Tumor mutational load is prognostic for progression to therapy among high-count monoclonal B-cell lymphocytosis.

ABSTRACT: High-count monoclonal B-cell lymphocytosis (HCMBL) is a precursor condition to chronic lymphocytic leukemia (CLL). We have shown that among individuals with HCMBL, the CLL-International Prognostic Index (CLL-IPI) is prognostic for time-to-first therapy (TTFT). Little is known about the prognostic impact of somatically mutated genes among individuals with HCMBL. We sequenced DNA from 371 individuals with HCMBL using a targeted sequencing panel of 59 recurrently mutated genes in CLL to identify high-impact mutations. We compared the sequencing results with that of our treatment-naïve CLL cohort (N = 855) and used Cox regression to estimate hazard ratios and 95% confidence intervals (CIs) for associations with TTFT. The frequencies of any mutated genes were lower in HCMBL (52%) than CLL (70%). At 10 years, 37% of individuals with HCMBL with any mutated gene had progressed requiring treatment compared with 10% among individuals with HCMBL with no mutations; this led to 5.4-fold shorter TTFT (95% CI, 2.6-11.0) among HCMBL with any mutated gene vs none, independent of CLL-IPI. When considering individuals with low risk of progression according to CLL-IPI, those with HCMBL with any mutations had 4.3-fold shorter TTFT (95% CI, 1.6-11.8) vs those with none. Finally, when considering both CLL-IPI and any mutated gene status, we observed individuals with HCMBL who were high risk for both prognostic factors had worse prognosis than patients with low-risk CLL (ie, 5-year progression rate of 32% vs 21%, respectively). Among HCMBL, the frequency of somatically mutated genes at diagnosis is lower than that of CLL. Accounting for both the number of mutated genes and CLL-IPI can identify individuals with HCMBL with more aggressive clinical course.

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.

Lymphocytosis and chronic lymphocytic leukaemia: investigation and management.

Lymphocytosis is a common blood-test finding. Establishing whether the cause of lymphocytosis is benign or malignant is key to managing patients appropriately. A lymphocytosis should always prompt clinical review including a thorough history, examination and appropriate preliminary investigations (blood tests, blood film). The majority of patients with chronic lymphocytic leukaemia (CLL) present incidentally due to a lymphocytosis found on routine blood tests. Patient outcomes vary considerably based on genetic pre-disposition and various prognostic markers (age, Binet or Rai staging, and B2-microglobulin). Although not curative, chemo-immunotherapy is an effective treatment strategy for the majority of CLL patients with progressive disease. More recently, novel oral therapies have been developed that target key signalling and apoptosis pathways and that are being used in relapse settings and as first-line treatments for certain patients.

Development of Monoclonal B-cell Lymphocytosis Shortly After Treatment with Nivolumab and Subsequent Progression to Chronic Lymphocytic Leukemia.

INTRODUCTION: Immune checkpoint inhibitors, such as programmed death (PD)-1 inhibitor nivolumab, are currently widely used in treatment of various malignancies. Due to their widespread application, any new potential adverse effects due to these agents necessitate careful assessment. CASE REPORT: We report a case of an 81-year-old man with recurrent high-risk malignant melanoma who underwent a 12-month adjuvant treatment with nivolumab. Shortly after the course of nivolumab, he developed monoclonal B-cell lymphocytosis (MBL) which subsequently progressed to chronic lymphocytic leukemia (CLL). MANAGEMENT AND OUTCOME: The patient is currently doing clinically well in Rai stage 0. Malignant melanoma remains in remission. CONCLUSION: Considering the pathophysiologic plausibility of nivolumab inducing B-cell dysregulation via PD-1 inhibition, we suggest further studies on potential association between nivolumab and B-cell malignancies.

Lymphocytic Esophagitis: Current Understanding and Controversy.

This review summarizes our current understanding of lymphocytic esophagitis (LE), a novel form of chronic esophagitis that incorporates distinctive histologic, clinical, and endoscopic features. First described as a histologic entity, a diagnosis of LE requires intraepithelial lymphocytosis without significant granulocytic inflammation and some evidence of epithelial damage; the rationale for and studies supportive of these histologic criteria are discussed within. Clinically, the majority of patients who present with histologically confirmed LE are older women or patients with underlying immunologic abnormalities, such as Crohn disease, rheumatologic disorders, or common variable immunodeficiency. The most common presenting symptom of LE is dysphagia, and the endoscopic findings can vary from normal mucosa to mucosal changes that resemble eosinophilic esophagitis: edema, rings, furrows, and plaques. The incidence of luminal strictures and the persistent dysphagia and/or lymphocytosis present in some patients provide evidence that LE is a chronic inflammatory disorder, at least within a subset of individuals. Several histologic mimics of LE are examined, as are disagreements surrounding the LE diagnosis.

Clinical and demographic characteristics of patients with COVID-19 infection: Statistics from a single hospital in Iran.

Coronavirus disease 2019 (COVID-19) has caused a global pandemic in early 2020. This infectious disorder has a heterogeneous course ranging from asymptomatic disorder to a critical situation needing intensive cares. In the current study, we present a report of affected patients admitted in a single hospital in Iran. Eighty-two hospitalized patients with COVID-19 were assessed. Demographic, clinical, and paraclinical parameters were gathered and statistically analyzed. The median age (IQR) of the patients was 57.32 (45.75, 70) years. At primary evaluation, fever was present in 45.12% of the affected individuals. The most common clinical symptoms were dyspnea (81.71%) and cough (65.85%). Totally, 12 (14.63%) and 14 (17.07%) of patients had low and high WBC counts, respectively. Lymphopenia was detected in 36 (43.9%) of patients, while 6 (7.32%) of patients had lymphocytosis. High levels of Il-6 were detected in 4 (4.88%) of patients. CRP levels were elevated in 69 (84.1%) of patients. The median (IQR) of hospitalization was 7 (5, 9) days. Totally, 26 patients (31%) were hospitalized in ICU. All patients were discharged with good health conditions except for one patient who died. The current study shows the heterogeneous clinical manifestations and paraclinical parameters of COVID-19 patients.

Peripheral blood T lymphocytosis in thymoma: an insight into immunobiology.

PURPOSE: Peripheral blood T lymphocytosis (PBTL) is a rare, yet poorly understood manifestations of thymoma, which is postulated to be linked with autoimmune/paraneoplastic manifestations such as myasthenia gravis (MG), pure red cell aplasia (PRCA), etc.; more commonly encountered in this neoplasm. METHOD: We aim to describe the flowcytometric immunophenotypic data of PBTL in a 43-year-old male; 6 months after successful completion of chemoradiotherapy (CT/RT) for a large, invasive, and metastatic type B1 thymoma; and present a comprehensive review of all such cases reported over last 42 years (N = 21) (1977-2019). RESULT: A larger size of the tumors (≥ 10 cm), presence of local invasion and/or distant metastasis, and type B (cortical or lymphocyte rich) histology were more likely to be associated with PBTL. Tumors associated with MG/PRCA (N = 9/21) tend to have lower PBTL compared to those without such manifestations; and PBTL subsided following thymectomy with or without CT/RT. Immunophenotypic analysis of PB revealed a CD8 + > CD4 + mature (naïve) polyclonal T cells resembling late cortical thymocytes. CONCLUSION: Thymic intratumoral microenvironment might influence occurrence PBTL that may have a pathophysiologic link to development of autoimmune manifestations. Immunophenotypic characteristics of peripheral blood lymphoid cells should be the clue for accurate characterization and to avoid a misdiagnosis of a lymphoproliferative neoplasm.

HaNDL Syndrome: Case Report and Literature Review.

Headache and Neurologic Deficits with cerebrospinal fluid Lymphocytosis (HaNDL) syndrome is a rare stroke mimicker characterized by moderate to severe headache temporally associated with transient neurologic deficits, typically hemiparesis, hemisensory disturbance, and/or aphasia. Cerebrospinal fluid studies reveal a lymphocytosis and elevated protein. Episodes recur over a period no longer than 3 months. Here we describe the case of a 16-year-old boy who presented with 3 episodes of self-resolving neurologic deficits, papilledema on fundoscopic examination, and leptomeningeal enhancement on magnetic resonance imaging (MRI). We additionally review the 30 previously reported pediatric cases of HaNDL syndrome, with a focus on possible etiologic and pathophysiologic mechanisms of disease. The reported case and literature review highlight the benign episodic nature of this likely underrecognized syndrome as well as the higher than expected frequency of abnormal neuroimaging findings.

Monoclonal B-cell lymphocytosis: Does the elderly patient need a specialistic approach?

Monoclonal B-cell lymphocytosis (MBL) is defined by the presence of a monoclonal B-cell population in the peripheral blood (PB) at a concentration of <5 × 109/l and no signs or symptoms of a lymphoproliferative disorder. In around 75% of cases, the immunophenotype of the clonal B-cell expansions is superimposable to that of chronic lymphocytic leukemia (CLL), thus defined "CLL-like". Other cases may coexpress CD19, CD5, bright CD20, and lack CD23 ("atypical CLL"), while others are CD5-negative ("non-CLL"). Beside the immunophenotypic profile, a key distinction is based on the B-cell count, stratifying the MBL category in low (<0.5 × 109/l) or high-count (≥0.5 × 109/l). Low-count (LC) MBL is recognized in general population studies and it is not associated with lymphocytosis. High-count (HC) MBL is identified during the clinical work-up for lymphocytosis and carries a risk of progression to CLL requiring therapy of 1-2% per year in most series, warranting clinical monitoring over time. At the time of MBL diagnosis, the key point is the careful evaluation and exclusion of differential diagnoses. After the initial workup, the follow-up at a referral center by a hematologist would be desirable as, in addition to the obvious risk of progression to clinically relevant CLL, the appropriate management of MBL individuals should take into account the risk of developing infections, other cancers and autoimmune disorders. For those cases who indeed bear a risk, though limited, of clinical consequences, such as the majority of HC-MBL cases, current evidences suggest that they may benefit from a tailored and specialized approach.

Lymphocytic esophagitis: an update on histologic diagnosis, endoscopic findings, and natural history.

Lymphocytic esophagitis is a histologic pattern of injury characterized by increased intraepithelial lymphocytes (>20/high-power field) with rare, or absent granulocytes. Lymphocytes tend to be more numerous in the peripapillary epithelium, and are often associated with evidence of mucosal injury, edema, and scattered dyskeratotic cells. More than a decade following its original description, lymphocytic esophagitis remains an enigmatic entity with variable clinical presentations, associated disorders, etiologies, treatment, and natural history. Most of the confusion regarding the clinical significance of this disorder stems from its diagnostic criteria: lymphocytic esophagitis is currently defined based entirely on histologic criteria, despite the common occurrence of lymphocytosis in a variety of unrelated inflammatory conditions of the esophagus. The goal of this review is to summarize the literature regarding lymphocytic esophagitis and focus on key clinicopathologic features that distinguish it from other esophageal disorders that can show increased numbers of intraepithelial lymphocytes.

The syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) / HaNDL ­ viktig men gåtfull differentialdiagnos med svår migränliknande huvudvärk - Förknippat med neurologiska symtom och lymfocytär pleocytos.

The syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) is a self-limited disorder with an unknown pathogenesis, characterized by one or more transient episodes of severe headache accompanied with neurologic deficits, and lymphocytic pleocytosis in the cerebrospinal fluid (CSF). Despite being uncommon and benign it is important for clinicians to identify and differentiate HaNDL from other potentially fatal neurologic disorders. We present six HaNDL patients from our institution. All had a relatively typical course with repeated migraine-like headaches accompanied by various transient neurologic deficits and a mean CSF lymphocytic pleocytosis of 178 cells/mm3. Most of the patients were disorientated during the attacks, which has been described previously. When neurofilament light in CSF was measured, there was a substantial increase of this marker which normalized after several months, suggesting certain nerve damage.

Syndrome of Transient Headache and Neurologic Deficits With Cerebrospinal Fluid Lymphocitosis Should Be Considered in Children Presenting With Acute Confusional State.

BACKGROUND: Transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) is benign and self-limited, with neurologic deficits including sensory disturbance of one body side, aphasia, nausea/vomiting, weakness, decreased vision, homonymous hemianopsia, photophobia. Acute confusional state can rarely occur. Papilledema and intracranial hypertension have also been described. It is a rare entity mainly affecting adults; however, it has been sporadically described in children and adolescents. MAIN FINDINGS: In this clinical observational study, we describe a clinical series of three consecutive pediatric patients being diagnosed with HaNDL after presenting with altered consciousness, papilledema, and increased intracranial pressure. They all recovered without relapses. CONCLUSION: Presentation during childhood and adolescence is rare; the majority of pediatric cases presented with altered consciousness, which is infrequent in HaNDL. This may suggest that in childhood this symptom might be more common than in adults. All three patients presented with increased intracranial pressure and papilledema, thus suggesting that these aspects should be investigated in all patients presenting with this clinical pattern. Finally, all our patients began to suffer from migraine. This feature, together with the benign course of the disease, could favor the hypothesis of a migrainous pathophysiology of this syndrome, although this remains a speculative.

How to Approach Lymphocytic Esophagitis.

PURPOSE OF REVIEW: Lymphocytic esophagitis (LE) is an unusual esophageal condition defined by an increased number of lymphocytes in the esophageal epithelium. With few published studies of LE available, it is unclear whether LE is a truly distinct clinical entity or a histological manifestation of other known gastrointestinal disorders. This review summarizes recent studies of lymphocytic esophagitis. RECENT FINDINGS: Studies have suggested that LE may be related to eosinophilic esophagitis (EoE) or a manifestation of gastroesophageal reflux disease (GERD). There is an association between LE and Crohn's disease in children, but not in adults. Patients with LE frequently report symptoms of dysphagia and GERD. Treatment options for LE are limited and involve symptom management similar to treatment of EoE or GERD, including proton pump inhibitors (PPI), swallowed topical steroids, and endoscopic dilation. With no formal definition and a variety of clinical presentations and endoscopic findings, diagnosis and management of symptomatic LE patients is challenging for clinicians.

Unique CT Perfusion Imaging in a Case of HaNDL: New Insight into HaNDL Pathophysiology and Vasomotor Principles of Cortical Spreading Depression.

BACKGROUND: The etiology of HaNDL is not known. Recent neuroimaging studies have suggested that there may be altered cerebrovascular blood flow during acute episodes. However, what exactly these vascular changes represent and how they may relate to the overall pathogenesis of HaNDL is uncertain. CASE: A 42-year-old, right-handed male, presented with acute aphasia and right arm weakness. Urgent CT/CT-angiogram were normal except for an incidental hypoplastic right anterior cerebral artery (ACA) A1 segment. However, CT perfusion revealed global left hemisphere hypoperfusion in the range of oligemia. Also, the right ACA territory, supplied by the dominant left A1, shared the same pattern of hypoperfusion. Further investigations and clinical course were consistent with HaNDL. DISCUSSION/CONCLUSIONS: The pattern of global left hemispheric hypoperfusion seen in this case of HaNDL supports a hypothesis of secondary oligemia induced by a hemispheric wave of cortical spreading depression (CSD). However, the extension of hypoperfusion to the right ACA territory represents a phenomenon not previously reported in this field. We speculate that the direct spread of CSD-induced vasomotor changes across the anomalous vasculature could account for this finding. This case provides a valuable contribution toward understanding HaNDL pathophysiology and in doing so may also yield broader implications regarding neurophysiological principles of CSD.

Chronic Localized Fibrosing Leukocytoclastic Vasculitis Associated With Lymphedema, Intralymphatic and Intravascular Lymphocytosis, and Chronic Myelogenous Leukemia: A Case Report of Unilateral Erythema Elevatum Diutinum.

One of the pathogenic causes of cutaneous inflammatory pseudotumors is chronic localized fibrosing leukocytoclastic vasculitis (CLFLCV), a vasculitic reaction pattern seen in granuloma faciale (GF), a localized vasculitis, and erythema elevatum diutinum (EED), a generalized vasculitis. Patients with myelodysplastic syndromes (MDSs) are at risk for a diverse spectrum of cutaneous neutrophilic dermatoses such as EED. Herein, we report a 74-year-old man who presented with a large ulcerative, fungating tumor affecting the right flexor ankle caused by CLFLCV. During his workup and management, MDS and Philadelphia chromosome-negative chronic myeloid leukemia was diagnosed. Surgical excision of the inflammatory mass promptly triggered tumor recurrence, whereas antineutrophil therapy (dapsone coupled with hydroxyurea, and prednisone) lead to tumor regression. Histopathologic examination revealed an eosinophilic-rich small-vessel neutrophilic vasculitis associated with storiform and angiocentric fibrosis (GF-like). In the regions of fibrosis, dilated lymphatic and vascular spaces were numerous, some of which were congested with small CD3-positive lymphocytes (intralymphatic and intravascular lymphocytosis). These findings indicate coexisting localized lymphedema. By direct immunofluorescence, IgM and C4d vessel deposits were detected. The pathogenesis of the fibrotic nodules and plaques of CLFLCV is suspected to be due to recurring bouts of immune-complex vasculitis, creating a cycle of vessel damage followed by reparative granulation tissue. Poor lymphatic drainage may be the underlying factor initiating and maintaining recurrent, localized episodes of immune-complex vasculitis and progressive fibrosis. Although his tumor histopathology resembled GF-eosinophilic rich CLFLCV-the clinical context points to a solitary and paraneoplastic case of EED.

What does it mean I have a monoclonal B-cell lymphocytosis?: Recent insights and new challenges.

Monoclonal B-cell lymphocytosis (MBL) is defined as a laboratory abnormality where small (<5 x 10(9)/L) clonal B-cell populations are detected in the peripheral blood of otherwise healthy subjects. According to the immunophenotype, MBL is labeled as chronic lymphocytic leukemia (CLL)-like (75% of cases), atypical CLL, and CD5-negative. Concentration of clonal B cells differentiates low- (LC) and high-count (HC)-MBL (< or ≥ 0.5 x 10(9)/L, respectively). Thanks to technical improvements, we are able to identify CLL-like clonal B-cell populations at increased frequency with age, but we are still far from understanding its relationship with clinically overt CLL. LC-MBL, requiring high-throughput screening technique to be identified in population studies, seems to be a bird of a different feather and several hints suggest that LC-MBL is related to aging and/or chronic antigenic stimulation. Immunogenetic, cytogenetic and genetic data support the notion that HC-MBL, usually identified in the clinical setting, is a premalignant condition and, based on biological parameters, it is frequently difficult to differentiate it from early stage CLL. The rapid improvement and widespread availability of cutting-edge technology, in particular next-generation sequencing (NGS), raises hope that we are getting closer to unveiling the fundamental nature of MBL and CLL and how they are related to each other.