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Lymphoma and peripheral neuropathy a literature review Jack El SawdaUniversity of Illinois at Peoria/OSFNeurology rotation Case report Introduction to Lymphoma Pathogenesis of lymphomatous neuropathyNeurological syndromes in individual lymphomas Clinical presentation Neurolymphomatosis Diagnosis Management Treatment Outcome

Outlines A 56-year-old woman was diagnosed with Stage IV diffuse large B-cell lymphoma (DLBCL) after presenting to the hospital. She was treated with 8 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) and achieved a complete remission. Three months later, she presented with a right wrist drop and a right Bell's palsy.

Case Report Coronal T1 MRI images of right brachial plexus showing no mass lesion (A) and normal enhancement pattern (B).

Hui K. Gan et al. Neuro Oncol 2010;12:212-215 The Author(s) 2009. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.Coronal T1 MRI images of right brachial plexus showing no mass lesion (A) and normal enhancement pattern (B). Intense abnormal FDG uptake in the right proximal arm (black arrow) on coronal PET scan (C).She was commenced on high-dose methotrexate Her disease continued to progress despite treatment, with persistence of her initial neurological problems and development of new left cranial nerve IX/X palsies. After consultation with the patient and family, active treatment was withdrawn because of poor performance status and toxicity. The patient was palliated until her death 4 months after the diagnosis of NL.

Case report Case report Introduction to Lymphoma Pathogenesis of lymphomatous neuropathyNeurological syndromes in individual lymphomas Clinical presentation Neurolymphomatosis Diagnosis Management Treatment Outcome

Outlines Lymphomas are hematopoietic neoplasms originating from immunocompetent cellsThe lymphocytes, spread to other lymphoid and nonlymphoid tissues either by direct infiltration or hematogenous dissemination. Lymphoma Classification of lymphomaNHLHLFurther divided into B and TAssd with EBV HTLV-1 immunosupression HIVMore common to cause disease outside lymphoreticular system.Has reed sternberg Young pt, immunocompetent2 age peaksBetter prognosis

8Lymphoma variants:Neurolymphomatosis (NL)Intravascular lymphoma (IVL)

Lymph proliferative disorders Castelman syndrome Lymphoid granulomatosis

Classification of lymphomaCase report Introduction to Lymphoma Pathogenesis of lymphomatous neuropathyNeurological syndromes in individual lymphomas Clinical presentation Neurolymphomatosis Diagnosis Management Treatment Outcome

Outlines Pathogenesis of lymphomatous neuropathy CNS directly access cranial nerves or nerve rootPNS lymphocytes need to cross the BBB usually at spinal or dorsal root ganglion (epi and endoneurium!)Most are B cells

Direct access 12Looks like GBS, CIDP, multifocal neuropathy, anti-hu neuropathy, neuromyotonia.

Relies on molecular mimickery

Inflammatory, dysimmune neuropathies13Local intravascular proliferation or direct pressure, hence nerve infarct.

Patient present with vasculitic like mononeuropathy multiplex syndromeHematogenous metastases 14Patients with HIV and lymphoma may develop neuropathy associated with tumor infiltration of the nerves

Rarer causes of mononeuropathy and asymmetric neuropathy syndrome in lymphoma are vasculitis, amyloidosis cryoglobulinemia

Others15Generalized neuropathy:NHLchronic lymphocytic leukemia Waldenstrm's macroglobulinemiaosteosclerotic myeloma

Others

16Nonmalignant lymphopoliferative disorders, such as Castleman's disease (angiofollicular lymph node hyperplasia), may cause neuropathy

Sometimes associated with CrowFukase syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes; POEMS syndrome).

Others17Case report Introduction to Lymphoma Pathogenesis of lymphomatous neuropathyNeurological syndromes in individual lymphomas Clinical presentation Neurolymphomatosis Diagnosis Management Treatment Outcome

Outlines Can infiltrate CN roots plexus peripheral nerves by local invasion or hematogenous spread.

Can cause mononeuropathy, polyneuropathy when extensive, GBS like

in late stages can cause distal neuropathyNHLNHL and, rarely, HL can also present as neurolymphomatosis (NL). This disorder is generally defined as clinical neuropathy with associated malignant, lymphomatous infiltration of peripheral nerves proven by biopsy or autopsyCan cause mononeuropathy, asymmetric regional polyneuropathy, polyraducolopathy, cauda equina syndrome

Neurolymphomatosis

Mainly autoimmune rarely infiltrativeHLIntravascular large B-cell lymphoma,also known as angiotrophic lymphoma or malignant angioendotheliomatosis, patients can present with a cauda equina syndrome or a mononeuropathy. Diagnosis is made by biopsy or, more commonly, by autopsy.Miscelaneous Lymphomatoid granulomatosisChronic lymphocytic leukemiaandWaldenstrm's macroglobulinemiamay cause polyneuropathy by nerve infiltration or autoimmunity. Waldenstrm's macroglobulinemia can cause amyloid neuropathy and neuropathy with antibodies directed at myelin-associated glycoproteins.MiscelaneousIn addition to these disorders, osteosclerotic myeloma and Castleman's disease (angiofollicular lymph node hyperplasia), a nonmalignant lymphoproliferative syndrome, can also cause neuropathies. They are often accompanied by monoclonal gammopathies that can aid recognition but likely do not cause the disorder.Castleman's disease and osteosclerotic myeloma may have multiorgan involvement characteristic of CrowFukase or POEMS syndrome.

MiscelaneousCranial Nerve diseaseSpinal Nerve root diseasePlexopathyMononeuropathiesPolyneuropathyMotor neuron disease and motor neuropathy

Clinical presentationRarestAssd with NHL rather than NL or IVLMechanism: NL, Herpes infection, Cryglobulenimia, Infarct with IVL, vasculitis.Often confused with plexopathyEMG: Mixed axonal and demyelinating process

MononeuropathiesCase report Introduction to Lymphoma Pathogenesis of lymphomatous neuropathyNeurological syndromes in individual lymphomas Clinical presentation Neurolymphomatosis Diagnosis Management Treatment Outcome

Outlines

Rarely is the primary manifestation of NHL.Disseminate to PNS from peripheral sites or CNS.Needs to R/O: Toxic compressive inflammatory paraneoplastic neuropathyNLMainly B cells

Similar to primary CNS lymphoma Assd with autoimmune disease

Follows similar rule of lymphocytic spread

Pathogenesis

Painful polyneuropathy or polyradiculopathy (Lumbosacral roots >thoracic roots)

Cranial neuropathy

Painless polyneuropathy

Peripheral mononeuropathy (sciatic Nerve)Clinical presentation32Needs integration of multiple dataUncommonly response to empiric Tx MRI: most sensitive and specific non invasive toolFluorodeoxyglucose PET: for possible Bx sitesBX is gold standardCSF analysis Diagnosis

2012 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc.2

Diagnosis and Management of Neurolymphomatosis.Baehring, Joachim; MD, DSc; Batchelor, Tracy

Cancer Journal. 18(5):463-468, September/October 2012.DOI: 10.1097/PPO.0b013e31826c5ad5FIGURE 1 . A 46-year-old woman with widespread diffuse large B-cell NHL was found to have leptomeningeal dissemination at the time of her first prophylactic intrathecal chemotherapy administration. Complete cytopathologic remission was achieved in CSF. However, 2 months later, she developed Bell palsy and pain in her left arm and leg. An MRI scan of the brachial plexus after gadolinium administration (upper image) revealed thickening and enhancement of the left C6 nerve root (arrowheads). An MRI scan of the pelvis after gadolinium administration (lower image) demonstrated enhancement and thickening of the left femoral nerve (arrowhead). Salvage chemotherapy with high-dose methotrexate and cytarabine resulted in partial remission.

2012 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc.5

Diagnosis and Management of Neurolymphomatosis.Baehring, Joachim; MD, DSc; Batchelor, Tracy

Cancer Journal. 18(5):463-468, September/October 2012.DOI: 10.1097/PPO.0b013e31826c5ad5FIGURE 3 . 18Fluorodeoxyglucose positron emission tomography demonstrates uptake of metabolic tracer in a thickened left T1 nerve root of a patient with NL in the setting of systemic NHL.

Treatment principle similar to primary CNS lymphoma hence systemic chemo +/- intrathecal chemo, or external beam radiation.Needs ACCURATE STAGINGBiggest challenge is to distinguish between NL and meningeal lymphomatosis, or coexistance.Primary NL complete staging should be followedTreatment 37Systemic chemo: 82% response rate, but its not durableIntraathecal MTX when CNS involvedClinical and radiologic improvement after 6 cyclesPolychemo for patients with concomitant lymphoma

Myoablative chemotherapy with autologous stem cell transplant for NL pt with complete remission with conventional chemotherapy should be considered.Treatment Ritiuximab: significant improve in survival

Radiation therapy: curative or palliationChemosensitive tumor: unclear benefitLocalized Bulky disease in systemic NHL: ReportsSalvage therapy of drug refractory localized lymphomatous aggregates: Indicated

TreatementHOWEVERPatient relapse rate is highIn one case series: patient with conventional therapy died in 4 month after NL diagnoses.Another showed patient remained relapse free for 1 y after salvage ESHAP therapy followed by BEAM therapy and stem cell transplant.Median survival of NL is 10 month of diagnoses.Primary NL have better outcome

Prognosis NL is an aggressive tumor with poor prognosis Mainly NHL, B cell typeHave diverse presentationsMutiple modalities for diagnosisTx involes Chemo, radio, rituximab, steroidsHigh relapse rate despite tx

Conclusion Neurolymphomatosis: diagnosis, management, and outcomes in patients treated with rituximab Diagnoses and management of neurolymphomatosis Lymphoma and peripheral neuropathy a clinical review Lymphoma presenting as a mononeuritis mutiplex Mononeuropathy multiplex due to infiltration of lymphoma in hematologic remissionNeurolymphomatosis an international primary CNS lymphoma collaborative group report Neurolymphomatosis the challenge of diagnoses and treatment Neurolymphomatosis mimicking guillaume barre Neurolymphomatosis an atypical presentation

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