Lymphomas Paraneoplastic Neurological Syndromes in Hodgkin and Non-Hodgkin

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2014 123: 3230-3238 doi:10.1182/blood-2014-03-537506 originally published online April 4, 2014

Paraneoplastic neurological syndromes in Hodgkin and non-Hodgkin lymphomas

Francesc Graus, Helena Ariño and Josep Dalmau

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From bloodjournal.hematologylibrary.org by guest on July 21, 2014. For personal use only. Review Article

Paraneoplastic neurological syndromes in Hodgkin and non-Hodgkin lymphomas

Francesc Graus,1,2 Helena Arin˜o,1,2 and Josep Dalmau1,3,4

1Neuroimmunology Program, Institut d’Investigacions BiomèdiquesAugust Pi i Sunyer, Barcelona, Spain; 2Department of Neurology, Hospital Clinic, Barcelona, Spain; 3Department of Neurology, University of Pennsylvania, Philadelphia, PA; and 4Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain

Paraneoplastic neurological syndromes PNSs such as sensory neuronopathy or the tumor itself does not trigger the PNS. (PNSs) rarely associate with Hodgkin lym- Lambert-Eaton myasthenic syndrome Third, unlike patients with solid tumors in phoma (HL) and non-HLs (NHLs). Except rarely occur in lymphomas, whereas others, patients with lymphoma, the PNSs often for paraneoplastic cerebellar degeneration such as granulomatous angiitis, are only develops at advanced stages of the dis- (PCD) in HL and dermato/ polymyositis in described in HL. Second, onconeural anti- ease. Furthermore, the type and frequency both HL and NHL, other PNSs are un- bodies are absent in most PNSs associated of PNSs are different between HL and NHL; common and have only been reported as with lymphomas with the exceptions of whereas LE and PCD occur almost exclu- isolated case reports or short series. Tr (d/notch-like epidermal growth factor- sively in patients with HL, sensorimotor neu- There are several important differences related receptor) in PCD and mGluR5 in ropathies and dermatomyositis are more in PNSs when occurring in association limbic encephalitis (LE). The antigens frequent in NHL. (Blood. 2014;123(21): with HL and NHL compared with those recognized by these antibodies are not 3230-3238) associated with solid tumors. First, some expressed in lymphoma cells, suggesting Introduction

Paraneoplastic neurological syndromes (PNSs) occur with increased sensorimotor neuropathy,”“neuromyotonia,”“Lambert-Eaton myasthenic frequency in patients with cancer and are not caused by metastasis, syndrome,”“polymyositis,”“dermatomyositis,” and “myasthenia.” Articles direct infiltration of the tumor, or known indirect mechanisms such as were also identified by searches of the authors’ files. toxicity, ectopic secretion of hormones, or induced coagulopathies. When originally described, the cause of PNSs was unknown. Pres- ently, the accepted hypothesis is that many PNSs are caused by immune mechanisms triggered against antigens that are normally Diagnostic criteria of PNSs present in the nervous system and ectopically expressed by the tumor (onconeural antigens). The basis of this hypothesis is the identifi- The presence of a neurological syndrome of unclear etiology at cation of antibodies against onconeural antigens in serum and cerebral the time of the diagnosis of a tumor does not necessarily mean that the spinal fluid (CSF) of many patients with PNSs.1 neurological syndrome is paraneoplastic, as this could represent the The frequency of PNSs is low; they occur in ,1% of patients with coincidental occurrence of 2 unrelated events. In 2004, 2 levels of fi solid tumors, particularly small-cell lung carcinoma (SCLC), breast, diagnostic certainty were proposed for PNSs: de nite and possible. The criteria used to define the level are based on the type of neu- and ovarian cancers. The frequency is probably lower in Hodgkin rological syndrome, the detection of well-characterized onconeural lymphoma (HL) and other lymphomas. However, the correct diag- 2 nosis of PNS is important because an early recognition of a neu- antibodies, and the presence of a cancer (Figure 1). Some PNSs are rological syndrome as paraneoplastic often leads to the discovery and termed classical because they almost always indicate the presence of treatment of the underlying tumor, which is a crucial step in the an underlying tumor (Table 1). These syndromes are considered fi management of the PNS.1 de nite PNSs if the tumor is found or the patient has a well- characterized onconeural antibody. Nonclassical syndromes, such as sensorimotor neuropathy, would qualify as a definite PNS only if the patient has a well-characterized onconeural antibody or the syndrome improves after successful treatment of the underlying tumor Methods (Figure 1).2 Well-characterized onconeural antibodies are those that are demonstrated with validated tests, and for which there are a References for this review were identified through searches of PubMed for number of published reports defining the specificity and sensitivity articles published in English until December 31, 2013 with the search terms fi fi “ ”“ ” “ ” of the antibody for PNS and con rmation of the ndings by several Hodgkin disease, lymphoma, in combination with Ophelia syndrome, 2 2 “limbic encephalitis,”“granulomatous angiitis,”“paraneoplastic cerebellar investigators. Since the publication of the PNS criteria in 2004, degeneration,”“paraneoplastic chorea,”“opsoclonus,”“stiff-person syn- 2 onconeural antibodies should be added to the list of well- drome,”“motor-neuron disease,”“paraneoplastic sensory neuropathy,” characterized onconeural antibodies: Sox1 antibodies which are autoimmune autonomic neuropathy and/or ganglionopathy,”“paraneoplastic markers of an underlying SCLC in patients with paraneoplastic

3230 BLOOD, 22 MAY 2014 x VOLUME 123, NUMBER 21 From bloodjournal.hematologylibrary.org by guest on July 21, 2014. For personal use only.

BLOOD, 22 MAY 2014 x VOLUME 123, NUMBER 21 PARANEOPLASTIC NEUROLOGICAL SYNDROMES IN LYMPHOMAS 3231

Figure 1. Flowchart showing the level of diagnostic evidence for the diagnosis of PNSs. Reprinted with permission from J Neurol Neurosurg Psychiatry 2004; 75:1135-1140.2

cerebellar degeneration (PCD) or Lambert-Eaton myasthenic 3,4 syndrome (LEMS), and Tr antibodies, which are markers of General overview of PNSs in lymphomas HL in patients with PCD.5 The Tr antigen has been recently identified as d/notch-like epidermal growth factor-related re- PNSs are rare in lymphomas. Except for PCD in HL and dermato/ 6 ceptor (DNER). polymyositis in both HL and non-HL (NHL), other PNSs have rarely The recently described antibodies against neuronal cell surface or been reported in these patients. The frequency of PNSs associated synaptic receptors are not included in the group of well-characterized with lymphomas was analyzed by the PNS Euronetwork consortium onconeural antibodies because they are excellent markers (and that includes 20 European centers. Between 2000 and 2008, the appear to be pathogenic) of the neurological syndrome, but may consortium collected 53 patients with PNSs, 29 of them with NHL 7-16 occur in patients with or without cancer (Table 2). For these cell and 24 with HL. The most commonly associated PNS was PCD in surface or synaptic antibodies, the frequency of an underlying tumor 21 patients, 16 of them with HL, and demyelinating neuropathies in varies with the type of antibody, age, and sometimes gender of 11, 9 with NHL.17 the patient; in some cases (eg, a-amino-3-hydroxy-5-methyl-4- PNSs that occur in lymphomas have several important differ- isoxazolepropionic acid[AMPA]org-aminobutyric acid B [GABAB] ences compared with those in solid tumors. First, lymphomas as- receptor antibodies), a search for an underlying tumor is indicated sociate with unique PNSs (granulomatous angiitis, hypothermia), because cancer may be present in up to 60% of the patients whereas classical PNSs (sensory neuronopathy, LEMS) rarely occur. 7 (Table 2). Second, onconeural antibodies are absent in most PNSs (Table 1); only Tr and metabotropic glutamate receptor type 5 (mGluR5) are considered good markers of an underlying HL. This is a limitation to Table 1. Paraneoplastic neurological syndromes define as definite many PNS that associate with lymphomas. Third, Associated Predominant Selected onconeural antigens are not expressed in the tumor cells, suggesting Syndrome antibodies lymphoma type references the tumor itself may not trigger the PNS. Fourth, unlike solid tumors, LE mGluR5 HL 16 lymphomas of patients with PNSs do not usually have limited Granulomatous angiitis None HL 40, 41 extension at the time of diagnosis. In Table 1 and the text, we sum- Cerebellar degeneration Tr (DNER) HL 5, 6 marize the PNSs that have been described in HL and NHL. The type Paraneoplastic chorea CV2/ ,10 cases (NHL in 4) 57, 58 and frequency of PNSs is different between HL and NHL. The global CRMP5* incidence of PNSs is probably higher in HL. Limbic encephalitis , Opsoclonus-myoclonus None 10 cases (NHL in 3) 64, 66 (LE) and PCD are almost exclusively seen in patients with HL, Stiff-person syndrome None HL 67, 72 whereas sensorimotor neuropathies and dermatomyositis are more Paraneoplastic myelopathy None HL and NHL 73, 74 Motor neuronopathy None HL 79, 80 common in NHL. Sensory neuronopathy None† ,10 cases (5 with HL) 81, 82 Autonomic ganglionopathy nAChR‡ ,10 cases (HL, NHL) 87, 88 Sensorimotor neuropathy None HL and NHL 94 Vasculitic neuropathy None NHL 97 LE Neuromyotonia None ,10 cases (HL, NHL) 104 Lambert-Eaton myasthenic VGCC‡ ,10 cases (NHL) 102 Patients with LE develop short-term memory loss or amnesia, dis- syndrome orientation, confusion, depression, anxiety, or frank psychosis with Myasthenia AChR‡ HL and NHL 105 visual or auditory hallucinations or paranoid ideation. Generalized or Dermatomyositis p155 NHL 99 partial complex seizures occur in ;50% of the patients. HL is the third Classical syndromes are underlined. nAChR, nicotinic acetylcholine receptor; most common cause of LE after SCLC and testicular germ cell VGCC, voltage-gated calcium channel. tumors.18 The cases reported in the English literature are sum- *Not present in all cases. 16,18-29 †One patient with NHL and Ma2 antibodies (not published). marized in Table 3. The association of LE with HL is also 19 ‡Marker of the syndrome, not predictor of cancer. known as Ophelia syndrome. The clinical and magnetic resonance From bloodjournal.hematologylibrary.org by guest on July 21, 2014. For personal use only.

3232 GRAUS et al BLOOD, 22 MAY 2014 x VOLUME 123, NUMBER 21

Table 2. Antibodies against cell surface or synaptic antigens allogeneic bone marrow transplant, raising the concern for a 38,39 Antibody Syndrome Cancer possible infection by herpes virus type 6. NMDAR Encephalitis Ovarian teratoma (rare in children, present in 58% older than 18 y)8 LGI1 LE None9 VGCC LEMS SCLC (50%)10 Granulomatous angiitis of the central 11 GABABR LE SCLC (70%) nervous system CASPR2 Morvan syndrome Thymoma (38%)12 AMPAR LE SCLC, breast, thymus (60%)13 This disorder is histopathologically characterized by the presence of DPPX Encephalitis None14 necrotizing vasculitis involving small arteries and veins along with mGluR1 Cerebellar ataxia A few cases reported, two with HL15 noninfectious granulomas composed of lymphocytes, monocytes, mGluR5 LE HL (only two cases reported)16 and plasma cells. Leptomeningeal vessels are preferentially affected. The cause of this vasculitis is unknown, but there is evidence that it AMPAR, AMPA receptor; CASPR2, contactin-associated protein 2; DPPX, 40 dipeptidyl-peptidase-like protein-6; GABABR, GABAB receptor; LGI1, leucine-rich, could be related to the varicella-zoster virus. The disorder may glioma inactivated 1 protein; NMDAR, N-methyl-D-aspartate receptor; SCLC, small- precede or occur shortly after the diagnosis of HL. In the majority of cell lung cancer; VGCC, voltage-gated calcium channel. cases, the vasculitis has not been linked to a recent infection of varicella-zoster, and the pathological studies ruled out the presence imaging (MRI) features (Figure 2) are not different from those re- of viral particles in the affected vessel walls, supporting a possible autoimmune mechanism.41 Table 441-46 summarizes the cases de- ported in LE associated with other tumors. However, the LE of fi patients with HL has a better prognosis; frequently, successful treat- scribed since 2000 with a con rmed pathological diagnosis (pre- ment of the tumor is sufficient to result in full neurological recovery. vious cases are reviewed in ref. 42). Patients develop headache, subacute cognitive decline or con- This is probably related to the finding that this type of LE occurs in fusion, and focal neurological symptoms. The CSF analysis shows association with an antibody against the mGluR5 that probably results in reversible neuronal dysfunction rather than neuronal lymphocytic pleocytosis. Brain MRI may demonstrate bilateral death (Figure 3).16,30 areas of leukoencephalopathy, gadolinium-enhancing lesions that follow a perivascular pattern, or, less frequently, hemorrhagic lesions.41 The diagnosis of LE requires electroencephalographic, neurora- Cerebral angiography may show small vessel beading, suggestive of diological, or pathological evidence of involvement of the medial 40 temporal lobes and amygdala.18 It is important to apply these criteria vasculitis, but in general, it has low sensitivity. Unlike patients reported in previous decades, recent cases of granulomatous angiitis of the central to avoid labeling, as LE, patients with other disorders that may also associate with HL.31 The application of these criteria revealed 2 nervous system (CNS) and HL had full recovery after treatment patients, 14 and 18 years of age, reported as LE who in fact probably with steroids and chemotherapy for the underlying HL (Table 4). had other forms of encephalitis. Both cases presented with fever, headache, nausea, and vomiting, and CSF pleocytosis followed in a few days by progressive confusion, agitation, hallucinations (1 patient), PCD and seizures, requiring intubation. Brain MRI was initially normal, and both patients made excellent recovery after treatment of the PCD is one of the best-characterized PNS and occurs preferentially HL.32,33 associated with ovarian, breast, SCLC or HL.47 Only a few cases of Unlike HL, LE is extremely rare in patients with NHL, with only a PCD associated with NHL have been reported.17,48-50 The path- few cases described, mostly in the Japanese literature.34,35 As in some ological hallmark of PCD is a severe loss of Purkinje cells of the HL cases, the criteria for LE were not fulfilled in 2 patients.36,37 cerebellum that results in subacute pancerebellar dysfunction. The In a third patient, the syndrome attributed to LE occurred after an usual presentation is dizziness and vertigo that rapidly progress to

Table 3. LE and HL Reference Age (y)/gender Delay* (months) Type (stage) Antibody Treatment Outcome

18 15/F 4-6 Unknown ND Oncological Full recovery 19 36/M 9 NS (IV) ND Oncological, steroids No improvement 20 33/M 0 NS (IV) ND Oncological Full recovery 21 23/M 10 NS (III) ND Steroids,† Oncological Full recovery 22 13/F ? NS (?) ND Oncological No improvement 23 53/F 6 NS (II) Negative‡ Oncological Full recovery 24 42/M 52 MC (II) ND Oncological No improvement 25 69/F 6 MC (II) Negative‡ Oncological Unknown 26 61/M 0 MC (III) Hu‡ Oncological Full recovery 27 49/M 0§ NS (?) NMDAR Steroids, IVIG, PLEX, oncological Partial improvement 16 46/F 0 ? (III) mGluR5 Steroids, oncological Full recovery 28 62/F ? ? (I) Hu‡,{ None Full recovery 29 35/M 6 NS (II) mGluR5 Oncological Full recovery

IVIG, intravenous immunoglobulins; MC, mixed cellularity; ND, not done; NS, nodular sclerosis; PLEX, plasma exchange. *Delay between onset of LE and HL diagnosis. †No improvement. ‡Antibodies to surface antigens were not tested. §At relapse. {CSF negative. From bloodjournal.hematologylibrary.org by guest on July 21, 2014. For personal use only.

BLOOD, 22 MAY 2014 x VOLUME 123, NUMBER 21 PARANEOPLASTIC NEUROLOGICAL SYNDROMES IN LYMPHOMAS 3233

likely to improve, and a few had spontaneous improvement. The Tr (or DNER) antibody titers usually disappear after treatment of the HL.5

Paraneoplastic chorea

A paraneoplastic etiology is rarely considered in the differential diagnosis of chorea. However, 56 well-documented cases have been reported, 4 of them associated with NHL and 1 with HL.57,58 The chorea was generalized and associated with peripheral neuropathy or encephalopathy in 2 patients. Brain MRI may demonstrate bilateral hyperintensity of caudate nuclei and putamen, as can be seen in paraneoplastic chorea associated with other tumors, mainly SCLC.59 The most useful diagnostic test is determination of CV2/collapsin response mediator protein 5 (CRMP5) antibodies, which are often detected in patients with paraneoplastic chorea regardless of the tumor association.60 However, almost 50% of patients with paraneoplastic chorea with solid tumors or lymphomas do not have onconeural antibodies. Neurological improvement may occur after immunotherapy or treatment of the lymphoma but a complete remission is rarely achieved.57 Figure 2. Coronal T2-weighted MRI scan of a patient with LE, mGluR5 antibodies, and HL. There is increased T2 signal of the head of both hippocampi. Study is slightly affected by motion artifact. Opsoclonus-myoclonus syndrome severe usually symmetrical truncal and limb ataxia, with dysarthria, Opsoclonusisdefined by irregular, continuous, large amplitude diplopia, and frequent down-beat nystagmus. CSF examination conjugate saccades in all directions of gaze. In opsoclonus- usually shows moderate pleocytosis, and the MRI studies are initially myoclonus syndrome, the abnormal eye movements are associ- normal and later show cerebellar atrophy.1 ated with arrhythmic action myoclonus that involves trunk, PCD antedates the diagnosis of HL in 80% of the patients.5 The limbs, and head, along with truncal ataxia, dysarthria, and, in some most useful diagnostic test is the detection of onconeural antibodies. patients, confusion and coma. Opsoclonus may result from a wide Patients with PCD and HL may harbor Tr antibodies (named after variety of causes, the most frequent being postinfectious, idiopathic, the author that first identified them51)intheirserumandCSF and paraneoplastic.61 In children, paraneoplastic opsoclonus- (Figure 4).52 The target antigen of these antibodies is DNER,6 a trans- myoclonus occurs in association with neuroblastoma. In adults, the membrane protein that is preferentially expressed in the dendrites syndrome is mainly associated with breast cancer and gynecologic of Purkinje cells and likely plays a regulatory role in dendrite tumors (usually accompanied by the presence of Ri antibodies) and patterning.53 Unlike other PNS antigens, DNER has not been iden- SCLC (usually without paraneoplastic antibodies),62 Only 4 patients tified in tissue samples of HL, suggesting that the immune response is with this syndrome and NHL or HL have been reported. None of the not triggered by ectopic tumor expression of the antigen.6 Antibodies 3 patients with NHL improved63-65; the patient with HL developed against the mGluR1 were initially described in 2 patients who de- opsoclonus-myoclonus 7 weeks after autologous hematopoietic cell veloped subacute cerebellar ataxia 2 and 9 years after HL. Sub- transplantation, and therefore a postinfectious etiology could have sequent case reports have not confirmed the association of PCD been the cause of the disorder.66 and mGluR1 antibodies with HL.54,55 Although DNER is a cell surface antigen, PCD related to antibodies against this antigen does not respond as well to treatment as other disorders associated to antibodies against cell surface antigens Paraneoplastic stiff-person and related (Table 2). However, the prognosis is still better than that of PCD syndromes associated with solid tumors.47 In the 2 largest series of PCD and HL with a total of 49 patients, 7 (14%) had full recovery or partial Stiff-person syndrome is a rare CNS disorder characterized by neurological improvement.5,56 Patients ,40 years of age were more progressive muscular rigidity, predominantly of the trunk with

Figure 3. Immunoreactivity of mGluR5 antibodies. (A) Sagittal section of rat brain immunostained with the CSF of a patient with mGluR5 antibodies. There is a diffuse staining of the neuropil. (B) Immunore- activity was particularly robust in the hippocampus that shows the typical staining of antibodies against neuronal cell surface antigens. From bloodjournal.hematologylibrary.org by guest on July 21, 2014. For personal use only.

3234 GRAUS et al BLOOD, 22 MAY 2014 x VOLUME 123, NUMBER 21

Table 4. Pathologically (biopsy or autopsy) confirmed cases of granulomatous angiitis of the CNS and HL since the year 2000 Reference Age (y)/gender Presentation No. WBC/mL in CSF MRI Outcome 42 27/F Headache Not done Gd-enhancing lesion Full recovery 43 52/M Seizures, confusion Not specified Diffuse leukoencephalopathy Full recovery 41 26/F Headache, seizures 55 Gd-enhancing lesions Full recovery 44 16/M Aphasia, vomiting 15 Hemorrhage Full recovery 45 37/M Gait ataxia 42 Diffuse Gd-enhancing lesions Unknown 46 58/M Left hemiparesis 15 Bilateral leukoencephalopathy Full recovery

Gd, gadolinium; WBC, white blood cells. superimposed spasms. The diagnosis is based on established clinical reported developed a severe and irreversible paraplegia, and post- and neurophysiological findings, including continuous co-contraction mortem studies of 2 cases revealed widespread spinal cord necrosis of agonist and antagonist muscles caused by involuntary firing of without prominent inflammatory infiltrates or vasculitis (necrotizing motor units at rest. Many cases of stiff-person syndrome associate myelopathy).74 This type of myelopathy has been described in a few with glutamic acid decarboxylase antibodies.67 A related syndrome, cases with HL and NHL.75,76 In the last decade, patients reported progressive encephalomyelitis with rigidity and myoclonus (PERM), with paraneoplastic myelopathies have had better outcomes, and in is characterized by subacute onset of muscular rigidity, stimulus- 1 study, 31% of cases improved with treatment.73 The MRI usually sensitive spasms, brainstem dysfunction, and pathological findings of shows a longitudinally extensive (.3 vertebral segments) T2 in- perivascular lymphocyte cuffing and neuronal loss in the brainstem creased signal abnormality that may enhance with gadolinium. and spinal cord.68 It is unclear if PERM is a completely different Onconeural antibodies (mainly amphiphysin and CV2/CRMP5 disease from stiff-person syndrome or a particularly severe form of antibodies) may be present in serum or CSF, supporting the para- the disorder. Recently, glycine receptor antibodies were described neoplastic origin of the myelitis. However, patients with HL or NHL in some patients with PERM; these antibodies have also been de- can be seronegative, and some cases were not tested for onconeural scribed in some patients with stiff-person syndrome.69 Less than antibodies.73,77 1% of cases with stiff-person syndrome are paraneoplastic, and some with breast cancer or SCLC associate with amphiphysin antibodies. This syndrome has been reported in 5 patients with HL. None of them presented known antibodies, but the neurological symptoms recovered when the HL was successfully treated, sug- Paraneoplastic neuronopathies gestingthesyndromecouldhavebeenmediatedbyantibodies 67,70-72 The term neuronopathy indicates that the primary damage occurs in against surface antigens. the cell body of neurons that form the peripheral nerves. There are PNSs that target a specific neuronal type and cause pure motor, sensory, or autonomic neuronopathies and others that damage more than cell type, leading to a mixed neuronopathy. The latter situation Paraneoplastic myelopathy is more frequent in the setting of SCLC and Hu antibodies.78 Paraneoplastic motor neuronopathies have been described in a few Paraneoplastic involvement of the spinal cord presents with subacute patients who almost always had HL. The syndrome defined as myelitis and rapidly ascending paralysis accompanied by a sensory subacute motor neuropathy has only rarely been reported since the level.73 The syndrome has been described in patients with solid initial description in 1979.79 Patients develop motor weakness tumors and lymphomas. In the latter, the possibility of a toxic or that tends to be greater in the legs and proximal muscles. Muscle infectious origin was not completely ruled out.74 The initial patients weakness is rarely severe and sometimes stabilizes or improves

Figure 4. Immunoreactivity of Tr(DNER) antibodies. (A) Section of rat cerebellum immunostained with a serum from a patient with Tr antibodies. There is robust staining of the cytoplasm and the main dendrites of the Purkinje cells and a dot-like pattern of staining of the cerebellar molecular layer that is characteristic of Tr immunoreactivity. (B-D) Cell-based assay to confirm that Tr antibodies identify the DNER antigen. HEK293 cells transfected with DNER cDNA plasmid show intense reactivity with the human serum positive for Tr antibodies (green) and that colocalizes (yellow) with the labeling of a commercial monoclonal antibody to DNER (red). From bloodjournal.hematologylibrary.org by guest on July 21, 2014. For personal use only.

BLOOD, 22 MAY 2014 x VOLUME 123, NUMBER 21 PARANEOPLASTIC NEUROLOGICAL SYNDROMES IN LYMPHOMAS 3235

Figure 5. Sural nerve biopsy of a patient with a final diagnosis of neurolymphomatosis. (A) Low power figure of the sural nerve biopsy showing infiltration by lymphomatous cells. (B) The infiltrate involves all layers of the nerve. Arrowheads indicate the perineurium.

without any specific treatment. The symptoms appear when the HL 17 patients with advanced stage HL usually during chemotherapy. is already diagnosed or in remission. Some patients developed the The cause of these episodes is unknown.90 disorder after treatment with mantle and para-aortic radiotherapy, and radiation toxicity could not be completely ruled out.79 In other cases, the patients had more severe and diffuse weakness antedating the diagnosis of HL. Although some pathological reports show loss of Paraneoplastic sensorimotor neuropathies motor neurons in the anterior horn of the spinal cord, the clinical improvement in some patients suggest the presence of mecha- Paraneoplastic sensorimotor neuropathies that precede the diagnosis nisms affecting neuronal function rather than causing irreversible of lymphomas are mainly demyelinating neuropathies that may degeneration.80 fulfill diagnostic criteria of Guillain-Barre´ syndrome or chronic Sensory neuronopathy is caused by damage of sensory neurons in inflammatory demyelinating polyneuropathy (CIDP).91 The clin- the dorsal root ganglia and is one of the most common and well- ical course is usually subacute, and onconeural antibodies are characterized PNSs, usually occurring in association with SCLC and negative. Paraneoplastic neuropathies are more common in HL and Hu antibodies.78 The syndrome typically runs a subacute clinical NHL with monoclonal bands. Although the frequency of cancer in course with pain and paresthesias in the upper or lower limbs. The patients with Guillain-Barre´ syndrome is not increased, the asso- presenting symptoms are usually asymmetric or affect only 1 ex- ciation between this neuropathy and HL is well established.92 tremity. Neurological examination reveals involvement of all modal- Patients with NHL and monoclonal gammopathy can develop ities of sensation with severe impairment of joint position and typical CIDP or predominantly sensory neuropathies that are likely vibratory senses. Deep tendon reflexes are abolished or diminished. mediated by antibody activity of the monoclonal IgM against myelin- Electromyography and nerve conduction velocities are helpful in associated glycoprotein or gangliosides.93,94 Conversely, neurop- confirming that the involvement is restricted to the sensory nerves. athies associated with large B-cell lymphomas may be caused by The prognosis is poor and patients rarely improve. direct infiltration of the peripheral nerves (neurolymphomatosis).95 Paraneoplastic sensory neuronopathy has only been reported In a recent study of 32 patients with neuropathy and NHL, 15 were in a few patients mainly with HL; onconeuronal antibodies are considered to have neurolymphomatosis, whereas only 5 were negative.81-84 However, we evaluated a patient with this neuropathy paraneoplastic. In the other 12 patients, the etiology was uncertain, and NHL who had Ma2 antibodies (F. Graus, 2013, unpublished data). and all but 2 developed a syndrome of multifocal mononeuropathy There are also a few case reports of patients with a subacute sensory suggestive of neurolymphomatosis.94 Although infiltrative neu- neuropathy that had complete recovery after treatment of the HL. ropathies usually are asymmetric or show a pattern of multifocal These cases probably represent sensory variants of inflammatory mononeuropathy, they can be indistinguishable from CIDP and demyelinating neuropathies rather than true neuronopathies.85 even respond to steroids.94 Thediagnosisisusuallyconfirmed When the neuronal bodies of autonomic ganglia are affected, by the demonstration of malignant cells in the nerve biopsy or patients develop subacute pandysautonomia with impairment of more rarely in the CSF (Figure 5). Fluorodeoxyglucose positron sympathetic (orthostatic hypotension, anhydrosis) and parasympa- emission tomography/computed tomography may help in iden- thetic function (impaired pupillary responses, dry mouth, gastroin- tifying abnormal areas in peripheral nerves or plexuses suscep- testinal dysmotility, erectile dysfunction, and fixed heart rate).86 The tible to biopsy.94 syndrome rarely has a paraneoplastic origin and is frequently associated with nicotinic acetylcholine receptor antibodies. The presence of these antibodies helps to confirm the neurological diagnosis but does not establish a paraneoplastic etiology.86 The association Vasculitic neuropathy of autoimmune autonomic ganglionopathy with lymphomas is exceptional.87,88 One of the reported cases improved after treat- Isolated vasculitis of peripheral nerves has been reported in a few ment with rituximab.88 A limited form of autonomic ganglion- patients with solid tumors and lymphomas.96 The clinical course opathy is the occurrence of an isolated tonic (Adie) pupil that has is characterized by a progressive, initially asymmetric, painful sen- been described in patients with cancer, including one with HL sorimotor neuropathy. Electromyography and nerve conduction stud- andTr(DNER)antibodies.89 ies demonstrate findings compatible with multifocal neuropathy or An intriguing symptom identified in a few patients with HL is diffuse axonal polyneuropathy with asymmetric involvement.97 hypothermia. Severe episodes of hypothermia were reported in Combined biopsy of nerve and muscle is indicated because this From bloodjournal.hematologylibrary.org by guest on July 21, 2014. For personal use only.

3236 GRAUS et al BLOOD, 22 MAY 2014 x VOLUME 123, NUMBER 21 increases the chance of identifying the vasculitis. Nerve biopsy many years, suggesting the presence of an underlying immunolog- shows intramural and perivascular inﬂammatory inﬁltrates, usually ical disturbance caused by the tumor or immunosuppression that without necrotizing vasculitis.98 predisposes to the paraneoplastic immune-mediated syndrome.

Paraneoplastic syndromes of the Acknowledgments neuromuscular junction and muscle The authors thank Dr Josep Maria Grau for providing the pathological The most frequent PNS of the muscle in patients with lymphoma specimen of Figure 5. is dermatomyositis.99 Some patients with lymphoma develop poly- This work was supported in part by grants 11/01780 (to J.D.) and myositis, but the frequency of this association is much lower than PI12/00611 (to F.G.) from the Fondo Investigaciones Sanitarias, that with dermatomyositis. Cancer-associated myositis (dermato- and Fundacio´ la Marato´ TV3 (J.D.) and National Institutes of Health, polymyositis) occurs in patients .50 years of age and is more pre- National Institute of Neurological Disorders and Stroke grant dominant in NHL.99 In ;50% of patients, the myositis is diagnosed RO1NS077851 (to J.D.). before the discovery of the lymphoma. Thus, a search for an underlying cancer is indicated in these patients, and whole body positron emission tomography/computed tomography is the preferred test.100 Immunological studies may also help in identifying patients at risk Authorship of developing cancer. The presence of anti-synthetase antibodies is a negative predictor for the presence of cancer. In contrast, detection Contribution: F.G. participated in the literature search, creating of the antibody p155, against human transcriptional intermediary figures, study design, data collection, data analysis, data interpreta- factor 1-g, shows a sensitivity of 70% and a specificity of 89% for tion, writing, and critical approval of the final manuscript; H.A. predicting an occult malignancy. The data are more robust for pa- participated in data collection, data interpretation, critical approval of tients with dermatomyositis, with only 5% of p155 antibody-negative the final manuscript, and funding; and J.D. participated in creating patients subsequently developing cancer.101 figures, study design, data collection, data analysis, data interpreta- Lymphomas are a rare cause of PNSs of the neuromuscular tion, writing, and critical approval of the final manuscript. junction. Only a few patients, usually with NHL and LEMS102 or Conflict-of-interest disclosure: J.D. receives royalties from licens- neuromyotonia, have been reported.103,104 A few cases of myasthe- ing fees from Euroimmun for a patent for the use of NMDAR as nia gravis have been described in association with HL and T-cell autoantibody test. The remaining authors declare no competing NHL with involvement of the mediastinum.105 In 50% of the cases financial interests. with lymphoma and LEMS or myasthenia, the neurological disorder Correspondence: Francesc Graus, IDIBAPS-Hospital Cl´ınic, develops around the time of the diagnosis of lymphoma. For the rest Universitat de Barcelona, Department of Neurology, Villarroel 170, of patients, the lymphoma and neurological disorder are separated by Barcelona 08036, Spain; e-mail: [email protected].

References

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