[Bing-Neel syndrome successfully treated with tirabrutinib].

Bing-Neel syndrome (BNS) is a rare disease manifestation of Waldenström's macroglobulinemia characterized by abnormal lymphoplasmacytoid cells infiltration of the central nervous system. In September 2019, a 46-year-old man presented to a previous hospital with hand tremors, nausea, and dysuria. Demyelination of cerebral white matter and the spinal cord was discovered using MRI. Steroid pulse therapy was used to treat inflammatory demyelinating disease, and it provided temporary relief, but the symptoms returned when the steroids were stopped. He was referred to our hospital in June 2020, for further evaluation with the possibility of hematological malignancy. BNS was diagnosed based on the presence of abnormal lymphoplasmacytoid cells in the bone marrow and cerebrospinal fluid (CSF), as well as the presence of the MYD88L265P mutation in the CSF specimen. In July 2020, BR (bendamustine, rituximab) therapy was administered, but it was ineffective. Oral administration of tirabrutinib, which was recently approved for WM, began in August 2020. He has achieved long-term remission and steroid withdrawal, with no notable side effects. This is the second report of successful treatment of BNS with tirabrutinib. More research is needed to confirm tirabrutinib's efficacy in the treatment of BNS.

MYD88 L265P mutation and interleukin-10 detection in cerebrospinal fluid are highly specific discriminating markers in patients with primary central nervous system lymphoma: results from a prospective study.

Reliable biomarkers are needed to avoid diagnostic delay and its devastating effects in patients with primary central nervous system (CNS) lymphoma (PCNSL). We analysed the discriminating sensitivity and specificity of myeloid differentiation primary response (88) (MYD88) L265P mutation (mut-MYD88) and interleukin-10 (IL-10) in cerebrospinal fluid (CSF) of both patients with newly diagnosed (n = 36) and relapsed (n = 27) PCNSL and 162 controls (118 CNS disorders and 44 extra-CNS lymphomas). The concordance of MYD88 mutational status between tumour tissue and CSF sample and the source of ILs in PCNSL tissues were also investigated. Mut-MYD88 was assessed by TaqMan-based polymerase chain reaction. IL-6 and IL-10 messenger RNA (mRNA) was assessed on PCNSL biopsies using RNAscope technology. IL levels in CSF were assessed by enzyme-linked immunosorbent assay. Mut-MYD88 was detected in 15/17 (88%) PCNSL biopsies, with an 82% concordance in paired tissue-CSF samples. IL-10 mRNA was detected in lymphomatous B cells in most PCNSL; expression of IL-6 transcripts was negligible. In CSF samples, mut-MYD88 and high IL-10 levels were detected, respectively, in 72% and 88% of patients with newly diagnosed PCNSL and in 1% of controls; conversely, IL-6 showed a low discriminating sensitivity and specificity. Combined analysis of MYD88 and IL-10 exhibits a sensitivity and specificity to distinguish PCNSL of 94% and 98% respectively. Similar figures were recorded in patients with relapsed PCNSL. In conclusion, high detection rates of mut-MYD88 and IL-10 in CSF reflect, respectively, the MYD88 mutational status and synthesis of this IL in PCNSL tissue. These biomarkers exhibit a very high sensitivity and specificity in detecting PCNSL both at initial diagnosis and relapse. Implications of these findings in patients with lesions unsuitable for biopsy deserve to be investigated.

Detection of the MYD88L265P and CXCR4S338X mutations by cell-free DNA in Waldenström macroglobulinemia.

We aimed to detect the MYD88L265P and CXCR4S338X mutations in cell-free DNA (cfDNA) in patients with Waldenström macroglobulinemia (WM). We collected peripheral blood and paired bone marrow aspirates from 27 WM patients (including 16 patients with newly diagnosed WM, 3 patients with WM in relapse and 8 patients with WM during treatment). cfDNA was extracted from peripheral blood using a QIAamp Circulating Nucleic Acid Kit. The MYD88L265P and CXCR4S338X mutations were detected by real-time allele-specific PCR (AS-PCR) in cfDNA and genomic DNA (gDNA) extracted from bone marrow aspirates. The sensitivity of real-time AS-PCR for detecting MYD88L265P in cfDNA was determined using a serial dilution of 10%, 2%, 0.4% and 0.08% MYD88L265P cfDNA in wild-type cfDNA. Among the 27 patients, MYD88L265P was detected in 88.9% of them in gDNA and in 85.2% of them in cfDNA, with a concordance rate of 96.3%. The concordance rates were 93.8%, 100% and 100% in patients with newly diagnosed WM, patients with WM in relapse and patients with WM during treatment, respectively. The sensitivity of real-time AS-PCR for detecting MYD88L265P in cfDNA was 0.4%. CXCR4S338X was detected in 6.3% of the 16 newly diagnosed WM patients in both gDNA and cfDNA, with a concordance rate of 100.0%. It is feasible to apply cfDNA to detect MYD88L265P and CXCR4S338X in WM patients with a high concordance rate.

Cutaneous Involvement in Waldenström's Macroglobulinaemia.

Cutaneous involvement in Waldenström's macroglobulinaemia (WM) has been poorly characterized. To describe this involvement, a retrospective study of 19 patients with WM and cutaneous involvement of tumour B cells was performed. Twelve patients (group 1) had lymphoplasmacytic, non-transformed cutaneous proliferation, while in 7 cases (group 2) cutaneous involvement corresponded to histological transformation. In group 1, skin involvement was inaugural in 6 cases. The lesions were infiltrated plaques (83%), papules (25%) and tumours (42%). Four patients had a similar clinical picture (purplish, bilateral and symmetrical infiltration on the face). MYD88 L265P mutation was detected in the skin biopsy in all 6 cases tested. The 3-year specific survival rate was 88%. In group 2, cutaneous transformation occurred during the follow-up of the WM (71%). Lesions presented as ulcerated tumours (86%) of the trunk (57%) and lower limbs (57%). The 3-year specific survival rate was 22%. Skin involvement in WM has distinctive characteristics (e.g. clinical, histological, immunohistochemical, MYD88 L265P mutation).

[Successful detection of MYD88 L265P mutation in Waldenström's macroglobulinemia complicated with myelofibrosis using highly sensitive digital PCR].

A 78-year-old man with anemia (Hb 9.6 g/dl) and elevated serum immunoglobulin M (IgM 3,577 mg/dl) levels was referred to our hospital. Bone marrow aspiration yielded a dry tap, and bone marrow biopsy revealed the infiltration of CD20 positive lymphoplasmacytic lymphoma cells and myelofibrosis. The patient was diagnosed with Waldenström's macroglobulinemia complicated with myelofibrosis. TGF-ß plasma concentration was elevated. Further, after chemotherapy with bendamustine and rituximab, remission of both Waldenström's macroglobulinemia and myelofibrosis was achieved, and TGF-ß levels normalized. MYD88 L265P mutation was detected using highly sensitive digital PCR, which compared with currently used direct PCR product sequencing, has a superior sensitivity. The use of digital PCR has additional advantages toward MYD88 L265P detection, particularly when the available amount of sample DNA is limited owing to myelofibrosis.

[Successful diagnosis of lymphoplasmacytic lymphoma with IgG paraprotein using MYD88 L265P mutation analysis].

A 76-year-old woman presented to our hospital with leukocytosis and abnormal lymphocytes. M protein of the immunoglobulin G (IgG) type was detected using immunoelectrophoresis. A bone marrow biopsy revealed infiltration of small mature lymphocytes, lymphoplasmacytoid cells with Dutcher bodies, grape cells, and Russell bodies. The MYD88 L265P mutation was detected in the abnormal peripheral lymphocytes, and a diagnosis of lymphoplasmacytoid lymphoma was established. MYD88 L265P mutation analysis is useful for making a diagnosis of non-IgM lymphoplasmacytoid lymphoma because it enables the differentiation from other low-grade B-cell malignancies.

[MALT lymphoma accompanied by elevated serum IgM levels mimicking Waldenström's macroglobulinemia].

A 60-year-old man with chronic hepatitis C was referred to our hospital with significantly elevated total protein and serum IgM (9,500 mg/dl) levels identified via a routine checkup. Blood examination revealed increased serum IgM-monoclonal protein and serum-soluble IL-2 receptor (sIL2R) levels. Computed tomography and fluorodeoxyglucose positron emission tomography revealed pulmonary masses, abnormal soft tissue masses surrounding the bilateral kidneys, and thickened mucous membrane of the bladder with high fluorodeoxyglucose uptake. Pathological examination of the pulmonary mass revealed infiltration of medium-sized lymphocytes and plasma cells. Immunohistochemical analysis revealed tumor cells positive for CD138 and IgM, with a low positive rate of Ki-67 expression. Notably, the tumor cell-surrounding lymphocytes were positive for CD20. Although the patient was initially regarded as having Waldenström's macroglobulinemia owing to the significantly increased serum IgM levels, based on positive IgH-MALT1 translocation and negative MYD88 L265P mutation findings, he was further diagnosed with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Complete remission was achieved following six cycles of rituximab + CHOP therapy. This study data suggest that analysis of the MYD88 L265P mutation in tumor cells is suitable for accurately diagnosing hematopoietic malignancies with increased IgM monoclonal protein.

Detection of L265P MYD-88 mutation in a series of clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ).

Clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ) is a recently described entity characterized by the presence of clonal B cells in the blood and/or bone marrow (BM) with morphologic and immunophenotypic features consistent with marginal zone derivation in otherwise healthy individuals. CBL-MZ is commonly associated with paraproteinemia, usually immunoglobulin M (IgM), raising diagnostic difficulties from Waldenstrom macroglobulinemia (WM). The aim of the present study was to determine the presence of MYD-88 L265P mutation in a well-characterized series of CBL-MZ to identify cases that may in fact represent WM. Fifty-three CBL-MZ cases were retrospectively evaluated. MYD-88 L265P mutation was determined by allele-specific polymerase chain reaction in blood and/or BM mononuclear cells. Almost half of the CBL-MZ cases (49%) were associated with paraproteinemia mainly of the IgM type (65%). MYD-88 L265P mutation was identified in 10 cases (19%). These cases may truly represent WM, whereas 43 cases (81%) are still classified as CBL-MZ. Mutated cases were all associated with paraproteinemia compared with 37% of the nonmutated ones (P < .0001). In addition, mutated cases displayed more frequently CD38 and CD25 positivity (P = .002 and P = .005, respectively). Moreover, cases without paraproteinemia presented more frequently with lymphocytosis, irrespective of the presence of the MYD-88 mutation (P = .02). The present study demonstrates that MYD-88 L265P mutation may represent the only sensitive marker for the differentiation of CBL-MZ from probable WM. However, further studies are warranted to better define the biological significance of MYD-88 L265P mutation and to clarify whether the presence of the mutation establishes WM diagnosis or that it can also be present in borderline cases associated with paraproteinemia.

Detection of MYD88 L265P and WHIM-like CXCR4 mutation in patients with IgM monoclonal gammopathy related disease.

A broad spectrum of diseases are associated with IgM monoclonal gammopathy, including Waldenstrom macroglobulinemia (WM), various types of B cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), primary amyloidosis (AL), and monoclonal gammopathy of undetermined significance (MGUS); these are called IgM monoclonal gammopathy related diseases (IgM-RD). We investigated MYD88 L265P and WHIM-like CXCR4 mutations in various IgM-RD. Patients with serum immunofixation electrophoresis confirmed IgM monoclonal gammopathy who had enough material for DNA extraction and presented between January 2008 and October 2016 at Peking Union Medical College Hospital were enrolled in this cohort. We performed real-time allele-specific-polymerase chain reaction and Sanger sequencing to explore the presence of MYD88 L265P and WHIM-like CXCR4 mutations. One hundred and twelve patients (64 male and 48 female patients) were included in this retrospective study. The median age at diagnosis was 62 years (range, 30-84 years). In total, 64 patients (57.1%) carried the MYD88 L265P mutation and 14 patients (12.5%) carried the CXCR4 WHIM-like mutation. We identified the MYD88 L265P somatic variant in cases with WM (39/42), MGUS (8/18), NHL (14/41, including 4/13 diffuse large B cell lymphoma (DLBCL), 1/8 mucosa-associated lymphoid tissue, 3/6 splenic marginal zone lymphoma (SMZL), 1/4 chronic lymphocytic leukemia, 2/3 nodal marginal zone lymphoma (NMZL), 1/2 mantle cell lymphoma, 1 Burkitt lymphoma, and 1 B cell NHL that could not be classified), primary AL (2/2), and IgM-PN (1/1). The mutation was absent in five patients with Cryoglobulinemia, two with primary cold agglutinin disease and one with MM. The CXCR4 WHIM-like mutation was present in 10/42 patients with WM, 3/41 with NHL (1 DLBCL, 1 SMZL, and 1 NMZL), and 1/18 patients with IgM MGUS. Among the patients with NHL, those with the mutated MYD88 L265P genotype were younger and had lower level of IgG and IgA than the patients with the wild-type genotype. Patients with the mutated MYD88 L265P genotype with WM and MZL were compared. More male patients, higher levels of IgM and lower levels of LDH were found in the WM group. There was no significant difference in overall survival between the two groups. We present a study of the prevalence of the MYD88 L265P mutation and CXCR4 WHIM-like mutation in IgM RD. The MYD88 L265P mutation may play a key role in the pathogenesis of IgM monoclonal gammopathies. It would be interesting in the future to use MYD88 mutation status to differentiate among diseases.

MYD88 L265P mutation in cutaneous involvement by Waldenström macroglobulinemia.

Cutaneous manifestations of Waldenström macroglobulinemia (WM) may occur because of several mechanisms, the least common being direct skin infiltration by neoplastic cells. We report a case of patient that after 4-year history of indolent WM developed skin infiltration by lymphoplasmacytoid cells in the form of a small, mildly indurated plaque on the anterior chest. MYD88 L265P mutation was detected both in the previous bone marrow biopsy and in the cutaneous lesion. We review the impact of this new genetic tool in the diagnosis and treatment of lymphoplasmacytic proliferations.

Myelodysplastic syndrome with 5q deletion following IgM monoclonal gammopathy, showing gene mutation MYD88 L265P.

Patients affected by monoclonal gammopathy of undetermined significance (MGUS) very rarely develop a myelodysplastic syndrome (MDS). However, it was also demonstrated that MGUS patients had a significantly increased risk of developing MDS compared to the general population. We report a case of 5q-syndrome following a MGUS IgMk with mutation of MYD88 L256P. To our knowledge, this is the first case of del(5q) MDS following MGUS IgMk with the MYD88 L256P mutation in which there is coexistence of the markers of the two clonal diseases, but as an expression of distinct pathological features.

Transient Bacillary Layer Detachment During the Disease Course of Primary Vitreoretinal Lymphoma.

PURPOSE: To report the clinical course and the retinal imaging features of a case of cytology-proven primary vitreoretinal lymphoma (PVRL) presenting with a transient bacillary layer detachment (BALAD) during the disease course. METHODS: Observational case report. RESULTS: A 50 year-old woman was referred to us with a 2-month history of vitritis in both eyes, poorly responding to oral prednisolone. After discontinuation of oral prednisolone, worsening of vitritis and the appearance of multiple creamy-like subretinal infiltrates in the mid-peripheral retina of both eyes, along with the exclusion of common causes of intermediate/posterior uveitis, made us consider PVRL. Aqueous humor sampling detected MYD88 L265P mutation, and subsequent diagnostic pars plana vitrectomy in the left eye yielded a positive cytology for large B cell lymphoma consistent with PVRL. During the disease course, optical coherence tomography of the macula showed a BALAD in the right eye, which resolved during follow-up. CONCLUSION: Our case indicates that BALAD is a possible rare manifestation of PVRL, and this should be considered in the differential diagnosis process in order to avoid diagnostic delays.

Aqueous Humor-Derived MYD88 L265P Mutation Analysis in Vitreoretinal Lymphoma: A Potential Less Invasive Method for Diagnosis and Treatment Response Assessment.

PURPOSE: To investigate whether MYD88 L265P mutation, which is frequently present in vitreoretinal lymphoma, can be detected in aqueous humor, a specimen that can be obtained in a clinic setting, potentially mitigating the need for more invasive vitrectomy procedures, and whether this approach can be used to monitor treatment response. DESIGN: Observational case series. SUBJECTS: Patients who were diagnosed with biopsy-confirmed or clinically diagnosed vitreoretinal lymphoma or biopsy-confirmed vitritis. METHODS: We evaluated aqueous humor-derived (AHD) MYD88 L265P mutation during vitreous biopsy or at the initial presentation in the clinic if vitreous biopsy was not feasible. Demographic or clinical features of patients were retrospectively reviewed. Aqueous humor-derived MYD88 L265P mutation was re-evaluated after patients completed a course of intravitreal methotrexate and rituximab injection therapy. The NM_002468.4: c.794T>C (p.L265P) mutation in the MYD88 gene was evaluated in AHD cellular and cell-free DNA using allele-specific polymerase chain reaction. MAIN OUTCOME MEASURES: Detection of AHD MYD88 L265P mutation at the initial diagnosis and to monitor the treatment response. RESULTS: Aqueous humor from 18 eyes of 14 patients with biopsy-confirmed or clinically diagnosed vitreoretinal lymphoma and 3 eyes of 3 patients with biopsy-confirmed vitritis were evaluated. Aqueous humor-derived MYD88 L265P mutation was detected in cell-based and cell-free DNA from 15 (83%) of 18 eyes with biopsy-confirmed or clinically diagnosed vitreoretinal lymphoma but not identified in any of the 3 eyes with vitritis. The mutation was less readily detectable in cellular DNA (10 of 18) compared with cell-free DNA (15 of 18). Furthermore, aqueous sampling after intravitreal methotrexate and rituximab injection therapy revealed absence of this mutation after complete response in 7 eyes. The mutation was detected in 1 eye that developed recurrence in a posttreatment window of 6 months. After a mean of follow-up of 9 months, there was no clinical evidence of vitreoretinal lymphoma recurrence in the 7 eyes with no detectable AHD MYD88 L265P mutation. CONCLUSIONS: This investigational study suggests that AHD MYD88 L265P can be detected in eyes with lymphoma and may thus serve as a surrogate, less invasive biopsy in the diagnosis and follow-up of vitreoretinal lymphoma, particularly when cell-free DNA is evaluated.

Evaluation and Management of Disease Transformation in Waldenström Macroglobulinemia.

Histologic transformation (HT) to diffuse large B-cell lymphoma occurs rarely in Waldenström macroglobulinemia, with higher incidence in MYD88 wild-type patients. HT is suspected clinically when rapidly enlarging lymph nodes, elevated lactate dehydrogenase levels, or extranodal disease occur. Histologic assessment is required for diagnosis. HT carries a worse prognosis compared with nontransformed Waldenström macroglobulinemia. A validated prognostic score based on three adverse risk factors stratifies three risk groups. The most common frontline treatment is chemoimmunotherapy, such as R-CHOP. Central nervous system prophylaxis should be considered if feasible and consolidation with autologous transplant should be discussed in fit patients responding to chemoimmunotherapy.

Prognosis of a Chinese patient with chronic lymphocytic leukemia who acquired a TP53 mutation following treatment with a BTK inhibitor.

Chronic lymphocytic leukemia (CLL) is a common type of adult leukemia that occurs in Western countries, and its incidence has gradually increased in China in recent years. The characteristics of CLL are highly heterogeneous. Despite promising response rates achieved with targeted therapy, new targets still need to be expanded due to the heterogeneous of disease. Bruton's tyrosine kinase inhibitor (BTKi) has been used in the treatment of TP53 mutation. In this report, we present a case with myeloid differentiation primary response 88 (MYD88) mutation who developed a TP53 mutation after application of BTKi. Here, the patient was CLL unmutated (U-CLL) with MYD88 (L265P) mutation before initial treatment. After traditional treatment, the effect was not good, and BTKi was used for treatment, then TP53 mutation appeared. It is well known that immunoglobulin heavy chain unmutated (IGHV-U) and TP53 mutation in CLL indicate poor prognosis. The case suggests that whenever TP53 mutation occurs, BTKi is the best choice. This result is considered to be related to signal pathways. We aim to add to the collective knowledge by highlighting this rare cases of CLL with MYD88 (L265P) mutation in an Asian patient.

IgM Plasma Cell Myeloma.

OBJECTIVES: Immunoglobulin M plasma cell myeloma (IgMPCM) is a rare entity that is difficult to distinguish from other IgM-related neoplasms. The study aims to characterize the clinicopathologic features of IgMPCM, including MYD88 L265P and CXCR4 mutations. METHODS: From our institutional archives, bone marrow biopsy specimens from January 1, 2008, to December 1, 2018, with monotypic plasma cells (PCs) expressing IgM that met current International Myeloma Working Group/World Health Organization criteria for PCM were included. Sanger sequencing was used to test for MYD88 L265P and WHIM-like CXCR4 mutations. RESULTS: Nine cases of IgMPCM were identified. Serum IgM paraproteins were detected in eight cases. CD138-positive PC burden averaged 41.9% (5%-80%). In four cases, PCs had lymphoplasmacytic morphology with cyclin D1 expression by immunohistochemistry. Three of four tested cases were positive for t(11;14) by fluorescence in situ hybridization, one with monosomy 13. The remaining case was positive for del13q14. All were negative for MYD88 L265P and WHIM-like CXCR4 mutations. Eight patients received immunochemotherapy, with four receiving autologous hematopoietic stem cell transplant. Median follow-up was 61 months (range, 11-120). All patients were alive except one. CONCLUSIONS: Distinguishing IgMPCM from other IgM-related disorders requires correlation with clinical, laboratory, and radiologic findings. Exclusion of MYD88 L265P and WHIM-like CXCR4 mutations may be useful to diagnose IgMPCM.

Lymphoplasmacytic lymphoma with IgG-κ paraproteinemia presenting as a hepatic bulky mass.

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.

A Case of Spontaneous Regression and Recurrence of Primary Vitreoretinal Lymphoma.

PURPOSE: To report a case of primary vitreoretinal lymphoma (PVRL) showing recurrence after spontaneous regression, diagnosed with the aid of next-generation sequencing (NGS). METHODS: Retrospective case report. RESULTS: A 61-year-old immunocompetent Korean woman presented with subretinal lesions suspected of PVRL, which resolved spontaneously in 2 months. After 8 months, the lesion recurred and diagnostic vitrectomy was performed. The cytologic examination of the vitreous was indeterminate as there was only minimal vitreous opacity present at the time of surgery. NGS identified significant mutations including single nucleotide variants in MYD88 L265P, which is a unique hallmark of VRL, in vitreous sample, and the diagnosis of PVRL was made. CONCLUSION: This case showed PVRL can spontaneously regress almost completely, then recur, so careful ophthalmic and systemic follow-ups are warranted. When cytological confirmation is challenging due to the minimal disease involvement in the vitreous, NGS is effective in confirming the mutation profiles of PVRL.

Monitoring of MYD88 L265P mutation by droplet digital polymerase chain reaction for prediction of early relapse in a patient with Bing-Neel syndrome.

Bing-Neel syndrome (BNS) is a rare neurologic complication of lymphoplasmacytic lymphoma (LPL) characterized by direct infiltration of lymphoplasmacytic cells (LPCs). Although no standard treatment has yet been established, patients with BNS harboring the MYD88 L265P mutation have been reported to respond favorably to ibrutinib, which can cross the blood-brain barrier and trigger apoptosis of MYD88 L265P-positive LPCs. However, it is still unclear whether monitoring of MYD88 L265P mutation status would be useful for predicting relapse/progression or for assisting diagnosis and evaluating response to chemotherapy. Here, we report the case of a patient with BNS receiving ibrutinib in whom we detected relapse early by monitoring for molecular residual disease (MRD) based on the presence of the MYD88 L265P mutation in cerebrospinal fluid (CSF) on droplet digital polymerase chain reaction assay. Persistent MRD increased 2 weeks before the onset of relapse symptoms without any abnormal imaging findings or evidence of clonal LPCs on CSF cytology, flow cytometry analysis, or immunofixation electrophoresis. Our findings suggest that an increase in MRD levels is correlated with relapse in patients with BNS.

Clinicopathologic significance of MYD88 L265P mutation and expression of TLR4 and P-STAT3 in primary central nervous system diffuse large B-cell lymphomas.

Patients with primary central nervous system lymphoma (PCNSL) have a prognosis poorer than that of systemic lymphoma patients. In patients with this condition, TLR4/STAT3 pathway alterations and the MYD88 L265P mutation may be viable targets for therapeutic intervention. The present study was, therefore, designed to identify clinicopathologic correlates of MYD88 mutations and TLR4/STAT3 pathway alterations in PCNSL. We detected TLR4 and p-STAT3 in 41.5% (22/53) and 43.4% (23/53) of PCNSL patients, respectively, while 60.4% of these patients (32/53) were found to harbor the MYD88 L265P mutation. TLR4 expression was found to be significantly associated with the presence of multiple brain lesions, while p-STAT3 expression was significantly linked to advanced age, the presence of multiple brain lesions, non-GCB histological findings, and non-CR status. The presence of the MYD88 L265P mutation was significantly linked to advanced age, the presence of multiple brain lesions, and DLBCL molecular subtype. Multivariate analyses additionally confirmed that elevated TLR4 and p-STAT3 expression levels are associated with a poorer PCNSL patient prognosis. Based on these findings, we hypothesize that signaling through the TLR4/MYD88/STAT3 pathway plays a key role in the pathogenesis of PCNSL.