Cytomegalovirus-driven early-onset lymphocytosis in hematopoietic allogeneic transplant mimicking a T-cell lymphoma progression.

Hepatosplenic T-cell lymphoma (HSTCL) is an uncommon and highly aggressive subtype of peripheral T-cell lymphoma characterized by liver, spleen, and bone marrow involvement. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative treatment for HSTCL, but it carries a significant risk of relapse. Cytomegalovirus (CMV) reactivation is a frequent complication after alloHSCT, particularly in patients undergoing lymphocyte-toxic therapies. A 27-year-old man diagnosed with HSTCL underwent an alloHSCT with active disease after six lines of therapy. A CMV reactivation was successfully treated with foscarnet. A sudden reappearance of symptomatic lymphocytosis (15,550/µL) by day +20, prior to engraftment, raised suspicion of disease progression. A comprehensive diagnostic work-up revealed an oligoclonal expansion of donor lymphocytes along with complete donor chimerism, leading to an alternative diagnosis of a CMV-driven T-cell expansion. This was confirmed by an in vitro assay testing T-cell specificity against CMV. The patient achieved both complete response and complete donor chimerism despite persisting lymphocytosis, but ultimately relapsed. This case highlights the importance of diagnostic tools in understanding disease progression and guiding treatment decisions.

[Lymphocytic " itis", from esophagus to large bowel]. / « ites ¼ lymphocytaires, de l'œsophage au côlon.

Intra-epithelial lymphocytosis is an elementary lesion frequently observed in the gastrointestinal tract, which can be found from the esophagus to the colon. Many conditions of a varied nature (dysimmunitary diseases, drugs, infections…) are associated with intra-epithelial lymphocytosis, and the etiological diagnosis most often requires an anatomo-clinical correlation. The pathologist will have to identify histological lesions associated with intra-epithelial lymphocytosis allowing the diagnosis to be oriented in order to propose appropriate treatment. In this review, the main entities associated with digestive intra-epithelial lymphocytosis will be presented, detailing the key elements allowing their diagnosis.

Monoclonal B-cell Lymphocytosis - a review of diagnostic criteria, biology, natural history, and clinical management.

Since first described almost two decades ago, there has been significant evolution in our definition and understanding of the biology and implications of monoclonal B-cell lymphocytosis (MBL). This review provides an overview of the definition, classification, biology, and natural history of MBL, mainly focused on the dominant CLL-like phenotype form of MBL. The increasingly recognized implications of MBL with respect to immune dysfunction are discussed, particularly in view of the COVID-19 pandemic, along with management recommendations for MBL in the clinic.

Monoclonal B lymphocytosis in a kidney transplant recipient.

Monoclonal B lymphocytosis (MBL) is a lymphoproliferative condition characterised by expansion of a B-cell clone in peripheral blood, with an often indolent clinical course. The presence of a B clonal population alone is several hundred times more common in the general population than chronic lymphocytic leukaemia and other non-Hodgkin's lymphoma subtypes, it usually does not represent a malignant condition and it requires follow-up only, without specific treatment. There are few studies describing MBL in solid organ transplant recipients, thus, the concern is raised when enrolling MBL affected subjects in waiting lists. We report the experience of a patient affected by MBL who underwent kidney transplantation, with particular attention to preoperative screening and immunosuppressants impact on post-transplant lymphoproliferative disease risk, to aid clinicians in the evaluation process of transplant candidates affected by similar conditions.

Acute superior mesenteric vein thrombosis in the setting of cytomegalovirus mononucleosis: a case report and review of the literature.

Cytomegalovirus is a viral genus of the overarching family Herpesviridae, and is of particular importance because of its relevance to human disease. This association is predominantly due to human cytomegalovirus, a well-studied pathogen. In addition to the mononucleosis syndrome that can occur during acute cytomegalovirus viraemia, this virion has been recurrently implicated as a provoking factor for thromboembolic disease in the published scientific literature. As physicians increasingly forgo extensive laboratory investigation in the setting of clinical hypercoagulability, it has also become evident that in some circumstances whether or not a particular investigation alters clinical management is not necessarily the only important question. Viraemia as a provoking factor for thrombosis stands as such an example. The aim of this Grand Round is to further explore the role of cytomegalovirus as it pertains to thromboembolic disease, especially in the present era of viral-associated thromboembolism.

Population PK-PD Modeling of Circulating Lymphocyte Dynamics in Chronic Lymphocytic Leukemia Patients Under Ibrutinib Treatment.

Ibrutinib is indicated for the treatment of chronic lymphocytic leukemia (CLL). Absolute lymphocyte count (ALC) is a clinical criterion used for the monitoring of CLL. Ibrutinib has several effects on lymphocytes, and has highly variable pharmacokinetics (PK). The objective of this work was to build a PK-pharmacodynamic (PD) model describing ALC dynamics under ibrutinib treatment in patients with CLL. ALC observations before and after ibrutinib treatment initiation in patients with CLL were included in the analysis. A population PK-PD model was developed based on physio-pharmacological knowledge. Individual PK concentrations at each hospital visit were included in the model. The association between PD parameters and lymphocytosis, and between PD parameters and response to treatment were assessed. A total of 94 patients, 658 ALC and 1,501 PK observations were included in model development. The final PK-PD model accurately described ALC dynamics for different patient profiles. It consisted in two compartments (tissues and blood circulation) with ibrutinib plasmatic concentration inducing two drug effects: stimulation of lymphocyte redistribution and death. Patients with hyperlymphocytosis had significantly higher tissues to circulation baseline lymphocyte count ratio, and lower death effect. Patients who progressed under ibrutinib had significantly lower baseline lymphocyte counts in tissues (2-fold lower) and blood (3-fold lower). The first PK-PD model for ALC in patients with CLL under ibrutinib treatment was developed. This model suggests that estimated lymphocyte counts in tissues and blood could be used as an early predictor of response in patients with CLL.

Natural history of monoclonal B-cell lymphocytosis among relatives in CLL families.

Chronic lymphocytic lymphoma (CLL) has one of the highest familial risks among cancers. Monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, has a higher prevalence (13%-18%) in families with 2 or more members with CLL compared with the general population (5%-12%). Although, the rate of progression to CLL for high-count MBLs (clonal B-cell count ≥500/µL) is ∼1% to 5%/y, no low-count MBLs have been reported to progress to date. We report the incidence and natural history of MBL in relatives from CLL families. In 310 CLL families, we screened 1045 relatives for MBL using highly sensitive flow cytometry and prospectively followed 449 of them. MBL incidence was directly age- and sex-adjusted to the 2010 US population. CLL cumulative incidence was estimated using Kaplan-Meier survival curves. At baseline, the prevalence of MBL was 22% (235/1045 relatives). After a median follow-up of 8.1 years among 449 relatives, 12 individuals progressed to CLL with a 5-year cumulative incidence of 1.8%. When considering just the 139 relatives with low-count MBL, the 5-year cumulative incidence increased to 5.7%. Finally, 264 had no MBL at baseline, of whom 60 individuals subsequently developed MBL (2 high-count and 58 low-count MBLs) with an age- and sex-adjusted incidence of 3.5% after a median of 6 years of follow-up. In a screening cohort of relatives from CLL families, we reported progression from normal-count to low-count MBL to high-count MBL to CLL, demonstrating that low-count MBL precedes progression to CLL. We estimated a 1.1% annual rate of progression from low-count MBL, which is in excess of that in the general population.

From the archives of MD Anderson Cancer Center: Untreated leukemic non-nodal mantle cell lymphoma with relapse as pleomorphic variant mantle cell lymphoma 21 years later.

Leukemic, non-nodal mantle cell lymphoma (MCL) is a distinct, rare, indolent variant of mantle cell lymphoma, but can relapse aggressively. It can present with lymphocytosis with chronic lymphocytic leukemia (CLL)-like morphologic and immunophenotypic features as was initially considered in the index case. However, at time of splenectomy, two years later cyclin D1 overexpression was shown and the disease was realized to be leukemic non-nodal MCL. The patient was followed for 21 years, without therapy, before he developed clinically aggressive MCL with lymphadenopathy. Lymph node biopsy showed MCL, pleomorphic variant. We review the literature and discuss the features of leukemic non-nodal MCL as well as the potential pitfalls in diagnosis. Furthermore, we are not aware of another cases reported with a 21 year interval from initial diagnosis of leukemic non-nodal MCL to aggressive MCL.

Leukocytosis and Tobacco Use: An Observational Study of Asymptomatic Leukocytosis.

PURPOSE: This study aimed to characterize the white blood cell differential of tobacco smoking-induced leukocytosis and describe the longitudinal impact of smoking cessation on this peripheral blood abnormality. METHODS: Medical records of patients undergoing evaluation by hematologists for persistent leukocytosis were reviewed. Patients in whom leukocytosis was determined to be secondary to tobacco use after exclusion of other causes were identified. Demographic and laboratory data were collected at time of diagnosis. Patients were longitudinally followed and information regarding smoking cessation and follow-up white blood cell values were recorded. RESULTS: Forty patients were determined to have smoking-induced leukocytosis. The median age was 49.5 years (range: 28-75 years), 24 patients were female, and the mean body mass index (BMI) was 31.5 kg/m2. The mean white blood cell count was 13.3 × 109/L (range: 9.8-20.9 × 109/L); 39 patients had absolute neutrophilia (98%), 21 had lymphocytosis (53%), 20 had monocytosis (50%), and 19 had basophilia (48%). During follow-up, 11 patients either quit (n = 9) or reduced (n = 2) tobacco use. Reduction in tobacco smoking led to a significant decrease in mean white blood cell count (13.2 × 109/L vs 11.1 × 109/L, P = 0.02). The median time to decrease in white blood cell count following reduction in tobacco use was 8 weeks (range: 2-49 weeks). CONCLUSIONS: Tobacco-induced leukocytosis was characterized by a mild elevation in total white blood cell count and was most commonly associated with neutrophilia, lymphocytosis, monocytosis, and basophilia. Cessation of smoking led to improvement in leukocytosis. Tobacco history should be elicited from all patients presenting with leukocytosis to limit unnecessary diagnostic testing, and counseling regarding smoking cessation should be offered.

Estudio de un paciente con esplenomegalia: a propósito de un caso / Study of a splenomegaly: a case report

El crecimiento patológico del bazo se denomina esplenomegalia. Su detección supone un reto en las consultas de Atención Primaria por el amplio abanico de posibilidades diagnósticas que supone, siendo las principales causas a descartar: infecciosas, tumorales y hematológicas. En nuestro trabajo presentamos un paciente varón de mediana edad que acude a consulta por vez primera porque presenta una tumoración abdominal palpable y no dolorosa de larga evolución. Su diagnóstico se basa en la obtención de imagen a través de alguna prueba de imagen para confirmar la presencia de esplenomegalia, siendo la ecografía la técnica de elección en Atención Primaria. Mediante la sospecha clínica y la realización de la ecografía en consulta llegamos al diagnóstico clínico

The pathological growth of the spleen is called splenomegaly. Its detection is a challenge in Primary Care due to the wide range of diagnostic possibilities involved, including as the main causes to be ruled out: infections, tumors, and hematological causes. We present the case of a middle-aged male patient who seeks care for the first time because he presents a palpable, painless abdominal lump of long evolution. The diagnosis is based on imaging tests to confirm the presence of splenomegaly, with ultrasound as the technique of choice in Primary Care. Clinical suspicion and ultrasound testing in the office lead to clinical diagnosis

Paraprotein associated syndrome treated successfully with chemotherapy.

We report a 50-year-old Caucasian woman who presented with recurrent erythema nodosum, leg swelling, malaise, weight loss and abdominal pain associated with an IgM lambda paraprotein. She was treated with six courses of an anti-CD20 monoclonal antibody and bendamustine chemotherapy over 6 months with a good clinical response.

Systemic Sarcoidosis Associated with Certolizumab Pegol Treatment for Rheumatoid Arthritis: A Case Report and Review of the Literature.

A 69-year-old woman presented with appetite loss, fatigue, and a low-grade fever. She had been receiving certolizumab pegol for rheumatoid arthritis for six years. Computed tomography of the chest showed multiple micronodules in both lungs and bilateral hilar and mediastinal lymphadenopathy. An ophthalmic examination showed the findings of uveitis. Lymphocytosis with an increased CD4/CD8 ratio was seen in the bronchoalveolar lavage fluid. Video-assisted thoracoscopic biopsy specimens obtained from the right lung and a right hilar lymph node showed noncaseous epithelioid cell granulomas. Anti-tumor necrosis factor-α-induced sarcoidosis was diagnosed, and she was successfully treated with cessation of certolizumab pegol and systemic corticosteroid therapy.

The coeliac stomach: A review of the literature.

Beyond the small intestine, coeliac disease (CeD) may affect other gastrointestinal tracts, including the stomach. However, various studies have reported conflicting results regarding the association between CeD and gastric manifestations. The aim of this study was to analyze the existing literature on gastric involvement in CeD. A literature search was conducted in bibliographic databases of Embase, PubMed, Scopus, and Web of Science. Studies reporting the association between CeD and gastric disorders were examined in detail and are fully described in the review. Both in children and adults, a strong correlation between lymphocytic gastritis and CeD was found at CeD diagnosis, and lymphocytic gastritis seemed to improve on a gluten-free diet. Most of the literature described a lower risk of gastritis related to Helicobacter pylori infection in CeD subjects compared to controls. However, due to the discordance among studies in terms of study design and population, a clear association could not be determined. Finally, the relationship between CeD and reflux or dyspepsia has yet to be defined, as well as the association between CeD and autoimmune gastritis. CeD appears to be a multiform entity associated with different gastric disorders with a different degree of relationship. Thus, gastric biopsies should be routinely taken during upper endoscopy in CeD patients.

Causes of double-negative T-cell lymphocytosis in children and adults.

AIMS: The causes and diagnosis of 'double-negative' (CD3+CD4-CD8-) T-cell lymphocytosis are not well studied. We aimed to define the causes of double-negative T-cell lymphocytosis in children and adults, and to identify simple clinical and laboratory features that would help to differentiate between the underlying conditions. METHODS: We collected clinical and laboratory data on 10 children and 30 adults with significantly increased peripheral-blood double-negative T-cells (>10% of total lymphocytes). We identified conditions associated with double-negative T-lymphocytosis with flow cytometry, peripheral-blood morphology and T-cell receptor-gene rearrangement studies. Patients were assigned to diagnostic categories on the basis of these test results. RESULTS AND CONCLUSIONS: The causes of double-negative T-cell lymphocytosis in children were autoimmune lymphoproliferative syndrome (ALPS) and reactive γ/δ Τ-lymphocytosis. T-cell large granular lymphocyte (T-LGL) leukaemia, reactive γ/δ T-lymphocytosis and hepatosplenic T-cell lymphoma (HSTL) were the the most common disorders underlying double-negative T-cell lymphocytosis in adults. Less common causes included hypereosinophilic syndrome, peripheral T-cell lymphoma, ALPS and monoclonal, double-negative T-lymphocytosis of uncertain significance. CD5/CD7/Vδ2 expression and absolute double-negative lymphocyte count (<1.8×109/L) were useful discriminators for distinguishing patients with reactive γ/δ T-lymphocytosis from those with γ/δ lymphoproliferative disorders. Differentiating between γ/δ T-LGL and HSTL can be difficult. Expression of CD57 and cellular morphology (pale cytoplasm with distinct granules) would support a diagnosis of γ/δ T-LGL.

Lung Involvement in Destombes-Rosai-Dorfman Disease: Clinical and Radiological Features and Response to the MEK Inhibitor Cobimetinib.

BACKGROUND: Destombes-Rosai-Dorfman disease (RDD) is a rare multisystemic histiocytosis. Pulmonary involvement during RDD has been poorly described. The goal of this study was to examine the clinical presentations, radiological features, and outcomes of 15 patients with RDD and lung involvement. METHODS: The cases of RDD with lung involvement were extracted from the French National Histiocytosis registry. Efficacy of the MEK inhibitor cobimetinib in treating lung disease was evaluated with an 18fluorodeoxyglucose PET scanner and chest CT scans. RESULTS: Fifteen patients (six women; median age, 40 years at RDD diagnosis) were included. All patients had evidence of systemic disease with extrapulmonary localizations of the disease (lymphadenopathy [n = 12], skin [n = 9], bones [n = 6], retroperitoneal involvement [n = 3], sinuses [n = 3], parotid gland [n = 2], submandibular gland [n = 1], and breast [n = 1]). Presenting symptoms were dominated by dyspnea and dry cough in seven patients. Restrictive physiology was observed in two of five patients. BAL showed lymphocytosis in one of five cases. Eight patients received corticosteroids, all but one with variable immunosuppressive or immunomodulatory therapies. Two patients received cobimetinib for severe lung disease, with dramatic pulmonary metabolic and tumoral responses. Two patients died during follow-up: one of hemoptysis, and the other of an unrelated cerebral tumor. CONCLUSIONS: Pulmonary involvement in RDD is rare, proteiform, and sometimes severe. The MEK inhibitor cobimetinib can lead to dramatic responses.