Interference in HbA1c measurement: a case of electropherogram shift due to hyperleukocytosis leading to the discovery of leukemic mantle cell lymphoma.

HbA1c is a pivotal biomarker in diabetes management, reflecting long-term glycaemic control. HbA1c is often measured with capillary electrophoresis, which generally is a very precise technique, but there can be interference, especially in the case of haemoglobin diseases. Thus, in patients with underlying conditions, the accurate measurement of HbA1c can be challenging. We present a case of special interference in a 74-year-old female patient referred to a HbA1c test, in whom the measurement was thought to be significantly affected by hyperleukocytosis and led to an unexpected diagnosis of leukemic low-grade lymphoma. This case report highlights the underrecognized potential interference of leukocytosis in HbA1c measurement. It underscores the importance of clinical vigilance when interpreting HbA1c results in patients with underlying haematological conditions.

Warthin tumor concomitant with mantle cell lymphoma: a case report and review of literature.

RATIONALE: Warthin tumor (WT) is the second most common benign tumor in salivary gland. It has a slow growth rate and most frequently occurs in the parotid gland. Most patients present with an incidental finding of a painless mass inferior/anterior to the ear. Besides the epithelial component of the tumor, WT is characteristically associated with lymphoid stroma that is considered benign. While there have been a few reports of malignant transformation of the lymphoid components in WT, cases of WT concomitant with mantle cell lymphoma (MCL) are extremely rare. To the best of our knowledge, two cases have been described in the English literature. Herein, we report a case of WT concomitant with MCL in a 70-year-old female patient, and emphasize the importance of careful examination of lymphoid stroma in WT so that concurrent lymphoma is not missed. PATIENT CONCERNS: A 70-year-old Chinese woman with a 40-year history of cigarette smoking presented with a one year history of a right submaxillary mass with recent enlargement. DIAGNOSIS: Cervical ultrasound (US) and computed tomography (CT) scans of the neck revealed a well-circumscribed mass in the right parotid with a maximum diameter of 3.1 cm. Surgical resection of the mass was performed. Histopathological examination revealed a characteristic double-layer of neoplastic epithelium with prominent lymphoid stroma, suggesting WT. In addition, morphology and immunohistochemistry studies confirmed the coexistence of MCL. Thereafter, the final diagnosis of this case was WT concomitant with MCL. INTERVENTIONS: The patient was staged as stage I after clinical assessment. Due to the slow growth of parotid lesions, close observation was decided with periodic clinical and radiological monitoring. OUTCOMES: Currently, the patient demonstrates a stable disease by clinical evaluation. LESSONS: To the best of our knowledge, reported cases of WT concomitant with MCL are very rare. This case highlights the importance of a comprehensive assessment of the lymphoid stroma of WT to avoid missed diagnosis of a lymphoma component in a collision tumor.

Diagnosis and treatment of secondary nephrotic syndrome with rash as the first symptom: a case report.

BACKGROUND: Membranous nephropathy (MN) is a common type of nephrotic syndrome (NS) in adults, accounting for about 20-30% of cases. Although secondary to specific factors, the coexistence of MN and mantle cell lymphoma (MCL) has been scarcely reported in clinical literature. CASE PRESENTATION: A 59-year-old Chinese male was admitted to the hospital with a generalized pruritic rash with bilateral lower extremity edema, which did not improve significantly after symptomatic treatment. He had undergone renal biopsy, and the diagnosis was thought to be secondary MN (SMN), therefore, we did a lymph node biopsy on the patient and found that MN was complicated with MCL. Soon after, the patient was admitted to the hematology department for a BR chemotherapy regimen (composed of bendamustine 90 mg/m2 BSA (body surface area), rituximab 375 mg/m2 BSA and dexamethasone 5 mg), and during the post-treatment follow-up, both his symptoms and renal function improved. CONCLUSIONS: The mechanism underlying the combination of SMN and MCL remains elusive and exceedingly rare, consequently often overlooked in clinical practice. This case serves to offer valuable clinical insights for diagnosis and treatment, while emphasizing the pivotal role of renal pathology in clinical assessment.

Insight into Mantle Cell Lymphoma Pathobiology, Diagnosis, and Treatment Using Network-Based and Drug-Repurposing Approaches.

Mantle cell lymphoma (MCL) is a rare, incurable, and aggressive B-cell non-Hodgkin lymphoma (NHL). Early MCL diagnosis and treatment is critical and puzzling due to inter/intra-tumoral heterogeneity and limited understanding of the underlying molecular mechanisms. We developed and applied a multifaceted analysis of selected publicly available transcriptomic data of well-defined MCL stages, integrating network-based methods for pathway enrichment analysis, co-expression module alignment, drug repurposing, and prediction of effective drug combinations. We demonstrate the "butterfly effect" emerging from a small set of initially differentially expressed genes, rapidly expanding into numerous deregulated cellular processes, signaling pathways, and core machineries as MCL becomes aggressive. We explore pathogenicity-related signaling circuits by detecting common co-expression modules in MCL stages, pointing out, among others, the role of VEGFA and SPARC proteins in MCL progression and recommend further study of precise drug combinations. Our findings highlight the benefit that can be leveraged by such an approach for better understanding pathobiology and identifying high-priority novel diagnostic and prognostic biomarkers, drug targets, and efficacious combination therapies against MCL that should be further validated for their clinical impact.

Epidemiological, clinical and therapeutic profiles of mantle cell lymphoma cared for in a Moroccan center: a review of 14 cases.

Mantle cell lymphoma (MCL) accounts for 3-10% of non-Hodgkin's lymphomas (NHL). We identified 14 patients with mantle cell lymphoma, with an average number of 3.5 new cases/year. A male predominance was observed with a sex ratio equal to 6. The average age of our patients was 64.4±14.1 years, with an average diagnostic delay of 6.57 months. Regarding the clinical presentation, adenopathy was the most reported physical sign (78.6%) followed by B symptoms (57.1%). Disseminated stages were the most frequent in our series: stages IV (78.5%) and III (7.1%) versus stages I (0%) and II (7.1%). The extra-ganglionic localizations observed were hepatic 5 cases (31.1%), pulmonary 04 cases (25%), medullary 4 cases (25%), pleural 2 cases (12.5%) and prostate 1 case (6.2%). All diagnosed cases are mantle cell lymphomas, of which 12 cases (85.7%) are classical and 2 cases (14.3%) indolent. The high-risk group is, according to international prognostic index (MIPI) MCL prognostic score, the most represented in our series: 0-3 = 6 cases (42.9%), 6-11 = 8 cases (57.1%). The therapeutic protocol chosen 1st line: 9 patients treated with R-DHAP, three with R-CHOP, one with DHAOX and one with R-CVP. Second line: two patients treated with R-DHAP, one after R-CHOP and the other after R-CVP. Two patients received autologous hematopoietic stem cell transplant at the end of the treatment. The evolution was marked by the death of 7 patients, 3 lost to follow-up and 4 still followed. Additionally, the study highlights characteristics and treatment patterns of mantle cell lymphoma, emphasizing its predominance in males, delayed diagnosis, frequent dissemination, and high-risk classification, with chemotherapy as the primary treatment modality and a challenging prognosis contributing to a comprehensive understanding of mantle cell lymphoma presentation and management.

Colonic lymphomatous polyposis mantle cell lymphoma: a case report and review of literature.

INTRODUCTION: Mantle cell lymphoma is a rare lymphoma of the gastrointestinal tract that may present as multiple lymphomatous polyposis. We report a case of lymphomatous polyposis with a review of the literature. CASE REPORT: A 56-year-old man of Black ethnicity and Ivorian nationality with no relevant past medical history, consulted for a sudden onset symptoms of gastrointestinal obstruction, which evolved over 2 days. Macroscopic examination revealed the presence of multiple polyploid formations of the colonic mucosa. Histology showed diffuse lymphomatous proliferation of submucosa consisting off small lymphoid cells with a hyperchromatic crenelated nucleus, suggesting lymphomatous polyposis. Immunohistochemical examination showed expression by the tumor cells of antibodies to CD20, CD5, Bcl2, and cyclin D1. They did not express antibodies to CD10 and CD23. The Ki67 proliferation index was 25%. We have thus retained the diagnosis of mantle cell lymphomatous polyposis. CONCLUSION: Multiple lymphomatous polyposis is a rare entity characterized by the presence of numerous gastrointestinal polyploid lesions sometimes involving several segments of the gastrointestinal tract. Typical lymphoma presenting as lymphomatous polyposis is mantle cell lymphoma; although, other tumors may have this aspect.

Identification of CD5/SOX11 double-negative pleomorphic mantle cell lymphoma.

Cyclin D1 protein-positive diffuse large B cell lymphoma (DLBCL) has an immunophenotype of CD5(-) cyclin D1(+) SOX11(-), and most cases lack a CCND1 rearrangement and have a gene expression profile of DLBCL. Rarely, cyclin D1 protein-positive DLBCL harbors a CCND1 rearrangement, and some genetic copy number features typical of mantle cell lymphoma (MCL) have been detected. Since gene expression studies have not been performed, whether such CCND1-rearranged cases represent cyclin D1 protein-positive DLBCL or CD5/SOX11 double-negative pleomorphic MCL remains unclear. To date, no cases of CD5/SOX11 double-negative MCL have been reported. In this study, we collected eight cases initially diagnosed as cyclin D1 protein-positive DLBCL, including four with a CCND1 rearrangement and four without. Immunohistochemically, all four CCND1-rearranged cases had >50% of tumor cells positive for cyclin D1 protein, whereas only one (25%) non-rearranged case had >50% positive tumor cells. Analysis of genome-wide copy number, mutational, and gene expression profiles revealed that CCND1-rearranged cases were similar to MCL, whereas CCND1-non-rearranged cases resembled DLBCL. Despite the SOX11 negativity by immunohistochemistry, CCND1-rearranged cases had a notable trend (P = 0.064) of higher SOX11 mRNA levels compared to non-rearranged cases. Here, we show for the first time that CCND1 rearrangement could be useful for identifying CD5/SOX11 double-negative pleomorphic MCL in cases diagnosed as cyclin D1 protein-positive DLBCL. Cases with >50% cyclin D1 protein-positive tumor cells immunohistochemically and higher SOX11 mRNA levels are more likely to have a CCND1 rearrangement, and fluorescence in situ hybridization can be used to detect the rearrangement.

Biological and clinical determinants shaping heterogeneity in mantle cell lymphoma.

ABSTRACT: Mantle cell lymphoma (MCL) is an uncommon mature B-cell lymphoma that presents a clinical spectrum ranging from indolent to aggressive disease, with challenges in disease management and prognostication. MCL is characterized by significant genomic instability, affecting various cellular processes, including cell cycle regulation, cell survival, DNA damage response and telomere maintenance, NOTCH and NF-κB/ B-cell receptor pathways, and chromatin modification. Recent molecular and next-generation sequencing studies unveiled a broad genetic diversity among the 2 molecular subsets, conventional MCL (cMCL) and leukemic nonnodal MCL (nnMCL), which may partially explain their clinical heterogeneity. Some asymptomatic and genetically stable nnMCL not requiring treatment at diagnosis may eventually progress clinically. Overall, the high proliferation of tumor cells, blastoid morphology, TP53 and/or CDKN2A/B inactivation, and high genetic complexity influence treatment outcome in cases treated with standard regimens. Emerging targeted and immunotherapeutic strategies are promising for refractory or relapsed cases and a few genetic and nongenetic determinants of refractoriness have been reported. This review summarizes the recent advances in MCL biology, focusing on molecular insights, prognostic markers, and novel therapeutic approaches.

A Rare Case of Laryngeal Mantle Cell Lymphoma.

This case report describes an 80-year-old woman presenting to her primary care practitioner after several months of a persistent globus sensation and throat fullness.

Monocyte-to-platelets ratio (MPR) at diagnosis is associated with inferior progression-free survival in patients with mantle cell lymphoma: a multi-center real-life survey.

Mantle cell lymphoma (MCL) pathogenesis is strongly related to the role of the tumor immune microenvironment (TIME) in which MCL cells proliferate. TIME cells can produce growth signals influencing MCL cells' survival and exert an antitumoral immune response suppression. The activity of TIME cells might be mirrored by some ratios of peripheral blood cell subpopulations, such as the monocyte-to-platelet ratio (MPR). We reviewed the clinical features of 165 consecutive MCL patients newly diagnosed and not eligible for autologous stem cell transplantation (both for age or comorbidities) who accessed two Italian Centers between 2006 and 2020. MPR was calculated using data obtained from the complete blood cell count at diagnosis before any cytotoxic treatment and correlated with PFS. Univariate analysis showed that MPR ≥ 3 was associated with inferior PFS (p = 0.02). Multivariate analysis confirmed that MPR ≥ 3, LDH > 2.5 ULN, and bone marrow involvement were significant independent variables in predicting PFS. For these reasons, MPR ≥ 3 seems the most promising prognostic factor in patients with MCL, and it could be considered a variable in new predictive models.

Mantle Cell Lymphoma Under the Scope of Personalized Medicine: Perspective and Directions.

Mantle cell lymphoma (MCL) is a rare, incurable non-Hodgkin's lymphoma characterized by naive B cells infiltrating the lymphoid follicle's mantle zone. A key feature of MCL is the cytogenetic abnormality t(11;14) (q13:q14), found in 95% of cases, leading to Cyclin D1 overexpression resulting in uncontrolled cell cycle progression and genetic instability. Occasionally, Cyclin D2 or D3 overexpression can substitute for Cyclin D1, causing similar effects. The transcription factor SOX11 is a hallmark of classical Cyclin D1-positive MCL and also in cases without the typical t(11;14) abnormality, making it an important diagnostic marker. MCL's development necessitates secondary genetic changes, including mutations in the ATM, TP53, and NOTCH1 genes, with the TP53 mutation being the only genetic biomarker with established clinical prognostic value. The Mantle Cell Lymphoma International Prognostic Index (MIPI) score, which considers age, performance status, serum LDH levels, and leukocyte count, stratifies patients into risk groups. Histologic variants of MCL, such as classic, blastoid, and pleomorphic, offer additional prognostic information. Recent research highlights new mutations potentially tied to specific populations among MCL patients, suggesting the benefit of personalized management for better predicting outcomes like progression-free survival. This approach could lead to more effective, risk-adapted treatment strategies. However, challenges remain in patient stratification and in developing new therapeutic targets for MCL. This review synthesizes current knowledge on genetic mutations in MCL and their impact on prognosis. It aims to explore the prognostic value of genetic markers related to population traits, emphasizing the importance of tailored molecular medicine in MCL.

Front-line and second-line treatment for mantle cell lymphoma in clinical practice: A multicenter retrospective analysis.

BACKGROUND: There are few reports of clinical practice treatment patterns and efficacy in mantle cell lymphoma (MCL). MATERIALS AND METHODS: We retrospectively studied a large, multicenter, cohort of patients with MCL diagnosed between 2000 and 2020 in eight institutions. RESULTS: 536 patients were registered (73% male, median of 70 years). Front-line treatment was based on high-dose cytarabine, bendamustine, and anthracyclines in 42%, 12%, and 15%, respectively. The median PFS for all patients was 45 months; 68, 34, and 30 months for those who received high-dose cytarabine-based, bendamustine-based and anthracycline-based therapy. 204 patients received second-line. Bendamustine-based treatment was the most common second-line regimen (36% of patients). The median second-line PFS (sPFS) for the entire cohort was 14 months; 19, 24, and 31 for bendamustine-, platinum-, and high-dose cytarabine-based regimens, with broad confidence intervals for these latter estimates. Patients treated with cytarabine-based therapies in the front-line and those with front-line PFS longer than 24 months had a substantially superior sPFS. CONCLUSION: Front-line treatment in this cohort of MCL was as expected and with a median PFS of over 3.5 years. Second-line treatment strategies were heterogeneous and the median second-line PFS was little over 1 year.

The influence of marital status at diagnosis on survival of adult patients with mantle cell lymphoma.

PURPOSE: Marital status has been reported to influence the survival outcomes of various cancers, but its impact on patients with mantle cell lymphoma (MCL) remains unclear. This study aimed to assess the influence of marital status at diagnosis on overall survival (OS) and cancer-specific survival (CSS) in patients with MCL. METHODS: The study utilized data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)-18 databases, including 6437 eligible individuals diagnosed with MCL from 2000 to 2018. A 1:1 propensity matching method (PSM) minimized confounding factor. Univariate and multivariate analyses determined hazard ratios (HR). Stratified hazard models were developed for married and unmarried statuses across time intervals. RESULTS: Married patients exhibited better 5-year OS and CSS rates compared to unmarried patients (54.2% vs. 39.7%, log-rank p < 0.001; 62.6% vs. 49.3%, log-rank p < 0.001). Multivariate analysis indicated that being unmarried was an independent risk factor for OS (adjusted HR 1.420, 95% CI 1.329-1.517) and CSS (adjusted HR 1.388, 95% CI 1.286-1.498). After PSM, being unmarried remained an independent risk factor for both OS and CSS. Among unmarried patients, widowed individuals exhibited the poorest survival outcomes compared to patients with other marital statuses, with 5-year OS and CSS rates of 28.5% and 41.0%, respectively. Furthermore, in the 10-year OS and CSS hazard model for widowed individuals had a significantly higher risk of mortality, with the probability of overall and cancer-specific mortality increased by 1.7-fold and 1.6-fold, respectively. CONCLUSION: Marital status at diagnosis is an independent prognostic factor for MCL patients, with widowed individuals showing worse OS and CSS than those who are married, single, or divorced/separated. Adequate psychological and social support for widowed patients is crucial for improving outcomes in this patient population.

Mixed-methods research to support the use of new lymphoma-specific patient-reported symptom measures derived from the EORTC item library.

BACKGROUND: No specific measures exist to assess patient-reported symptoms experienced by individuals with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or mantle cell lymphoma (MCL). This study was conducted to elicit patient-reported CLL/SLL- and MCL-related symptoms and their impact on patients' lives. The study qualitatively and quantitatively evaluated sets of conceptually-selected EORTC Item Library items for assessing CLL/SLL- and MCL-related symptoms. METHODS: The qualitative component of the research included a literature review, clinician consultations, and patient interviews. Concepts important to patients were identified and coded; cognitive debriefing of the selected library items was completed with patients. CLL/SLL and MCL-related symptoms and impacts were organized in a structured conceptual model, which was mapped to item sets from the Item Library. The quantitative component comprised exploratory macro-level Rasch measurement theory (RMT) analysis conducted to provide supportive quantitative insight on the item sets. RESULTS: 41 patients (21-MCL; 20-CLL/SLL) and 5 clinicians participated in the qualitative study; 57 unique patients (30-MCL; 27-CLL/SLL) completed the EORTC items. The conceptual models generated from the qualitative work included symptoms and functional impacts of CLL/SLL and MCL. Symptom domains included swollen lymph nodes, B symptoms, abdominal issues, pain, fatigue, subjective cognitive impairment, anemia-related symptoms, bleeding, infection, and other issues (appetite loss, temperature fluctuation, rash, weight gain, sleep problems, cough). Impacts included physical function, role function, and other functions (psychological, social). Cognitive debriefing demonstrated that the separate item sets for CLL/SLL and MCL-related symptoms were well understood and aligned with patients' experiences. All selected items were included in the conceptual models. The exploratory RMT analysis showed that the item sets provided adequate coverage of the continuum of CLL/SLL- and MCL-related symptom severity. CONCLUSIONS: This study gathered qualitative and early quantitative evidence supporting use of the EORTC Item Library to assess CLL/SLL- and MCL-related symptoms and impacts. These items are promising candidates for measurement of patient-reported disease symptoms in these populations. A larger sample size will be essential to establish the psychometric properties necessary to support use in clinical trials. Patients who suffer from rare cancers of the blood, bone marrow, and lymph nodes can experience chronic and debilitating symptoms. At present, however, there are no dedicated instruments for assessing the patient's experience of symptoms of conditions like chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or mantle cell lymphoma (MCL), or for assessing their impact on patients' lives. This research project aimed to address that need. The researchers selected relevant and clinically meaningful symptoms from the EORTC Item Library that assess fatigue, B symptoms, and CLL/SLL- and MCL-specific symptoms. Using patients and clinician interviews as well as quantitative analyses, the research revealed no major concerns with using these item sets to assess symptoms of CLL/SLL and MCL. Interviews with patients demonstrated that the separate item sets for CLL/SLL and MCL-related symptoms were well understood and aligned with patients' experiences. All selected items were included in the conceptual models. Item sets identified in this study can potentially be used to assess patient-reported symptom endpoints in clinical trial settings in these disease areas.

Immunoglobulin High Throughput Sequencing (Ig-HTS) Minimal Residual Disease (MRD) Analysis is an Effective Surveillance Tool in Patients With Mantle Cell Lymphoma.

INTRODUCTION: Mantle cell lymphoma (MCL) accounts for 4% to 6% of B-cell non-Hodgkin lymphoma with historically poor outcomes. With the advent of intensive first-line, targeted, and cellular therapies, outcomes have improved, and initial remission can be 8 to 10 years or longer. As patients experience longer remissions, this raises the question of the optimal surveillance modality. Peripheral blood minimal residual disease (MRD) analysis offers a potential alternative to surveillance imaging that is sensitive, less costly, and eliminates the risk of radiation exposure. MATERIALS AND METHODS: The clonoSEQ assay (Adaptive Biotechnologies) is an FDA-cleared commercially available Ig-HTS MRD assay with a sensitivity of 1 cell in 1,000,000. We performed a retrospective analysis of 34 patients from 2015 to 2021, who underwent MRD testing after achieving remission with first-line therapy. RESULTS: With a median follow-up of 6.5 years, 10-year progression free survival (PFS) was 60% and 10-year overall survival was 92% of the entire cohort. Among 12 patients who sustained a radiographic relapse, peripheral blood became MRD+ either at or prior to the time of relapse in 11 patients (92%). The first MRD+ test had a lead time of 0 to 24 months (median 34 days) prior to radiographic relapse. Only 1 patient had a MRD- result while being found to have progressive disease on imaging. Among 22 patients who sustained continuous clinical remission, 21 have remained MRD-. Several patients were able to enjoy 2 to 4-year intervals without surveillance imaging. CONCLUSIONS: Our data suggest that the clonoSEQ MRD assay is an effective surveillance tool for MCL patients following first-line therapy and is predictive of relapse prior to imaging.

MYC protein is a high-risk factor in mantle cell lymphoma and identifies cases beyond morphology, proliferation and TP53/p53 - a Nordic Lymphoma Group study.

The transcription factor MYC is a well-described oncogene with an important role in lymphomagenesis, but its significance for clinical outcome in mantle cell lymphoma (MCL) remains to be determined. We performed an investigation of the expression of MYC protein in a cohort of 251 MCL patients complemented by analyses of structural aberrations and mRNA, in a sub-cohort of patients. Fourteen percent (n=35) of patients showed high MYC protein expression with >20% positive cells (MYChigh), among whom only one translocation was identified, and 86% (n=216) of patients showed low MYC protein expression. Low copy number gains of MYC were detected in ten patients, but with no correlation to MYC protein levels. However, MYC mRNA levels correlated significantly to MYC protein levels with a R2 value of 0.76. Patients with a MYChigh tumor had both an independent inferior overall survival and an inferior progression-free survival (hazard ratio [HR]=2.03, 95% confidence interval [95% CI]: 1.2-3.4 and HR=2.2, 95% CI: 1.04-4.6, respectively) when adjusted for additional high-risk features. Patients with MYChigh tumors also tended to have additional high-risk features and to be older at diagnosis. A subgroup of 13 patients had concomitant MYChigh expression and TP53/p53 alterations and a substantially increased risk of progression (HR=16.9, 95% CI: 7.4-38.3) and death (HR=7.8, 95% CI: 4.4-14.1) with an average overall survival of only 0.9 years. In summary, we found that at diagnosis a subset of MCL patients (14%) overexpressed MYC protein, and had a poor prognosis but that MYC rearrangements were rare. Tumors with concurrent MYC overexpression and TP53/p53 alterations pinpointed MCL patients with a dismal prognosis with a median overall survival of less than 3 years. We propose that MYC needs to be assessed beyond the current high-risk factors in MCL in order to identify cases in need of alternative treatment.