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Lymphoma-associated dysimmune polyneuropathies

  • Joerg-Patrick Stübgen
    Correspondence
    Department of Neurology, Weill Cornell Medical College/New York Presbyterian Hospital, 525 East 68th Street, New York, NY 10065-4885, USA.
    Affiliations
    Department of Neurology, Weill Cornell Medical College/New York Presbyterian Hospital, New York, NY 10065-4885, USA
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      Highlights

      • Lymphoma is a group of lymphatic system malignancies.
      • A complex inter-relationship exists between lymphoma and autoimmunity.
      • Peripheral nervous system abnormalities occur in 5% of lymphoma patients.
      • Autoimmune neuropathy occurs rarely in lymphoma patients.
      • Accurate neuropathy diagnosis is important for correct treatment plan.

      Abstract

      Lymphoma consists of a variety of malignancies of lymphocyte origin. A spectrum of clinical peripheral neuropathy syndromes with different disease mechanisms occurs in about 5% of lymphoma patients. There exists a complex inter-relationship between lymphoproliferative malignancies and autoimmunity. An imbalance in the regulation of the immune system presumably underlies various immune-mediated neuropathies in patients with lymphoma. This article reviews lymphoma and more-or-less well-defined dysimmune neuropathy subgroups that are caused by humoral and/or cell-mediated immune disease mechanisms directed against known or undetermined peripheral nerve antigens.

      Keywords

      1. Introduction

      Lymphoma is a group of lymphatic system malignancies. Many lymphoma classification systems were devised over the years; most hematologists/oncologists adopted the WHO International Classification of Diseases (ICD) system (presently ICD-10 version of 2010) (www.lymphomainfo.net). About 90% of lymphomas are of the non-Hodgkin type (NHL), a diverse group of diseases each distinguished by the specific characteristics of lymphocytes (85% B-cells, less commonly T- or NK-cells). About 10% of lymphomas are of the Hodgkin type (HL), characterized by the presence of germinal center B-lymphocyte-derived Reed–Sternberg cells. This review includes patients with chronic lymphocytic leukemia (CLL), because it is considered the same disease as small lymphocytic lymphoma (SLL), a NHL subtype, though with abnormal cells in the blood (www.lymphomas.org.uk).
      A wide variety of peripheral nervous system abnormalities occur in 5% of patients with lymphoma [
      • Hughes R.A.
      • Britton T.
      • Richards M.
      Effects of lymphoma on the peripheral nervous system.
      ]; however, electrophysiological evidence of mostly sub-clinical neuropathy was reported in as many as 35% of patients with various types of lymphoma [
      • Walsh J.C.
      Neuropathy associated with lymphoma.
      ]. Neuropathy can be the presenting feature of lymphoma or develop at any stage of disease, even during remission [
      • Kelly J.J.
      • Karcher D.S.
      Lymphoma and peripheral neuropathy: a clinical review.
      ]. Lymphoma can involve any part of the peripheral nervous system. The mechanisms of lymphoma-associated neuropathy (i.e., excluding chemotherapy exposure, viral infections [e.g., HIV/Herpes zoster], and established nutritional disturbances) may entail [
      • Kelly J.J.
      • Karcher D.S.
      Lymphoma and peripheral neuropathy: a clinical review.
      ,
      • Vital C.
      • Vital A.
      • Julien J.
      • Rivel J.
      • de Mascarel A.
      • Vergier B.
      • Henry P.
      • Barat M.
      • Reiffers J.
      • Broustet A.
      Peripheral neuropathies and lymphoma without gammopathy: a new classification.
      ,
      • Vallat J.M.
      • De Mascarel H.A.
      • Bordessoule D.
      • Jauberteau M.O.
      • Tabaraud F.
      • Gelot A.
      • Vallat A.V.
      Non-Hodgkin malignant lymphomas and peripheral neuropathies—13 cases.
      ,
      • Tomita M.
      • Koike H.
      • Kawagashira Y.
      • Iijima M.
      • Adachi H.
      • Taguchi J.
      • Abe T.
      • Sako K.
      • Tsuji Y.
      • Nakagawa M.
      • Kanda F.
      • Takeda F.
      • Sugawara M.
      • Asano N.
      • Sobue G.
      Clinicopathological features of neuropathy associated with lymphoma.
      ]: (a) local or diffuse peripheral nerve lymphomatous (specifically NHL/T-) cell invasion i.e., neurolymphomatosis; (b) deposition in the endoneurium of circulating monoclonal antibodies (mostly IgM paraprotein) secreted by malignant or non-malignant lymphocytes/plasma cells; (c) autoantibodies directed against specific peripheral nerve antigens (e.g., myelin-associated glycoprotein or gangliosides) probably produced by non-lymphomatous clonal B-cell expansion due to immune “escape” mechanisms [
      • Hughes R.A.
      • Britton T.
      • Richards M.
      Effects of lymphoma on the peripheral nervous system.
      ]; (d) lymphoma-induced (particularly HL) immune dysregulation that underlies immune-mediated inflammatory neuropathy; (e) ischemic neuropathy due to: (1) hematogenous metastases (angiotropic B-cell lymphoma) that occlude vessels by local intravascular proliferation, direct pressure, or tumor emboli; (2) cryoglobulin deposition (types I and II) [
      • Meerman L.
      • Slingerland R.
      • Bulens C.
      • Gratama S.
      • Busch H.F.
      • de Jong M.
      Cryoglobulinemic neuropathy in a patient with a malignant lymphoma.
      ,
      • Gemignani F.
      • Marchesi G.
      • Di Giovanni G.
      • Salih S.
      • Quaini F.
      • Nobile-Orazio E.
      Low-grade non-Hodgkin B-cell lymphoma presenting as sensory neuropathy.
      ,
      • Gemignani F.
      • Melli G.
      • Inglese C.
      • Marbini A.
      Cryoglobulinemia is a frequent cause of peripheral neuropathy in undiagnosed referral patients.
      ], or (3) immune/“paraneoplastic” vasculitis; (f) focal amyloid deposition in the vasa nervorum, endoneurium and perineurium in the setting of monoclonal paraprotein (IgM-λ type) [
      • Wokke J.H.
      • Morris J.H.
      • Donaghy M.
      Lymphoma, paraproteinemia, and neuropathy.
      ]; and (g) “other”/unclear explanation, possibly toxic/metabolic/nutritional.
      This article reviews lymphoma-associated peripheral nerve disorders with presumed immune-mediated pathogeneses. Specifically, this review concentrates on lymphoma and more-or-less well-defined immune neuropathy subgroups that are caused by humoral and/or cell-mediated immune attacks against either known or undetermined peripheral nerve antigens. The selective approach to this topic entailed careful screening of the literature and the exclusion of reports with variables that interfered with the interpretation of chosen, defined neuropathy subgroups: (a) cryoglobulinemic neuropathy (mechanism is vasculitic ischemic damage to nerves); (b) plasma cell dyscrasias that are not usually classified with the lymphomas [
      • Hughes R.A.
      • Britton T.
      • Richards M.
      Effects of lymphoma on the peripheral nervous system.
      ] e.g., Waldenström's macroglobulinemia/IgM-secreting lymphoplasmacytic lymphoma (although deposits of endoneurial monoclonal IgM secreted by plasma cells may lead to immune-mediated neuropathy) [
      • Baehring J.M.
      • Hochberg E.P.
      • Raje N.
      • Uirickson M.
      • Hochberg F.H.
      Neurological manifestations of Waldenström macroglobulinemia.
      ,
      • Silberman J.
      • Lional S.
      Review of peripheral neuropathy in plasma cell disorders.
      ,
      • Sobol U.
      • Stiff P.
      Neurologic aspects of plasma cell disorders.
      ]; (c) “paraneoplastic” primarily sensory [
      • Horwich M.S.
      • Cho L.
      • Porro R.S.
      • Posner J.B.
      Subacute sensory neuropathy: a remote effect of carcinoma.
      ,
      • Jones H.R.
      • Richardson E.P.
      Case records of the Massachusetts General Hospital. Case 8-1990.
      ,
      • Oztürk K.
      • Akgün Aksoy Y.
      Follicular lymphoma patient relapsing with paraneoplastic sensory neuronopathy (ganglioneuropathy).
      ] or motor [
      • Schold S.C.
      • Cho E.S.
      • Somasundaram M.
      • Posner J.B.
      Subacute motor neuronopathy: a remote effect of lymphoma.
      ,
      • Recine U.
      • Longhi C.
      • Pelosio A.
      • Massini R.
      An unusually severe subacute motor neuronopathy in Hodgkin's disease.
      ,
      • Flanagan E.P.
      • Sandroni P.
      • Pittock S.J.
      • Inwards D.J.
      • Jones Jr., L.K.
      Paraneoplastic lower motor neuronopathy associated with Hodgkin lymphoma.
      ] neuronopathies (immune attack presumably directed at nerve cell body antigens); (d) initial presentation as, or exacerbation of, an acquired inflammatory demyelinating neuropathy but: (1) biological treatment likely contributed significantly to immune dysregulation e.g., rituximab introduction [
      • Terenghi F.
      • Ardolino G.
      • Nobile-Orazio E.
      Guillain–Barré syndrome after combined CHOP and rituximab therapy in non-Hodgkin lymphoma.
      ] or maintenance therapy [
      • Carmona A.
      • Alonso J.D.
      • de las Heras M.
      • Navarette A.
      Guillain–Barré syndrome in a patient with diffuse large B-cell lymphoma, and rituximab maintenance therapy. An association beyond anecdotal evidence?.
      ], or recent completion of a course of alemtuzumab [
      • Abbi K.K.
      • Rizvi S.M.
      • Sivik J.
      • Thyagarajan S.
      • Loughran T.
      • Drabick J.J.
      Guillain–Barré syndrome after use of alemtuzumab (Compath) in a patient with T-cell prolymphocytic leukemia: a case report and review of the literature.
      ]; (2) effects of therapy resulted in severe superimposed immune disturbance e.g., acute tumor lysis syndrome [
      • Kurata H.
      • Hirai M.
      • Miwa A.
      • Murai Y.
      • Mori M.
      B-cell non-Hodgkin's lymphoma associated with lactic acid, recurrent tumor lysis syndrome, and at the end stage, Guillain–Barré syndrome.
      ], mobilization therapy with “pyrexia of unknown origin” [
      • D'Arena G.
      • Vigliotti M.L.
      • Pizza V.
      • Tartarone A.
      • Volpe G.
      • Iodice G.
      • Di Renzo N.
      Guillain–Barré syndrome complicating mobilization therapy in a case of B-cell chronic lymphocytic leukemia.
      ], or after autologous bone marrow transplantation [
      • Openshaw H.
      • Hinton D.R.
      • Slatkin N.E.
      • Bierman P.J.
      • Hoffman P.M.
      • Snyder D.S.
      Exacerbation of inflammatory demyelinating polyneuropathy after bone marrow transplantation.
      ,
      • Bashir R.M.
      • Bierman P.
      • McComb R.
      Inflammatory peripheral neuropathy following high dose chemotherapy, and autologous bone marrow transplantation.
      ]; (3) preceded by virus infection/reactivation e.g., Varicella zoster reactivation [
      • Laurenti L.
      • Garzia M.
      • Sabatelli M.
      • Piccioni P.
      • Sora F.
      • Leone G.
      Guillain–Barré syndrome following Varicella zoster reactivation in chronic lymphocytic leukemia treated with fludarabine.
      ], or (4) eventual evidence was found of malignant lymphocytic spread to CSF/nerve roots [
      • Allison R.S.
      • Gordon D.S.
      Reticulosis of the nervous system simulating acute infective polyneuritis.
      ,
      • Toren A.
      • Mandel M.
      • Shahar E.
      • Rimmoni E.
      • Roizin H.
      • Neuman Y.
      • Brok-Simoni F.
      • Mark Z.
      • Biniaminov M.
      • Rosenthal E.
      Primary central nervous system Burkitt's lymphoma presenting as Guillain–Barré syndrome.
      ,
      • Phan T.G.
      • Manoharan A.
      • Pryor D.
      Relapse of central nervous system Burkitt's lymphoma presenting as Guillain–Barré syndrome and syndrome of inappropriate ADH secretion.
      ] or peripheral nerves [
      • Sumi S.M.
      • Farrell D.F.
      • Knauss T.A.
      Lymphoma and leukemia manifested by steroid-responsive polyneuropathy.
      ]. A systematic search was conducted of relevant publications using databases such as MEDLINE [PubMed], EMBASE and DynaMed, and included case reports and series, retrospective studies, and reviews. Search terms included “neuropathy”, “immune-mediated”, “autoantibody”, “autoimmune”, and “lymphoma”. Publications were retrieved and scrutinized, and article bibliographies were cross-referenced to ensure that this review is accurate and comprehensive.

      2. Immune-mediated polyneuropathies

      2.1 Pathogenesis

      Reviews exist on the presumed immunopathogenesis of the acquired inflammatory demyelinating polyneuropathies [
      • Kieseier B.C.
      • Kiefer R.
      • Gold R.
      • Hemmer B.
      • Willison H.J.
      • Hartung H.P.
      Advances in understanding and treatment of immune-mediated disorders of the peripheral nervous system.
      ,
      • Lehmann H.C.
      • Meyer Zu Hörste G.
      • Kieseier B.C.
      • Hartung H.P.
      Pathogenesis and treatment of immune-mediated neuropathies.
      ,
      • Chavada G.
      • Willison H.J.
      Autoantibodies in immune-mediated neuropathies.
      ,
      • Kieseier B.C.
      • Lehmann H.C.
      • Meyer Zu Hörste G.
      Autoimmune diseases of the peripheral nervous system.
      ,
      • Mori M.
      • Kuwabara S.
      • Yuki N.
      Fisher syndrome; clinical features, immunopathogenesis and management.
      ,
      • Dalakas M.C.
      Pathophysiology of autoimmune polyneuropathies.
      ] and autoantibody-mediated polyneuropathies [
      • Steck A.J.
      • Stalder A.K.
      • Renaud S.
      Anti-myelin-associated glycoprotein neuropathy.
      ,
      • Willison H.J.
      Gangliosides as targets for autoimmune injury to the nervous system.
      ,
      • Dalakas M.C.
      Pathogenesis and treatment of anti-MAG neuropathy.
      ,
      • Suzuki K.
      • Yuki N.
      • Schafer D.P.
      • Hirata K.
      • Zhang G.
      • Funakoshi K.
      • Rasband M.N.
      Dysfunction of nodes of Ranvier: a mechanism for anti-ganglioside antibody-mediated neuropathies.
      ,
      • Uncini A.
      A common mechanism and new categorization for anti-ganglioside antibody-mediated neuropathies.
      ], and will not be discussed in detail here. To summarize, in inflammatory demyelinating polyneuropathies, cellular and humoral immune responses both participate in the disease mechanism (Fig. 1, Fig. 2). This immune response is directed against the myelin or axon of the peripheral nerve; no specific antigen has been consistently identified. Cellular immunity participation is supported by evidence of T-cell activation, crossing of the blood–nerve barrier by activated T-cells followed by macrophage-mediated demyelination, and by expression of cytokines, tumor necrosis factor, interferons, and interleukins. Humoral immunity is implicated by the demonstration of immunoglobulin and complement deposition on Schwann cells and myelinated nerve fibers, and by passive transfer experiments that induce conduction block and demyelination (by injecting serum or purified IgG from patients into rodent nerves).
      Figure thumbnail gr1
      Fig. 1Summary of the cellular immune response in inflammatory neuropathies: autoreactive T-cells recognize autoantigen presented by MHC class II on antigen presenting cells (with release of co-stimulatory signals) in systemic immune compartment. Activated T-cells cross the blood–nerve barrier into the peripheral nervous system. T-cells activate macrophages releasing mediators that promote demyelination and axonal loss. Termination of inflammation is promoted by macrophages that induce T-cell apoptosis and release of anti-inflammatory cytokines.
      [
      • Kieseier B.C.
      • Kiefer R.
      • Gold R.
      • Hemmer B.
      • Willison H.J.
      • Hartung H.P.
      Advances in understanding and treatment of immune-mediated disorders of the peripheral nervous system.
      ] [with permission Wiley and Sons]
      Figure thumbnail gr2
      Fig. 2Summary of humoral immune response in inflammatory neuropathies. Autoantibodies (cross blood–nerve barrier or produced locally by B-cells) contribute to demyelination and axonal injury by: (a) antibody-dependent cytotoxicity; (b) blocking functionally relevant epitopes for nerve conduction, and (c) activating the classic pathway of the complement system.
      [
      • Kieseier B.C.
      • Kiefer R.
      • Gold R.
      • Hemmer B.
      • Willison H.J.
      • Hartung H.P.
      Advances in understanding and treatment of immune-mediated disorders of the peripheral nervous system.
      ] [with permission Wiley and Sons]
      Anti-MAG antibodies have been implicated in a chronic demyelinating peripheral neuropathy. There is compelling evidence that anti-MAG antibodies play a causative role in the pathogenesis of neuropathy e.g., intraneural injection of serum from patients with demyelinating neuropathy and anti-MAG antibodies induced nerve demyelination in animal models. Studies of nerve biopsy specimens showed loss of myelinated fibers, thinned myelin sheaths, segmental demyelination, and occasionally tomacula and onion bulbs. Antibodies bind to an oligosaccharide determinant that is shared by MAG and the glycolipid sulfoglucuronyl paragloboside (SGPG).
      Anti-GM1 IgM antibodies are presumed to be pathogenic in the development of MMNCB, but it is not absolutely established whether antibodies are disease causative or merely an associated abnormality.

      2.2 Autoantibody-mediated polyneuropathies

      In this literature search 23 cases were retrieved of polyneuropathy associated with autoantibodies directed against specific peripheral nerve antigens in patients with various types of lymphoma (Table 1a and b ). The temporal association between neuropathy onset and lymphoma diagnosis varied: (1) In most patients, onset of neuropathy preceded by variable periods the diagnosis of lymphoma: (a) lymphoma was diagnosed only at autopsy in a patient with a 3-year history of polyradiculoneuropathy [
      • Baba H.
      • Miyatani N.
      • Sato S.
      • Yuasa T.
      • Miyatake T.
      Antibody to glycolipid in a patient with IgM paraproteinemia and polyradiculoneuropathy.
      ,
      • Miyatani N.
      • Baba H.
      • Sato S.
      • Nakamura K.
      • Yuasa T.
      • Miyatake T.
      Antibody to sialosyllactoaminosylparagloboside in a patient with IgM paraproteinemia and polyradiculoneuropathy.
      ]; (b) a patient with a 6-year progressive sensory demyelinating polyneuropathy associated with MGUS (? undetected lymphoma) developed fatal EBV+ intracerebral lymphoma after treatment with various courses of immunotherapy [
      • Ellie E.
      • Vital A.
      • Steck A.J.
      • Julien J.
      • Henry P.
      • Vital C.
      High-grade B-cell cerebral lymphoma in a patient with anti-myelin-associated glycoprotein IgM paraneoplastic neuropathy.
      ]; analyses of intrathecal and peripheral M-protein as well as brain immunocytochemical studies suggested a common clonal origin of both immunoblastic cerebral proliferation and the serum paraprotein-secreting cells. Presumably, immune deficiency due to monoclonal B-cell proliferation and/or immunosuppressive therapy resulted in EBV-reactivation and dysregulation of CNS-restricted T-cell control of B-cell proliferation; autopsy did not include search for systemic lymphoma; (c) chronic (up to 3-year duration), slowly progressive [
      • Gemignani F.
      • Marchesi G.
      • Di Giovanni G.
      • Salih S.
      • Quaini F.
      • Nobile-Orazio E.
      Low-grade non-Hodgkin B-cell lymphoma presenting as sensory neuropathy.
      ,
      • Albany C.
      Anti-myelin-associated glycoprotein peripheral neuropathy as the only presentation of low-grade lymphoma: a case report.
      ,
      • Stübgen J.P.
      Autoantibody-mediated sensory polyneuropathy associated with indolent B-cell non-Hodgkin lymphoma.
      ] or relapsing–remitting [
      • Kobayashi M.
      • Kato K.
      • Funakoshi K.
      • Watanabe S.
      • Toyoshima I.
      Neuropathology of paraneoplastic neuropathy with anti-disialosyl antibody.
      ] neuropathies preceded diagnoses of either indolent/low grade or diffuse large cell lymphoma, respectively; (d) a patient with a 2-year slowly progressive sensorimotor neuropathy developed B-cell CLL [
      • Mitsui Y.
      • Kusunoki S.
      • Hiruma S.
      • Akamatsu M.
      • Kihara M.
      • Hashimoto S.
      • Takahashi M.
      Sensorimotor polyneuropathy associated with chronic lymphocytic leukemia, IgM antigangliosides antibody and human T-cell leukemia virus 1 infection.
      ]; in this case, HTLV-1 co-infection could have triggered malignant transformation of an antigen-committed B-cell clone [
      • Mann D.L.
      • DeSantis P.
      • Mark G.
      • Pfeifer A.
      • Newman M.
      • Gibbs N.
      • Popovic M.
      • Sarngadharan M.G.
      • Gallo R.C.
      • Clark J.
      • Blattner W.
      HTLV-1-associated B-cell CLL: indirect role for retrovirus in leukomonogenesis.
      ], or HTLV-1-infected T-cells activated autologous B-cells in a contact-dependent manner [
      • Higuchi M.
      • Nagasawa K.
      • Horiuchi T.
      • Oike M.
      • Ito Y.
      • Yasukawa M.
      • Niho Y.
      Membrane tumor necrosis factor-α (TNF-α) expressed on HTLV-1 infected T cells mediates co-stimulatory signal for B cell activation-characterization of membrane TNFα.
      ]. (2) In some patients lymphoma diagnosis preceded onset of neuropathy: (a) in 1 report, relapsing–remitting cranial polyneuropathy occurred in a patient with established cutaneous lymphoma in remission and subsequent recurrence [
      • Blanche P.
      • Sicard D.
      IgM neuropathy, disclosed by isolated involvement of the cranial nerves, in type B cutaneous lymphoma.
      ]; (b) recurrent, treated [
      • Milnik A.
      • Roggenbuck D.
      • Conrad K.
      • Bartels C.
      Acute inflammatory neuropathy with monoclonal anti-GM2 IgM antibodies, IGM-k paraprotein and additional autoimmune processes in association with a diffuse large B-cell non-Hodgkin's lymphoma.
      ,
      • Mori A.
      • Ueno Y.
      • Kuroki T.
      • Hoshino Y.
      • Shimura H.
      • Sekiguchi Y.
      • Noguchi M.
      • Hamada Y.
      • Kusunoki S.
      • Hattori N.
      • Urabe T.
      Motor-dominant polyneuropathy due to IgM monoclonal antibody against disialosyl gangliosides in a patient with mantle cell lymphoma.
      ] or indolent, untreated [
      • Stübgen J.P.
      Autoantibody-mediated sensory polyneuropathy associated with indolent B-cell non-Hodgkin lymphoma.
      ] lymphoma preceded the onset of neuropathy symptoms at intervals of 2 years, 10 and 6 months in 3 patients, respectively. (3) In the remainder of patients, lymphoma was diagnosed during the initial presentation and evaluation of neuropathies of variable duration [
      • Gemignani F.
      • Marchesi G.
      • Di Giovanni G.
      • Salih S.
      • Quaini F.
      • Nobile-Orazio E.
      Low-grade non-Hodgkin B-cell lymphoma presenting as sensory neuropathy.
      ,
      • Andrés E.
      • Vinzio S.
      • Maloisel F.
      • Carre S.
      • Perrin A.E.
      • Goichot B.
      • Schlienger J.L.
      Autoimmune peripheral neuropathies with anti-MAG antibodies and hematological disorders. Five cases.
      ,
      • Noguchi M.
      • Mori K.
      • Yamazaki S.
      • Suda K.
      • Sato N.
      • Oshimi K.
      Multifocal motor neuropathy caused by a B-cell lymphoma producing monoclonal IgM autoantibody against nerve myelin glycolipids GM1 and GD1b.
      ,
      • Marfia G.A.
      • Pachatz C.
      • Terracciano C.
      • Leone G.
      • Bernardini S.
      • Massa R.
      Subacute demyelinating polyneuropathy in B-cell lymphoma with IgM antibodies against glycolipid GD1b.
      ,
      • Albany C.
      Anti-myelin-associated glycoprotein peripheral neuropathy as the only presentation of low-grade lymphoma: a case report.
      ].
      Table 1Lymphoma-associated autoantibody-mediated neuropathy.
      ReferenceAge/sexTarget antigenNeuropathyLymphoma subtype
      • Baba H.
      • Miyatani N.
      • Sato S.
      • Yuasa T.
      • Miyatake T.
      Antibody to glycolipid in a patient with IgM paraproteinemia and polyradiculoneuropathy.
      ,
      • Miyatani N.
      • Baba H.
      • Sato S.
      • Nakamura K.
      • Yuasa T.
      • Miyatake T.
      Antibody to sialosyllactoaminosylparagloboside in a patient with IgM paraproteinemia and polyradiculoneuropathy.
      65/MSLPGPolyradiculoneuropathyDMBCL
      • Blanche P.
      • Sicard D.
      IgM neuropathy, disclosed by isolated involvement of the cranial nerves, in type B cutaneous lymphoma.
      70/FMAGMultiple cranial/axonal polyneuropathyCutaneous B-cell
      • Ellie E.
      • Vital A.
      • Steck A.J.
      • Julien J.
      • Henry P.
      • Vital C.
      High-grade B-cell cerebral lymphoma in a patient with anti-myelin-associated glycoprotein IgM paraneoplastic neuropathy.
      74/FMAG/SGPGDemyelinating polyneuropathyHG EBV+ NHL-CNS
      • Gemignani F.
      • Marchesi G.
      • Di Giovanni G.
      • Salih S.
      • Quaini F.
      • Nobile-Orazio E.
      Low-grade non-Hodgkin B-cell lymphoma presenting as sensory neuropathy.
      78/FGM1/asialo-GM1Predominant sensory polyneuropathyLG NHL
      75/MSulfatidePredominant sensory polyneuropathyLG NHL
      78/FIgMκ/λ/IgGκPredominant sensory polyneuropathyLG NHL
      • Maillot F.
      • Gelot A.
      • Diot E.
      • Larmande P.
      • Guilmot J.L.
      IgM anti-MAG neuropathy with involvement of the cranial nerves disclosing B-cell lymphoma.
      79/MMAGDemyelinating poly-/cranial neuropathyCentroblastic DLBCL
      • Baud P.
      • Parant E.
      • Loison F.
      • Ménage J.J.
      IgM kappa lymphoma with antisulfatide antibodies revealed by cervical motor neuropathy simulating amyotrophic lateral sclerosis.
      79/MSulfatideCervical motor neuropathyB-cell NHL
      • Mitsui Y.
      • Kusunoki S.
      • Hiruma S.
      • Akamatsu M.
      • Kihara M.
      • Hashimoto S.
      • Takahashi M.
      Sensorimotor polyneuropathy associated with chronic lymphocytic leukemia, IgM antigangliosides antibody and human T-cell leukemia virus 1 infection.
      65/MDisialosyl ganglio+CIDP-likeCLL (HTLV-1+)
      • Andrés E.
      • Vinzio S.
      • Maloisel F.
      • Carre S.
      • Perrin A.E.
      • Goichot B.
      • Schlienger J.L.
      Autoimmune peripheral neuropathies with anti-MAG antibodies and hematological disorders. Five cases.
      80/MMAGPredominant sensory polyneuropathyNodular sclerosing NHL
      62/MMAGPredominant sensory polyneuropathyCLL IIB
      • Donfrid M.
      • Apostolski S.
      • Suvajdziç N.
      • Jankoviç G.
      • Cemenrikiç-Martinoviç V.
      • Atkinson H.D.
      • Colovic M.
      Monocytoid B cell lymphoma associated with antibodies to myelin-associated glycoprotein and sulphated glucuronyl paragloboside.
      53/MMAG/SGPGDemyelinating polyneuropathyNodal marginal zone NHL
      • Ishida K.
      • Takeuchi H.
      • Takahashi R.
      • Yoshimura K.
      • Yamada M.
      • Mizusawa H.
      A possible novel isoform of peripheral myelin P0 protein: a target antigen recognized by an autoantibody in a patient with malignant lymphoma and peripheral neuropathy.
      33/FP0 isoformCranial/sensory polyneuropathyMalignant B-cell NHL
      • Noguchi M.
      • Mori K.
      • Yamazaki S.
      • Suda K.
      • Sato N.
      • Oshimi K.
      Multifocal motor neuropathy caused by a B-cell lymphoma producing monoclonal IgM autoantibody against nerve myelin glycolipids GM1 and GD1b.
      52/MGM1/GD1b
      Galβ1–3GalNAc terminal disaccharide.
      Multifocal motor neuropathyDLBCL
      • Kobayashi M.
      • Kato K.
      • Funakoshi K.
      • Watanabe S.
      • Toyoshima I.
      Neuropathology of paraneoplastic neuropathy with anti-disialosyl antibody.
      63/MDisialosyl ganglio+
      NeuAc(α2-8)NeuAc(α2-3)Gal disialosyl epitope.
      Predominant sensory polyneuropathyDLBCL
      • Marfia G.A.
      • Pachatz C.
      • Terracciano C.
      • Leone G.
      • Bernardini S.
      • Massa R.
      Subacute demyelinating polyneuropathy in B-cell lymphoma with IgM antibodies against glycolipid GD1b.
      76/FGD1b
      NeuAc(α2-8)NeuAc(α2-3)Gal disialosyl epitope.
      Subacute demyelinating polyneuropathyLG B-cell NHL
      • Albany C.
      Anti-myelin-associated glycoprotein peripheral neuropathy as the only presentation of low-grade lymphoma: a case report.
      59/MMAGChronic demyelinating polyneuropathyLG B cell NHL
      • Launay M.
      • Delmont E.
      • Benaim C.
      • Sacconi S.
      • Butori C.
      • Desnuelle C.
      Anti-MAG paraproteinemic demyelinating polyneuropathy: a clinical, biological, electrophysiological and anatomopathological descriptive study of a 13-patients' cohort.
      76/MMAGDemyelinating polyneuropathyB-cell NHL
      68/MMAG/SGPGDemyelinating polyneuropathyB-cell NHL
      79/FMAG/SGPGDemyelinating polyneuropathyB-cell NHL
      • Milnik A.
      • Roggenbuck D.
      • Conrad K.
      • Bartels C.
      Acute inflammatory neuropathy with monoclonal anti-GM2 IgM antibodies, IGM-k paraprotein and additional autoimmune processes in association with a diffuse large B-cell non-Hodgkin's lymphoma.
      75/MGM2Acute inflammatory neuropathyDLCBL
      • Mori A.
      • Ueno Y.
      • Kuroki T.
      • Hoshino Y.
      • Shimura H.
      • Sekiguchi Y.
      • Noguchi M.
      • Hamada Y.
      • Kusunoki S.
      • Hattori N.
      • Urabe T.
      Motor-dominant polyneuropathy due to IgM monoclonal antibody against disialosyl gangliosides in a patient with mantle cell lymphoma.
      60/MDisialosyl ganglio+Predominant motor polyneuropathyMantle cell NHL
      • Stübgen J.P.
      Autoantibody-mediated sensory polyneuropathy associated with indolent B-cell non-Hodgkin lymphoma.
      77/FAsialo-GM1/GD1aPredominant sensory polyneuropathyMantle cell NHL
      70/MMAG/SGPGPredominant sensory polyneuropathyMarginal zone NHL
      ReferenceRx NeuropathyRx lymphomaOutcome/follow-up
      • Baba H.
      • Miyatani N.
      • Sato S.
      • Yuasa T.
      • Miyatake T.
      Antibody to glycolipid in a patient with IgM paraproteinemia and polyradiculoneuropathy.
      ,
      • Miyatani N.
      • Baba H.
      • Sato S.
      • Nakamura K.
      • Yuasa T.
      • Miyatake T.
      Antibody to sialosyllactoaminosylparagloboside in a patient with IgM paraproteinemia and polyradiculoneuropathy.
      Po CS/CPHDMBCL diagnosis at autopsy (35 months)
      • Blanche P.
      • Sicard D.
      IgM neuropathy, disclosed by isolated involvement of the cranial nerves, in type B cutaneous lymphoma.
      Po CSCHOPNeuropathy/lymphoma remission (6 months)
      • Ellie E.
      • Vital A.
      • Steck A.J.
      • Julien J.
      • Henry P.
      • Vital C.
      High-grade B-cell cerebral lymphoma in a patient with anti-myelin-associated glycoprotein IgM paraneoplastic neuropathy.
      Po CS/CHB/IVIGIv CSDied of NHL-CNS (68 months)
      • Gemignani F.
      • Marchesi G.
      • Di Giovanni G.
      • Salih S.
      • Quaini F.
      • Nobile-Orazio E.
      Low-grade non-Hodgkin B-cell lymphoma presenting as sensory neuropathy.
      Symptomatic onlyNeuropathy stable (12 months)
      Po CSNeuropathy stable (12 months)
      Po CSCHB/IFNα2aNeuropathy stable (24 months)
      • Maillot F.
      • Gelot A.
      • Diot E.
      • Larmande P.
      • Guilmot J.L.
      IgM anti-MAG neuropathy with involvement of the cranial nerves disclosing B-cell lymphoma.
      Po CS/CPHNot startedDied respiratory distress (11 months)
      • Baud P.
      • Parant E.
      • Loison F.
      • Ménage J.J.
      IgM kappa lymphoma with antisulfatide antibodies revealed by cervical motor neuropathy simulating amyotrophic lateral sclerosis.
      PPH pendingPo CS/CHBNeuropathy worsened/died of PE (3 months)
      • Mitsui Y.
      • Kusunoki S.
      • Hiruma S.
      • Akamatsu M.
      • Kihara M.
      • Hashimoto S.
      • Takahashi M.
      Sensorimotor polyneuropathy associated with chronic lymphocytic leukemia, IgM antigangliosides antibody and human T-cell leukemia virus 1 infection.
      Iv CS/CPHNeuropathy improved (6 months)
      • Andrés E.
      • Vinzio S.
      • Maloisel F.
      • Carre S.
      • Perrin A.E.
      • Goichot B.
      • Schlienger J.L.
      Autoimmune peripheral neuropathies with anti-MAG antibodies and hematological disorders. Five cases.
      ABVD/XRTImproved neuropathy/NHL remission (3 months)
      CHBLost to follow-up
      • Donfrid M.
      • Apostolski S.
      • Suvajdziç N.
      • Jankoviç G.
      • Cemenrikiç-Martinoviç V.
      • Atkinson H.D.
      • Colovic M.
      Monocytoid B cell lymphoma associated with antibodies to myelin-associated glycoprotein and sulphated glucuronyl paragloboside.
      ChlVPPNeuropathy improved/NHL remission (NR)
      • Ishida K.
      • Takeuchi H.
      • Takahashi R.
      • Yoshimura K.
      • Yamada M.
      • Mizusawa H.
      A possible novel isoform of peripheral myelin P0 protein: a target antigen recognized by an autoantibody in a patient with malignant lymphoma and peripheral neuropathy.
      Iv CSCHOPNeuropathy improved (NR)
      • Noguchi M.
      • Mori K.
      • Yamazaki S.
      • Suda K.
      • Sato N.
      • Oshimi K.
      Multifocal motor neuropathy caused by a B-cell lymphoma producing monoclonal IgM autoantibody against nerve myelin glycolipids GM1 and GD1b.
      IVIG/PPHCHOPDied of multi-organ failure (<3 months)
      • Kobayashi M.
      • Kato K.
      • Funakoshi K.
      • Watanabe S.
      • Toyoshima I.
      Neuropathology of paraneoplastic neuropathy with anti-disialosyl antibody.
      PPH/po CS/IVIGNot startedDied of DIC (84 months)
      • Marfia G.A.
      • Pachatz C.
      • Terracciano C.
      • Leone G.
      • Bernardini S.
      • Massa R.
      Subacute demyelinating polyneuropathy in B-cell lymphoma with IgM antibodies against glycolipid GD1b.
      IVIG/po CSNot startedDied of intestinal pseudo-obstruction (2 months)
      • Albany C.
      Anti-myelin-associated glycoprotein peripheral neuropathy as the only presentation of low-grade lymphoma: a case report.
      RNeuropathy/NHL improved (3 months)
      • Launay M.
      • Delmont E.
      • Benaim C.
      • Sacconi S.
      • Butori C.
      • Desnuelle C.
      Anti-MAG paraproteinemic demyelinating polyneuropathy: a clinical, biological, electrophysiological and anatomopathological descriptive study of a 13-patients' cohort.
      NRNRNR
      NRNRNR
      NRNRNR
      • Milnik A.
      • Roggenbuck D.
      • Conrad K.
      • Bartels C.
      Acute inflammatory neuropathy with monoclonal anti-GM2 IgM antibodies, IGM-k paraprotein and additional autoimmune processes in association with a diffuse large B-cell non-Hodgkin's lymphoma.
      IVIG/PPHNRNeuropathy improved (2 months)
      • Mori A.
      • Ueno Y.
      • Kuroki T.
      • Hoshino Y.
      • Shimura H.
      • Sekiguchi Y.
      • Noguchi M.
      • Hamada Y.
      • Kusunoki S.
      • Hattori N.
      • Urabe T.
      Motor-dominant polyneuropathy due to IgM monoclonal antibody against disialosyl gangliosides in a patient with mantle cell lymphoma.
      IVIG/Iv/po CS/PPHBNeuropathy improved/NHL stable (15 months)
      • Stübgen J.P.
      Autoantibody-mediated sensory polyneuropathy associated with indolent B-cell non-Hodgkin lymphoma.
      IVIGNeuropathy stable (7 months)
      IVIGNeuropathy stable (8 months)
      CLL = chronic lymphocytic leukemia; disialosyl ganglio+ = GD1a/GD1b/GD2/GD3/GQ1b/GT1a and/or GT1b; DLBCL = diffuse large B-cell lymphoma; DMBCL = diffuse medium B-cell lymphoma; EBV = Epstein–Barr virus; GD = ganglioside disialic acid; GM = ganglioside monosialic acid; HG = high grade; HL = Hodgkin lymphoma; HTLV-1 = human T-lymphotropic virus-1; LG = low grade; MAG = myelin-associated glycoprotein; NHL = non-Hodgkin lymphoma; P0 = myelin protein zero; SGPG = sulfated glucoronyl paragloboside; SLPG = sialosyl lactosaminyl paragloboside.
      ABVD = Adriamycin/bleomycin/vinblastine/dacarbarbazine; B = bendamustine hydrochloride; CHB = chlorambucil; ChlVPP = chlorambucil/vincristine/procarbazine/prednisolone; CHOP = cyclophosphamide/hydroxydaunorubicin/Oncovin/prednisone; CS = corticosteroids; CPH = cyclophosphamide; IFN = interferon; iv-intravenous; po = oral; PPH = plasmapheresis; R = rituximab; XRT = radiation therapy.
      a Galβ1–3GalNAc terminal disaccharide.
      b NeuAc(α2-8)NeuAc(α2-3)Gal disialosyl epitope.
      In this non-uniform group of patients, serum autoantibodies were detected against a spectrum of peripheral nerve antigens. Presumably, these antibodies played a pathogenic role in the development of neuropathies. There was no evidence to suggest that autoantibodies were produced in response to peripheral nerve damage of direct lymphoma spread; moreover, any fortuitous association was minimized by adequate search for other causes of polyneuropathy in these patients. In most, but not all [
      • Gemignani F.
      • Marchesi G.
      • Di Giovanni G.
      • Salih S.
      • Quaini F.
      • Nobile-Orazio E.
      Low-grade non-Hodgkin B-cell lymphoma presenting as sensory neuropathy.
      ,
      • Baud P.
      • Parant E.
      • Loison F.
      • Ménage J.J.
      IgM kappa lymphoma with antisulfatide antibodies revealed by cervical motor neuropathy simulating amyotrophic lateral sclerosis.
      ], patients the clinical presentation of neuropathy conformed to the literature descriptions of the specific autoantibody-associated polyneuropathy subtypes.
      Serum paraprotein (IgMκ or λ) was detected in all but 4 patients [
      • Mitsui Y.
      • Kusunoki S.
      • Hiruma S.
      • Akamatsu M.
      • Kihara M.
      • Hashimoto S.
      • Takahashi M.
      Sensorimotor polyneuropathy associated with chronic lymphocytic leukemia, IgM antigangliosides antibody and human T-cell leukemia virus 1 infection.
      ,
      • Kobayashi M.
      • Kato K.
      • Funakoshi K.
      • Watanabe S.
      • Toyoshima I.
      Neuropathology of paraneoplastic neuropathy with anti-disialosyl antibody.
      ,
      • Stübgen J.P.
      Autoantibody-mediated sensory polyneuropathy associated with indolent B-cell non-Hodgkin lymphoma.
      ]; however, 3 patients showed tri-clonal bands, specifically IgMκ/λ and IgGκ [
      • Maillot F.
      • Gelot A.
      • Diot E.
      • Larmande P.
      • Guilmot J.L.
      IgM anti-MAG neuropathy with involvement of the cranial nerves disclosing B-cell lymphoma.
      ]; IgMκ and bi-IgGκ [
      • Andrés E.
      • Vinzio S.
      • Maloisel F.
      • Carre S.
      • Perrin A.E.
      • Goichot B.
      • Schlienger J.L.
      Autoimmune peripheral neuropathies with anti-MAG antibodies and hematological disorders. Five cases.
      ] or tri-IgMκ [
      • Milnik A.
      • Roggenbuck D.
      • Conrad K.
      • Bartels C.
      Acute inflammatory neuropathy with monoclonal anti-GM2 IgM antibodies, IGM-k paraprotein and additional autoimmune processes in association with a diffuse large B-cell non-Hodgkin's lymphoma.
      ]. Serum mixed cryoglobulins were detected in 3 cases, and possibly played a pathogenic role in neuropathy in 2 patients [
      • Gemignani F.
      • Marchesi G.
      • Di Giovanni G.
      • Salih S.
      • Quaini F.
      • Nobile-Orazio E.
      Low-grade non-Hodgkin B-cell lymphoma presenting as sensory neuropathy.
      ], but were deemed causally unrelated to neuropathy in 1 patient [
      • Baud P.
      • Parant E.
      • Loison F.
      • Ménage J.J.
      IgM kappa lymphoma with antisulfatide antibodies revealed by cervical motor neuropathy simulating amyotrophic lateral sclerosis.
      ].
      CSF analyses were reported on 12 patients: protein was elevated in 9 patients; cell count was elevated in 3 patients. By definition, any patient with malignant cells in CSF was not included in this review.
      Peripheral nerve specimens were obtained by biopsy or autopsy from 7 patients: all showed a predominant decrease of large myelinated fibers; in some samples there was evidence also of active or chronic (i.e., sparse onion bulb formation) demyelination [
      • Maillot F.
      • Gelot A.
      • Diot E.
      • Larmande P.
      • Guilmot J.L.
      IgM anti-MAG neuropathy with involvement of the cranial nerves disclosing B-cell lymphoma.
      ,
      • Baud P.
      • Parant E.
      • Loison F.
      • Ménage J.J.
      IgM kappa lymphoma with antisulfatide antibodies revealed by cervical motor neuropathy simulating amyotrophic lateral sclerosis.
      ,
      • Mitsui Y.
      • Kusunoki S.
      • Hiruma S.
      • Akamatsu M.
      • Kihara M.
      • Hashimoto S.
      • Takahashi M.
      Sensorimotor polyneuropathy associated with chronic lymphocytic leukemia, IgM antigangliosides antibody and human T-cell leukemia virus 1 infection.
      ,
      • Donfrid M.
      • Apostolski S.
      • Suvajdziç N.
      • Jankoviç G.
      • Cemenrikiç-Martinoviç V.
      • Atkinson H.D.
      • Colovic M.
      Monocytoid B cell lymphoma associated with antibodies to myelin-associated glycoprotein and sulphated glucuronyl paragloboside.
      ,
      • Noguchi M.
      • Mori K.
      • Yamazaki S.
      • Suda K.
      • Sato N.
      • Oshimi K.
      Multifocal motor neuropathy caused by a B-cell lymphoma producing monoclonal IgM autoantibody against nerve myelin glycolipids GM1 and GD1b.
      ,
      • Kobayashi M.
      • Kato K.
      • Funakoshi K.
      • Watanabe S.
      • Toyoshima I.
      Neuropathology of paraneoplastic neuropathy with anti-disialosyl antibody.
      ,
      • Launay M.
      • Delmont E.
      • Benaim C.
      • Sacconi S.
      • Butori C.
      • Desnuelle C.
      Anti-MAG paraproteinemic demyelinating polyneuropathy: a clinical, biological, electrophysiological and anatomopathological descriptive study of a 13-patients' cohort.
      ].
      Nerve immunohistochemical analysis (IA) was performed on 5 patients. Direct study on a sural nerve biopsy revealed deposition of IgM along myelin sheaths of nerve fibers [
      • Mitsui Y.
      • Kusunoki S.
      • Hiruma S.
      • Akamatsu M.
      • Kihara M.
      • Hashimoto S.
      • Takahashi M.
      Sensorimotor polyneuropathy associated with chronic lymphocytic leukemia, IgM antigangliosides antibody and human T-cell leukemia virus 1 infection.
      ,
      • Donfrid M.
      • Apostolski S.
      • Suvajdziç N.
      • Jankoviç G.
      • Cemenrikiç-Martinoviç V.
      • Atkinson H.D.
      • Colovic M.
      Monocytoid B cell lymphoma associated with antibodies to myelin-associated glycoprotein and sulphated glucuronyl paragloboside.
      ]. IA showed that serum from a patient exclusively labeled isolated rat sciatic nerve myelin sheath as if it had been labeled by anti-P0 antibody [
      • Ishida K.
      • Takeuchi H.
      • Takahashi R.
      • Yoshimura K.
      • Yamada M.
      • Mizusawa H.
      A possible novel isoform of peripheral myelin P0 protein: a target antigen recognized by an autoantibody in a patient with malignant lymphoma and peripheral neuropathy.
      ]. Thin layer chromatography (TLC) immunostaining of patient neural tissue extract stained with patient serum IgMλ antibody, and bound preferentially to glycolipids GM1 and Gd1b [
      • Noguchi M.
      • Mori K.
      • Yamazaki S.
      • Suda K.
      • Sato N.
      • Oshimi K.
      Multifocal motor neuropathy caused by a B-cell lymphoma producing monoclonal IgM autoantibody against nerve myelin glycolipids GM1 and GD1b.
      ]. However, in another patient with elevated serum anti-disialosyl IgM antibodies, immunoblotting against human and rat sciatic nerve was deemed not significant [
      • Kobayashi M.
      • Kato K.
      • Funakoshi K.
      • Watanabe S.
      • Toyoshima I.
      Neuropathology of paraneoplastic neuropathy with anti-disialosyl antibody.
      ].
      Based on the presumed autoimmune pathogenesis of neuropathy, the majority of patients was offered and responded to some form of immunomodulatory therapy. Any neuropathy clinical response was independent of time of discovery or any treatment of the underlying lymphoma. Less frequently, cytotoxic therapy was aimed at lymphoma, and proved either effective [
      • Andrés E.
      • Vinzio S.
      • Maloisel F.
      • Carre S.
      • Perrin A.E.
      • Goichot B.
      • Schlienger J.L.
      Autoimmune peripheral neuropathies with anti-MAG antibodies and hematological disorders. Five cases.
      ,
      • Albany C.
      Anti-myelin-associated glycoprotein peripheral neuropathy as the only presentation of low-grade lymphoma: a case report.
      ] or ineffective [
      • Baud P.
      • Parant E.
      • Loison F.
      • Ménage J.J.
      IgM kappa lymphoma with antisulfatide antibodies revealed by cervical motor neuropathy simulating amyotrophic lateral sclerosis.
      ] treatment also for the neuropathy. Lymphoma was not treated when the nature of disease was presumed indolent, or when lymphoma was discovered only at autopsy [
      • Baba H.
      • Miyatani N.
      • Sato S.
      • Yuasa T.
      • Miyatake T.
      Antibody to glycolipid in a patient with IgM paraproteinemia and polyradiculoneuropathy.
      ,
      • Miyatani N.
      • Baba H.
      • Sato S.
      • Nakamura K.
      • Yuasa T.
      • Miyatake T.
      Antibody to sialosyllactoaminosylparagloboside in a patient with IgM paraproteinemia and polyradiculoneuropathy.
      ]. Any reported deaths among patients during the varying length observation periods were ascribed to the lymphoma or associated systemic complications; no patient death was directly related to polyneuropathy.
      An apparent pathogenic role of circulating antibody with affinity for peripheral nerve antigen(s) was demonstrated by immunofluorescent study on some reported lymphoma patients [
      • Mitsui Y.
      • Kusunoki S.
      • Hiruma S.
      • Akamatsu M.
      • Kihara M.
      • Hashimoto S.
      • Takahashi M.
      Sensorimotor polyneuropathy associated with chronic lymphocytic leukemia, IgM antigangliosides antibody and human T-cell leukemia virus 1 infection.
      ,
      • Donfrid M.
      • Apostolski S.
      • Suvajdziç N.
      • Jankoviç G.
      • Cemenrikiç-Martinoviç V.
      • Atkinson H.D.
      • Colovic M.
      Monocytoid B cell lymphoma associated with antibodies to myelin-associated glycoprotein and sulphated glucuronyl paragloboside.
      ,
      • Ishida K.
      • Takeuchi H.
      • Takahashi R.
      • Yoshimura K.
      • Yamada M.
      • Mizusawa H.
      A possible novel isoform of peripheral myelin P0 protein: a target antigen recognized by an autoantibody in a patient with malignant lymphoma and peripheral neuropathy.
      ,
      • Noguchi M.
      • Mori K.
      • Yamazaki S.
      • Suda K.
      • Sato N.
      • Oshimi K.
      Multifocal motor neuropathy caused by a B-cell lymphoma producing monoclonal IgM autoantibody against nerve myelin glycolipids GM1 and GD1b.
      ,
      • Kobayashi M.
      • Kato K.
      • Funakoshi K.
      • Watanabe S.
      • Toyoshima I.
      Neuropathology of paraneoplastic neuropathy with anti-disialosyl antibody.
      ], or was otherwise presumed. Some evidence suggested that circulating anti-nerve monoclonal autoantibodies, usually immunoglobulin-M paraprotein, were actually produced by lymphoma B-cells. A single report provided evidence of production of monoclonal IgMλ anti-GM1/GD1b autoantibody by tumor cells in a patient with diffuse large B-cell NHL [
      • Noguchi M.
      • Mori K.
      • Yamazaki S.
      • Suda K.
      • Sato N.
      • Oshimi K.
      Multifocal motor neuropathy caused by a B-cell lymphoma producing monoclonal IgM autoantibody against nerve myelin glycolipids GM1 and GD1b.
      ]: (a) on immunofluorescent flow cytometry simultaneous expression of CD79b (part of a heterodimer transmembrane protein) and IgMλ on the surface of CD19-positive lymphoma cells indicated that most IgMλ antibodies were not adherent to the lymphoma cells; rather, they were present on the surface in a secretory form; and (b) levels of monoclonal antibody (with affinity for Galβ1-3GalNAc terminal disaccharide antigenic determinant) were significantly higher in the supernatant from a 2-d culture of lymphoma cells compared to normal lymphocytes.
      In another report, the clonal origin of monocytoid B-cell lymphoma suggested that lymphoma cells synthesized IgMκ paraproteins, and were determined to be autoantibodies to MAG and SGPG [
      • Donfrid M.
      • Apostolski S.
      • Suvajdziç N.
      • Jankoviç G.
      • Cemenrikiç-Martinoviç V.
      • Atkinson H.D.
      • Colovic M.
      Monocytoid B cell lymphoma associated with antibodies to myelin-associated glycoprotein and sulphated glucuronyl paragloboside.
      ]. The clinical improvement of neuropathy in response to chemotherapy also favored the production of these autoantibodies by neoplastic lymphoid proliferation.
      In conclusion, in patients with established lymphoma an accurate neuropathy diagnosis should guide the appropriateness of serum autoantibody determination, with consequent treatment implications. Based on reviewed literature it is difficult to advise on the value of such antibody determination in patients with “atypical” neuropathy syndromes, or of the yield of a comprehensive lymphoma screen in patients with antibody-mediated polyneuropathies.

      2.3 Inflammatory demyelinating polyneuropathies (IDP)

      2.3.1 Guillain–Barré syndrome (GBS)

      GBS occurs rarely in patients with lymphoma. The frequency of GBS may be slightly higher in HL compared to NHL [
      • Hughes R.A.
      • Britton T.
      • Richards M.
      Effects of lymphoma on the peripheral nervous system.
      ,
      • Kelly J.J.
      • Karcher D.S.
      Lymphoma and peripheral neuropathy: a clinical review.
      ], and probably relates to the persistent defect in cellular immunity with relatively intact humoral immune responses common to patients with HL [
      • Slivnick D.J.
      • Ellis T.M.
      • Nawrocki J.F.
      • Fisher R.I.
      The impact of Hodgkin's disease on the immune system.
      ]. A retrospective study assessed the neurological complications in 229 patients with the “reticuloses” (a group of disorders characterized by the usually malignant proliferation of any of the cells of the reticuloendothelial system) [
      • Hutchinson E.C.
      • Leonard B.J.
      • Maudsley C.
      • Yates P.O.
      Neurological complications of the reticuloses.
      ]: 4 patients were diagnosed with peripheral neuropathy (2 severe; 2 mild) without evidence of a primary demyelinating process on post-mortem examination (reported on 3 patients). Another retrospective study of the non-metastatic neurological syndromes “of obscure origin” in 774 patients with the “reticuloses”, established 5 cases of peripheral neuropathy in patients with HL, lymphosarcoma and CLL: resolved GBS was reasonably diagnosed in 1 patient with HL in remission [
      • Currie S.
      • Henson R.A.
      • Morgan H.G.
      • Poole A.J.
      The incidence of the non-metastatic neurological syndromes of obscure origin in the reticuloses.
      ]. A combined prospective (in-patients) and retrospective (out-patients) study evaluated for peripheral nervous system and spinal cord involvement in 989 patients with lymphoma (563 NHL; 426 HL): GBS was diagnosed in only 1 patient with HL [
      • Correale J.
      • Monteverde D.A.
      • Bueri J.A.
      • Reich E.G.
      Peripheral nervous and spinal cord involvement in lymphoma.
      ]. A smaller, prospective clinical and electrophysiological study of 30 patients with lymphoma established 1 patient each with acute/remitting and subacute/unremitting severe demyelinating polyneuropathies; the main histological abnormality was segmental demyelination/remyelination, but with negative immunofluorescence studies [
      • Graus F.
      • Ferrer I.
      • Lamarca J.
      Mixed carcinomatous neuropathy in patients with lung cancer and lymphoma.
      ]. A series of 16 patients with peripheral neuropathy and lymphoma without monoclonal gammopathy included 3 patients with GBS (insufficient information to tabulate cases); other cases of neuropathy were not immune-mediated [
      • Vital C.
      • Vital A.
      • Julien J.
      • Rivel J.
      • de Mascarel A.
      • Vergier B.
      • Henry P.
      • Barat M.
      • Reiffers J.
      • Broustet A.
      Peripheral neuropathies and lymphoma without gammopathy: a new classification.
      ].
      Conversely, lymphoma is also rarely detected in patients with GBS. In a retrospective study of 1100 patients with GBS reported in the literature since 1949, an associated/underlying malignancy was found in 33 patients; HL accounted for only 3 of these cases [
      • Leneman F.
      The Guillain–Barré syndrome: definition, etiology and review of 1100 cases.
      ]. In a retrospective study of 38 patients with polyradiculoneuritis, an association with HL was determined in only 2 cases [
      • Boudin G.
      • Pepin P.
      • Barraine R.
      Symptomatic polyradiculoneuritis. Clinical and etiological study apropos of 38 cases.
      ].
      Case histories and series report on lymphoma-associated GBS (Table 2). Sufficient information existed on 35 patients (16 females; 19 males) for inclusion in this review; this included 3 children (<18 years) and 11 elderly (>65 years) patients. From these case reports it could not be established that there exists particular age or gender susceptibility to lymphoma-associated GBS, despite the observation that lymphoma occurs more common in older patients and in men (for NHL) (www.cancer.org). The type of lymphoma varied, and included 11 patients with HL, 7 patients with CLL, with various subtypes of NHL comprising the remainder. Thus, this collected case report information could not support published statements that HL (more than other types of lymphoma) is more commonly associated with immune-mediated polyneuropathies [
      • Hughes R.A.
      • Britton T.
      • Richards M.
      Effects of lymphoma on the peripheral nervous system.
      ,
      • Kelly J.J.
      • Karcher D.S.
      Lymphoma and peripheral neuropathy: a clinical review.
      ,
      • Re D.
      • Schwenk A.
      • Hegener P.
      • Bamborschke S.
      • Diehl V.
      • Tesch H.
      Guillain–Barré syndrome in a patient with non-Hodgkin's lymphoma.
      ,
      • Viala K.
      • Béhin A.
      • Maisonobe T.
      • Léger J.M.
      • Stoikovic T.
      • Davi F.
      • Leblond V.
      • Bouche P.
      Neuropathy in lymphoma: a relationship between the pattern of neuropathy, type of lymphoma and prognosis?.
      ].
      Table 2Case reports of Guillain–Barré syndrome associated with lymphoma.
      ReferenceSex/ageClassificationRx neuropathyRx lymphomaOutcome/follow-up
      • Cameron D.G.
      • Howell D.A.
      • Hutchinson J.L.
      Acute peripheral neuropathy in Hodgkin's disease; a report of a fatal case with histological features of allergic neuritis.
      30/FHLSupportiveNH/XRTDied (12 days)
      • Gupta N.N.
      • Mittal S.P.
      Polyneuritis preceding lymphoblastic lymphoma.
      30/MLymphoblastic NHLPo CSRecovered (1 month)
      • Klingon G.H.
      The Guillain–Barré syndrome associated with cancer.
      30/MHL IIIBSupportiveXRT/NHDied (5 days)
      • Powles R.L.
      • Malpas J.S.
      Guillain–Barré syndrome associated with chronic lymphatic leukemia.
      60/MCLLPo CSCABImproved (NR)
      59/FCLLPo CSRecovered (1 year)
      • Sahadevan M.G.
      • Raman P.T.
      • Hoon R.S.
      Landry-Guillain–Barre syndrome complicating lymphosarcoma. A case report.
      35/MLymphosarcomaIv CSCPHImproved (NR)
      • Lisak R.P.
      • Mitchell M.
      • Zweiman B.
      • Orrechio E.
      • Asbury A.K.
      Guillain–Barré syndrome and Hodgkin's disease: three cases with immunologic studies.
      ,
      • Lisak R.P.
      • Mitchell M.
      • Zweiman B.
      • Orrechio E.
      • Asbury A.K.
      Guillain–Barré syndrome and Hodgkin's disease: three cases with immunological studies.
      19/MHL IVBPo CSVCR/VBLRecovered (8 months)
      27/MHL IIIBIv/po CSNRImproved (18 months)
      52/MHL IVBSupportiveVCRDied/NR
      • Cuttner J.
      • Meyer R.
      Guillain–Barré syndrome in a patient with Hodgkin's disease.
      23/MHL IIIPo CSCBPPRecovered (10 weeks)
      • Julien J.
      • Vital C.
      • Aupy G.
      • Lagueny A.
      • Darriet D.
      • Brechenmacher C.
      Guillain–Barree syndrome and Hodgkin's disease — ultrastructural study of a peripheral nerve.
      46/MHL IIcobalt XRT/CTXRecovered (3 months)
      • Sagar H.J.
      • Read D.J.
      Subacute sensory neuropathy with remission: an association with lymphoma.
      48/FHL IIIBPo CSPCZ/NH/VBLRecovered (15 months)
      • Amundson D.E.
      • Goodman J.C.
      Hodgkin's disease in association with Guillain–Barre–Strohl syndrome: case report.
      31/MHL IVMOPPRecovered (NR)
      • Cros D.
      • Harris N.L.
      • Hedley-White E.T.
      Case records of the Massachusetts General Hospital. Case 39-1990.
      66/MMCHL IIIPPH/iv/po CSCTXImpaired (10 months)
      • Jackson M.
      Guillain–Barré syndrome in a patient with chronic lymphocytic leukemia.
      77/FCLL IIIBIVIGCABImproved (3 weeks)
      • Gücüyener K.
      • Keskil S.
      • Baykaner M.K.
      • Bilir E.
      • Oguz A.
      • Ceviker N.
      Co-incidence of Guillain–Barré syndrome and spinal cord compression in non-Hodgkin lymphoma.
      21/2/MT-cell lymphoblastic NHL IVIVIGModified LSA2L2Died (6 weeks)
      • Vallat J.M.
      • De Mascarel H.A.
      • Bordessoule D.
      • Jauberteau M.O.
      • Tabaraud F.
      • Gelot A.
      • Vallat A.V.
      Non-Hodgkin malignant lymphomas and peripheral neuropathies—13 cases.
      67/MLymphocytic lymphomaCPH/VND/po CSRecovered (2 years)
      • Créange A.
      • Théodorou I.
      • Sabourin J.-C.
      • Vital C.
      • Farcet J.-P.
      • Gherardi R.K.
      Inflammatory neuromuscular disorders associated with chronic lymphoid leukemia: evidence for clonal B cells within muscle and nerve.
      54/FCLLNRCHOP/MOPPNR
      • Drake W.M.
      • Monson J.P.
      • Trainer P.J.
      • Sharief M.
      • Dick J.P.R.
      • Kelsey S.M.
      Acute polyneuropathy with chronic lymphocytic leukemia and paraproteinemia: response to chlorambucil and prednisolone.
      73/FCLLPo CSCABImproved (16 weeks)
      • Gutknecht D.R.
      Guillain–Barré syndrome and SIADH in a patient with chronic lymphocytic leukemia.
      84/FCLLPPHCAB/po CSRecovered (23 days)
      • Re D.
      • Schwenk A.
      • Hegener P.
      • Bamborschke S.
      • Diehl V.
      • Tesch H.
      Guillain–Barré syndrome in a patient with non-Hodgkin's lymphoma.
      21/FPrecursor T-cell NHL IVIVIG/PPHStandard BFMImproved (3 months)
      • Zuk E.
      • Nowacki P.
      • Fabian A.
      Guillain–Barré syndrome in a patient with Burkitt's lymphoma and type 2 diabetes mellitus.
      59/FSporadic BL IVBCEVEP/CHOPDied (12 days)
      • Naidech A.
      • Weiberg L.
      • Palliyath S.
      • Kahn M.
      Sudden weakness in a patient with lymphoma.
      42/FAngioimmunoblastic NHL IIIBPPHCHOPRecovered (4 months)
      • Eniko A.
      • Aniko M.
      • Edina M.
      Guillain–Barré syndrome in patients treated for Hodgkin disease.
      14/MHL IIAIv CSOEPARecovered
      • Magné N.
      • Foa C.
      • Castadot P.
      • Otto J.
      • Birtwisle-Peyrottes I.
      • Thyss A.
      Guillain–Barré syndrome and non-Hodgkin's lymphoma. Report of one case and review of the literature.
      74/MPrecursor B-cell BLL IIv CSCHOPDied (3 days)
      • Kivity S.
      • Shalmon B.
      • Sidi Y.
      Guillain–Barré syndrome: an unusual presentation of intravascular lymphoma.
      78/FIVBCLIVIGDied (≈17 days)
      • Wanschitz J.
      • Dichtl W.
      • Budka H.
      • Loscher W.N.
      • Boesch S.
      Acute motor and sensory axonal neuropathy in Burkitt-like lymphoma.
      36/FBLL IVIVIG/PPHCHOP/RSlightly better (3 months)
      • Gutiérrez-Lopez C.
      • Plascencia-Alvarez N.I.
      • Quiñones-Aguilar S.
      • Venegas-Torres A.
      • Nuñez-Orozco L.
      Sîndrome de Guillain–Barré como manifestacion paraneoplastica de limfoma No Hodgkin.
      59/MfNHL IINRNRNR
      • Song J.H.
      • Park G.W.
      • Sim Y.J.
      • Jeon J.Y.
      • Lee S.J.
      • Hyun J.K.
      • Cho Y.Y.
      • Park S.D.
      Guillain–Barré syndrome associated with non-Hodgkin's lymphoma.
      67/MDLCBL IIIIv CSCHOPWorsened (>2 months)
      • Bahl A.
      • Chakrabarty B.
      • Gulati S.
      • Raju V.
      • Raja A.
      • Bakhshi S.
      Acute onset flaccid quadriparesis in pediatric non-Hodgkin lymphoma: vincristine induced or Guillain–Barré syndrome?.
      8//MNHL IIIBIVIGBFM-90 protocolRecovered (8 weeks)
      • Seffo F.
      • Daw H.A.
      Non-Hodgkin lymphoma and Guillain–Barré syndrome: a rare association.
      70/FT/NK-cell NHL IEANRCHOPWorsened (hospice)
      • Terui K.
      • Takahashi Y.
      • Sasaki S.
      • Kudo K.
      • Kamio T.
      • Ito E.
      Guillain–Barré syndrome mimicking acute methotrexate-associated encephalopathy in an adolescent patient with lymphoblastic lymphoma.
      14/FT-cell lymphoblastic NHL IIIIVIGTHP-COP/IT MTXResolved (4 weeks)
      • Polo-Romero F.J.
      • Sånchez-Beteta P.
      • Perona-Buendia P.
      • Pérez-Garcia A.M.
      Guillain–Barré syndrome as the first presentation of non-Hodgkin lymphoma.
      74/FNHL IVIVIGCHOP-R/IT CYSlightly better (died)
      • Sasannejad P.
      • Azarpazhooh M.R.
      • Rahimi H.
      • Ahmadi A.M.
      • Ardani A.M.
      • Saber H.R.
      Guillain–Barré syndrome, as a rare presentation of adult T-cell leukemia–lymphoma (ATLL): a case report.
      21/FATLLIVIGCTXDied (3 weeks)
      • Tzachanis D.
      • Hamdan A.
      • Uhlmann E.J.
      • Joyce R.M.
      Successful treatment of refractory Guillain–Barré syndrome with alemtuzumab in a patient with chronic lymphocytic leukemia.
      79/MCLLIVIG/PPH/alemtuzumabB+RRecovered (1 year)
      ATLL = adult T-cell lymphoma/leukemia; B = bendamustine; BFM = Berlin–Frankfurt–Munster regimen; BL/L = Burkitt's/like lymphoma; BLM = bleomycin; CAB = chlorambucil; CBPP = CCNU/bleomycin/procarbazine/prednisone; CCNU = lomustine; CEVEP = cyclophosphamide/epirubicin/vinblastine/etoposide/prednisone; CHOP = cyclophosphamide/hydroxydaunorubicin/oncovin/prednisone; CPH = cyclophosphamide; CS = corticosteroids; CTX = chemotherapy (unspecified); CY-cytarabine; IT = intra-thecal; iv = intravenous; IVBCL = intravascular B-cell lymphoma; LSA2L2 = cyclophosphamide/vincristine/methotrexate/daunomycin/prednisone/cytarabine/thioguanine/asparaginase/hydroxyurea/carmustine; MOPP = mustargen/oncovin/procarbazine/prednisone; NH = nitrogen mustard; NR = not reported; OEPA = oncovin/etoposide/prednisone/adriamycin; PCZ = procarbazine; po = oral; PPH = plasmapheresis; R = rituximab; THP-COP = pirarubicin-cyclophosphamide/oncovin/prednisone; VBL = vinblastine; VCR = vincristine; VND = vindesine; XRT = radiation therapy.
      The time correlate between the diagnosis of GBS and discovery of lymphoma followed no consistent pattern: (1) In 11 patients, lymphoma was diagnosed during the initial hospitalization/evaluation for GBS (with delay up to 274 days) [
      • Vallat J.M.
      • De Mascarel H.A.
      • Bordessoule D.
      • Jauberteau M.O.
      • Tabaraud F.
      • Gelot A.
      • Vallat A.V.
      Non-Hodgkin malignant lymphomas and peripheral neuropathies—13 cases.
      ,
      • Gupta N.N.
      • Mittal S.P.
      Polyneuritis preceding lymphoblastic lymphoma.
      ,
      • Sagar H.J.
      • Read D.J.
      Subacute sensory neuropathy with remission: an association with lymphoma.
      ,
      • Amundson D.E.
      • Goodman J.C.
      Hodgkin's disease in association with Guillain–Barre–Strohl syndrome: case report.
      ,
      • Cros D.
      • Harris N.L.
      • Hedley-White E.T.
      Case records of the Massachusetts General Hospital. Case 39-1990.
      ,
      • Gücüyener K.
      • Keskil S.
      • Baykaner M.K.
      • Bilir E.
      • Oguz A.
      • Ceviker N.
      Co-incidence of Guillain–Barré syndrome and spinal cord compression in non-Hodgkin lymphoma.
      ,
      • Kivity S.
      • Shalmon B.
      • Sidi Y.
      Guillain–Barré syndrome: an unusual presentation of intravascular lymphoma.
      ,
      • Gutiérrez-Lopez C.
      • Plascencia-Alvarez N.I.
      • Quiñones-Aguilar S.
      • Venegas-Torres A.
      • Nuñez-Orozco L.
      Sîndrome de Guillain–Barré como manifestacion paraneoplastica de limfoma No Hodgkin.
      ,
      • Polo-Romero F.J.
      • Sånchez-Beteta P.
      • Perona-Buendia P.
      • Pérez-Garcia A.M.
      Guillain–Barré syndrome as the first presentation of non-Hodgkin lymphoma.
      ,
      • Sasannejad P.
      • Azarpazhooh M.R.
      • Rahimi H.
      • Ahmadi A.M.
      • Ardani A.M.
      • Saber H.R.
      Guillain–Barré syndrome, as a rare presentation of adult T-cell leukemia–lymphoma (ATLL): a case report.
      ]. In 3 patients, probable lymphoma-associated symptoms had not been recognized before subsequent presentation/evaluation of GBS e.g., alcohol-induced bone pain for 2 years [
      • Sagar H.J.
      • Read D.J.
      Subacute sensory neuropathy with remission: an association with lymphoma.
      ], pruritis for 9 months [
      • Amundson D.E.
      • Goodman J.C.
      Hodgkin's disease in association with Guillain–Barre–Strohl syndrome: case report.
      ] or erythema nodosum-like skin lesions for 2 years [
      • Kivity S.
      • Shalmon B.
      • Sidi Y.
      Guillain–Barré syndrome: an unusual presentation of intravascular lymphoma.
      ]. In 1 patient a retrospective diagnosis of intravascular lymphoma was made on a skin biopsy only posthumously [
      • Kivity S.
      • Shalmon B.
      • Sidi Y.
      Guillain–Barré syndrome: an unusual presentation of intravascular lymphoma.
      ]. (2) In most patients, lymphoma was diagnosed before the development of GBS. Also this temporal correlation varied, so that the onset of GBS developed: (a) with lymphoma relapse [
      • Cameron D.G.
      • Howell D.A.
      • Hutchinson J.L.
      Acute peripheral neuropathy in Hodgkin's disease; a report of a fatal case with histological features of allergic neuritis.
      ,
      • Cuttner J.
      • Meyer R.
      Guillain–Barré syndrome in a patient with Hodgkin's disease.
      ,
      • Julien J.
      • Vital C.
      • Aupy G.
      • Lagueny A.
      • Darriet D.
      • Brechenmacher C.
      Guillain–Barree syndrome and Hodgkin's disease — ultrastructural study of a peripheral nerve.
      ,
      • Zuk E.
      • Nowacki P.
      • Fabian A.
      Guillain–Barré syndrome in a patient with Burkitt's lymphoma and type 2 diabetes mellitus.
      ,
      • Naidech A.
      • Weiberg L.
      • Palliyath S.
      • Kahn M.
      Sudden weakness in a patient with lymphoma.
      ,
      • Tzachanis D.
      • Hamdan A.
      • Uhlmann E.J.
      • Joyce R.M.
      Successful treatment of refractory Guillain–Barré syndrome with alemtuzumab in a patient with chronic lymphocytic leukemia.
      ]; (b) during lymphoma maintenance therapy [
      • Sahadevan M.G.
      • Raman P.T.
      • Hoon R.S.
      Landry-Guillain–Barre syndrome complicating lymphosarcoma. A case report.
      ]; (c) at varying intervals (2 weeks and 3 months) after completion of chemotherapy for lymphoma deemed in remission [
      • Klingon G.H.
      The Guillain–Barré syndrome associated with cancer.
      ,
      • Powles R.L.
      • Malpas J.S.
      Guillain–Barré syndrome associated with chronic lymphatic leukemia.
      ,
      • Lisak R.P.
      • Mitchell M.
      • Zweiman B.
      • Orrechio E.
      • Asbury A.K.
      Guillain–Barré syndrome and Hodgkin's disease: three cases with immunologic studies.
      ,
      • Lisak R.P.
      • Mitchell M.
      • Zweiman B.
      • Orrechio E.
      • Asbury A.K.
      Guillain–Barré syndrome and Hodgkin's disease: three cases with immunological studies.
      ,
      • Jackson M.
      Guillain–Barré syndrome in a patient with chronic lymphocytic leukemia.
      ]; (d) while undergoing (interval 6 days to 3 weeks) chemotherapy for lymphoma (cycles #1 to #6) [
      • Magné N.
      • Foa C.
      • Castadot P.
      • Otto J.
      • Birtwisle-Peyrottes I.
      • Thyss A.
      Guillain–Barré syndrome and non-Hodgkin's lymphoma. Report of one case and review of the literature.
      ,
      • Wanschitz J.
      • Dichtl W.
      • Budka H.
      • Loscher W.N.
      • Boesch S.
      Acute motor and sensory axonal neuropathy in Burkitt-like lymphoma.
      ,
      • Song J.H.
      • Park G.W.
      • Sim Y.J.
      • Jeon J.Y.
      • Lee S.J.
      • Hyun J.K.
      • Cho Y.Y.
      • Park S.D.
      Guillain–Barré syndrome associated with non-Hodgkin's lymphoma.
      ,
      • Seffo F.
      • Daw H.A.
      Non-Hodgkin lymphoma and Guillain–Barré syndrome: a rare association.
      ,
      • Terui K.
      • Takahashi Y.
      • Sasaki S.
      • Kudo K.
      • Kamio T.
      • Ito E.
      Guillain–Barré syndrome mimicking acute methotrexate-associated encephalopathy in an adolescent patient with lymphoblastic lymphoma.
      ]; (e) after induction chemotherapy for lymphoma (interval 11 to 16 days) [
      • Re D.
      • Schwenk A.
      • Hegener P.
      • Bamborschke S.
      • Diehl V.
      • Tesch H.
      Guillain–Barré syndrome in a patient with non-Hodgkin's lymphoma.
      ,
      • Bahl A.
      • Chakrabarty B.
      • Gulati S.
      • Raju V.
      • Raja A.
      • Bakhshi S.
      Acute onset flaccid quadriparesis in pediatric non-Hodgkin lymphoma: vincristine induced or Guillain–Barré syndrome?.
      ], or (f) during the course (as long as 10 years) of indolent disease not under active treatment e.g., CLL [
      • Powles R.L.
      • Malpas J.S.
      Guillain–Barré syndrome associated with chronic lymphatic leukemia.
      ,
      • Gutknecht D.R.
      Guillain–Barré syndrome and SIADH in a patient with chronic lymphocytic leukemia.
      ,
      • Tzachanis D.
      • Hamdan A.
      • Uhlmann E.J.
      • Joyce R.M.
      Successful treatment of refractory Guillain–Barré syndrome with alemtuzumab in a patient with chronic lymphocytic leukemia.
      ].
      The clinical presentation of GBS associated with lymphoma has been regarded no different from the presentation of sporadic/post-infectious GBS [
      • Giglio P.
      • Gilbert M.R.
      Neurologic complications of non-Hodgkin's lymphoma.
      ]. In cases reported herein, cranial nerve involvement was documented in 20 patients. Respiratory muscle involvement was reported in 11 patients; 8 of these 11 patients required ventilation assistance. CSF analysis was performed on 31 patients; findings were compatible with GBS, and by definition showed no evidence of lymphomatous spread or infectious disease. Electrodiagnostic studies were performed on 25 patients and were consistent with acquired, mostly acquired IDP; predominant axonal injury was recorded in 3 of these patients [
      • Wanschitz J.
      • Dichtl W.
      • Budka H.
      • Loscher W.N.
      • Boesch S.
      Acute motor and sensory axonal neuropathy in Burkitt-like lymphoma.
      ,
      • Bahl A.
      • Chakrabarty B.
      • Gulati S.
      • Raju V.
      • Raja A.
      • Bakhshi S.
      Acute onset flaccid quadriparesis in pediatric non-Hodgkin lymphoma: vincristine induced or Guillain–Barré syndrome?.
      ,
      • Sasannejad P.
      • Azarpazhooh M.R.
      • Rahimi H.
      • Ahmadi A.M.
      • Ardani A.M.
      • Saber H.R.
      Guillain–Barré syndrome, as a rare presentation of adult T-cell leukemia–lymphoma (ATLL): a case report.
      ]. Pathological study of peripheral nerves confirmed acquired IDP (with/without secondary axonal injury) at autopsy in 4 patients [
      • Cameron D.G.
      • Howell D.A.
      • Hutchinson J.L.
      Acute peripheral neuropathy in Hodgkin's disease; a report of a fatal case with histological features of allergic neuritis.
      ,
      • Klingon G.H.
      The Guillain–Barré syndrome associated with cancer.
      ,
      • Lisak R.P.
      • Mitchell M.
      • Zweiman B.
      • Orrechio E.
      • Asbury A.K.
      Guillain–Barré syndrome and Hodgkin's disease: three cases with immunologic studies.
      ,
      • Lisak R.P.
      • Mitchell M.
      • Zweiman B.
      • Orrechio E.
      • Asbury A.K.
      Guillain–Barré syndrome and Hodgkin's disease: three cases with immunological studies.
      ,
      • Zuk E.
      • Nowacki P.
      • Fabian A.
      Guillain–Barré syndrome in a patient with Burkitt's lymphoma and type 2 diabetes mellitus.
      ] and on biopsy in 5 patients [
      • Lisak R.P.
      • Mitchell M.
      • Zweiman B.
      • Orrechio E.
      • Asbury A.K.
      Guillain–Barré syndrome and Hodgkin's disease: three cases with immunologic studies.
      ,
      • Lisak R.P.
      • Mitchell M.
      • Zweiman B.
      • Orrechio E.
      • Asbury A.K.
      Guillain–Barré syndrome and Hodgkin's disease: three cases with immunological studies.
      ,
      • Cros D.
      • Harris N.L.
      • Hedley-White E.T.
      Case records of the Massachusetts General Hospital. Case 39-1990.
      ,
      • Créange A.
      • Théodorou I.
      • Sabourin J.-C.
      • Vital C.
      • Farcet J.-P.
      • Gherardi R.K.
      Inflammatory neuromuscular disorders associated with chronic lymphoid leukemia: evidence for clonal B cells within muscle and nerve.
      ,
      • Wanschitz J.
      • Dichtl W.
      • Budka H.
      • Loscher W.N.
      • Boesch S.
      Acute motor and sensory axonal neuropathy in Burkitt-like lymphoma.
      ]. Such study is important because lymphomatous nerve/root infiltration may mimic GBS [
      • Vallat J.M.
      • De Mascarel H.A.
      • Bordessoule D.
      • Jauberteau M.O.
      • Tabaraud F.
      • Gelot A.
      • Vallat A.V.
      Non-Hodgkin malignant lymphomas and peripheral neuropathies—13 cases.
      ,
      • Allison R.S.
      • Gordon D.S.
      Reticulosis of the nervous system simulating acute infectious polyneuritis.
      ,
      • Moore R.Y.
      • Oda Y.
      Malignant lymphoma with diffuse involvement of the peripheral nervous system.
      ] i.e., there exists a risk of GBS misdiagnosis.
      The treatment protocols for GBS varied. In earlier reports, patients were offered only supportive care or treatment with oral corticosteroids; treatment of more recent cases reflects modern “standard” care of GBS with intravenous corticosteroids, IVIG and/or plasmapheresis. Additional immune therapy was offered to patients who developed GBS after completing or while undergoing chemotherapy for lymphoma. Immunomodulatory treatment for GBS was not offered when: (a) onset of GBS coincided with relapsed [
      • Julien J.
      • Vital C.
      • Aupy G.
      • Lagueny A.
      • Darriet D.
      • Brechenmacher C.
      Guillain–Barree syndrome and Hodgkin's disease — ultrastructural study of a peripheral nerve.
      ] or newly diagnosed [
      • Vallat J.M.
      • De Mascarel H.A.
      • Bordessoule D.
      • Jauberteau M.O.
      • Tabaraud F.
      • Gelot A.
      • Vallat A.V.
      Non-Hodgkin malignant lymphomas and peripheral neuropathies—13 cases.
      ] lymphoma i.e., treatment was directed primarily at lymphoma, and (b) GBS improved spontaneously before chemotherapy commenced for newly diagnosed lymphoma [
      • Amundson D.E.
      • Goodman J.C.
      Hodgkin's disease in association with Guillain–Barre–Strohl syndrome: case report.
      ]. In a case with recurrent Burkitt's lymphoma, no specific treatment for GBS was offered (no explanation given) so that the patient died of rapidly progressive bulbar weakness and respiratory failure [
      • Zuk E.
      • Nowacki P.
      • Fabian A.
      Guillain–Barré syndrome in a patient with Burkitt's lymphoma and type 2 diabetes mellitus.
      ].
      Therapy for the various types of lymphoma was offered according to preferred chosen protocol. However, patients were not treated specifically for lymphoma when: (a) the patient refused therapy [
      • Gupta N.N.
      • Mittal S.P.
      Polyneuritis preceding lymphoblastic lymphoma.
      ]; (b) the nature of disease was indolent [
      • Powles R.L.
      • Malpas J.S.
      Guillain–Barré syndrome associated with chronic lymphatic leukemia.
      ], and (c) the diagnosis was made at autopsy [
      • Kivity S.
      • Shalmon B.
      • Sidi Y.
      Guillain–Barré syndrome: an unusual presentation of intravascular lymphoma.
      ].
      The prognosis of GBS was mostly favorable, so that most patients improved or recovered. A total of 8 patients died in the acute phase of illness: (a) 5 patients died of cardio-/respiratory failure within 3 to 12 days after onset of GBS; (b) 1 patient died after approximately 17 days of sepsis/organ failure [
      • Kivity S.
      • Shalmon B.
      • Sidi Y.
      Guillain–Barré syndrome: an unusual presentation of intravascular lymphoma.
      ]; (c) 1 patient died after 3 weeks due to complications of lymphoma treatment [
      • Sasannejad P.
      • Azarpazhooh M.R.
      • Rahimi H.
      • Ahmadi A.M.
      • Ardani A.M.
      • Saber H.R.
      Guillain–Barré syndrome, as a rare presentation of adult T-cell leukemia–lymphoma (ATLL): a case report.
      ], and (d) a child died after 6 weeks of neutropenic septicemia [
      • Gücüyener K.
      • Keskil S.
      • Baykaner M.K.
      • Bilir E.
      • Oguz A.
      • Ceviker N.
      Co-incidence of Guillain–Barré syndrome and spinal cord compression in non-Hodgkin lymphoma.
      ]. Later deaths during the observation periods were due to lymphoma e.g., septic shock 2 months after chemotherapy was suspended [
      • Polo-Romero F.J.
      • Sånchez-Beteta P.
      • Perona-Buendia P.
      • Pérez-Garcia A.M.
      Guillain–Barré syndrome as the first presentation of non-Hodgkin lymphoma.
      ] i.e., unrelated to GBS.

      2.3.2 Miller Fisher syndrome (MFS)

      Four cases of lymphoma-associated somewhat “atypical” MFS were retrieved from the literature (Table 3). The temporal association between a diagnosis of MFS and lymphoma varied: (a) onset of MFS coincided with the 2nd relapse of lymphoma [
      • Rubio-Nazabal E.
      • Marey-Lopez J.
      • Torres-Carrete J.P.
      • Alvarez-Perez P.
      • Rey Del Corral P.
      Miller-Fisher syndrome and Hodgkin's disease.
      ]; (b) MFS coincided with the discovery of lymphoma in a renal transplant recipient on anti-rejection therapy [
      • Gentile S.
      • Messina M.
      • Rainero I.
      • Lo Guidice R.
      • De Martino P.
      • Pinessi L.
      Miller Fisher syndrome associated with Burkitt's lymphoma.
      ]; (c) MFS developed in a patient with CLL during chemotherapy [
      • Aki Z.
      • Aksoy O.
      • Sucak G.
      • Kuruoglu R.
      • Yagci M.
      Miler-Fisher syndrome associated with chronic lymphocytic leukemia.
      ], and (d) a detailed evaluation during recurrence of MFS detected lymphoma [
      • Usmani N.
      • Bhatia R.
      • Ikpatt O.F.
      • Sharma K.R.
      Diffuse large B-cell lymphoma presenting as Miller Fisher syndrome.
      ]. An elevated serum anti-GQ1b antibody titer is deemed useful supportive evidence for (? post-infectious) MFS [
      • Chiba A.
      • Kusunoki S.
      • Obata H.
      • Machinami R.
      • Kanazawa I.
      Serum anti-GQ1b IgG antibody is associated with ophthalmoplegia in Miller Fisher syndrome and Guillain–Barré syndrome: clinical and immunohistochemical studies.
      ,
      • Nishimoto Y.
      • Odaka M.
      • Hirata K.
      • Yuki N.
      Usefulness of anti-GQ1b IgG antibody testing in Fisher syndrome compared with cerebrospinal fluid examination.
      ], but was recorded in only 1 of 4 lymphoma patients [
      • Rubio-Nazabal E.
      • Marey-Lopez J.
      • Torres-Carrete J.P.
      • Alvarez-Perez P.
      • Rey Del Corral P.
      Miller-Fisher syndrome and Hodgkin's disease.
      ]. CSF analysis on 3 patients showed only elevated protein concentration [
      • Rubio-Nazabal E.
      • Marey-Lopez J.
      • Torres-Carrete J.P.
      • Alvarez-Perez P.
      • Rey Del Corral P.
      Miller-Fisher syndrome and Hodgkin's disease.
      ,
      • Gentile S.
      • Messina M.
      • Rainero I.
      • Lo Guidice R.
      • De Martino P.
      • Pinessi L.
      Miller Fisher syndrome associated with Burkitt's lymphoma.
      ,
      • Usmani N.
      • Bhatia R.
      • Ikpatt O.F.
      • Sharma K.R.
      Diffuse large B-cell lymphoma presenting as Miller Fisher syndrome.
      ]; however, “atypical”, non-neoplastic lymphocytes were detected on repeat CSF evaluation in the patient with recurrent MFS [
      • Usmani N.
      • Bhatia R.
      • Ikpatt O.F.
      • Sharma K.R.
      Diffuse large B-cell lymphoma presenting as Miller Fisher syndrome.
      ]. Electrodiagnostic studies were variably interpreted as: (a) axonal sensory polyneuropathy [
      • Rubio-Nazabal E.
      • Marey-Lopez J.
      • Torres-Carrete J.P.
      • Alvarez-Perez P.
      • Rey Del Corral P.
      Miller-Fisher syndrome and Hodgkin's disease.
      ]; (b) diffuse, predominantly axonal sensorimotor polyneuropathy [
      • Gentile S.
      • Messina M.
      • Rainero I.
      • Lo Guidice R.
      • De Martino P.
      • Pinessi L.
      Miller Fisher syndrome associated with Burkitt's lymphoma.
      ,
      • Aki Z.
      • Aksoy O.
      • Sucak G.
      • Kuruoglu R.
      • Yagci M.
      Miler-Fisher syndrome associated with chronic lymphocytic leukemia.
      ], or (c) sensorimotor demyelinating polyradiculoneuropathy [
      • Usmani N.
      • Bhatia R.
      • Ikpatt O.F.
      • Sharma K.R.
      Diffuse large B-cell lymphoma presenting as Miller Fisher syndrome.
      ].
      Table 3Lymphoma-associated Miller Fisher syndrome.
      ReferenceAge/sexlymphomaRx neuropathyRX lymphomaOutcome
      • Rubio-Nazabal E.
      • Marey-Lopez J.
      • Torres-Carrete J.P.
      • Alvarez-Perez P.
      • Rey Del Corral P.
      Miller-Fisher syndrome and Hodgkin's disease.
      27/MMixed cellularity HL IVBIVIGESHAPRecovered (3 months)
      • Gentile S.
      • Messina M.
      • Rainero I.
      • Lo Guidice R.
      • De Martino P.
      • Pinessi L.
      Miller Fisher syndrome associated with Burkitt's lymphoma.
      42/MBurkitt's lymphomaIVIGCTXRecovered (2 years)
      • Aki Z.
      • Aksoy O.
      • Sucak G.
      • Kuruoglu R.
      • Yagci M.
      Miler-Fisher syndrome associated with chronic lymphocytic leukemia.
      47/MB-cell CLL Rai IVPPHCHB/RRecovered (≈16 months)
      • Usmani N.
      • Bhatia R.
      • Ikpatt O.F.
      • Sharma K.R.
      Diffuse large B-cell lymphoma presenting as Miller Fisher syndrome.
      61/MDLBCLIVIG/IT MTXR-CHOPImproved/died of PE
      CHB = chlorambucil; CTX = chemotherapy (not specified); DLBCL = diffuse large B-cell lymphoma; ESHAP = etoposide/methylprednisolone/ara-C/platinum; IT MTX = intrathecal methotrexate; PE = pulmonary embolus; PPH = plasmapheresis; R-CHOP = rituximab with cyclophosphamide/hydroxydaunorubicin/oncovin/prednisone; R = rituximab.
      Immunomodulating therapy was offered to all patients. Three patients showed neurological response to treatment [
      • Rubio-Nazabal E.
      • Marey-Lopez J.
      • Torres-Carrete J.P.
      • Alvarez-Perez P.
      • Rey Del Corral P.
      Miller-Fisher syndrome and Hodgkin's disease.
      ,
      • Aki Z.
      • Aksoy O.
      • Sucak G.
      • Kuruoglu R.
      • Yagci M.
      Miler-Fisher syndrome associated with chronic lymphocytic leukemia.
      ,
      • Usmani N.
      • Bhatia R.
      • Ikpatt O.F.
      • Sharma K.R.
      Diffuse large B-cell lymphoma presenting as Miller Fisher syndrome.
      ]; 1 treatment-unresponsive patient showed neurological improvement to systemic chemotherapy for lymphoma [
      • Gentile S.
      • Messina M.
      • Rainero I.
      • Lo Guidice R.
      • De Martino P.
      • Pinessi L.
      Miller Fisher syndrome associated with Burkitt's lymphoma.
      ]. The patient with recurrent MFS and CSF atypical pleocytosis showed neurological improvement to a combined systemic/intrathecal chemotherapy regimen [
      • Usmani N.
      • Bhatia R.
      • Ikpatt O.F.
      • Sharma K.R.
      Diffuse large B-cell lymphoma presenting as Miller Fisher syndrome.
      ]; neurological response to systemic chemotherapy was interpreted as evidence of a “paraneoplastic” pathogenesis (herein defined as the production of a specific antibody against an antigen of malignant cells that cross-reacts with an antigen of normal neurological tissue).

      2.3.3 Chronic/subacute inflammatory demyelinating polyneuropathy (CIDP/SIDP)

      Lymphoma-associated CIDP has a potential for misdiagnosis. A study assessed the clinical, electrophysiological and histopathological features of 32 patients with treatment-unrelated neuropathy associated with NHL [
      • Tomita M.
      • Koike H.
      • Kawagashira Y.
      • Iijima M.
      • Adachi H.
      • Taguchi J.
      • Abe T.
      • Sako K.
      • Tsuji Y.
      • Nakagawa M.
      • Kanda F.
      • Takeda F.
      • Sugawara M.
      • Asano N.
      • Sobue G.
      Clinicopathological features of neuropathy associated with lymphoma.
      ]. Eleven patients fulfilled the European Federation of Neurological Societies/Peripheral Nerve Society electrodiagnostic criteria of “definite” CIDP. However, neuropathology established 5 patients with neurolymphomatosis, 1 patient with sensory ganglionopathy, and 3 patients with primary axonal degeneration and secondary demyelination (clinically manifesting as multiple mononeuropathy). Moreover, some patients (including cases of neurolymphomatosis) at least initially responded to immune modulation therapy. Therefore, peripheral nerve pathological study is recommended to guide appropriate treatment, because neurolymphomatosis may mimic CIDP in patients with lymphoma.
      Case histories and short series report on lymphoma-associated SIDP (evolution 4–8 weeks) in 8 patients and CIDP (evolution >8 weeks) in 15 patients (Table 4). Most patients were diagnosed with various types of NHL at various stages of disease, and also did not support (see GBS) literature statements that immune disorders of the nervous system more commonly affect patients with HL compared to NHL [
      • Kelly J.J.
      • Karcher D.S.
      Lymphoma and peripheral neuropathy: a clinical review.
      ,
      • Viala K.
      • Béhin A.
      • Maisonobe T.
      • Léger J.M.
      • Stoikovic T.
      • Davi F.
      • Leblond V.
      • Bouche P.
      Neuropathy in lymphoma: a relationship between the pattern of neuropathy, type of lymphoma and prognosis?.
      ]. The significance of an apparent male preponderance is unclear, and may reflect the observation that most types of NHL occur more common in men [
      • Ansell S.M.
      Annual clinical updates in hematological malignancies: a continuing medical education series. Hodgkin lymphoma: 2011 update on diagnosis, risk-stratification, and management.
      ]. A wide age-spectrum of lymphoma-associated SIDP/CIDP included 5 elderly (>65 years) patients, but no children.
      Table 4Lymphoma-associated subacute/chronic inflammatory (demyelinating) polyneuropathy.
      ReferenceAge/sexLymphomaRx neuropathyRx lymphomaOutcome/follow-up
      • Rowland L.P.
      • Schneck S.A.
      Neuromuscular disorders associated with malignant neoplastic disease.
      64/MReticulum cell NHLPo CSDied (6 months)
      • Shafar J.
      Brill-Symmer's disease presenting as multiple symmetrical peripheral polyneuropathy.
      64/MGiant follicular NHLPo CSNRImproved (4 months)
      • Patten J.P.
      Remittent peripheral neuropathy and cerebellar degeneration complicating lymphosarcoma.
      70/MLymphosarcoma–/intra-thecal MTXCAB/ThdRecurred/died (9 years)
      • Vital C.
      • Bonnaud E.
      • Arne L.
      • Barrat M.
      • Leblanc M.
      Polyneuritis in chronic lymphoid leukemia. Ultrastructural study of the peripheral nerve.
      75/MCLLNRNRNR
      • Brunet P.
      • Schadeck B.
      • Moriceau M.
      Subacute sensory neuropathy with remission: an association with lymphoma.
      48/F*HL IIPCVImproved (9 months)
      31/M*HL IIIMOPP/CCNU-VPPImproved (40 months)
      • Sumi S.M.
      • Farrell D.F.
      • Knauss T.A.
      Lymphoma and leukemia manifested by steroid-responsive polyneuropathy.
      51/MDiffuse histiocytic NHLPo CS/AZACHOPRecurred/died (35 months)
      58/MCLLPo CSCAB/po CSRecovered (20 months)
      • Plante-Bordeneuve V.
      • Baudrimont M.
      • Gorin N.C.
      • Gherardi R.K.
      Subacute sensory neuropathy associated with Hodgkin's disease.
      55/F*Nodular sclerosing HL IVBCTXRecovered (>5 months)
      40/F*Nodular sclerosing HL IIAResection/XRT/CTXRecovered (20 months)
      • Barth P.
      • Roegel-Demuynck C.
      • Pflumio F.
      • Geisler F.
      Subacute distal motor neuropathy revealing non-Hodgkin's lymphoma: improvement under chemotherapy.
      60/M*NHL IEModified CVPRecovered (40 months)
      • Griggs J.J.
      • Commichau C.S.
      • Rapoport A.P.
      • Griggs R.C.
      Chronic inflammatory demyelinating polyneuropathy in non-Hodgkin's lymphoma.
      42/MDLCBL IIIPPHResection/CN(O)PRecovered (18 months)
      • Algayres J.P.
      • Schmoor P.
      • Coutant G.
      • Renard J.L.
      • Souleau B.
      • Nedellec G.
      • Daly J.P.
      Polyradiculonévrite chronique paranéoplasique révélatrice d'une maladie de Hodgkin.
      39/–HL IIIBMOPP ABV hybridRecovered (6 months)
      • Navellou J.C.
      • Michel F.
      • Vuillier J.
      • Toussirot E.
      • Wendling D.
      Chronic polyradiculoneuropathy in a patient with Hodgkin's disease.
      27/MHL IIAIv CSMOPP/ABVDRecovered (6 months)
      • Kasamon Y.L.
      • Nguyen T.N.
      • Chan J.A.
      • Nascimento A.F.
      EBV-associated lymphoma and chronic inflammatory demyelinating polyneuropathy in an adult without overt immunodeficiency.
      73/FEBV-associated NHL IIIBCHEP-RImproved (2 months)
      • Wada M.
      • Kurita K.
      • Tajima K.
      • Kawanami T.
      • Kato T.
      A case of inflammatory demyelinating polyradiculoneuropathy associated with T-cell lymphoma.
      58/M“Unspecified” T-cell NHLPo CSRecurred/died (31 months)
      • Cardinali P.
      • Serrao M.
      • Rossi P.
      • De Dominicis L.
      • De Santis F.
      • Pierelli F.
      Chronic axonal-demyelinating polyradicular neuropathy associated with mycosis fungoides: a case report.
      58/MMycosis fungoides IBPo CS/IVIGMTXImproved (6 months)
      • Wills A.J.
      • O'Connor S.
      • McMillan A.
      Subacute demyelinating neuropathy associated with an NK/T cell lymphoma.
      29/F*NK/T-cell lymphoma IEPo CSCODOX-M//IVACRecovered (>1 year)
      • Lee J.H.
      • Sohn E.H.
      • Lee A.Y.
      • Kim J.M.
      • Kim S.
      A case of chronic inflammatory demyelinating polyneuropathy associated with immune-mediated thrombocytopenia and cutaneous T-cell lymphoma.
      60/MCutaneous T-cell NHLIVIG/po CSTopical CSImproved (10 months)
      • Tomita M.
      • Koike H.
      • Kawagashira Y.
      • Iijima M.
      • Adachi H.
      • Taguchi J.
      • Abe T.
      • Sako K.
      • Tsuji Y.
      • Nakagawa M.
      • Kanda F.
      • Takeda F.
      • Sugawara M.
      • Asano N.
      • Sobue G.
      Clinicopathological features of neuropathy associated with lymphoma.
      65/M*AITLMST-16/VP-16/CS/L-PAMImproved/died (80 months)
      61/MLymphoplasmacytic lymphomaIVIGR/CPH/po CSImproved (46 months)
      61/M*Cutaneous T-cell NHLIv CSINFγ/PUV/rINNImproved/died (132 months)
      • Ammannagari N.
      • Chikoti S.
      • Bravin E.
      Hodgkin's lymphoma presenting as a complex paraneoplastic neurological syndrome: a case report.
      74/MNodular sclerosing HLPo CS/IVIGABVDImproved (NR)
      * = SIDP; ABV(D) = adriamycin/bleomycin/vinblastine/(±)dacarbazine; AITL = angioimmunoblastic T-cell lymphoma; AZA = azathiprine; CAB = chlorambucil; CCNU-VPP = CCNU/vincristine/procarbazine/prednisone; CHOP = cyclophosphamide/hydroxydaunorubicin/oncovin/prednisone; CHEP–R = cyclophosphamide/hydroxydaunorubicin/etoposide/prednisone–rituximab; CS = corticosteroids; CODOX-M//IVAC = cyclophosphamide/oncovin/doxorubicin-methotrexate//ifosphamide//VP-16/ara-C; CN(O)P = cyclophosphamide/mitoxantrone/(±oncovin)/prednisone; CPH = cyclophosphamide; CTX = high dose cytotoxic chemotherapy; DLCBL = diffuse large B-cell lymphoma; IFN = interferon; iv = intravenous; L-PAM = melphelan; modified CVP = cyclophosphamide/vincristine/prednisone; MOPP = mechlorethamine/oncovin/procarbazine/prednisone; MST16 = perazolin; MTX = methotrexate; NR = not reported; PCV = procarbazine/CCNU/vincristine; PPH = plasmapheresis; po = oral; PUVA = ultraviolet light therapy; rINN = vorinostat; R = rituximab; Thd = thalidomide; VCR = vincristine; VP16 = etoposide.
      The temporal correlation between onset of CIDP/SIDP and the diagnosis/treatment of lymphoma varied: (a) onset of CIDP followed a diagnosis of recurrent/untreated lymphoma by periods as long as 132 months [
      • Tomita M.
      • Koike H.
      • Kawagashira Y.
      • Iijima M.
      • Adachi H.
      • Taguchi J.
      • Abe T.
      • Sako K.
      • Tsuji Y.
      • Nakagawa M.
      • Kanda F.
      • Takeda F.
      • Sugawara M.
      • Asano N.
      • Sobue G.
      Clinicopathological features of neuropathy associated with lymphoma.
      ,
      • Vital C.
      • Bonnaud E.
      • Arne L.
      • Barrat M.
      • Leblanc M.
      Polyneuritis in chronic lymphoid leukemia. Ultrastructural study of the peripheral nerve.
      ,
      • Navellou J.C.
      • Michel F.
      • Vuillier J.
      • Toussirot E.
      • Wendling D.
      Chronic polyradiculoneuropathy in a patient with Hodgkin's disease.
      ,
      • Cardinali P.
      • Serrao M.
      • Rossi P.
      • De Dominicis L.
      • De Santis F.
      • Pierelli F.
      Chronic axonal-demyelinating polyradicular neuropathy associated with mycosis fungoides: a case report.
      ]; (b) CIDP/SIDP preceded diagnosis of new lymphoma by 3 to 15 months [
      • Tomita M.
      • Koike H.
      • Kawagashira Y.
      • Iijima M.
      • Adachi H.
      • Taguchi J.
      • Abe T.
      • Sako K.
      • Tsuji Y.
      • Nakagawa M.
      • Kanda F.
      • Takeda F.
      • Sugawara M.
      • Asano N.
      • Sobue G.
      Clinicopathological features of neuropathy associated with lymphoma.
      ,
      • Brunet P.
      • Schadeck B.
      • Moriceau M.
      Subacute sensory neuropathy with remission: an association with lymphoma.
      ,
      • Sumi S.M.
      • Farrell D.F.
      • Knauss T.A.
      Lymphoma and leukemia manifested by steroid-responsive polyneuropathy.
      ,
      • Plante-Bordeneuve V.
      • Baudrimont M.
      • Gorin N.C.
      • Gherardi R.K.
      Subacute sensory neuropathy associated with Hodgkin's disease.
      ,
      • Wills A.J.
      • O'Connor S.
      • McMillan A.
      Subacute demyelinating neuropathy associated with an NK/T cell lymphoma.
      ,
      • Lee J.H.
      • Sohn E.H.
      • Lee A.Y.
      • Kim J.M.
      • Kim S.
      A case of chronic inflammatory demyelinating polyneuropathy associated with immune-mediated thrombocytopenia and cutaneous T-cell lymphoma.
      ]; (c) onset of SIDP/CIDP coincided with diagnosis of new lymphoma [
      • Brunet P.
      • Schadeck B.
      • Moriceau M.
      Subacute sensory neuropathy with remission: an association with lymphoma.
      ,
      • Algayres J.P.
      • Schmoor P.
      • Coutant G.
      • Renard J.L.
      • Souleau B.
      • Nedellec G.
      • Daly J.P.
      Polyradiculonévrite chronique paranéoplasique révélatrice d'une maladie de Hodgkin.
      ,
      • Kasamon Y.L.
      • Nguyen T.N.
      • Chan J.A.
      • Nascimento A.F.
      EBV-associated lymphoma and chronic inflammatory demyelinating polyneuropathy in an adult without overt immunodeficiency.
      ]; (d) onset of SIDP/CIDP coincided with clinical or subsequent autopsy evidence of lymphoma recurrence [
      • Rowland L.P.
      • Schneck S.A.
      Neuromuscular disorders associated with malignant neoplastic disease.
      ,
      • Patten J.P.
      Remittent peripheral neuropathy and cerebellar degeneration complicating lymphosarcoma.
      ,
      • Plante-Bordeneuve V.
      • Baudrimont M.
      • Gorin N.C.
      • Gherardi R.K.
      Subacute sensory neuropathy associated with Hodgkin's disease.
      ,
      • Griggs J.J.
      • Commichau C.S.
      • Rapoport A.P.
      • Griggs R.C.
      Chronic inflammatory demyelinating polyneuropathy in non-Hodgkin's lymphoma.
      ]; (e) relapse of CIDP/SIDP (also interpreted as recurrent GBS [
      • Barth P.
      • Roegel-Demuynck C.
      • Pflumio F.
      • Geisler F.
      Subacute distal motor neuropathy revealing non-Hodgkin's lymphoma: improvement under chemotherapy.
      ]) coincided with diagnosis of new lymphoma [
      • Shafar J.
      Brill-Symmer's disease presenting as multiple symmetrical peripheral polyneuropathy.
      ,
      • Sumi S.M.
      • Farrell D.F.
      • Knauss T.A.
      Lymphoma and leukemia manifested by steroid-responsive polyneuropathy.
      ,
      • Wada M.
      • Kurita K.
      • Tajima K.
      • Kawanami T.
      • Kato T.
      A case of inflammatory demyelinating polyradiculoneuropathy associated with T-cell lymphoma.
      ,
      • Ammannagari N.
      • Chikoti S.
      • Bravin E.
      Hodgkin's lymphoma presenting as a complex paraneoplastic neurological syndrome: a case report.
      ], and (f) in hindsight, erythematous skin papules (probably related to T-cell lymphoma) preceded initial diagnosis of CIDP by 6 months [
      • Wada M.
      • Kurita K.
      • Tajima K.
      • Kawanami T.
      • Kato T.
      A case of inflammatory demyelinating polyradiculoneuropathy associated with T-cell lymphoma.
      ].
      The clinical presentation of CIDP associated with lymphoma has been regarded no different from the presentation of sporadic CIDP [
      • Giglio P.
      • Gilbert M.R.
      Neurologic complications of non-Hodgkin's lymphoma.
      ]. Cranial nerve involvement was reported in 9 patients with lymphoma. One patient required mechanical ventilation for respiratory failure [
      • Lee J.H.
      • Sohn E.H.
      • Lee A.Y.
      • Kim J.M.
      • Kim S.
      A case of chronic inflammatory demyelinating polyneuropathy associated with immune-mediated thrombocytopenia and cutaneous T-cell lymphoma.
      ]. CSF analysis commonly showed albuminocytologic dissociation compatible with acquired IDP; by definition no patient showed evidence of lymphomatous meningitis.
      Electrodiagnostic study findings on 18 patients were compatible with acquired IDP; predominant axonal findings were reported in 5 of these patients [
      • Brunet P.
      • Schadeck B.
      • Moriceau M.
      Subacute sensory neuropathy with remission: an association with lymphoma.
      ,
      • Plante-Bordeneuve V.
      • Baudrimont M.
      • Gorin N.C.
      • Gherardi R.K.
      Subacute sensory neuropathy associated with Hodgkin's disease.
      ,
      • Barth P.
      • Roegel-Demuynck C.
      • Pflumio F.
      • Geisler F.
      Subacute distal motor neuropathy revealing non-Hodgkin's lymphoma: improvement under chemotherapy.
      ,
      • Cardinali P.
      • Serrao M.
      • Rossi P.
      • De Dominicis L.
      • De Santis F.
      • Pierelli F.
      Chronic axonal-demyelinating polyradicular neuropathy associated with mycosis fungoides: a case report.
      ]. In earlier case reports, such studies had not yet become a routine part of patient evaluation.
      Peripheral nerve specimens were obtained by biopsy or at autopsy from 11 patients: findings were consistent with an inflammatory demyelinating process with variable loss of myelinated fibers; however, in 2 patients the pathology was interpreted as a predominantly axonal variant of acquired IDP [
      • Plante-Bordeneuve V.
      • Baudrimont M.
      • Gorin N.C.
      • Gherardi R.K.
      Subacute sensory neuropathy associated with Hodgkin's disease.
      ,
      • Barth P.
      • Roegel-Demuynck C.
      • Pflumio F.
      • Geisler F.
      Subacute distal motor neuropathy revealing non-Hodgkin's lymphoma: improvement under chemotherapy.
      ].
      Treatment protocols for CIDP varied. Immunomodulatory treatment was offered when: (a) a new diagnosis or recurrence of CIDP/SIDP preceded the diagnosis of lymphoma; (b) treatment of CIDP preceded treatment of relapsed lymphoma; (c) treatment of CIDP followed completed treatment of lymphoma (i.e., in remission), or (d) onset of CIDP coincided with unrecognized lymphoma recurrence. Eight patients were not offered immunotherapy for neuropathy: a decision was made to aim chemotherapy at the malignancy when a diagnosis of new lymphoma [
      • Brunet P.
      • Schadeck B.
      • Moriceau M.
      Subacute sensory neuropathy with remission: an association with lymphoma.
      ,
      • Plante-Bordeneuve V.
      • Baudrimont M.
      • Gorin N.C.
      • Gherardi R.K.
      Subacute sensory neuropathy associated with Hodgkin's disease.
      ,
      • Barth P.
      • Roegel-Demuynck C.
      • Pflumio F.
      • Geisler F.
      Subacute distal motor neuropathy revealing non-Hodgkin's lymphoma: improvement under chemotherapy.
      ,
      • Kasamon Y.L.
      • Nguyen T.N.
      • Chan J.A.
      • Nascimento A.F.
      EBV-associated lymphoma and chronic inflammatory demyelinating polyneuropathy in an adult without overt immunodeficiency.
      ] or recurrent lymphoma [
      • Tomita M.
      • Koike H.
      • Kawagashira Y.
      • Iijima M.
      • Adachi H.
      • Taguchi J.
      • Abe T.
      • Sako K.
      • Tsuji Y.
      • Nakagawa M.
      • Kanda F.
      • Takeda F.
      • Sugawara M.
      • Asano N.
      • Sobue G.
      Clinicopathological features of neuropathy associated with lymphoma.
      ,
      • Plante-Bordeneuve V.
      • Baudrimont M.
      • Gorin N.C.
      • Gherardi R.K.
      Subacute sensory neuropathy associated with Hodgkin's disease.
      ] temporally coincided with the onset or relapse of CIDP/SIDP. In a case with immunotherapy-unresponsive CIDP, the neuropathy clinically responded to chemotherapy directed at lymphoma [
      • Cardinali P.
      • Serrao M.
      • Rossi P.
      • De Dominicis L.
      • De Santis F.
      • Pierelli F.
      Chronic axonal-demyelinating polyradicular neuropathy associated with mycosis fungoides: a case report.
      ].
      Treatment programs of lymphoma varied, so that appropriate or preferred protocols were chosen according to the biology and staging of the malignancy. Lymphoma was not treated when the patient refused treatment [
      • Wada M.
      • Kurita K.
      • Tajima K.
      • Kawanami T.
      • Kato T.
      A case of inflammatory demyelinating polyradiculoneuropathy associated with T-cell lymphoma.
      ] or when the diagnosis of lymphoma was subsequently made only at autopsy [
      • Rowland L.P.
      • Schneck S.A.
      Neuromuscular disorders associated with malignant neoplastic disease.
      ].
      Prognosis of CIDP/SIDP was favorable during the reported observation periods; benefit was observed both in patients treated with immunotherapy for neuropathy and in patients treated with chemotherapy directed at lymphoma. Patients died of ventilatory failure [
      • Rowland L.P.
      • Schneck S.A.
      Neuromuscular disorders associated with malignant neoplastic disease.
      ], broncho-/pneumonia complicating lymphoma treatment [
      • Patten J.P.
      Remittent peripheral neuropathy and cerebellar degeneration complicating lymphosarcoma.
      ,
      • Sumi S.M.
      • Farrell D.F.
      • Knauss T.A.
      Lymphoma and leukemia manifested by steroid-responsive polyneuropathy.
      ], cardiac arrest without known cause [
      • Wada M.
      • Kurita K.
      • Tajima K.
      • Kawanami T.
      • Kato T.
      A case of inflammatory demyelinating polyradiculoneuropathy associated with T-cell lymphoma.
      ], or was not specified [
      • Tomita M.
      • Koike H.
      • Kawagashira Y.
      • Iijima M.
      • Adachi H.
      • Taguchi J.
      • Abe T.
      • Sako K.
      • Tsuji Y.
      • Nakagawa M.
      • Kanda F.
      • Takeda F.
      • Sugawara M.
      • Asano N.
      • Sobue G.
      Clinicopathological features of neuropathy associated with lymphoma.
      ].
      The immunopathogenesis of acquired IDP in patients with lymphoma has not been much studied. A report showed variable depression of indices of cell-mediated immunity, transient abnormality in B:T cell ratios, and abnormal serum immunoglobulin levels [
      • Lisak R.P.
      • Mitchell M.
      • Zweiman B.
      • Orrechio E.
      • Asbury A.K.
      Guillain–Barré syndrome and Hodgkin's disease: three cases with immunologic studies.
      ,
      • Lisak R.P.
      • Mitchell M.
      • Zweiman B.
      • Orrechio E.
      • Asbury A.K.
      Guillain–Barré syndrome and Hodgkin's disease: three cases with immunological studies.
      ]. It was postulated that selective/unique depression of cell-mediated immunity in NHL allowed the development of a humoral and/or cellular immune reaction to peripheral nerve antigens; the rare association between GBS and lymphoma was attributed to the role of host genetic control on the development of antigen-reactive cells in the pathogenesis of disease. Support for this autoimmune hypothesis came from an electron microscopic study that showed activated (i.e., immune competent) lymphocytes penetrating Schwann cells [
      • Julien J.
      • Vital C.
      • Aupy G.
      • Lagueny A.
      • Darriet D.
      • Brechenmacher C.
      Guillain–Barree syndrome and Hodgkin's disease — ultrastructural study of a peripheral nerve.
      ].
      The rarity of an association between CLL and GBS was explained by the almost invariable hypogammaglobulinemia in patients while the cell-mediated immune system remains largely intact [
      • Jackson M.
      Guillain–Barré syndrome in a patient with chronic lymphocytic leukemia.
      ]. In a report, the distinction between neoplastic and autoimmune/paraneoplastic processes was somewhat blurred in a patient with IDP associated with T-cell type CLL because tumor cells appeared the likely effectors of active demyelination [
      • Vital C.
      • Vital A.
      • Julien J.
      • Rivel J.
      • de Mascarel A.
      • Vergier B.
      • Henry P.
      • Barat M.
      • Reiffers J.
      • Broustet A.
      Peripheral neuropathies and lymphoma without gammopathy: a new classification.
      ]. In addition, the local release of immunoglobulins [
      • Spatz L.A.
      • Wong K.K.
      • Williams M.
      • Desai R.
      • Golier J.
      • Berman J.E.
      • Alt F.W.
      • Latov N.
      Cloning and sequence analysis of the VH and VL regions of an anti-myelin/DNA antibody from a patient with peripheral neuropathy and chronic lymphocytic leukemia.
      ] and pro-inflammatory cytokines [
      • Di Celle P.F.
      • Carbone A.
      • Marchis D.
      • Zhou D.
      • Sozanni S.
      • Zupo S.
      • Pini M.
      • Mantovani A.
      • Foa R.
      Cytokine gene expression in B-cell chronic lymphocytic leukemia: evidence of constitutive interleukin-8 (IL-8) mRNA expression and secretion of biologically active IL-8 protein.
      ] by infiltrating CLL B-cells may contribute to the mechanism of a demyelinating component of the inflammatory response.
      In conclusion, the uncommon occurrence of acquired IDP in patients with lymphoma requires complete evaluation (including CSF analysis and nerve biopsy) to rule out lymphomatous polyneuropathy; results have management implications. The rare association between acquired IDP and lymphoma suggests that the yield is bound to be low of a “routine” search for neoplasm, and should be guided by other more specific clinical suspicions.

      2.4 Multifocal motor neuropathy with conduction block (MMNCB)

      There exist 2 case reports of lymphoma-associated, anti-ganglioside antibody-negative MMNCB; a case with anti-GM1-associated MMNCB was included in the discussion on autoantibody-associated polyneuropathies earlier [
      • Noguchi M.
      • Mori K.
      • Yamazaki S.
      • Suda K.
      • Sato N.
      • Oshimi K.
      Multifocal motor neuropathy caused by a B-cell lymphoma producing monoclonal IgM autoantibody against nerve myelin glycolipids GM1 and GD1b.
      ]. A 67-year-old man was diagnosed with MMNCB and prurigo nodularis. MMNCB responded slightly to pulse IVIG and moderately to intravenous methylprednisolone. Diffuse large B-cell NHL was detected 19 months later. Treatment with CHOP and consolidation radiotherapy resulted in a “dramatic” improvement also of MMNCB, so that no further immune treatment was required. Based on sequence of events, the authors proposed that the undetected/preclinical lymphoma caused “paraneoplastic” skin and nerve disease via an undefined common autoimmune pathogenic mechanism [
      • Garcia-Moreno J.M.
      • Castilla J.M.
      • Garcia-Escudero A.
      • Izquierdo G.
      Multifocal motor neuropathy with conduction block and prurigo nodularis. A paraneoplastic syndrome in a patient with non-Hodgkin B-cell lymphoma?.
      ].
      A 47-year-old woman with recurrent DLBCL isolated to the CNS developed MMNCB. Neuraxis MRI showed parenchymal mass lesions and leptomeningeal enhancement. CSF analysis confirmed recurrent lymphoma. Despite imaging and CSF response to combined systemic and intra-thecal chemotherapy, the patient developed progressive limb weakness. Electrodiagnostic study fulfilled the criteria for MMNCB. Pulse and maintenance IVIG achieved neurological improvement over a 22-month follow-up period; cycles of chemotherapy resulted in lymphoma remission [
      • Stern B.V.
      • Baehring J.M.
      • Kleopa K.A.
      • Hochberg F.H.
      Multifocal motor neuropathy with conduction block associated with metastatic lymphoma of the nervous system.
      ]. In this patient, more than a single cause of weakness existed, so that a precise electrophysiological study diagnosis was important to determine the appropriate management decisions.
      In conclusion, based on the strong association between well-defined MMNCB and positive serum anti-GM1 antibodies at least some suspicion should arise of a possible lymphoproliferative disease in antibody-negative patients.

      2.5 Diverse retrospective studies

      In a report of 62 patients with various types of lymphoma, sural nerve biopsy was performed on 5 of 22 patients with clinical and/or electrophysiological evidence of generalized peripheral neuropathy [
      • Walsh J.C.
      Neuropathy associated with lymphoma.
      ]. Teased fiber preparation showed segmental demyelination/remyelination (2 patients), mixed segmental demyelination/axonal degeneration (2 patients), or predominant axonal degeneration (1 patient), without evidence of cellular infiltration. The authors speculated about an unidentified lymphoma-associated toxic/metabolic disorder affecting Schwann cells and/or nerve cells; to the reviewer an immune-mediated mechanism seems more likely.
      In a series of 13 patients with NHL and neuropathy, an immune-mediated pathogenesis included 1 case of GBS (see Table 2) [
      • Vallat J.M.
      • De Mascarel H.A.
      • Bordessoule D.
      • Jauberteau M.O.
      • Tabaraud F.
      • Gelot A.
      • Vallat A.V.
      Non-Hodgkin malignant lymphomas and peripheral neuropathies—13 cases.
      ]; Waldenström's macroglobulinemia (usually not included under NHL) was associated with CIDP (1 patient) and “dysglobulinemic” polyneuropathy i.e., serum ± endoneurial deposits of monoclonal IgMκ with antimyelin activity (3 patients).
      In a subset of 26 patients with lymphoma and neuropathy (unrelated to drugs or IgM-antimyelin antibodies), 13 patients were diagnosed with demyelinating polyneuropathy [
      • Viala K.
      • Béhin A.
      • Maisonobe T.
      • Léger J.M.
      • Stoikovic T.
      • Davi F.
      • Leblond V.
      • Bouche P.
      Neuropathy in lymphoma: a relationship between the pattern of neuropathy, type of lymphoma and prognosis?.
      ]. Onset of neuropathy was acute (<4 weeks) or subacute (4–8 weeks) in 10 patients, and progressive (>8 weeks) in 3 patients. Neuropathy preceded lymphoma diagnosis in 9 patients (mean = 13 months); lymphoma diagnosis preceded onset of neuropathy in 4 patients (mean = 48 months). HL was exclusively associated with demyelinating polyneuropathy, but not vice versa. Immunotherapy (IVIG/PPH) combined with chemotherapy offered the best neurological prognosis. Neurological and hematological improvement was observed in 69% and 46% of patients, respectively. With the application of appropriate investigations, the identification of the etiopathogenesis of neuropathy in patients with lymphoma was deemed important to limit diagnostic delay and error, define therapeutic options, and improve the neurological prognosis.

      3. Autoimmunity and non-Hodgkin lymphoma

      There exists a complex bi-directional inter-relationship between lymphoproliferative malignancies and autoimmunity. The development of lymphatic malignancy during the course of autoimmune and chronic inflammatory conditions is well established; conversely, biological and/or clinical evidence of autoimmunity can be detected at any stage of the lymphoma disease course [
      • Jardin F.
      • Lévesque H.
      • Tilly H.
      Auto-immune manifestations in non-Hodgkin's lymphoma.
      ,
      • Jardin F.
      Development of autoimmunity in lymphoma.
      ]. An accurate assessment of the prevalence of autoimmunity in patients with lymphoma has not been ascertained due to lack of systematic study [
      • Jardin F.
      Development of autoimmunity in lymphoma.
      ]. Autoimmunity is observed in all lymphoma subtypes; however, it appears that biological and/or clinical autoimmunity is more common in patients with indolent B-cell NHL subtypes (e.g., marginal zone or follicular lymphoma, and CLL) compared to more aggressive types of lymphoma [
      • Guyomard S.
      • Salles G.
      • Coudurier M.
      • Rousset H.
      • Coiffier B.
      • Bienvenu J.
      • Fabien N.
      Prevalence of pattern of antinuclear autoantibodies in 347 patients with non-Hodgkin's lymphoma.
      ]. In T-cell NHL subtypes immune manifestations are frequent and polymorphous [
      • Granel B.
      • Bouabdallah R.
      • Serratrice J.
      • Swiader L.
      • Veit V.V.
      • Horschowski N.
      • Xerri L.
      • Disdier P.
      • Weiller P.
      Prelymphomatous presentation of T-cell non-Hodgkin lymphoma. A clinical and histopathological study of 11 cases.
      ]. Biological autoimmunity is detected more frequently than clinically manifest autoimmune disease [
      • Jardin F.
      • Lévesque H.
      • Tilly H.
      Auto-immune manifestations in non-Hodgkin's lymphoma.
      ]; there exists a significant increase in the incidence of serum autoantibodies (e.g., anti-RNP, anti-Sm and ANA) among patients with lymphoma compared to controls [
      • Swissa M.
      • Cohen Y.
      • Shoenfeld Y.
      Autoantibodies in the sera of patients with lymphoma.
      ].
      Hypotheses exist regarding the biological mechanisms of autoimmunity in lymphoma. More-or-less consistent immune system dysfunction has been established in patients with the relatively well-defined lymphoma subtypes, i.e., HL (Table 5) and CLL (Table 6), but not in patients with NHL (an umbrella term for a large number of distinct lymphoma subtypes divided according to a spectrum of growth pattern aggressiveness and involved lymphocyte types). The development of autoimmunity in NHL patients has been proposed to entail any of the following mechanisms.
      Table 5Immune dysfunction in Hodgkin's disease.
      • Slivnick D.J.
      • Ellis T.M.
      • Nawrocki J.F.
      • Fisher R.I.
      The impact of Hodgkin's disease on the immune system.
      1. Normal antigen-induced antibody production
      2. Neutrophil function
       a. Decreased chemotaxis
       b. Decreased metabolic activity
      3. Delayed hypersensitivity skin tests
       a. Recall antigens: anergic
       b. Neoantigens: anergic
      4. Decreased E-rosette formation
      5. Decreased mitogen-induced T-cell proliferation
      6. Mixed lymphocyte-induced proliferation
       a. Decreased autologous
       b. Minimally decreased allogenic
      7. Enhanced sensitivity to suppressor monocytes
      8. Enhanced sensitivity to suppressor T-cells
      9. Minimally decreased CD4:CD8 ratio
      Table 6Immune dysfunction in chronic lymphocytic leukemia.
      • Dearden C.
      Disease-specific complications of chronic lymphocytic leukemia.
      1. B-cells
       a. Hypogammaglobulinemia
       b. Production of inhibitory cytokines IL-6, IL-10, TNF, TGFβ
       c. Poor response to vaccination
      2. T-cells
       a. Quantitative: increased number
       b. Qualitative
      i. Skewed repertoire, inversion CD4:CD8 ratio
      ii. Th2 polarization
      iii. Abnormal CD30 response
      iv. Reversible acquired CD40L deficiency
      v. Gene expression abnormalities (cytoskeleton/granules)
      3. NK-cells
       a. Lack of granules
       b. Reduced killing activity
      4. Neutrophils
       a. Reduced phagocytic and bactericidal function
       b. Abnormal migration and chemotaxis
      5. Monocytes/macrophages
       a. Reduced cytotoxicity
      6. Complement
       a. Reduction in levels and defects in activation and binding
      Firstly, autoantibodies produced by a malignant transformation of the normal repertoire of autoreactive B-cells [
      • Dighiero G.
      Autoimmunity and B-cell malignancies.
      ], share characteristics of natural autoantibodies (NAA). NAA represent a proportion of circulating normal immunoglobulins, and production does not require antigenic stimulation of secretory CD5+ B-cells. NAA are directed against well-conserved public isotopes i.e., low affinity to bind a wide range of self and non-self antigens [
      • Jønsson V.
      • Wiik A.
      • Hou-Jensen K.
      • Christiansen M.
      • Ryder L.P.
      • Madsen H.O.
      • Geisler C.
      • Hansen M.M.
      • Thompsen K.
      • Vorstrup S.
      • Svejgaard A.
      Autoimmunity and extranodal lymphocytic infiltrates in lymphoproliferative disorders.
      ]. Molecular analysis of V-genes in lymphoma favors a malignant transformation of autoreactive B-cells provoked by continuous challenge by self-antigens (e.g., CDR3 sequence and adjacent regions of immunoglobulin genes from B-cell lymphoma display homology with autoantibody-associated lymphocyte clones) [
      • Yumoto N.
      • Kurosu K.
      • Furukawa M.
      • Mikata A.
      CDR3 sequences of MALT lymphoma show homology with those of autoreactive B-cell lines.
      ]. Also, the asymmetric pattern of usage of the VH4-21 gene (encodes for heavy chain variable region of immunoglobulins with autoantibody activity) by different B-cell tumor types seems to correlate with the frequency of associated autoimmune manifestations [
      • Stevenson F.K.
      • Spellerberg M.B.
      • Chapman C.J.
      • Hamblin T.J.
      Differential usage of an antibody-associated VH gene, VH4-21, by human B-cell tumors.
      ]. CD5-B-cells retain capacity to produce autoantibodies despite the frequent loss of CD5 antigen expression during lymphomagenesis [
      • Dighiero G.
      • Hart S.
      • Lim A.
      • Borche L.
      • Levy R.
      • Miller R.A.
      Autoantibody activity of immunoglobulins isolated from B-cell follicular lymphomas.
      ].
      Secondly, non-lymphoma cells may be the source of autoantibody production in patients with lymphoma. The detection of serum autoantibodies directed against various, yet distinct, antigens implies that a single tumoral clone cannot secrete these immunoglobulins. Thus, autoantibody production results from a lymphoma-induced generalized, more-or-less disordered immune regulation. Such a mechanism appears likely in angioimmunoblastic T-cell lymphoma and Hodgkin disease (Reed–Sternberg cells are incapable of antibody production) [
      • Slivnick D.J.
      • Ellis T.M.
      • Nawrocki J.F.
      • Fisher R.I.
      The impact of Hodgkin's disease on the immune system.
      ,
      • Jardin F.
      Development of autoimmunity in lymphoma.
      ]. The role of Treg cells in lymphoma-associated autoimmunity has not been established. Treg cells suppress autoreactive T-cells as well as the immune response to malignancy. Treg cells are over-represented in biopsy samples of B-cell NHL, and B-cells may help to recruit Treg cells into lymphoma tissue [
      • Yang Z.Z.
      • Novak A.J.
      • Ziesmer S.C.
      • Witzig T.E.
      • Ansell S.M.
      Attenuation of CD8+ T-cell function by CD4+CD25+ regulatory T cells in B-cell non-Hodgkin's lymphoma.
      ]. Thus, a Treg population that regulates the immune response to lymphoma cells is conceivably involved in the development of autoimmunity. Thirdly, an alteration of the Fas/Fas-ligand pathway can lead to autoimmunity. Fas receptor (CD95) is a cell-surface receptor involved in programmed cell-death (i.e., apoptosis) signaling. Acquired somatic mutations of Fas receptor can occur during normal germinal center proliferation, and are prevalent in NHL (e.g., MALT) with autoimmune manifestations [
      • Gronbaek K.
      • Straten P.T.
      • Ralfkiaer E.
      • Ahrenkiel V.
      • Andersen M.K.
      • Hansen N.E.
      • Zeuthen J.
      • Hou-Jensen K.
      • Guldberg P.
      Somatic Fas mutations in non-Hodgkin's lymphoma: association with extranodal disease and autoimmunity.
      ]. Moreover, clues to lymphomagenesis were obtained from evidence that Fas-mediated apoptosis can be inhibited by exposure to surface-binding IgM antibody that engages anti-Fas antigen for which the malignant clone has affinity e.g., in Burkitt's lymphoma [
      • Schattner E.J.
      • Friedman S.M.
      • Casali P.
      Inhibition of Fas-mediated apoptosis by antigen: implications for lymphomagenesis.
      ].
      Lastly, a process of viral antigen-specific stimulation can lead to B-cell activation and clonal expansion that promote both lymphomagenesis and autoimmunity [
      • Mackay I.R.
      • Rose N.R.
      Autoimmunity and lymphoma: tribulations of B cells.
      ,
      • Curry M.P.
      • Golden-Mason L.
      • Doherty D.G.
      • Deignan T.
      • Norris S.
      • Duffy M.
      • Nolan N.
      • Hall W.
      • Hegarty J.E.
      • O'Farrelly C.
      Expansion of innate CD5pos B cells expressing high levels of CD81 in hepatitis C virus infected liver cells.
      ]. For instance, HCV-associated lymphomas are often indolent [
      • Mele A.
      • Pulsoni A.
      • Bianco E.
      • Musto P.
      • Szklo A.
      • Sanpaolo M.G.
      • Iannitto E.
      • De Renzo A.
      • Martino B.
      • Liso V.
      • Andrizzi C.
      • Pusterla S.
      • Dore F.
      • Maresca M.
      • Rapicetta M.
      • Marcucci F.
      • Mandelli F.
      • Franceschi S.
      Hepatitis C virus and B-cell non-Hodgkin lymphomas: an Italian multicenter case–control study.
      ] with frequent and varied autoimmune manifestations. The expression of a limited repertoire of immunoglobulin VH- and VL-genes by HCV-associated lymphoma B-cells due to viral E2 antigenic stimulation can lead to the development of autoimmunity [
      • Chan C.H.
      • Hadlock K.G.
      • Foung S.K.
      • Levy S.
      V(H) 1-69 gene is preferentially used by hepatitis C virus-associated B cell lymphomas and by normal B cells responding to the E2 viral antigen.
      ,
      • Quinn E.R.
      • Chan C.H.
      • Hadlock K.G.
      • Foung S.K.
      • Flint M.
      • Levy S.
      The B-cell receptor of a hepatitis C virus (HCV)-associated non-Hodgkin lymphoma binds the viral E2 envelope protein, implicating HCV in lymphomagenesis.
      ]. Moreover, viral antigen can promote production of certain cytokines that are involved in B-cell terminal differentiation via autocrine or paracrine mechanisms e.g., IL-6 can facilitate differentiation of lymphoma cells into antibody-producing cells and, thereby, autoimmunity [
      • Sawamura M.
      • Yamaguchi S.
      • Murakami H.
      • Kitahara T.
      • Itoh K.
      • Maehara T.
      • Kawada E.
      • Matsushima T.
      • Tamura J.
      • Naruse T.
      Multiple autoantibody production in a patient with splenic lymphoma.
      ,
      • Nobuoka A.
      • Sakamaki S.
      • Kogawa K.
      • Fujikawa K.
      • Takahashi M.
      • Hirayama Y.
      • Takayanagi N.
      • Ikeda H.
      • Sekiguchi S.
      • Niitsu Y.
      A case of malignant lymphoma producing antibody against platelet glycoprotein Ib.
      ].

      4. Autoimmunity and chronic lymphocytic leukemia

      CLL is characterized by the progressive accumulation of monoclonal lymphocytes with a distinctive immunophenotype (CD5+, CD19+, CD20dim, CD23+, SmIgdim) in peripheral blood, bone marrow, and lymphoid tissues [
      • Swerdlow S.
      International Agency for Research on Cancer, World Health Organization.
      ]. Non-hematologic autoimmunity occurs in 1 to 2% of patients with CLL, and tends to affect patients in early-stage disease due to underlying alterations in immune function [
      • Ward J.H.
      Autoimmunity in chronic lymphocytic leukemia.