Patient characteristics at the diagnosis of EMR, the prognostic significance of immunophenotyping and other factors were evaluated. RESULTS AND DISCUSSION: Extramedullary relapse was detected in 55 of 231 patients (23.8%). At the diagnosis of EMR, CD45, the leucocyte common antigen, was detected in 54.5% of cases. CD45 negativity in bone marrow correlated with thrombocytopenia and higher serum LDH levels. Moreover, high-risk cytogenetics was more frequently observed in CD45- than in CD45+ patients. A univariate analysis showed that overall survival (OS) was significantly shorter in CD45- than in CD45+ patients. Thrombocytopenia, higher serum LDH levels and high-risk cytogenesis were also associated with shorter OS. A multivariate analysis confirmed that CD45 negativity, higher serum LDH levels and high-risk cytogenesis were independent adverse prognostic factors for OS. A Kaplan-Meier analysis revealed the potential of CD45- as a prognostic factor in patients with EMR and that it correlated with shorter survival. WHAT IS NEW AND CONCLUSION: The present results showed that the expression of CD45 in the neoplastic plasma cells of MM patients with EMR was associated with patient prognosis independent of other prognostic factors. The establishment of a treatment strategy for EMR patients with CD45- MM cells is needed to improve poor outcomes.

Successful treatment with pomalidomide and intrathecal injections for central nervous system plasmacytoma in a patient under haemodialysis.

WHAT IS KNOWN AND OBJECTIVES: The involvement of the central nervous system (CNS) in multiple myeloma (MM) is uncommon and has an extremely poor prognosis, and optimal treatment strategies for the CNS MM patients have not yet been established. CASE SUMMARY: A 71-year-old MM patient with severe renal impairment exhibited extramedullary relapse in the CNS and progression while being treated with lenalidomide and dexamethasone. However, she achieved very good partial remission after a treatment with pomalidomide, cyclophosphamide and dexamethasone (PCD) in combination with intrathecal chemotherapy. WHAT IS NEW AND CONCLUSION: This is the first case report to describe MM with CNS involvement in a patient who had responded to PCD under haemodialysis. The combined intrathecal administration of cytotoxic agents and PCD may prolong survival and is tolerated well by patients with severe renal impairment.

Comparison of the Diagnostic Performance of Newly Designed 21-Gauge and Standard 22-Gauge Aspiration Needles in Patients with Solid Pancreatic Masses.

BACKGROUND: Although endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has been widely used for the diagnosis of pancreatic tumors, the ability to obtain adequate pancreatic tumor tissue needs to be improved. AIMS: This study was performed to compare a newly designed 21-gauge needle (EUS Sonopsy CY; Hakko Medical, Nagano, Japan) and a standard 22-gauge needle for tissue sampling of solid pancreatic masses. METHODS: Consecutive patients with solid pancreatic masses who underwent EUS-FNA with either the EUS Sonopsy CY or the 22-gauge needle from June 2014 to December 2016 were enrolled. The primary outcome was comparison of the diagnostic yield of the FNA samples. The secondary outcomes were comparison of technical success, diagnostic ability for malignancy, and complications. RESULTS: A total of 93 patients (40.9% female; mean age, 70.1 years) underwent EUS-FNA with the EUS Sonopsy CY (n = 47) or the standard 22-gauge needle (n = 46). The technical success rate was 100% in both groups, and the overall diagnostic accuracy for malignancy was similar between the groups (100% in the EUS Sonopsy CY group vs. 95.7% in the 22-gauge needle group, P = 0.242). Nevertheless, the EUS Sonopsy CY resulted in significantly higher scores for cellularity (P = 0.006) and lower scores for blood contamination (P < 0.001). The procedure-related complication rate was comparable between the groups (P = 0.148). CONCLUSIONS: The EUS Sonopsy CY provided higher-quality specimens for histological evaluation in terms of both sample cellularity and blood contamination for the diagnosis of solid pancreatic masses. TRIAL REGISTRATION: The study was registered in a clinical trial registry, No. UMIN000032598.

Successful retreatment with lenalidomide for relapsed and refractory multiple myeloma previously treated with bortezomib, lenalidomide and pomalidomide.

WHAT IS KNOWN AND OBJECTIVES: Optimal strategies for treating patients with very advanced relapsed and refractory multiple myeloma (RRMM) have not been clarified. CASE SUMMARY: A 80-year-old patient with RRMM experienced extramedullary relapse following treatment with bortezomib, lenalidomide and pomalidomide. However, he achieved very good partial remission after retreatment with lenalidomide. WHAT IS NEW AND CONCLUSION: This report illustrates that patients with very advanced RRMM can still respond to prior therapy even after being exposed and refractory to several agents. Considering the depth or duration of response to prior treatment, "retreatment" may improve the outcome of frail RRMM.

Macrocystic ductal adenocarcinoma of prostate: A rare gross appearance of prostate cancer.

Macroscopic cyst-formation by prostatic adenocarcinoma, herein referred to as macrocystic prostatic adenocarcinoma (MPA), is extremely rare. To date, no studies of prostate cancer performed based on gross cystic appearance have been reported. MPA can include various diseases, one of which is cystadenocarcinoma. Several cases of ductal adenocarcinoma exhibiting a macrocystic appearance have recently been reported; however, the histological and clinicopathological characteristics of MPAs have yet to be characterized and established. Therefore, we aimed to determine the histological and clinicopathological characteristics of MPA, via a multi-institutional investigation. We discovered five patients with MPA out of 1559 treated patients (0.32%); all cases were ductal adenocarcinomas. MPA was found to have three growth patterns: Two cases showed a prevalence of exuberant papillary proliferation with a fibrovascular core in the macroscopic multilocular cysts. Two others predominantly exhibited multilocular cysts lined by flat epithelium with foci of low papillae, and the fifth had a cystic lesion with intracancerous necrosis. Three of the cases showed extraprostatic invasion; however, none of the patients experienced recurrence during the follow-up period. Each predominant growth pattern tended to exhibit unique clinicopathological characteristics with respect to serum prostate specific antigen level and tumor size and location. In conclusion, we demonstrated that MPA is a ductal adenocarcinoma that is composed of intracystic exuberant papillary proliferation and flat proliferation with foci of low papillae, both of which might exhibit different clinicopathololgical appearances.

Perivascular epithelioid cell tumor of the descending colon mimicking a gastrointestinal stromal tumor: a case report.

BACKGROUND: We present a case of perivascular epithelioid cell tumor (PEComa), which clinically and histologically mimics a gastrointestinal stromal tumor (GIST). CASE PRESENTATION: A 42-year-old woman was found to have a mass in the left flank during her annual medical checkup. Computed tomography examination revealed a submucosal tumor of the descending colon. Surgeons and radiologists suspected that the lesion was a GIST, and left hemicolectomy was performed without biopsy. Microscopic examination showed that the lesion was composed of spindle and epithelioid cells, which were immunohistochemically negative for c-kit and positive for platelet-derived growth factor receptor (PDGFR) α. Initial diagnosis of PDGFRα-positive GIST was made. However, gene analysis did not reveal mutations in PDGFRα. Additional immunohistochemistry showed that tumor cells were positive for human melanin black 45 (HMB45), melanA, and the myogenic marker calponin. A final diagnosis of PEComa was made. CONCLUSION: PEComa should be included in the differential diagnosis of PDGFRα-positive spindle cell tumors in the wall of the gastrointestinal tract.

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.

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.

[A patient with primary breast cancer who responded remarkably well to neoadjuvant chemotherapy with FEC100 followed by Abraxane].

A 49-year-old woman visited our hospital presentind with a right breast lump. She underwent core needle biopsy, and her disease was diagnosed as breast cancer(invasive ductal carcinoma, ER slightly positive, PgR and HER2 negative). We chose neoadjuvant chemotherapy because the tumor size was over 3 cm in diameter with a histological grade III, and she asked to have her breast conserved. Because she had an allergy to alcohol, we treated her with FEC100 followed by Abraxane(260mg/ m2)q3W for 4 courses. After chemotherapy, she received breast conserving therapy. During the treatment with Abraxane, the patient was very well and showed no major side effects except for grade 3 neutropenia was found on an outpatient basis. After chemotherapy, breast MRI detected no invasive lesion. Pathological examination showed pCR. We concluded that Abraxane was a good option as neoadjuvant chemotherapy for early breast cancer.