淋巴浆细胞淋巴瘤的鉴别诊断

… enter into the differential diagnosis of small B-cell lymphomas with … diagnosis by 2008 World Health Organization criteria. … related to diagnosis and differential diagnosis of these other …

The diagnosis of lymphoplasmacytic lymphoma (LPL) in the bone marrow (BM) is challenged by aberrant phenotypes and by overlapping histological features with marginal zone lymphoma (MZL). To address these issues, we (i) assessed LPL immunophenotype on a large series of BM samples, (ii) drew possible correlations between LPL phenotype and clinical/molecular data and (iii) investigated the role of new phenotypical markers in the differential diagnosis between LPL and MZL.

… Lymphoplasmacytic lymphoma/WM is a rare disease, with an annual incidence of 3 to 4 … In rare instances, diffuse lymphoplasmacytic infiltration of the lung, stomach, or bowel may occur…

Lymphoplasmacytic lymphoma (LPL) is a distinct B-cell lymphoproliferative disorder primarily characterized by bone marrow infiltration of lymphoplasmacytic cells. When LPL produces a serum monoclonal immunoglobulin of the IgM class, it is termed Waldenström macroglobulinemia (WM). The differential diagnosis between LPL and other types of morphologically similar B-cell tumors that may also have plasmacytic differentiation and/or secretion of IgM paraproteins is not always clear-cut based solely on the pathologic and phenotypic features of the tumor. Although the current treatments for LPL/WM are initially effective in inducing responses in most patients, they are not curative and show decreasing efficacy with repeated administrations, ultimately resulting in the selection of a chemoresistant clone. Next-generation sequencing studies have identified somatic mutations of MYD88, a key component of the Toll-like receptor signaling machinery, in ∼90% of LPL/WM. Deregulated MYD88 signaling promoted by mutations sustains tumor cell survival in LPL/WM, demonstrating that they are gain-of-function driver events in this lymphoma. This review discusses the molecular and biological mechanisms underlying MYD88 mutations in LPL/WM, the role of MYD88 mutations as molecular biomarker for the refinement of diagnosis and the improvement classification of LPL/WM, and novel targeted therapeutic strategies for LPL/WM based on the pharmacological manipulation of MYD88 signaling to which this lymphoma is addicted.

Lymphoplasmacytic lymphoma (LPL) and marginal zone lymphoma (MZL) are indolent subtypes of non-Hodgkin lymphoma. Both are typically CD5 and CD10 negative. In recent years, there have been several scientific advances that have helped improve the diagnosis of these conditions. These conditions have been managed similarly in previous years with observation in asymptomatic patients and systemic therapy in advanced stages. However, there are specific differences. Differential responses are also seen with novel agents such as the BTK inhibitor ibrutinib. It is encouraging to see that there several clinical trials specific for patients with LPL and MZL ongoing.

Objective To investigate the clinicopathological characteristics, immunophenotype and prognostic factors of marginal zone lymphoma with plasmacytic differentiation (MZL-PD). Methods This was a single-center retrospective cohort study. A total of 49 patients with MZL-PD diagnosed and treated at the Second Xiangya Hospital of Central South University from January 2010 to December 2025 were enrolled. Based on serum M protein test results, patients were divided into an M protein-positive group (30 cases) and an M protein-negative group (19 cases). Clinicopathological data were collected, and survival analysis was performed using the Kaplan-Meier method. Results The 49 patients included 37 cases with pathological morphological plasmacytic differentiation and 12 cases with monoclonal plasma cells detected by flow cytometry. Among the 37 patients with morphological plasmacytic differentiation, 73% showed light chain restriction confirmed by immunohistochemistry, with κ light chain restriction being more common (81.5%). Among the 12 cases where monoclonal plasma cells were detected by flow cytometry, 9 cases simultaneously had monoclonal small B lymphocytes, with 8 cases showing the same type of light chain restriction in both cell populations. The immunophenotype of plasma cells in MZL-PD (CD38 + CD138+ MUM1 + CD20- CD56- CD19+) was highly similar to that of lymphoplasmacytic lymphoma (LPL). Clinically, MZL-PD had a high proportion of primary lesions in the lung (28.6%). The bone marrow infiltration rate in the M protein-positive group was significantly higher than that in the negative group (66.7% vs 10.5%, P < 0.01). Survival analysis showed a median follow-up of 32.8 months for the entire group; median PFS was not reached, the 2-year PFS rate was 83.6%, and the 2-year OS rate was 96.4%. The 2-year PFS of the M protein-positive group was significantly lower than that of the negative group (78.1% vs 91.7%, P = 0.037), but there was no significant difference in OS between the two groups. Conclusion MZL with plasmacytic differentiation frequently involves the lung and exhibits a plasma cell immunophenotype similar to that of lymphoplasmacytic lymphoma, necessitating differentiation via MYD88 testing. M protein positivity serves as an adverse prognostic factor, indicating a higher risk of bone marrow infiltration and early disease progression. Identification of this subgroup is therefore of great significance for precise diagnosis and the formulation of individualized treatment strategies.

Objective: Clinical and pathological differential diagnosis of small B-cell lymphomas (SBCLs) is still controversial and may be difficult due to their overlapping morphology, phenotype, and differentiation to plasma cells. We aimed to examine the expression of the immune receptor translocation-associated protein 1 (IRTA1), myeloid cell nuclear differentiation antigen (MNDA), lymphoid enhancer-binding factor-1 (LEF1), and stathmin 1 (STMN1) markers in SBCL cases involving different sites that may have plasma cell differentiation. Materials and Methods: We studied 154 tissue samples with lymphoma involvement from 116 patients and evaluated the staining distribution of the markers. Expressions were evaluated in 21 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 7 follicular lymphoma (FL), 14 nodal marginal zone lymphoma, 17 extranodal marginal zone lymphoma, 55 splenic marginal zone lymphoma, 22 marginal zone lymphoma-not otherwise specified, and 18 lymphoplasmacytic lymphoma/Waldenström macroglobulinemia cases by immunohistochemistry. Results: The results confirmed that LEF1 was the most sensitive and specific marker for CLL/SLL and STMN1 was the most sensitive and specific marker for FL (p<0.001). MNDA and IRTA1 were useful markers to distinguish marginal zone lymphomas. Conclusion: Our results suggest that LEF1 for CLL/SLL and STMN1 for FL are reliable markers. LEF1, MNDA, STMN1, and IRTA1 are helpful with other routinely used immunohistochemical markers in a diagnostic algorithm considering their limitations.

114 cases of malignant lymphoma consisting chiefly of lymphocytes were classified by histology as chronic lymphocytic leukemia of the B-cell type (B-CLL) or lymphoplasmacytic/…

Introduction: Flow cytometry (FC) holds a pivotal role in hematological diagnostics. Although capable of turn-around time within hours, the manual processing of these complex data remains challenging and resource consuming. Integration of artificial intelligence (AI) algorithms for the analysis and interpretation of FC data is poised to revolutionize the field by unlocking previously unexplored capabilities. Aims: 1) Development of an AI classification model for interpretation of flow cytometric data and identification of B-cell lymphoma (B-NHL) cases as well as B-NHL subclassification with high accuracy, 2) reliable automated visualization, 3) routine implementation. Methods: An XGBoost-based classification model was trained and validated using FC data from 12,015 cases, consisting of 5,015 B-NHL and 7,000 no B-NHL cases. Lymphoma diagnoses included: monoclonal B-cell lymphocytosis/chronic lymphocytic leukemia [MBL/CLL]: 2,000, marginal zone lymphoma/lymphoplasmacytic lymphoma [MZL/LPL]: 1,095, mantle cell lymphoma [MCL]: 809, hairy cell leukemia [HCL]: 795 and follicular lymphoma [FL]: 316), respectively. The ground truth of FC set diagnoses was further underpinned by relevant genetic data. The cloud-based Cytobank data analysis platform (Beckman Coulter, Miami, FL) was used for standardized gating and transformation of raw FC files prior to analysis by the in-house AI classification model. Cytobank's AutoGating algorithm was trained on 50 manually gated cases, enabling single cell labeling and generation of labeled datasets. The prediction by the in-house AI model was deployed in two stages, i.e. binary classification (B-NHL vs. no B-NHL) and identifying B-NHL subtypes. In addition, an in-house automated tool was deployed to visualize cell populations in scatter plots corresponding to manual processing. Classification model was trained with a training cohort (n=9,612), its performance was verified by a validation cohort (n=2,403). Subsequently the model was prospectively challenged with new data from routine workflow (n=915), where lymphoma was part of differential diagnosis. Concordance between manual and automated process was assessed in a blinded manner. From the 915 cases only those with high prediction probability (>90%) were used for the model's evaluation in order to reflect future application, i.e. routine operations' demand to minimize additional manual processing. Results: In the validation cohort, a total of 1,802/2,403 (75%) cases showed prediction probability above 75% and were used for assessment of the model. Overall, very high accuracies of 99.3% and 98.7% were achieved for both B-NHL detection and subclassification. The prediction accuracies for the respective subtypes were: MBL/CLL: 98.6%, MZL/LPL: 96.4%, MCL: 98.1%, HCL: 99.2% and FL: 100%. As to prospective evaluation with new data, 672/915 (73%) cases were predicted with probability above the set threshold of 90%. Classification accuracies were very high also in this context and reached 98.7% for B-NHL detection and 97.0% for B-NHL subclassification. Again, accuracies were very high for MBL/CLL (98.1%), MZL/LPL (100%), MCL (100%), and FL (100%) identification, respectively, with sole exception being HCL with an accuracy of 86.9%. The automatically generated dot plots were rated by diagnostic experts as qualitatively appropriate and equivalent to manual data analysis in all 672 cases. Also, diagnostic experts made identical diagnoses in all 672 cases, respectively, when reviewing both automatically generated and manually prepared dot plots. In particular, review of automatically generated dot plots enabled them to set the correct diagnosis in all out of 16 cases wrongly predicted by the AI algorithm. Compared with manual processing, the automated workflow reduced hands-on-time by up to 75%. Conclusion: The prediction performance of the AI classification model to detect B-NHL in FC was outstanding both in the validation cohort and in the real-life routine data: Further, the automatically generated dot plots enabled a correct diagnosis by the diagnostic expert at all times. Both these components are applicable to routine operations. Our data strongly support the integration of our AI lymphoma classifier model into our routine workflow, which will dramatically reduce the hands-on-time and open the way for further applications that are time-consuming and analyses requiring high expertise, such as minimal residual disease detection or immunoprofiling.

… symptoms known as Waldenstrom's macroglobulinemia. Tumor cells display the … differential diagnosis from B-cell chronic lymphocytic lymphoma (B-CLL)/ small lymphocytic lymphoma …

Our current understanding of the normal lymphoid system informs the modern classification of lymphomas. B-cell, T-cell and NK-cell neoplasms often recapitulate normal stages of lymphoid cell differentiation and function. Moreover, the clinical manifestations of lymphomas often reflect the normal function of lymphoid cells in vivo. The multiparameter approach to classification adopted by the REAL and subsequent WHO classifications facilitates the interpretation of clinical and translational studies, and provides a framework for the discovery of molecular alterations that drive these tumors. An accurate and precise classification of disease entities facilitates the discovery of the molecular basis of lymphoid neoplasms in the basic science laboratory, and leads to new diagnostic tools that play a role in clinical diagnosis.

… The clinical picture was compatible with lymphoplasmacytic lymphoma, and therefore, the patient received target and chemotherapy for lymphoma. He also … Differential Diagnosis …

… reviewed the immunophenotypic profile of 75 cases of lymphoplasmacytic lymphoma/… These results show that the immunophenotype of LPL/WM is variable and overlaps with …

… Lymphoplasmacytic lymphoma with focal marginal zone growth pattern (… lymphoplasmacytic proliferation with Dutcher bodies similar to that seen in other lymphoplasmacytic lymphomas …

Background: Lymphoplasmacytic lymphoma (LPL) is a small mature B-cell neoplasm that primarily involves the bone marrow. When associated with an IgM paraprotein, it is referred to as Waldenström macroglobulinaemia (WM). Variants in the MYD88 and CXCR4 genes are among the most common genetic alterations in LPL. Aim: To determine MYD88 and CXCR4 variant prevalence in South African LPL cases. Setting: National Health Laboratory Service, Charlotte Maxeke Johannesburg Academic Hospital. Methods: Samples were obtained from newly diagnosed, treatment-naïve patients with LPL or WM. MYD88L256P variants were detected using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR), and CXCR4 variants through Sanger sequencing. Clinical and laboratory data were compiled into a database, with statistical analyses performed using GraphPad Prism. Results: Twenty cases of LPL (90% WM) were diagnosed over a 7-year period. The median age of the cohort was 69 years (interquartile range [IQR]: 63–75) with a male predominance. Allele-specific oligonucleotide polymerase chain reaction confirmed MYD88L265P in 80%, and Sanger sequencing confirmed CXCR4 variants in 45%. The group with concurrent MYD88 and CXCR4 variants showed the highest risk stratification scores and the most severe cytopenias. The median overall survival for the cohort was 11.5 months (IQR: 1.9–20.8), with no clear survival difference between CXCR4-mutated and wild-type cases. Survivors tended to be younger and to have lower baseline serum paraprotein levels at presentation. Conclusion: In the South African public healthcare setting, CXCR4 variants are frequent in LPL or WM with high-risk profiles, most common among patients harbouring both MYD88 and CXCR4 variants. Contribution: This study presents the first South African description of LPL genetics.

… a MYD88 L265P mutation rate of 78.0% and a CXCR4 mutation rate of 12.82%, with MYD88… Subgroup analysis revealed that MYD88 L265P‐mutated patients responded best to BTKi …

Marginal zone lymphomas of all types (nodal, splenic, and extranodal mucosa-associated lymphoid tissue [MALT]) may show plasmacytic differentiation. Distinguishing marginal zone lymphomas from other small B-cell lymphomas with plasmacytic differentiation, especially lymphoplasmacytic lymphoma, or from plasma cell neoplasms may be challenging. Marginal zone lymphomas with plasmacytic differentiation were discussed in 2 sessions of the 2009 Society for Hematopathology/European Association for Haematopathology Workshop. Session 4 focused on nodal marginal zone lymphomas, including cases exhibiting classic features and cases displaying atypical phenotypes. The difficulties of classification of cases with increased numbers of large cells were also discussed. Session 5 examined nonnodal marginal zone lymphomas and related entities, including splenic marginal zone lymphoma, MALT lymphoma, γ heavy chain disease, and cryoglobulin-associated lymphoproliferative disorders. These cases illustrate the importance of clinical data and, in some cases, phenotypic and cytogenetic findings in appropriately applying the 2008 World Health Organization criteria.

Lymphoplasmacytic lymphoma (LPL) and marginal zone lymphoma (MZL) frequently infiltrate the bone marrow with similar histologic and immunohistochemical characteristics posing diagnostic problems. Bone marrow biopsy specimens from 25 LPL and 16 MZL have been studied, correlating with clinical, laboratory parameters and the MYD88_p.L265P mutation. Paratrabecular and interstitial infiltration pattern, serum IgM paraprotein levels, and MYD88_p.L265P mutation were significantly more frequent in LPL. Nodular or intrasinusoidal pattern with lymphocytosis and splenomegaly were associated with MZL diagnosis. Different clinical and histological parameters should be collected when LPL or MZL is suspected in bone marrow biopsy specimens.

… Introduction: The differential diagnosis between marginal zone lymphoma with plasmacytic differentiation (MZL-PD) and lymphoplasmacytic lymphoma (LPL) remains one of the most …

… lymphoma, in particular from lymphoplasmacytic lymphoma, is … in the large majority of lymphoplasmacytic lymphomas, and it is … A primary extranodal marginal zone lymphoma has to be …

… differentiation may be present and, when it is prevalent, problems of differential diagnosis with either lymphoplasmacytic lymphoma or even nodal plasma cell neoplasms may be arise. …

… Extranodal marginal zone B-cell lymphoma of mucosa-… as a form of primary lung lymphoma. However, until recently, pleural … EMZL/MALT-type or lymphoplasmocytic lymphoma (LPL). …

Some non-Hodgkin lymphomas show marked plasmacytic differentiation. In such cases, it may be difficult to differentiate these lymphomas from plasmacytoma or myeloma, especially with limited diagnostic material. However, there may be immunophenotypic differences in the plasma cells in these disorders that distinguish them. This study characterizes the immunophenotypes of neoplastic plasma cells in 41 cases of B-lineage non-Hodgkin lymphoma and compares them with those in plasma cell myeloma. We found that plasma cells in lymphoma were significantly more likely to express CD19, CD45, and surface immunoglobulin and less likely to express CD56 than those in myeloma. We further show that CD19 and CD56 expression can be used reliably to distinguish these entities. Myeloma-associated osseous lesions and solitary plasmacytoma of bone showed myeloma-like immunophenotypes. However, some extramedullary plasmacytomas showed lymphoma-like phenotypes, suggesting that, in reality, they may represent non-Hodgkin lymphomas with extensive plasmacytic differentiation.

Lymphoplasmacytic lymphoma (LPL) represents a distinct type of mature B-cell lymphoma with a substantial subset of cases being associated with Waldenström macroglobulinaemia (WM), defined as primarily bone marrow involvement and the presence of an IgM monoclonal paraprotein. MYD88 L265P mutation, although not specific, is present in the vast majority (>90%) of LPL cases and sheds light on the potential pathogenesis of this disease. This review offers an overview of current knowledge on the pathogenesis, clinical presentations, histological features and immunophenotype of LPL and WM. In addition, the differential diagnosis of LPL and WM from other mature B cell neoplasms is highlighted with a focus on distinction from marginal zone lymphoma and plasma cell neoplasms.

… Waldenstrom macroglobulinemia and plasma cell myeloma … of Waldenstrom macroglobulinemia and plasma cell myeloma … coexisting lymphoplasmacytic lymphoma (LPL) and …

… WM plasma cell samples segregated with multiple myeloma. B cells and plasma cells from … with B cells and plasma cells from patients with chronic lymphocytic leukemia and multiple …

… It may be easily misdiagnosed as other B cell lymphomas with plasmacytic differentiation such as lymphoplasmacytic lymphoma [4]. In this case, the plasmacytoid cells did not show the …

The management of Waldenström macroglobulinemia (WM) has evolved tremendously with recent genomic discoveries that correlate with clinical presentation and could help to tailor treatment approaches. The current diagnosis of WM requires clinicopathological criteria, including bone marrow involvement by lymphoplasmacytic lymphoma cells, a serum immunoglobulin M (IgM) monoclonal paraprotein, and presence of the MYD88 L265P mutation. Once the diagnosis is established, the relationship between the patient's symptoms and WM should be carefully investigated, because therapy should be reserved for symptomatic patients. Bone marrow involvement and serum levels of IgM, albumin, and β2-microglobulin can be used to estimate the time until treatment initiation. The treatment of WM patients should be highly personalized, and the patient's clinical presentation, comorbidities, genomic profile, and preferences, as well as toxicity of the treatment regimens, should be taken into account. Alkylating agents (bendamustine, cyclophosphamide), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), anti-CD20 monoclonal antibodies (rituximab, ofatumumab), and Bruton tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib) are safe and highly effective treatment options in patients with WM. Because novel covalent and noncovalent BTK inhibitors (tirabrutinib, vecabrutinib, LOXO-305, ARQ-531), BCL2 antagonists (venetoclax), and CXCR4-targeting agents (ulocuplumab, mavorixafor) are undergoing clinical development in WM, the future of WM therapy certainly appears bright and hopeful.

Similar to the inherent clinical heterogeneity of most, if not all, lymphoma entities, the genetic landscape of these tumors is markedly complex in the majority of cases, with a rapidly growing list of recurrently mutated genes discovered in recent years by next-generation sequencing technology. Whilst a few genes have been implied to have diagnostic, prognostic and even predictive impact, most gene mutations still require rigorous validation in larger, preferably prospective patient series, to scrutinize their potential role in lymphoma diagnostics and patient management. In selected entities, a predominantly mutated gene is identified in almost all cases (e.g. Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma and hairy-cell leukemia), while for the vast majority of lymphomas a quite diverse mutation pattern is observed, with a limited number of frequently mutated genes followed by a seemingly endless tail of genes with mutations at a low frequency. Herein, the European Expert Group on NGS-based Diagnostics in Lymphomas (EGNL) summarizes the current status of this ever-evolving field, and, based on the present evidence level, segregates mutations into the following categories: i) immediate impact on treatment decisions, ii) diagnostic impact, iii) prognostic impact, iv) potential clinical impact in the near future, or v) should only be considered for research purposes. In the coming years, coordinated efforts aiming to apply targeted next-generation sequencing in large patient series will be needed in order to elucidate if a particular gene mutation will have an immediate impact on the lymphoma classification, and ultimately aid clinical decision making.

We performed a molecular analysis of formalin-fixed paraffin embedded and decalcified bone marrow trephine biopsies of 41 patients with a B-cell disorder with lymphoplasmacytic differentiation to enable a more precise diagnosis and to describe potentially prognostic and therapeutic relevant mutations. Analysis was performed with a commercially available next-generation sequencing (NGS) lymphoma panel (Lymphoma Solution, SophiaGenetics). Results were correlated with clinical and pathological parameters. Our group covered a spectrum of B-cell disorders with plasmacytic differentiation ranging from Waldenstroem’s macroglobulinemia (WM), to small-B-cell lymphomas with plasmacytic differentiation (SBCL-PC) to IgM myeloma (MM). The most helpful diagnostic criteria included morphology and immuno-phenotype as a prerequisite for the interpretation of molecular analysis. MYD88 mutation was present in nearly all WM, but also in 50% of SBCL-PCs, while MM were consistently negative. Driver mutations, such as TP53, were already detectable early in the course of the respective diseases indicating a higher risk of progression, transformation, and reduced progression-free survival. In addition, we report on a novel BIRC3 frameshift mutation in one case of a progressive WM. Our data indicate that patients with LPL/WM might benefit from thorough pathological work-up and detailed molecular analysis in terms of precise diagnosis and targeted treatment allocation.

Consensus Panel 4 (CP4) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11) was tasked with reviewing the current criteria for diagnosis and response assessment. Since the initial consensus reports of the 2nd International Workshop, there have been updates in the understanding of the mutational landscape of IgM related diseases, including the discovery and prevalence of MYD88 and CXCR4 mutations; an improved recognition of disease related morbidities attributed to monoclonal IgM and tumor infiltration; and a better understanding of response assessment based on multiple, prospective trials that have evaluated diverse agents in Waldenstrom's macroglobulinemia. The key recommendations from IWWM-11 CP4 included: (1) reaffirmation of IWWM-2 consensus panel recommendations that arbitrary values for laboratory parameters such as minimal IgM level or bone marrow infiltration should not be used to distinguish Waldenstrom's macroglobulinemia from IgM MGUS; (2) delineation of IgM MGUS into 2 subclasses including a subtype characterized by clonal plasma cells and MYD88 wild-type, and the other by presence of monotypic or monoclonal B cells which may carry the MYD88 mutation; and (3) recognition of "simplified" response assessments that use serum IgM only for determining partial and very good partial responses (simplified IWWM-6/new IWWM-11 response criteria). Guidance on response determination for suspected IgM flare and IgM rebound related to treatment, as well as extramedullary disease assessment was also updated and included in this report.

OBJECTIVES To summarize the conclusions of the 2021 Society for Hematopathology/European Association for Haematopathology workshop regarding transformations of marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma (LPL). METHODS Nineteen cases were submitted to this portion of the workshop. Additional studies were performed in cases with sufficient material. RESULTS Cases included splenic MZL (n = 4), splenic diffuse red pulp small B-cell lymphoma (n = 2), nodal MZL (n = 4), extranodal MZL (n = 1), and LPL (n = 8). The most common transformation was to diffuse large B-cell lymphoma (DLBCL), but others included classic Hodgkin lymphoma, high-grade B-cell lymphomas with MYC and BCL6 rearrangements, plasmablastic lymphoma, and plasma cell leukemia. Two splenic MZLs with transformation to DLBCL contained t(14;19)(q32;q13.3) IGH::BCL3 rearrangements in both samples. Paired sequencing studies in 5 MZLs with transformation to clonally related DLBCL identified a variety of mutations and gene fusions at the time of transformation, including CARD11, IGH::MYC, NOTCH2, P2RY8, TBLX1X1, and IGH::CD274. CONCLUSIONS Marginal zone lymphoma and LPL may undergo a variety of transformation events, most commonly to DLBCL, which is usually, although not always, directly clonally related to the underlying low-grade lymphoma. Multiparameter analysis including broad-based sequencing studies can assist in the diagnosis and classification of these uncommon cases.

A woman in her 80 s presented with generalized lymphadenopathy, bone marrow (BM) involvement, and leukemic manifestation. Lymph node biopsy revealed typical histopathology of mantle cell lymphoma (MCL) and the CD5+ and immunoglobulin μ+δ+/λ+ immunophenotype, with unmutated IGHV. BM was infiltrated with not only MCL but also another B-cell tumor that was CD5- and μbright+δ+/κ+, being consistent with M proteins in the serum and urine, with mutated IGHV. As the latter lymphoma component carried the MYD88 L265P mutation, this case represented a composite of MCL and lymphoplasmacytic lymphoma. Next-generation sequencing revealed a cryptic insertion of IGK enhancer sequences into the CCND1-major translocation cluster, accounting for CCND1 expression in MCL cells recognized by immunohistochemistry. Composite lymphoma is rare, but a correct diagnosis is required because effective treatments for each component are now available.