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.

[Efficacy of highly active antiretroviral therapy alone in the treatment of diffuse lymphocytic infiltration syndrome in an ivorian patient living with HIV: a case report]. / Efficacité du traitement antirétroviral hautement actif seul dans le traitement du syndrome d'infiltration lymphocytaire diffus chez une patiente ivoirienne vivant avec le VIH : à propos d'un cas.

Objective: We report in this work the efficacy of highly active antiretrovirals (ARVs) alone in the treatment of diffuse infiltrative lymphocytosis syndrome (DILS) without the use of corticosteroids, which appears risky in patients living with HIV. Observation: This is a 60-year-old HIV-positive patient, discovered during the etiological workup of renal failure, which revealed a non-nephrotic glomerular profile. The renal biopsy found an interstitial infiltrate of CD8 suggestive of DILS. Management consisted in starting ARV treatment alone (lamuvidine, abacavir and raltegravir) without associated corticosteroid therapy. The clinical evolution under treatment was marked by a recovery of the renal function with a creatininemia at 99 µmol/l, a regression of the proteinuria, a CD4 rate at 293/mm3 and an HIV viral load at 533.3 copies or 1.6 log in the space of 3 months. Conclusion: DILS is a diffuse systemic disease in HIV patients who are usually under poor virological control. In view of the strong immunosuppression and the absence of other infiltrative diseases, it appeared to us to be risky and unjustified to add a corticosteroid therapy.

Accumulation of DNA damage and alteration of the DNA damage response in monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia.

Accumulation of DNA damage and alteration of the DNA damage response (DDR) are critical features of genetic instability that is presumed to be implicated in the pathogenesis of monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL). Here, we show increased numbers of γH2AX foci, a marker of DNA double-strand breaks (DSB), in CD19+ cells of CLL patients as compared to CD19+ cells of MBL patients and healthy individuals. Furthermore, numerous γH2AX/53BP1 foci in CLL cells suggest activation of error-prone non-homologous end-joining repair mechanisms. Signatures of DDR proteins further indicate alterations of the DDR in CLL in contrast to a largely regular activation in MBL and healthy controls. In summary, our results provide evidence for the stepwise accumulation of DNA damage in the progression of MBL towards CLL and suggest increased DNA damage, error-prone DNA repair and altered DDR signaling to be critical mechanisms of clonal evolution in MBL and CLL.

Monoclonal B-cell lymphocytosis with renal involvement.

We report the case of a 70-year-old man with no relevant past medical history who presented with acute kidney injury. Kidney biopsy showed diffuse interstitial infiltration with typical chronic lymphocytic leukemia (CLL) phenotype B-cells. Subsequent studies revealed a normal lymphocyte count in the peripheral blood, and there was no evidence of lymphadenopathy or hepatosplenomegaly. Blood flow cytometry demonstrated a clonal B-cell population with a CLL phenotype. Without renal involvement, this case should be classified as monoclonal B-cell lymphocytosis. Renal function improved with steroid therapy. However, the patient developed CLL with significant lymphocytosis approximately two years later.

Reasons for initiation of treatment and predictors of response for patients with Rai stage 0/1 chronic lymphocytic leukemia (CLL) receiving first-line therapy: an analysis of the Connect® CLL cohort study.

A 'watch-and-wait' strategy is recommended for most patients with early-stage chronic lymphocytic leukemia (CLL) prior to treatment initiation. In the Connect® CLL registry, a prospective observational cohort study of 1494 patients treated in 199 US centers, median time to first-line treatment initiation was 3.8, 1.5, and 0.6 years for patients with Rai stage 0, 1, and ≥2, respectively. Only 60% of patients with Rai stage 0/1 underwent FISH/cytogenetic testing prior to initiation of a new line of therapy. Lymphocytosis and lymphadenopathy were the most common reasons for treatment initiation. Lymphocytosis as a reason for treatment initiation was associated with inferior event-free survival at Rai stage 0/1. Short treatment duration was associated with inferior overall survival regardless of Rai stage; sensitivity analyses confirmed the association. The Connect CLL registry provides valuable information on a real-world population of patients with CLL, clarifying both the timing and rationale for initiating therapy.

Monoclonal B lymphocytosis and minimal change disease: a new monoclonal B-cell disorder of renal significance?

Chronic lymphocytic leukemia (CLL) may induce renal complications, which are becoming increasingly common, but in this context the occurrence of minimal change disease (MCD) remains rare. Monoclonal B lymphocytosis (MBL) is a precursor state of CLL and is currently under recognized. Since MBL is seen as a benign disorder that rarely evolves into CLL, screening for MBL is not standardized and does not require any treatment. When reviewing renal disease associated with MBL, there is very scant data in the literature and to date there is no case describing the association between MBL and MCD. Here, we describe the case of a 71-year old woman admitted for nephrotic syndrome (NS). We diagnosed a MBL. Kidney biopsy revealed MCD. Treatment with corticosteroids was introduced but no improvement was observed. Chemotherapy with rituximab and chlorambucil was thus started, leading to complete remission of both MBL and MCD. To our knowledge, this is the first description of the association of MBL and MCD. This case suggests that screening for MBL may have unexpected diagnostic and therapeutic implications in patients presenting with seemingly idiopathic NS.

Lymphocytic esophagitis: Still an enigma a decade later.

Lymphocytic esophagitis (LE) is a clinicopathologic entity first described by Rubio et al in 2006. It is defined as peripapillary intraepithelial lymphocytosis with spongiosis and few or no granulocytes on esophageal biopsy. This definition is not widely accepted and the number of lymphocytes needed to make the diagnosis varied in different studies. Multiple studies have described potential clinical associations and risk factors for LE, such as old age, female gender and smoking history. This entity was reported in inflammatory bowel disease in the pediatric population but not in adults. Other associations include gastroesophageal reflux disease and primary esophageal motility disorders. The most common symptom is dysphagia, with a normal appearing esophagus on endoscopy, though esophageal rings, webs, nodularities, furrows and strictures have been described. Multiple treatment modalities have been used such as proton pump inhibitors and topical steroids. Esophageal dilation seems to be therapeutic when dysphagia is present along with esophageal narrowing secondary to webs, rings or strictures. The natural history of the disease remains unclear and needs to be better delineated. Overall, lymphocytic esophagitis seems to have a chronic and benign course, except for two cases of esophageal perforation in the literature, thought to be secondary to this entity.

Hairy cell leukaemia-variant: Disease features and treatment.

Hairy cell leukaemia-variant (HCL-V) is a rare B-cell malignancy that affects elderly males and manifests with splenomegaly, lymphocytosis and cytopenias without monocytopenia. The neoplastic cells have morphological features of prolymphocytes and hairy cells. The immunophenotype is that of a clonal B-cell CD11c and CD103 positive but, unlike classical HCL, CD25, CD123 and CD200 negative. The spleen histology is similar to classical HCL and the pattern of bone marrow infiltration is interstitial and/or intrasinusoidal. Mutations of the immunoglobulin heavy chain (IGVH) are seen in two thirds of cases with a preferential VH4-34 family usage. There is no distinct chromosomal abnormality but del17p13 and mutations of the TP53 gene are frequent. Mutations in the MAP2K1 gene have been documented in half of the cases. The course is chronic with median survivals of 7-9 years. Patients are refractory to purine analogues and the most effective therapy is the combination of 2-chlorodeoxyadenosine and Rituximab.

Clinical course of IgG4-related hypophysitis presenting with focal seizure and relapsing lymphocytic hypophysitis.

BACKGROUND: This is the first case report of focal seizure as a manifestation of Immunoglobulin G4 (IgG4)-related hypophysitis. IgG4-related hypophysitis is a novel category of hypophysitis. The clinical presentations, imaging studies and initial pathology studies can mimic lymphocytic hypophysitis. Here we report additional clinical clues in differentiating these two conditions. CASE PRESENTATION: A 43-year-old Thai male presented with focal seizure, headache, and anterior pituitary hypofunction. His MRI study showed typical hypophysitis lesion with abnormal cerebral parenchymal signal intensity at right frontal lobe. The pituitary biopsied was obtained and the patient was initially diagnosed with lymphocytic hypophysitis. Following initial low-dose steroid therapy, his seizure and headache resolved but his anterior pituitary hormones remained deficient. However, during steroid tapering, he developed new onset acute visual loss. Upon rigorous pathologic review, his diagnosis of IgG4-related hypophysitis with suspected CNS involvement was established. He was subsequently treated with high-dose steroid and rapidly regained his sight. CONCLUSION: This case report highlights the important distinguishing features of IgG4-related hypophysitis from lymphocytic hypophysitis. These include the relapsing clinical course of hypophysitis after steroid decrement and concomitant pachymeningitis particularly in middle-aged to elderly Asian male who presented with hypophysitis. With appropriate dosage of steroids, medical treatment is usually sufficient to control the disease and surgical interventions are usually not required.

Getting a handle on complicated migraine.

We describe a case of a 45-year-old man who presented with a transient syndrome consisting of headache with neurological deficits. Neuroimaging including brain angiography was normal. Cerebrospinal fluid (CSF) analysis revealed an elevated protein and lymphocytic pleocytosis. The diagnosis of a syndrome of Headache and Neurological Deficits with CSF Lymphocytosis (HaNDL) was made after excluding all the other possible causes for the patient's presentation. He made an excellent recovery following a short course of naproxen sodium.

Renal complications in chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis: the Mayo Clinic experience.

While the renal complications of plasma cell dyscrasia have been well-described, most information in patients with chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis is derived from case reports. This is a retrospective analysis of patients with chronic lymphocytic leukemia or monoclonal B-cell lymphocytosis who underwent kidney biopsy for renal insufficiency and/or nephrotic syndrome. Between January 1995 and June 2014, 49 of 4,024 (1.2%) patients with chronic lymphocytic leukemia (n=44) or monoclonal B-cell lymphocytosis (n=5) had a renal biopsy: 34 (69%) for renal insufficiency and 15 (31%) for nephrotic syndrome. The most common findings on biopsy were: membranoproliferative glomerulonephritis (n=10, 20%), chronic lymphocytic leukemia interstitial infiltration as primary etiology (n=6, 12%), thrombotic microangiopathy (n=6, 12%), and minimal change disease (n=5, 10%). All five membranoproliferative glomerulonephritis patients treated with rituximab, cyclophosphamide and prednisone-based regimens had recovery of renal function compared to 0/3 patients treated with rituximab with or without steroids. Chronic lymphocytic leukemia infiltration as the primary cause of renal abnormalities was typically observed in relapsed/refractory patients (4/6). Thrombotic microangiopathy primarily occurred as a treatment-related toxicity of pentostatin (4/6 cases), and resolved with drug discontinuation. All cases of minimal change disease resolved with immunosuppressive agents only. Renal biopsy plays an important role in the management of patients with chronic lymphocytic leukemia or monoclonal B-cell lymphocytosis who develop renal failure and/or nephrotic syndrome.

Confusional state as first symptom of HaNDL syndrome.

HaNDL (transient headache and neurological deficits with cerebrospinal fluid lymphocytosis) syndrome is an infrequent condition included at group 7 "headache attributed to non-vascular intracranial disorder" in the recent International Classification of Headache Disorders (ICHD-3), code 7.3.5. The description states "migraine-like headache episodes (typically 1-12) accompanied by neurological deficits including hemiparaesthesia, hemiparesis and/or dysphasia, but positive visual symptoms only uncommonly, lasting several hours. There is lymphocytic pleocytosis. The disorder resolves spontaneously within 3 months". In this description confusional state is not considered as a main symptom, even if in the literature this aspect is frequently reported. Here, we report the cases of two young boys presenting with confusional state as the main complaint. The possible pathogenesis of the different clinical presentation is discussed.

The diffuse infiltrative lymphocytosis syndrome (DILS). A comprehensive review.

The Diffuse Infiltrative Lymphocytosis Syndrome (DILS) is a rare multisystemic syndrome described in HIV-infected patients. It is characterised by CD8(+) T-cell lymphocytosis associated with a CD8(+) T-cell infiltration of multiple organs. DILS is usually seen in uncontrolled or untreated HIV infection but can also manifest itself independently of CD4(+) T-cell counts. The syndrome may present as a Sjögren-like disease that generally associates sicca signs with bilateral parotiditis, lymphadenopathy, and extraglandular organ involvement. The latter may affect the lungs, nervous system, liver, kidneys, and digestive tract. Anomalies of the respiratory system are often identified as lymphocytic interstitial pneumonia. Facial nerve palsy, aseptic meningitis or polyneuropathy are among the more frequent neurological features. Hepatic lymphocytic infiltration, lymphocytic interstitial nephropathy and digestive tract lymphocytic infiltration account for more rarely noted complications. Sicca syndrome, organomegaly and/or organ dysfunction associated with polyclonal CD8(+) T-cell organ-infiltration are greatly suggestive of DILS in people living with HIV. Labial salivary gland biopsy is therefore helpful when the focus score is equal or greater than 1 (or Chisholm Score ≥ 3). Primary Sjögren syndrome, chronic HCV or HTLV1 infection, graft versus host disease, IgG4-related disease, and immune reconstitution inflammatory syndrome are among the differential diagnoses that need to be considered. Treatment consists in highly active anti-retroviral therapy (HAART), which is usually effective in resolving clinical signs and symptoms. Steroids, however, may also be occasionally required when organ infiltration does not respond to HAART. This review should provide an insight into this rare entity complicating the course of HIV infection.