Histiocytic neoplasms (HNs) include juvenile xanthogranuloma, Erdheim-Chester disease, Rosai-Dorfman disease, ALK-positive histiocytosis, and histiocytic sarcoma in the 5th edition of the World Health Organization Classification of Haematolymphoid Tumours. These entities are clinicopathologically distinctive, and typical histological findings have been established. However, the common feature of a proliferation of histiocytic cells often leads to morphological overlap among HNs, and also necessitates a differential diagnosis from several non-HNs or non-neoplastic conditions. In this review, we provide a brief summary of the clinical findings, molecular features, histopathologies, and immunophenotypes of HNs, as well as to discuss their differential diagnosis.

The interaction between cancer cells and stromal cells contributes to the pathogenesis of various types of tumors in the tumor microenvironment (TME). Macrophages (Mφs), a type of stromal cell, are transformed into tumor-associated Mφs (TAMs) after integrating within solid tumors. TAMs are known to interact with cancer cells and induce tumor progression. Thus, the cancer cells construct an organ-specific TME, which is advantageous for the survival of cancer cells in the TME. The density of stromal cells is known to be involved in the prognosis of patients with lymphomas. A higher density of stromal cells increases the interaction between lymphoma cells and stromal cells, promoting lymphoma progression. This review focuses on stromal cells in lymphoid tissues, such as TAMs, fibroblastic reticular cells (FRCs), and follicular dendritic cells (FDCs). This review also focuses on the signal transduction caused by stromal cells and tumor cells via factors such as cytokines. IL-10 and other cytokines secreted by TAMs activate the JAK/STAT pathway in lymphoma cells of follicular lymphoma, classic Hodgkin lymphoma, and diffuse large B-cell lymphoma. FRCs play roles in tumor promotion in follicular lymphoma and diffuse large B-cell lymphoma. Cytokines/chemokines secreted by FDCs play essential roles in lymphoma cell survival, proliferation, invasion, and migration in follicular lymphoma. In conclusion, TAMs, FRCs, and FDCs play crucial roles in the TME of lymphomas. Furthermore, histological spatial analysis revealing the positional relationship of each cell could highlight lymphoma-stromal interactions.

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HDC/ASCT) has been useful in relapsed or refractory classic Hodgkin lymphoma (RRcHL). Furthermore, a ranimustine, cytarabine, etoposide, and cyclophosphamide (MCVAC) conditioning regimen has been effective in diffuse large B-cell lymphoma. However, limited data are available regarding this conditioning regimen for cHL. In this study, we investigated the efficacy and toxicity of MCVAC for RRcHL. We retrospectively analyzed 10 patients with RRcHL who underwent ASCT preceded by the MCVAC conditioning regimen between January 2009 and December 2021 at our institution. A total of 10 patients (median [range] age, 36 [23–64] years), including 5 (50%) men and 5 (50%) women, were treated with the MCVAC regimen followed by ASCT. The median follow-up duration of the 10 patients was 25.0 months. The 36-month PFS and OS rates were 43.8% (95% CI, 11.9%–72.6%) and 64.0% (95% CI, 22.6%–87.5%), respectively. Two patients died because of treatment-related factors, and one patient died because of disease progression. Based on our findings, recognizing the risk factors for adverse events (AEs) associated with this treatment, MCVAC may be a valid treatment option for the management of RRcHL.

Kikuchi-Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenitis, is a rare condition characterized by benign localized lymphadenopathy and clinical symptoms such as fever, sore throat, odynophagia, and leukopenia. Though the etiology of KFD is unknown, this condition is similar to viral infection, including increased infiltration of activated plasmacytoid dendritic cells. KFD exhibits three histological phases that reflect its progression status: proliferative, necrotic, and xanthomatous lesions. The expression loss of pan T-cell markers, such as CD2, CD5, and CD7, of infiltrating T-cells is observed in KFD cases, complicating the distinction from T-cell lymphoma. However, reports on the loss of their expression in KFD have been limited. Furthermore, the precise population of the T-cell subset in KFD is still unclear. Here, we focused on surface markers and transcription factors for T-cell differentiation and analyzed them immunohistochemically in 46 KFD cases. We observed diminished CD5 expression of CD8-positive (CD5_^dim CD8+) T-cells in the proliferative lesion of KFD cases. Furthermore, these CD5_^dim CD8+ T-cells expressed T-BET, a master regulator of type 1 helper T-cells. The upregulation of T-BET and downregulation of CD5 in CD8+ T-cells causes dysregulated activation and proliferation of CD8+ T-cells, potentially contributing to the unique histopathological features of KFD. Recognizing the frequent infiltration of T-BET-positive CD5_^dim CD8+ T-cells in KFD is important for distinguishing it from mature T-cell lymphoma. Our findings suggest that the immune response in KFD shares similarities with viral infections and highlight the importance of characterizing T-BET-positive CD5_^dim CD8+ T-cell populations for understanding KFD pathogenesis.

Immune checkpoint inhibitors (ICI) are promising therapeutic agents for relapsed or refractory classical Hodgkin’s lymphoma (RRcHL). This retrospective study evaluated patients with RRcHL registered in the clinical research program Tohoku-Hematology-Forum-26, between 2016 and 2020, and treated with ICI in 14 centers in Northeast Japan. We analyzed the usage, efficacy, and safety of ICI therapy (ICIT). Among a total of 27 patients with RRcHL, 21 and nine were treated with nivolumab and/or pembrolizumab, respectively. The best response was complete response (CR), partial response (PR), stable disease (SD), and progressive disease in 11 (40.8%), seven (25.9%), eight (29.6%), and one (3.7%) patient, respectively. In all patients undergoing ICIT, the 2-year progression-free survival and 2-year overall survival (OS) were 48.6% and 87.4%, respectively. The 2-year OS for patients with CR, PR, and SD were 100%, 68.6%, and 87.5%, respectively. A total of 36 events of immune-related adverse events (irAEs) or immune-related like adverse events (irlAEs) were observed in 19 of the 27 patients (70.4%). Two thirds of these irAEs or irlAEs were grade 1–2 and controllable. During the observation period, ICIT was discontinued in 22 of 27 (81.4%) patients due to CR, inadequate response, irAE and patient circumstances in five (22.7%), seven (31.8%), eight (36.4%) and two patients (9.1%), respectively. Therapy-related mortality-associated irAE were observed in only one patient during ICIT. These results suggest that ICIT for RRcHL is effective and safe in real-world settings. The optimal timing of induction and duration of ICIT remains to be established.

Primary diffuse large B-cell lymphoma of the central nervous system (CNS-DLBCL) can be difficult to diagnose because of the limited amount of biopsy tissue. Here, we analyzed the utility of insulin-like growth factor II mRNA binding protein 3 (IMP3) immunohistochemistry (IHC) as an adjunctive diagnostic tool for CNS-DLBCL. IHC was performed on 57 biopsy samples (55 brain biopsy samples and two vitreous cell blocks) from 54 patients with CNS-DLBCL, including three biopsy samples initially diagnosed as negative or indeterminate for CNS-DLBCL. Additionally, IMP3 IHC was performed on 68 DLBCLs other than CNS-DLBCL and 12 inflammatory brain diseases. Cytoplasmic IMP3 expression was noted in ≥50% of tumor cells in 100% (57/57) of CNS-DLBCLs and 88.2% (60/68) of non-CNS-DLBCLs. In contrast, no IMP3-positive CD20-positive B cells were observed in the inflammatory brain disease (P < 0.0001). In conclusion, IMP3 is highly expressed in CNS-DLBCL. However, it is also expressed in other types of DLBCLs, making it less specific. Most CNS-DLBCL cases can be diagnosed without performing IHC for IMP3 expression, but it may be a useful adjunctive tool to differentiate from reactive lesions when tumor cells are few or deformed.

In diagnosing TAFRO syndrome, lymph node histology often may not be evaluated due to inapparent lymphadenopathy. In this study, we analyzed the differences in the pathophysiology of TAFRO syndrome with or without lymphadenopathy. We used an anonymous questionnaire to survey 70 hematologists at 50 hospitals in the Kanto Koshinetsu area of Japan from February to April 2020. We received 31 responses and collected 26 cases with TAFRO syndrome. Compared to cases with or without lymph node biopsy, clinical features and laboratory test findings in both groups were not significantly different, except for stronger renal insufficiency found in those without biopsy. It was also revealed that clinical features and laboratory test findings had no significant differences between the cases with and without lymphadenopathy. However, renal insufficiency was more pronounced in those without lymphadenopathy. There were no significant differences in pathophysiology between cases with or without lymphadenopathy in the group that did not undergo lymph node biopsy. In the treatment strategies, no significant differences were found dependent on lymphadenopathy. This study shows that lymphadenopathy in TAFRO syndrome may be secondary to inflammation and unrelated to the underlying disease.

Alemtuzumab is recommended as first-line and second-line therapies for T-cell prolymphocytic leukemia (T-PLL). This study retrospectively evaluated the efficacy and safety of alemtuzumab in nine Japanese patients with T-PLL at five participating institutions who were treated between January 2015 and August 2023. The median age at first administration of alemtuzumab was 72 years (range, 39 to 78). Two patients were treatment naïve, and seven had been treated with a median of one (range, 1 to 3) prior systemic therapy. Six patients were refractory to their most recent therapy. Three patients completed 12 weeks of treatment. The overall response rate and the complete response (CR) rate were 78% and 11%, respectively. Among the six patients who achieved a partial response, two achieved clinical CR but did not undergo bone marrow examination. One patient also achieved clinical CR but did not undergo CT and bone marrow examination for response evaluation. The median progression-free survival time was 8.1 months (95% confidence interval, 0.9 to 18.6). Three patients received readministration of alemtuzumab monotherapy after disease progression. There were no treatment-related deaths. The grade 3 or 4 nonhematologic adverse events included infusion reaction (grade 3, n = 2), cytomegalovirus reactivation (grade 3, n = 2), and pulmonary edema (grade 3, n = 1). One patient experienced Epstein‒Barr virus-positive diffuse large B-cell lymphoma 15 months after the last dose of alemtuzumab. These results confirm that the efficacy and safety of alemtuzumab monotherapy in Japanese patients are comparable to those previously reported.

IgG4-related sialadenitis (IgG4-SA) is one of the IgG4-related disease. The histological features of IgG4-SA include dense lymphoplasmacytic infiltrates and fibrosis. This study aimed to reveal the involvement of plasma cells in the development of fibrosis and the mechanism underlying fibrosis in IgG4-SA. Hematoxylin-eosin staining, Azan staining, silver staining, and immunohistochemistry (IHC) were performed on IgG4-SA and chronic sialadenitis specimens, and theses samples were analyzed by image analysis software. Histological spatial analysis was used to analyze the localization of IHC-positive cells and the distances between these cells. In the IgG4-SA group, many secondary lymphoid follicles with germinal centers were found, and many collagen fibers developed around these germinal centers. Collagen fibers composed mainly of type I collagen was abundant at sites away from secondary lymphoid follicles, and reticular fibers composed of type III collagen was abundant near secondary lymphoid follicles. Many FAP⁺ fibroblasts and MUM1⁺ plasma cells were localized near secondary lymphoid follicles. Histological spatial analysis demonstrated that 90.4% of MUM1⁺ plasma cells accumulated within 20 µm of FAP⁺ fibroblasts. Multiple immunofluorescence assays revealed that MUM1⁺ plasma cells expressed platelet-derived growth factor (PDGF) β, and FAP⁺ fibroblasts expressed PDGF receptor (PDGFR) β and pSTAT3 in IgG4-SA. We have shown that fibrosis is localized around secondary lymphoid follicles and that fibroblasts are activated by plasma cells via PDGF/PDGFR signaling in IgG4-SA.

Erdheim-Chester disease (ECD) is a rare, non-Langerhans cell histiocytosis with diverse clinical features. It is characterized by systemic histiocyte infiltration of the bone, skin, central nervous system, lung, kidney, and cardiovascular system. Pericardial involvement is frequently revealed through either pericardial effusion or pericardial thickening in patients with ECD. Although most patients remain asymptomatic, progressive pericarditis, effusion, or cardiac tamponade may occur. Herein, we report a rare and unusual presentation of ECD in a 51-year-old man who experienced severe constrictive pericarditis. The patient presented with uncontrolled fluid retention and heart failure. After the diagnosis of ECD, interferon alpha treatment was administered. The patient recovered dramatically with decreased pleural and pericardial effusion, as well as improvements in the echocardiographic signs of constrictive pericarditis. Despite several therapeutic options described in the literature for managing ECD-related pericardial disease, a standard treatment has not been established. This report highlights the importance of early treatment based on accurate diagnosis of an unusual ECD complication.

Since the identification of the TTMV::RARA fusion in pediatric cases resembling acute promyelocytic leukemia (APL) by Astolfi et al. in 2021, several similar cases have been reported worldwide. In this report, we present a case of relapsed APL in an adolescent patient, who exhibited the TTMV::RARA fusion gene. This patient exhibited extensive central nervous system involvement and experienced bone marrow necrosis during disease recurrence. Despite achieving complete remission after re-induction chemotherapy, the patient experienced a rapid second relapse, highlighting the extremely aggressive nature of this subtype. These clinical manifestations contribute to the growing recognition of this rare disease.

A 78-year-old Japanese man presented to the emergency department with a sore throat and fever that worsened over 3 weeks. A tonsil biopsy led to the diagnosis of pleomorphic mantle cell lymphoma (MCL) that had infiltrated the right adrenal gland, inferior vena cava, and right atrium (RA). Although the patient’s cardiac tumor had high mobility, his hemodynamic state was stable, and he did not present with fatal arrhythmia. Therefore, we first introduced chemotherapy. However, the patient developed recurrent pulmonary embolisms (PEs) and died after starting chemotherapy. An autopsy revealed that the MCL had invaded the large vessels, causing the PEs. Although the high mobility of cardiac tumors is known to increase the risk of PE in diffuse large B-cell lymphoma (DLBCL), optimal management of cardiac MCL remains to be elucidated owing to its rarity. To the best of our knowledge, this is the first report of cardiac MCL with posttreatment PE development in a Japanese patient. It is worth considering preventive surgery before treatment not only in DLBCL, but also in MCL based on the mobility of the cardiac tumors. Our case highlights the need for close communication between hematologists and cardiologists to treat cardiac MCL.

MYD88 p.L265P mutation occurs in over 90% of Waldenström’s macroglobulinemia (WM), which is characterized by lymphoplasmacytic lymphoma (LPL) with monoclonal IgM. WM requires careful diagnosis due to overlapping features with other B-cell malignancies. Bing–Neel syndrome (BNS), a rare complication of WM, involves central nervous system (CNS) invasion. This report describes two cases of morphologically low-grade B-cell lymphoma in the bone marrow accompanied by the presence of a large B-cell lymphoma in the brain and a common MYD88 p.L265P mutation, which were eventually established as BNS mimickers. Although the two components in these cases showed the same identical light-chain restriction, different immunoglobulin heavy-chain rearrangement peaks indicated distinct lymphoma stem cells for CNS and bone marrow lesions. These clinical cases emphasize the challenges in diagnosing BNS. Based on the findings, biopsy is recommended for accurate identification of the clonal relationship and MYD88 mutation status.

Cytokine release syndrome (CRS) is the most common adverse event of chimeric antigen receptor T (CAR-T) cell therapy and is usually characterized by systemic symptoms such as fever, hypotension, and hypoxia. However, there have been several recent reports of local CRS characterized by cervical swelling. This localized syndrome can cause life-threatening laryngeal edema and requires early diagnostic treatment. Here we report 3 cases of local CRS where bilateral salivary gland swelling emerged following anti-CD19 CAR-T cell therapy for relapsed or refractory diffuse large B-cell lymphoma. Following tocilizumab treatment for systemic CRS, all patients exhibited cervical swelling. Physical examinations revealed significant swelling of the bilateral submandibular glands, and computed tomography scans showed substantial enlargement of the bilateral parotid and submandibular glands. Immediate treatment with dexamethasone effectively managed the potentially life-threatening laryngeal or pharyngeal edema, thereby preventing severe airway obstruction. This study has demonstrated, for the first time to our knowledge, that salivary gland enlargement is a common finding in local CRS. This observation suggests that physicians should continue to closely monitor the risk of developing cervical edema leading to life-threatening airway obstruction after systemic CRS, even in patients treated with tocilizumab. If salivary gland swelling is observed, it would be better to consider prompt evaluation and dexamethasone administration.

Plasmacytoma is defined as a plasma cell neoplasm forming a solitary osseous or extramedullary tumor without evidence of myeloma or organ damage related to a plasma cell neoplasm. Epstein-Barr virus (EBV) is associated with various B-cell neoplasms, particularly in patients with immune dysregulation; however, plasmacytoma is typically negative for EBV. Here, a case of EBV-positive sternal plasmacytoma in an immunocompetent female is presented. A 76-year-old female with no immunodeficiency presented with a tumor on the anterior thoracic wall. Imaging analysis revealed a 6.3 cm-sized tumor at the manubrium, and a needle biopsy was performed. The tumor in the bone was composed of a diffuse proliferation of plasmacytes with eccentric nuclei and a perinuclear halo. By immunohistochemistry and in situ hybridization, tumor cells were CD20-, CD3-, CD138+, κ+, λ-, EBER+, and the Ki67-labeling index was approximately 20%. Subsequent studies identified IgG κ monoclonal protein in serum but no evidence of plasma cell neoplasm-related organ damage, such as hypercalcemia, anemia, or renal dysfunction. No plasma cell neoplasm was detected in the bone marrow in the morphological and flowcytometric studies. Accordingly, the diagnosis was EBV-positive plasmacytoma. The patient was treated with local radiation therapy and achieved complete remission. EBV-positive plasmacytoma is rare in immunocompetent patients and should be carefully distinguished from plasmablastic lymphoma, another EBV-positive neoplasm with a plasma cell phenotype and an aggressive clinical course. This case also raises an important question: “when to perform EBER in situ hybridization in diagnosing plasma cell neoplasm?”, which prompts further large case-series studies.