Hemophagocytic lymphohistiocytosis (HLH) complicating classic Hodgkin lymphoma (HL-HLH) is a rare but frequently life-threatening condition that is strongly associated with Epstein-Barr virus (EBV) infection, particularly in the mixed-cellularity and lymphocyte-depleted subtypes. No consensus has been reached regarding treatment for HL-HLH, and the myelotoxicity induced by etoposide-based HLH-directed therapy precludes its safe addition to intensive lymphoma-directed chemotherapy, particularly in older patients. We here report the case of a male in his early 70s with advanced EBV-positive mixed-cellularity classic Hodgkin lymphoma (CHL) who presented with cervical lymphadenopathy, fever, hepatosplenomegaly, and a markedly elevated soluble interleukin-2 receptor (sIL-2R) level, along with a high peripheral blood EBV DNA load. EBV-encoded small RNA in situ hybridization confirmed EBV positivity in lymphoma cells. His fever was steroid-refractory, and chemotherapy with brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (BV-AVD) was initiated immediately following the diagnosis was confirmed. However, the persistent high fever did not resolve, and progressive cytopenia, marked hyperferritinemia, and further increase in sIL-2R levels were observed. Repeat bone marrow examinations revealed macrophage activation with hemophagocytosis, confirming HLH as a complication. Rituximab was promptly administered, and the fever resolved within 3 days. Furthermore, ferritin, sIL-2R, and lactate dehydrogenase levels substantially declined within 1 week, with peripheral blood EBV DNA becoming undetectable. BV-AVD was continued without major complications and led to a complete response after six cycles. Rituximab may represent a strategically timed and reasonable adjunctive intervention for EBV-driven HL-HLH that is refractory to, or develops following, chemotherapy for CHL.
Although the use of bispecific antibodies for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) is expanding, reports of pseudoprogression following this therapy are scarce. A 58-year-old, male patient with DLBCL achieved a complete response (CR) after fourth-line therapy with lisocabtagene maraleucel. However, 26 months post-infusion, he experienced the development of pelvic lymphadenopathy, which was histologically confirmed as a relapse. Because the disease was refractory to radiotherapy and chemotherapy, epcoritamab was administered as the seventh-line treatment. A fever developing after the second step-up dose (Cycle 1, day 12) was diagnosed as grade 1 cytokine release syndrome and was treated with acetaminophen. Nonetheless, the fever was still present on day 14, when abdominal pain requiring opioid administration also developed. Computed tomography (CT) revealed enlargement of the pelvic lesions and increased ascites. Cytology of the ascites revealed no lymphoma cells and showed a predominantly inflammatory cell composition, while lactate dehydrogenase levels decreased, supporting the diagnosis of pseudoprogression. The treatment was continued and his symptoms gradually improved. After three cycles, positron emission tomography-CT confirmed the complete metabolic response (CMR), which was maintained through nine cycles. The present case highlights the potential for pseudoprogression to occur during epcoritamab therapy, suggesting that continued treatment may lead to durable remission even in patients with early clinical deterioration.
Nodal T-follicular helper cell lymphoma (nTFHL) may present with Hodgkin/Reed-Sternberg (HRS)-like cells and can morphologically mimic classic Hodgkin lymphoma (CHL), although these entities are usually distinguishable. We report an unusual case showing marked morphologic and molecular overlap with CHL, creating a diagnostic challenge but ultimately considered biologically consistent with nTFHL.An 81-year-old woman presented with stage IV disease involving the bone marrow and markedly elevated serum soluble interleukin-2 receptor levels. Excisional lymph node biopsy revealed scattered HRS cells in a T-cell-rich background, with strong CD30 and PD-L1 expression and weak PAX5 positivity, findings consistent with CHL. Fluorescence in situ hybridization demonstrated copy-number alterations at the 9p24.1 locus in HRS cells, further supporting molecular features characteristic of CHL.However, the presence of two T-follicular helper markers, detection of the RHOA p.Gly17Val (G17V) mutation, and oligoclonal T-cell receptor rearrangements with shared peaks in lymph node and bone marrow indicated an underlying nTFHL. The differential therapeutic response also supported a diagnosis of nTFHL, which could not have been established on morphology alone.In this case, although the HRS cells displayed morphological, immunophenotypic, and molecular features highly suggestive of CHL, the biological nature of the lesion was consistent with nTFHL. Compared with previously reported cases of nTFHL with HRS-like cells, this case more closely resembled CHL and may represent a distinct subset best described as "nTFHL with CHL features," a concept warranting greater recognition among pathologists and clinicians.
Acute promyelocytic leukemia (APL) arising during the clinical course of BCR::ABL1-positive chronic myeloid leukemia (CML) is rare and may represent either promyelocytic blast phase or the emergence of an independent Philadelphia chromosome-negative clone. We report an octogenarian man with chronic-phase CML who was intolerant to multiple tyrosine kinase inhibitors and underwent temporary discontinuation of asciminib. During molecular relapse, bone marrow examination revealed 88% abnormal promyelocytes with Auer rods and markedly elevated PML::RARA transcripts, whereas BCR::ABL1 transcript levels were more than 3 logs lower than at CML diagnosis. Conventional cytogenetics demonstrated t(15;17) without t(9;22) as the dominant clone, supporting de novo APL arising independently of the residual CML clone. All-trans retinoic acid plus arsenic trioxide achieved molecular remission of PML::RARA and was followed by an initial marked reduction in BCR::ABL1 transcript levels, which subsequently remained detectable at low levels during continued follow-up. This case highlights the importance of integrated cytogenetic and molecular evaluation to distinguish blast phase from independent leukemogenesis in patients with CML who develop cytopenias.
Diffuse large B-cell lymphoma (DLBCL) can occur at various sites and is rarely diagnosed as synchronous multiple primary malignancies. A treatment approach for this synchronous malignancy has not been established. Here, we report two cases of synchronous DLBCL and gynecological malignancy treated with the paclitaxel and carboplatin (TC) regimen. Patient #1: A 67-year-old female presented with right axillary lymphadenopathy. A computed tomography (CT) revealed a hepatic mass and an ovarian tumor. Biopsy of the lymphadenopathy diagnosed DLBCL (stage I). Ovarian and peritoneal biopsies confirmed ovarian cancer (stage IVB, peritoneal dissemination, and liver metastasis). She received 6 cycles of TC chemotherapy for ovarian cancer, followed by surgery (pT3cN0M1) and an additional 2 cycles of TC. A complete metabolic response (CMR) of both malignancies was confirmed 1 year later. Patient #2: A 77-year-old female presented with left knee discomfort. Biopsy of a left femoral tumor diagnosed DLBCL (stage I). PET-CT revealed abnormal fluorodeoxyglucose uptake in the left femur and in the uterus, with an endometrial biopsy confirming endometrial cancer. She received radiation therapy for DLBCL, followed by surgery for endometrial cancer (pT1bNxM0). Postoperatively, 6 cycles of TC chemotherapy were performed, and she achieved a CMR. No Grade 3/4 nonhematologic adverse events were observed in both patients. In conclusion, the TC regimen was safely administered in our two patients. In one of them, TC therapy alone was effective for DLBCL. The clinical courses may provide a valuable reference for the management of similar patients.
Histiocytic sarcoma (HS) is a rare, aggressive malignant neoplasm characterized by histiocytic features, frequently presenting in advanced clinical stages and associated with a poor prognosis. Although HS can occur sporadically or secondary to other hematological malignancies, cases with a long latency period have been rarely reported. This case report presents a unique case of secondary HS diagnosed 33 years and seven months after the initial diagnosis of B-cell precursor acute lymphoblastic leukemia. Both neoplasms shared identical immunoglobulin heavy chain and T-cell receptor gene rearrangements, confirming a clonal relationship. To the best of our knowledge, this case represents the longest reported interval between primary leukemia and secondary HS, highlighting the potential for lineage switching and transformation over extended periods. These findings underscore the need for ongoing research on the mechanisms underlying "transdifferentiation", including the roles of transcription factors, cytokine signaling, and epigenetic modifications.
Plasmablastic lymphoma (PBL) is a rare and aggressive subtype of B-cell lymphoma associated with immunodeficiency and Epstein-Barr virus (EBV) infection. Although PBL can develop from indolent lymphomas, its occurrence long after diffuse large B-cell lymphoma (DLBCL) is rare. A 67-year-old man was diagnosed with EBV-positive DLBCL 17 years ago and achieved a sustained remission following six cycles of R-CHOP therapy. Seventeen years after the initial DLBCL diagnosis, the patient developed PBL with EBV-positive tumor cells. After three cycles of EPOCH therapy, the patient achieved a partial response and underwent upfront autologous stem cell transplantation, resulting in complete remission. To investigate the clonal relationship between DLBCL and PBL, immunoglobulin gene repertoire analysis using next-generation sequencing was performed on both specimens. In the PBL specimen, immunoglobulin heavy chain rearrangement revealed a dominant clone with a complementarity-determining region 3 (CDR3) length of 38 amino acids. Although the DLBCL specimen lacked a dominant clone meeting the clonality criteria, a minor clone with a CDR3 sequence similar to that of the PBL dominant clone was detected. This clone exhibited an unusually long CDR3 sequence (37 amino acids), likely contained stop codons, and was considered a nonfunctional clone. These findings suggest that PBL originated through expansion of a pre-existing minor subclone that persisted since the initial DLBCL diagnosis, driven by long-term clonal dynamics. Our case highlights the potential utility of immunoglobulin repertoire analysis in identifying clonal relationships among lymphomas, supporting treatment decisions, and understanding the pathogenesis of secondary lymphomas.
Follicular lymphoma (FL) is an indolent B-cell non-Hodgkin lymphoma characterized by a relapsing clinical course. Recently, CD20×CD3 bispecific antibodies, including mosunetuzumab, have emerged as effective therapeutic options for relapsed or refractory FL. However, their efficacy in malignant effusions, including pleural effusion, remains unclear. We report a case of relapsed FL complicated by chylothorax that showed a rapid response to mosunetuzumab. A 74-year-old woman with a history of FL, initially treated with R-CHOP and later with rituximab monotherapy, presented with progressive dyspnea and was found to have bilateral pleural effusion. Analysis of pleural fluid revealed chylothorax with infiltration of CD20-positive lymphoma cells, confirmed by flow cytometry and cell-block immunohistochemistry. Following initiation of mosunetuzumab, pleural effusion decreased promptly, with a marked reduction in lymphoma cells in the pleural fluid observed as early as day 2. The patient achieved a complete metabolic response on positron emission tomography-computed tomography (PET-CT) after eight cycles of therapy. This case suggests that mosunetuzumab may exert rapid antitumor activity in both systemic disease and malignant effusions, possibly through distribution into pleural fluid and subsequent T-cell-mediated cytotoxicity. Further studies are warranted to clarify the role of bispecific antibodies in malignant effusions associated with lymphoma.
We report a case of adult T-cell leukaemia/lymphoma (ATLL) that exhibited different pathological subtypes within a single lymph node. The patient was a 76-year-old Japanese man who presented with decreased appetite and anemia, and a thorough examination was conducted. A peripheral blood analysis and imaging studies, including ultrasound and computed tomography, suggested malignant lymphoma, and cervical lymph node biopsy was subsequently performed. In the excised lymph node, the normal architecture was completely effaced, and areas showing the dense proliferation of pleomorphic atypical lymphocytes-consistent with the most common histology of ATLL (pleomorphic cell variant)-were identified. Regions exhibiting features reminiscent of classic Hodgkin lymphoma and others resembling angioimmunoblastic T-cell lymphoma were also observed. Serological testing was positive for human T-lymphotropic virus type 1 antibodies, and together with histological findings, this case was diagnosed as ATLL. To the best of our knowledge, there have been no cases exhibiting different histological patterns within a single lymph node.
To clarify the karyotype evolution of multiple myeloma (MM), multiple karyotypes of 22 patients with MM were analyzed using G-banding, and their karyotype evolutions were depicted as phylogenetic trees. Eleven patients exhibited highly complex karyotype evolutions, combining branched evolution, linear evolution, parallel evolution and macroevolution. While chromosomal structural abnormalities involving 14q32 were detected at the roots of the phylogenetic trees of karyotype evolution, aneuploidies and the other structural abnormalities were identified in both the initial clones and karyotypically evolved subclones. The findings indicated that aneuploidies might be caused by unequal chromosomal segregation, loss of the chromosome with unbalanced whole-arm translocation, and whole-chromosome doubling in patients with near-tetraploidy. Four patients had karyotype abnormalities (three del(20)(q) and one del(5)(q)) associated with myelodysplastic syndrome independent of the karyotype evolution of MM. In conclusion, the phylogenetic trees depicted by G-banding present the karyotype evolution of MM.
We report a case of Hodgkinoid histiocytosis (HH) with protracted skin manifestations. A 72-year-old Japanese woman presented with fever of unknown origin, lymphadenopathy, eosinophilia, and a generalized pruritic and erythematous maculopapular rash. Biopsy of an inguinal lymph node indicated a proliferation of large cells with clear cytoplasm, mimicking Hodgkin lymphoma (HL). Immunohistochemical analysis showed that the Hodgkin-like cells were positive for S-100 protein and CD30 but negative for langerin, CD20, PAX5, and CD3. The cells were also positive for PD-L1. The histological findings were similar to those of HL; conversely, immunohistochemical results suggested a histiocytic/dendritic cell origin. Therefore, the patient was diagnosed with HH. Systemic corticosteroid therapy markedly improved her systemic manifestations; nonetheless, cutaneous symptoms persisted. Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) was suspected because of the prolonged cutaneous manifestations, and the diagnostic criteria for these conditions were fulfilled. Discontinuation of the culprit drug resulted in the remission of cutaneous symptoms. Because lymph node lesions in DIHS/DRESS also demonstrate HL-like histology, this case suggests that HH, while a novel and distinct histiocytic/ dendritic cell disorder, may be associated with lymph nodal lesions occurring in the context of DIHS/DRESS.
Primary gastrointestinal lymphoma accounts for only 1-4% of all gastrointestinal malignancies, yet the gastrointestinal tract is the most common extranodal site of non-Hodgkin lymphoma, comprising 10-15% of all non-Hodgkin lymphomas. Among these, diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue lymphoma frequently affect the stomach and small intestine. Protein-losing enteropathy associated with malignant lymphoma is exceedingly rare, particularly when caused by CD5-positive DLBCL. We report the case of a 60-year-old woman with a four-year history of refractory diarrhea and progressive lower extremity edema, ultimately diagnosed with CD5-positive DLBCL of the small intestine. Diagnostic workup revealed hypoproteinemia with significant protein leakage in the ascending colon and distal small intestine. Double-balloon endoscopy demonstrated shallow, wide ulcers with patchy whitish exudates, and histopathology confirmed a diagnosis of de novo CD5-positive DLBCL. Chemotherapy with rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH-R) led to prompt improvement in serum albumin levels and resolution of the protein-losing enteropathy. Subsequent high-dose chemotherapy with autologous stem cell transplantation has maintained remission. Given the rarity of this presentation and its strong similarity to a previously reported case of CD5-positive DLBCL with protein-losing enteropathy, we propose that this might represent a distinct clinical entity.
Cold agglutinin disease (CAD) is an autoimmune hemolytic anemia triggered by exposure to cold. Primary CAD, defined as CAD not associated with malignant neoplasms or infections, has recently been recognized as a monoclonal B-cell lymphoproliferative disorder in the fifth edition of the World Health Organization Classification of Tumors: Hematolymphoid Tumors. This study aimed to clarify the clinicopathologic spectrum of primary CAD in a Japanese cohort through comprehensive clinicopathologic and molecular analyses. Twenty-one patients were clinically diagnosed with CAD, of whom eight were classified as having cold agglutinin syndrome (CAS) due to underlying conditions such as infections or neoplasms. The remaining 13 patients underwent detailed histologic and molecular evaluation and were stratified into three groups: Group 1, four patients with clinicopathologic features consistent with primary CAD; Group 2, six patients showing overlapping features with other indolent B-cell lymphomas; and Group 3, three patients in whom tumor cells were scarcely detectable histologically. Based on integrated clinicopathologic and molecular findings, nine patients (69%) were ultimately classified as having primary CAD, including all Group 1 patients, four from Group 2, and one from Group 3. These findings highlight the diagnostic challenges of primary CAD, even after exclusion of CAS-associated underlying conditions by standard clinical evaluation, and demonstrate that primary CAD encompasses a heterogeneous clinicopathologic spectrum. Our results suggest that further refinement of the current diagnostic criteria for primary CAD may be warranted.
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of methotrexate-associated lymphoma arising in immune deficiency/dysregulation (MTX-associated IDD-DLBCL) among rheumatoid arthritis patients treated with MTX and is characterized by frequent spontaneous regression (SR) after MTX withdrawal. However, some patients do not achieve SR and have poor outcomes. Epstein-Barr virus (EBV) infection correlates with frequent SR but does not fully explain clinical heterogeneity. We investigated prognostic factors irrespective of EBV infection status. We analyzed 21 MTX-associated IDD-DLBCL cases applying the nCounter PanCancer Immune Profiling Panel and immunohistochemistry (IHC) to identify predictors of non-SR cases. Ten patients were classified as SR and 11 as non-SR. Gene expression profiling revealed higher expression of CD83, ICOSLG, IL21R, BCL6, CD40, PAX5, CXCR5, CD79A, DMBT1, and TNFRSF13C in non-SR cases. We therefore focused on CD83, which showed the highest fold change and the most significant P value among these markers. Although CD83 is reported to be a surface marker of mature dendritic cells, IHC analysis revealed that CD83 was more frequently expressed on tumor cells than on dendritic cells. High CD83 IHC positivity (≥15%) in tumor cells correlated with mRNA levels and predicted non-SR after MTX withdrawal. Multivariate analysis identified CD83 IHC high expression as an independent predictor of non-SR cases. High CD83 expression is an independent prognostic factor in MTX-associated IDD-DLBCL, and combined evaluation may refine risk stratification and guide clinical decisions.
Tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, was approved in Japan in August 2020 for the treatment of Waldenström's macroglobulinemia (WM) and lymphoplasmacytic lymphoma (LPL). We report the findings of post-marketing surveillance (PMS) of tirabrutinib that was started following its approval. We conducted an all-case PMS of patients who started tirabrutinib treatment between August 21, 2020, and January 17, 2021, for WM/LPL in Japan. Safety and effectiveness data were recorded for up to 52 weeks after the first dose of tirabrutinib. Among 152 patients who started tirabrutinib, 67.1% were male, 77.6% were ≥ 65 years old, and 61.8% started treatment with tirabrutinib at 480 mg/day (once-daily). Among these 152 patients, any-grade and grade ≥ 3 adverse drug reactions (ADRs) occurred in 58.6% and 29.6% of patients, respectively. The main ADRs were platelet count decreased (9.2%) and rash (9.2%). Grade 5 ADRs were reported in four patients (2.6%). The outcomes of most ADRs associated with the safety specifications (myelosuppression, infections, interstitial lung diseases, clinically significant skin disorders, hemorrhages, hepatic function disorders, and hypersensitivities) were resolved or improved. The effectiveness was assessed by the physicians using the VIth International Workshop for Waldenström's Macroglobulinemia criteria. Among 85 patients (initial dose: 480 mg/day) included in the effectiveness analysis set, the major response and overall response rates were 63.5% and 74.1%, respectively. This PMS suggested that the safety profile of tirabrutinib for patients with WM/LPL in real-world clinical settings is in line with that observed in prior studies.
Hematological malignancy (HM) is developed in 2-6% patients with primary mediastinal germ cell tumor (MGCT). Symptoms of HM associated with MGCT usually appear after diagnosis of MGCT. Patients with MGCT underlying HM have poor prognosis. We report an extremely rare autopsy case of simultaneous presentation of MGCT, myelodysplastic neoplasm (MDS) with low blasts, and myeloid sarcoma (MS). A 27-year-old man presented with intermittent fever, general fatigue, and cough. Computed tomography revealed 11 cm mass in anterior mediastinum, hepatosplenomegaly, and gastric, pericholedochal, and mesenteric lymphadenopathies. The mass compressed the left pulmonary artery. Laboratory examination revealed thrombocytopenia (59,000 /mm3). Serological tests revealed elevated alpha-fetoprotein 7,219 ng/mL and human chorionic gonadotropin 899 IU/L. Bone marrow aspiration smear showed presence of micromegakaryocytes and blast count of 1.2%. G-banding detected monosomy 13 and complex karyotype. The autopsy revealed that MGCT was mainly composed of teratoma and also included yolk sac tumor, seminoma, and choriocarcinoma components. Transformation to acute myeloid leukemia was not observed in the bone marrow but CD33 and MPO-positive immature myeloid blasts proliferated in the lymph nodes, liver, spleen, and small intestine. Loss of p53 expression was observed in bone marrow and extramedullary immature myeloid blasts. Next gene sequencing detected TP53 c.919+3del splice site variant and KRAS N116H. It is important to consider HMs when extramediastinal lesions or thrombocytopenia appear in patients with MGCT.
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the management of relapsed/refractory large B-cell lymphoma. However, evidence in the ultra-elderly population remains scarce. We report a 90-year-old woman with relapsed/refractory diffuse large B-cell lymphoma transformed from follicular lymphoma who received lisocabtagene maraleucel. Despite advanced age, preserved cognition, intact instrumental activities of daily living, and acceptable organ reserve supported her candidacy for CAR T-cell therapy. Cytokine release syndrome (CRS) developed as grade 1 (day 1, 38.0 °C) and grade 2 (day 3, hypoxemia to 6 L/min), which resolved after early tocilizumab and dexamethasone. No immune effector cell-associated neurotoxicity syndrome or infectious complications occurred. Grade 2-4 cytopenia persisted transiently but was managed with supportive care, and she was discharged on day 28. To our knowledge, this represents the first reported case of a nonagenarian Asian patient successfully treated with CAR T-cell therapy, highlighting the feasibility and tolerability of this approach and emphasizing the importance of geriatric assessment and prompt CRS management for safe delivery in the very elderly.
