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Concept: Lymphoproliferative disorders

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BACKGROUND: Serum free light chain analysis is now well established in the investigation of monoclonal gammopathies. In the UK there has, until recently, been a single supplier of kits for such analysis. Recently, a second method using monoclonal antisera was introduced. We have compared the performance of these two kits in four routine laboratories. METHOD: Samples submitted for routine analysis (327 samples, 258 [79%] from patients with B-cell lymphoproliferative disease) for serum free light chains were tested by both technologies (Freelite, Binding Site and N Latex FLC, Siemens), according to the manufacturers' instructions. RESULTS: Qualitative data were available by both methods on 313 samples for serum free kappa chains and 324 samples for lambda free light chains. We found poor correspondence of 81% for kappa and 74% for lambda. Five percent of samples were significantly discordant in these assays. CONCLUSIONS: These assays perform very differently in clinical practice. They cannot be used interchangeably, especially if monitoring patient responses to therapy.

Concepts: Lymphocyte, Diseases and disorders, Lymphoproliferative disorders, Immunoglobulin light chain

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Non-Hodgkin lymphoma (NHL) constitutes a collection of lymphoproliferative disorders with widely varying biologic, histologic and clinical features. For the B-cell NHLs, great progress has been made due to the addition of monoclonal antibodies and, more recently, other novel agents such as B-cell receptor signaling inhibitors, immunomodulatory agents, and proteasome inhibitors. Autologous hematopoietic cell transplantation (auto-HCT) offers the promise of cure or prolonged remission in some NHL patients. For some patients, however, auto-HCT may never be a viable option, while in others their disease may progress despite auto-HCT. In those settings, allogeneic HCT (allo-HCT) offers the potential for cure. Over the past 10-15 years, considerable progress has been made in the implementation of allo-HCT, such that this approach now is a highly effective therapy for patients up to (and even beyond) age 75. Recent advances in conventional lymphoma therapy, peri-transplant supportive care, patient selection, and donor selection (including the use of alternative hematopoietic cell donors), has allowed broader application of allo-HCT to NHL patients. As a result, an ever-increasing number of NHL patients over age 60-65 years stand to benefit from allo-HCT. In this review, we present data in support of the use of allo-HCT for patients with diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma. These histologies account for a large majority of allo-HCT performed for patients over 60 in the U.S. Where possible, we highlight available data in older patients. This body of literature strongly supports the concept that allo-HCT should be offered to fit patients well beyond age 65 and, accordingly, that this treatment should therefore be covered by their insurance carriers.

Concepts: Lymphocyte, Types of cancer, Lymphoma, Hematopoietic stem cell transplantation, Follicular lymphoma, Lymphoproliferative disorders, Mantle cell lymphoma, T-cell lymphoma

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Lymphomatoid papulosis (LyP) belongs to the spectrum of primary cutaneous CD30-positive lymphoproliferative disorders. Clinically, LyP is characterized by a variable number of self-healing papulo-nodular lesions, with the typical waxing and waning course. Histologically, 4 types (A, B, C, and D) have been delineated. Angioinvasive growth and large ulcers are rare findings in LyP and simulate aggressive lymphoma. We retrospectively analyzed the clinicopathologic and molecular features of angioinvasive LyP in a series of 16 patients. This new form of LyP is characterized by oligolesional papules that rapidly ulcerate and evolve into large necrotic eschar-like lesions with a diameter of 1 to 4 cm and an angiocentric and angiodestructive infiltrate of small-sized to medium-sized atypical lymphocytes expressing CD30 and frequently CD8. As in other forms of LyP, the lesions underwent spontaneous regression after a few weeks. Recurrences were common, but the prognosis was excellent with no extracutaneous spread or disease-related deaths. Complete remission occurred in 9 of 16 patients (56%). This LyP variant should be distinguished from aggressive forms of angiocentric and angiodestructive and cytotoxic T-cell lymphomas. We propose the term LyP type E for this clinically and histologically unusual variant.

Concepts: Lymphocyte, Natural killer cell, B cell, Lymphoma, Cytotoxic T cell, Lymphomatoid papulosis, Follicular lymphoma, Lymphoproliferative disorders

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Lymphomatoid papulosis (LyP) and cutaneous anaplastic large cell lymphoma (ALCL) belong to the spectrum of cutaneous CD30+ lymphoproliferative disorders, an indolent form of T-cell lymphoproliferative disease. We reviewed 21 cases of CD30+ lymphoproliferative lesions expressing cytotoxic profile (CD8+). Seven cases of cutaneous ALCL, 2 cases of systemic ALCL involving the skin, and 12 cases of LyP. The cases of LyP were predominated by small lymphocytes exhibiting a prominent epidermotropic pattern consistent with either type B or type D LyP. Four cases showed co-expression of CD56. The ALCL cases included myxoid features, pseudoepitheliomatous change, and an intravascular component. In all cases that were primary in the skin an indolent clinical course was seen while one patient with systemic myxoid ALCL is in remission following systemic multiagent chemotherapy. The paucity of other neutrophils and eosinophils and concomitant granulomatous inflammation were distinctive features in cases of type B and type D LyP. CD30 and CD45 Ro positivity and a clinical course typical of LyP were useful differentiating features from an aggressive cytotoxic CD8+ T cell lymphoma. In all cases that were primary in the skin an indolent clinical course was observed. CD30 and CD45 Ro positivity and a clinical course typical of LyP were useful in preventing a misdiagnosis of an aggressive cytotoxic CD8+ T cell lymphoma.

Concepts: White blood cell, Lymphocyte, Diseases and disorders, Natural killer cell, Lymphoma, Lymphomatoid papulosis, Anaplastic large cell lymphoma, Lymphoproliferative disorders

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Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a polyclonal B-cell lymphoproliferative disorder. Human IL-6 and a KSHV-encoded homolog, viral IL-6, have been hypothesized to contribute to its pathogenesis but their relative contributions to disease activity is not well understood. We prospectively characterized KSHV viral load (VL), viral (v) and human (h) IL-6, and other cytokines during KSHV-MCD flare and remission in 21 patients with 34 flares and 20 remissions. KSHV-VL, vIL-6, hIL-6 , IL-10, and to a lesser extent TNF-α, and IL-1β were each elevated during initial flares compared with remission. Flares fell into three distinct IL-6 profiles: those associated with elevations of vIL-6 only (2 flares, 6%), hIL-6 elevations only (17 flares, 50%), and elevations in both hIL-6 and vIL-6 (13 flares, 38%). Compared with hIL-6-only flares, flares with elevated hIL-6 plus vIL-6 exhibited higher CRP (P=0.0009); worse hyponatremia (P=0.02); higher KSHV VL (P=0.016) and higher IL-10 (P=0.012). This analysis shows vIL-6 and hIL-6 can independently or together lead KSHV-MCD flares, and suggests that vIL-6 and hIL-6 may jointly contribute to disease severity. These findings have implications for the development of novel KSHV-MCD therapies targeting IL-6 and its downstream signaling. This study was registered at clinicaltrials.gov as NCT099073.

Concepts: Lymphocyte, Cancer, Kaposi's sarcoma, Sarcoma, Lymphoproliferative disorders, Post-transplant lymphoproliferative disorder, Kaposi's sarcoma-associated herpesvirus, Castleman's disease

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Angioedema is a rare but may be serious (laryngeal edema). This is a recurrent edema, subcutaneous and/or submucosal, whose cause is a hereditary or acquired deficiency in C1 inhibiteur (C1 inhibitor fraction of complement). We present the case of a 56 years old patient who showed recurrent episodes of swelling of the face and hands in association with chronic lymphocytic leukemia stage A. The exploration of the complement pathway has allowed retaining the diagnosis of acquired angioedema type I. The association of angioedema and lymphoproliferative syndrome is rare; we present this interesting case to discuss it from the literature data.

Concepts: Inflammation, Lymphocyte, Leukemia, Medical signs, Blood disorders, Complement system, Edema, Lymphoproliferative disorders

8

Hypereosinophilic syndrome (HES) is a group of rare blood disorders characterized by a persistent elevation of blood eosinophil count ⩾1.5×10(9)/L and clinical manifestations attributable to eosinophilia or tissue hypereosinophilia. Lymphocytic variant of HES (HES-L) is a known subtype according to World Health Organization classification. It is well documented in the literature that patients with HES-L are predisposed to develop T-cell lymphoma. We report a case of T-cell lymphoproliferation associated with hypereosinophilia, which has been successfully treated with mycophenolate mofetil, with resolution of skin lesions and normalization of eosinophil count and immunoglobulin E level. We believe this is a clinically relevant case since this is a rare disease with little known knowledge on its best treatment modality.

Concepts: AIDS, Immune system, White blood cell, Lymphocyte, Blood, Hematology, Lymphoproliferative disorders

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Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, was shown to eliminate skin test reactivity in vivo and IgE-dependent basophil activation testing ex vivo. Blockade of the BTK pathway may represent a novel therapeutic strategy for the effective reduction of allergic reactivity.

Concepts: Signal transduction, In vivo, Allergy, Protein kinase, Tyrosine kinase, Lymphoproliferative disorders, Post-transplant lymphoproliferative disorder

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Young-onset autoimmune diabetes associated with additional autoimmunity usually reflects a polygenic predisposition but rare cases result from monogenic autoimmunity. Diagnosing monogenic autoimmunity is crucial for patients' prognosis and clinical management. We sought to identify novel genetic causes of autoimmunity presenting with neonatal diabetes (NDM; diagnosis <6 months).We performed exome sequencing in a patient with NDM and autoimmune lymphoproliferative syndrome and his unrelated, unaffected parents and identified compound heterozygous null mutations in LRBA Biallelic LRBA mutations cause Common Variable Immunodeficiency-8, however NDM has not been confirmed in this disorder. We sequenced LRBA in 169 additional patients with diabetes diagnosed <1 year without mutations in the 24 known NDM genes. We identified recessive null mutations in 8 additional probands, of which 3 had NDM (<6 months). Diabetes was the presenting feature in 6 of 9 probands. Six of 17 (35%) patients both born to consanguineous parents and with additional early-onset autoimmunity had recessive LRBA mutations.LRBA testing should be considered in patients with diabetes diagnosed <12 months, particularly if they have additional autoimmunity or are born to consanguineous parents. A genetic diagnosis is important as it can enable personalized therapy with abatacept, a CTLA4 mimetic, and inform genetic counselling.

Concepts: Genetics, Mutation, Causality, Diagnosis, Rheumatoid arthritis, Autoimmunity, Compound heterozygosity, Lymphoproliferative disorders

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