Cholesterol uptake via LDL receptor (LDLR) is increased in some malignant tumors, and incorporated LDL contribute to lipid droplet formation. Burkitt’s lymphoma is known to have a large number of vacuoles in the cytoplasm, however, intracellular vacuoles are also seen in high-grade lymphomas such as adult T-cell leukemia/lymphoma, diffuse large B-cell lymphoma and primary central nervous system lymphoma. Recent studies have shown that esterified cholesterol is the main component of these vacuoles and the expression of cholesterol metabolism-related molecules such as LDLR, acetyl-CoA acetyltransferase 1 (ACAT1) which esterifies free cholesterol, and scavenger receptor class B type I (SR-BI) which effluxes free cholesterol, was significantly upregulated in lymphoma cells. Moreover, negative feedback of LDLR was not regulated even under cholesterol-rich conditions in lymphoma cells. We found that cytoplasmic free cholesterol was increased by ACAT and SR-BI inhibitors (CI-976 and BLT-1, respectively), and the accumulation of free cholesterol induced lymphoma cell apoptosis. In addition, overexpression of lipid droplet surface proteins has been correlated with poor prognosis in several malignant tumor such as ovarian cancer and clear cell renal cell carcinoma, and it is important to evaluate lipid droplet formation in malignant tumors including lymphomas.

It is difficult to histologically differentiate extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) from chronic gastritis (CG)/ reactive lymphoid hyperplasia (RLH). To determine whether immunohistochemistry for IRTA1 and MNDA can differentiate gastric MALT lymphoma from CG/RLH, we investigated 81 stomach biopsy specimens [Wotherspoon grade (WG) 1, 11 cases; WG 2, 9 cases; WG 3, 20 cases; WG 4, 31 cases; and WG 5, 10 cases]. According to a previously reported algorithm involving PCR for immunoglobulin heavy (IgH) chain locus rearrangement, all 81 cases were divided into three groups: CG/RLH (55 cases), MALT lymphoma (19 cases) groups, and IgH undetectable group (7 cases). We analyzed the CG/RLH and MALT lymphoma groups. The median percentage of IRTA1-positive cells was 0% (range 0%–90.6%) in the CG/RLH group and 43.5% (range 0%–97.6%) in the MALT lymphoma group (p < 0.0001). The median percentage of MNDA-positive cells was 32.4% (range 0%–97.6%) in the CG/RLH group and 55.1% (range 0%–97.6%) in the MALT lymphoma group (p = 0.0044). These results indicate that immunohistochemistry for IRTA1 and MNDA can help differentiate gastric MALT lymphoma from CG/RLH.

The cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) regimen, containing doxorubicin (DXR), which is a key drug for aggressive non-Hodgkin lymphoma (NHL), is a standard chemotherapeutic regimen; however, its administration in elderly patients is often intolerable. Pirarubicin (tetrahydropyranyl adriamycin [THP]) is an anthracycline developed in Japan. We have conducted a phase II trial of a full-dose THP-COP (modified CHOP regimen with DXR replaced by THP) regimen for elderly patients with newly diagnosed, advanced-stage, aggressive NHL. Patients aged 70–79 years old with previously untreated NHL according to the Working Formulation (D through H and J), disease stage I with a bulky mass or stage II–IV, and performance status of 0–1 were eligible. The THP-COP regimen, which consisted of 750-mg/m² cyclophosphamide, 50-mg/m² THP, 1.4-mg/m² vincristine (capped at 2.0 mg) on day 1, and 100-mg prednisolone daily on days 1 to 5, was delivered every 3 weeks for 6 cycles. The primary endpoint was complete response (CR) rate. Twenty-nine patients were enrolled in the study. The CR rate was 65.5% (95% confidence interval, 45.7–82.1%). The 3-year failure-free and overall survival rates were 54.1% and 53.9%, respectively. The most frequent observed grade 3 or 4 toxicity was neutropenia, which occurred in 80% of the patients. Grade 3 cardiac dysfunction was observed in one patient. The full-dose THP-COP regimen exhibited similar efficacy and safety, and a tendency for less cardiac toxicity, when compared with the standard CHOP regimen in elderly Japanese patients with newly diagnosed, advanced-stage, aggressive NHL.

Bone marrow necrosis (BMN) occurs most frequently in hematological malignancies and sometimes in non-hematological disorders. Lymphoid diseases causing necrosis are regarded as high-grade disease. B-lymphoblastic leukemia/lymphoma is the most common malignant cause of BMN. Here, we present two patients with follicular lymphoma (FL) and MYC gene abnormalities who developed BMN. In one case of BMN, the necrosis disappeared in response to chemotherapy, and the patient survived with complete remission. In the other case, BMN remained even after chemotherapy, and effective chemotherapy could not be administered due to suppressed hematopoiesis, which led to the lymphoma worsening and the patient’s death. Indolent lymphomas, such as FL, as in these cases, have the potential to develop BMN. It is important to detect the development of BMN and administer chemotherapy early to improve patient prognosis, since severe BMN prevents patients from receiving effective treatment.

Autoimmune pancytopenia is rarely seen with Hodgkin lymphoma, and only one pediatric case of pancytopenia after autologous hematopoietic stem cell transplantation (HSCT) has been reported. We herein report a case of autoimmune pancytopenia that developed after autologous HSCT for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). A 56-year-old Japanese woman underwent autologous HSCT for NLPHL. She developed autoimmune pancytopenia seven months after autologous HSCT. In this case, PSL was effective, and the blood cell counts normalized completely. However, the patient suffered from a fatal infection, probably because of immunosuppression caused by prolonged administration of PSL, as well as a history of several chemotherapies and autologous HSCT. To our knowledge, this is the first adult case of autoimmune pancytopenia after autologous HSCT for Hodgkin lymphoma. To further validate the optimal treatment strategy for autoimmune cytopenia after autologous HSCT, more cases are necessary.

In the 2016 update of the World Health Organization (WHO) classification of myeloid neoplasms, acute undifferentiated leukemia (AUL) was defined by a lack of lineage-specific markers. AUL has very poor prognosis and no established therapies due to its rarity. We report a case of a 31-year-old man with AUL who showed complete molecular response to an acute lymphoblastic leukemia (ALL)-based regimen and received allogeneic hematopoietic stem cell transplantation. The patient’s blast cells were CD7-positive and localized to lymph nodes in the neck and to a large mediastinal mass; there was also rearrangement of the T-cell receptor delta locus. Although the tumor showed characteristics of T-cell lymphoblastic lymphoma, it was categorized as AUL based on WHO classification. This case suggests that a high-intensity conditioning regimen could be effective for rare cases of AUL that present only in the extramedullary mass, and chemotherapy for AUL should be selected based on the characteristics of the blasts.

We report a patient with sarcoidosis who developed diffuse large B-cell lymphoma. A 71-year-old woman with persistent cough was diagnosed pathologically with sarcoidosis by resection of the right upper lung lobe with a nodule after an unsuccessful attempt of transbronchial needle aspiration for mediastinal lymphadenopathy. She was referred for an eye examination and found to have spotty retinal degeneration on the lower fundi of both eyes, together with residual macular edema and vitreous opacity in the left eye. At 76 years, she underwent cataract surgery and vitrectomy to gain a visual acuity of 0.6 in the left eye. At 77 years, she developed a cough and fever, and showed leukopenia and thrombocytopenia. Computed tomography showed multiple small nodular lesions in both lungs, and bilateral hilar, mediastinal, and hepatic lymphadenopathy. Fluorodeoxyglucose positron emission tomography demonstrated high uptake in the liver, spleen, pancreatic head, and lymph nodes. Bone marrow biopsy was intact, but liver biopsy revealed anomalous large lymphoid cells in the sinusoids which were positive for CD20 and showed a high Ki-67 index, leading to the diagnosis of diffuse large B-cell lymphoma. Chemotherapy with 8 courses of THP-COP (cyclophosphamide, pirarubicin, vincristine, and prednisolone) with rituximab, followed by intrathecal injection of methotrexate, cytarabine, and dexamethasone, resulted in complete remission. She maintained complete remission for 10 years until 88 years old at present. The literature review found 30 patients, including this case, who developed lymphoma in the course of sarcoidosis. A novel pathological diagnosis is required in the setting of acute symptomatic changes and novel lesions on imaging in patients with sarcoidosis.

Richter’s syndrome (RS) of the central nervous system (CNS) is known to have an extremely poor prognosis. Ibrutinib has been reported to have some activity in patients with RS, despite its poor prognosis. Although ibrutinib crosses the blood-brain barrier, its efficacy in RS patients with CNS involvement remains unknown. Here, we report a case of RS isolated in the CNS that was confirmed to be clonally related to chronic lymphocytic leukemia (CLL) by immunoglobulin heavy chain gene analysis. Although the median survival of patients with RS clonally related to CLL was significantly shorter than that of patients with RS clonally unrelated to CLL, the patient received ibrutinib monotherapy without experiencing any significant adverse events, and the disease remained stable with ibrutinib until 6 weeks later. Following whole-brain radiation therapy (40 Gy in 20 fractions) with dexamethasone, the patient has survived for five months after diagnosis. Thus, ibrutinib may be a safe and effective therapeutic option for patients with RS and CNS involvement.

We describe two patients with primary diffuse large B-cell lymphoma of the central nervous system (PCNS-DLBCL). The first patient (case 1) was a woman in her late 70s who presented with a tumor in the left frontal lobe, whereas the second patient (case 2) was a man in his early 70s who presented with a left frontal lobe tumor associated with intratumoral hemorrhage. The histopathology of the tumor specimen disclosed the proliferation of large cells with centroblastic (case 1) or immunoblastic/plasmablastic (case 2) cytomorphology and an accumulation of the tumor cells within the perivascular space. The cells in both cases were positive for CD20, CD79a, BCL6, IRF4/MUM1, MYC, and BCL2 and negative for CD5 and CD10. G-banding revealed t(8;14)(q24;q32) in case 1, and the tetraploid-range karyotype including two or three copies of der(3)t(3;14)(q27;q32) and der(14)t(3;14)(q27;q32) in case 2. Fluorescence in situ hybridization applied to metaphase spreads confirmed colocalization of MYC and IGH (case 1) and BCL6 and IGH (case 2) hybridization signals on the relevant derivative chromosomes. Case 1 carried the MYD88^L265P mutation. This case report provides clear evidence for the occurrence of t(8;14)(q24;q32) and t(3;14)(q27;q32) in PCNS-DLBCL using metaphase-based cytogenetic analysis.

In this study, we examined a cohort of Japanese patients with acute myeloid leukemia (AML) with cup-like nuclei. In particular, we attempted to provide a detailed definition of the clinical features of AML with cup-like nuclei. The clinical records of patients diagnosed with de novo AML were collected retrospectively. We showed that approximately 23% of all patients with AML diagnosed during the study period had AML with cup-like nuclei. All three cup-like AML cases had FLT3-ITD mutations. In addition, we reported a high incidence of disseminated intravascular coagulation and acute cerebral infarction in patients with AML with cup-like nuclei. Our results show that AML with cup-like nuclei may be more common than expected. Due to these unique characteristics, recognition of this morphology is recommended.

Histiocytic sarcoma (HS) is a rare malignancy showing morphologic and immunophenotypic features of histiocytes. HS has morphologic overlap with many other diseases, including various kinds of lymphomas. Gray zone lymphoma (GZL) is a rare B-cell lymphoma subtype characterized by overlapping features between diffuse large B-cell lymphoma and classic Hodgkin lymphoma. The histologic overlap with other diverse diseases of HS and the pathological diversity of GZL make it difficult to render a diagnosis. A 44-year-old woman who was initially diagnosed with HS was diagnosed with GZL after reexamination, including a genetic alteration test. After 6 cycles of brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine, she achieved a complete response. Genomic alteration assessment may be useful for the accurate diagnosis of malignant lymphomas, which are difficult to diagnose, such as GZL.

We describe two follicular lymphoma (FL) patients with MYC/BCL2 double- and MYC/BCL2/BCL6 triple-hit translocations. The first patient (case 1) was a man in his 30s who presented with stage IV disease with leukemic manifestation. The second patient (case 2) was a man in his 60s who presented with relapsed FL, but his disease was in a limited stage. Histopathology of the lymph node biopsies revealed grade 3A FL in both cases. MYC positivity and the Ki-67–labeling index were 60–70 and 20% in case 1 and 30 and 50% in case 2, respectively. G-banding revealed t(8;14;18)(q24;q32;q21) in both cases and fluorescence in situ hybridization using MYC, IGH, and BCL2 break-apart probes confirmed t(8;14;18)(+5′BCL2,−3′MYC;+3′MYC,−5′IGH;+5′IGH,−5′BCL2). In case 2, additional materials of der(8)t(8;14;18) were duplicated and translocated to chromosome Y, and t(3;16)(q27;p13)/BCL6::CIITA was identified. We obtained BCL2-major breakpoint region::IGHJ5::IGHG1 and MYC exon 2::IGHA2 fusion sequences by long-distance polymerase chain reaction in case 1, and proposed that t(8;14;18) was generated by two-step translocations and that BCL2::IGH and MYC::IGH involved the same IGH allele. Both patients responded to the standard chemotherapy for FL. We suggest that the presence of t(8;14;18) in FL does not immediately indicate high-grade transformation and aggressive clinical behavior requiring intensive chemotherapy.

3q27 chromosomal translocation involving the BCL6 gene is one of the most frequent forms of cytogenetic abnormality observed in B-cell lymphoma. We report a case with diffuse large B-cell lymphoma (DLBCL) presenting dual 3q27 translocations. The patient was a 71-year-old man who presented with swelling of multiple abdominal lymph nodes (LNs) and obstructive jaundice. LN biopsy exhibited dense proliferation of atypical large cells expressing CD20, MUM1/IRF4, BCL2, BCL6, and MYC, but not CD10. He was diagnosed with non-GCB/ABC type DLBCL and showed an initially good response to R-CHOP chemotherapy, but relapsed soon after the completion of therapy. Chromosomal analysis of the biopsied LN exhibited multiple abnormalities including t(3;14)(q27;q32) and t(3;22)(q27;q11). Fluorescence in situ hybridization (FISH) using BCL6 break-apart probes confirmed chromosomal breaks occurring on both BCL6 alleles. Molecular analysis revealed two independent rearrangements of BCL6, either with the IGH or the IGL gene. 3q27 breakpoints were located 1.2kb apart from each other within the first intron of BCL6, while the IGH and IGL breaks occurred at the 5’ of IGHG2 and within IGLV3-1, respectively. The results suggest that biallelic BCL6 rearrangements might be a rare but recurrent genetic event in B-cell lymphoma.

Lymphoplasmacytic lymphoma (LPL) usually involves bone marrow (BM) and sometimes lymph nodes and spleen. LPL presenting as a hepatic mass lesion is extremely rare, with only one case reported in the English literature. A 70-year-old Japanese female presented to us with a right hypochondriac mass with tenderness. Computed tomography (CT) revealed a 14 cm-sized bulky hepatic mass. Laboratory findings showed a normal white blood cell count of 4.1×10⁹/L with 4% plasmacytoid lymphocytes; normocytic anemia, Hb 9.4 g/dL; high soluble IL-2 receptor level, 2,290 U/mL; and elevated IgG, 10,306 mg/dL. Furthermore, IgG-κ monoclonal protein was detected. ¹⁸F-fluorodeoxyglucose-positron emission tomography/CT revealed abnormal uptake in the liver mass; left supraclavicular, parasternal, abdominal, and left inguinal lymph nodes; and bilateral lung bases. Magnetic resonance imaging showed no bone lesions. BM aspiration and liver biopsy showed predominant infiltration of small lymphocytes admixed with plasmacytoid lymphocytes and plasma cells. In the liver specimen, lymphoepithelial lesions were not observed. The small lymphocytes were positive for CD20, CD79a, and bcl-2, and negative for CD5, CD10, cyclin D1, and IRTA1; plasma cells in BM were positive for CD19, CD45, IgG, and κ-chain, and negative for CD20, and CD56. MYD88 L265P mutation, reported in approximately 40% of non-IgM LPL cases, was not detected in the liver specimen and BM cells. The frequency is lower than that of typical IgM LPL. These findings led us to a diagnosis of LPL with IgG-κ paraproteinemia. The patient underwent four courses of R-CHOP and two courses of Bendamustine-R. Partial remission was achieved.