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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 After consultation with the patient and family, active treatment was withdrawn because of poor performance status and toxicity.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

NHL and HL inferequenty cause periferal and central nervous system complicationDespite them having biological effect 8Lymphoma variants:Neurolymphomatosis (NL)Intravascular lymphoma (IVL)

Lymph proliferative disorders Castelman syndrome Lymphoid granulomatosis

Classification of lymphoma

Case 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 First, in central nervous system disease, lymphoma cells can gain direct access to nerves by infiltration of cranial nerves or nerve roots. In peripheral nerve disease, lymphocytes can infiltrate adjacent nerves from lymph nodes.61,100This may be facilitated at the spinal or dorsal root ganglion level where the bloodbrain barrier is deficient.90Malignant lymphocytes may adhere to neural cell adhesion molecules.4These molecules, found on neurons and meninges, allow passage of certain classes of lymphocytes across the bloodbrain or bloodnerve barrier.69,70Pathological samples typically show lymphoma cells surrounding vessels in the eipineurium,138suggesting hematogenous spread.24These infiltrates should not be mistaken for vasculitis since they do not infiltrate the vessel wall in most cases or cause fibrinoid necrosis.138Lymphoma also frequently invades the endoneurium, which is uncommon in carcinoma.106,138Endoneurial infiltrates are associated with a mix of segmental demyelination and axonal degeneration by mechanisms that are unclear.89,106,138The pathology may, in some cases, resemble Marek's disease in chickens, which is a well studied T-cell lymphoma affecting only peripheral nerves, caused by avian cytomegalovirus infection.80,87However, most infiltrative neuropathies in humans are due to B-cell lymphoma.5,2412Looks like GBS, CIDP, multifocal neuropathy, anti-hu neuropathy, neuromyotonia.

Relies on molecular mimickery

Inflammatory, dysimmune neuropathiesSecond, inflammatory, dysimmune neuropathies such as GBS83,136,155or CIDP132,141can occur in lymphoma due to the accompanying or preexisting immune perturbation. These disorders are more commonly reported with HL than NHL.82,140Since infiltrative lymphoma can mimic dysimmune neuropathies,1,32however, nerve biopsy with immunotyping is essential to diagnosis in most cases.74,140In some cases, antibodies likely derived from molecular mimicry of antigens in lymphoma cells or accompanying viral infections may attack similar antigens in nerve cells.2Examples include anti-Hu neuropathy,20,21,85multifocal motor neuropathy,96neuromyotonia,78and perhaps GBS and CIDP.13Local intravascular proliferation or direct pressure, hence nerve infarct.

Patient present with vasculitic like mononeuropathy multiplex syndromeHematogenous metastases Third, hematogenous metastases can occlude vessels by local intravascular proliferation or direct pressure, resulting in nerve infarcts.140In addition, tumor emboli can infarct nerves (and brain) especially in the setting of IVL, also known as malignant angioendothelioma or angiotrophic lymphoma.41,137,147These patients present with a vasculitic-like mononeuropathy multiplex syndrome often associated with stroke.137,14014Patients 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

OthersFourth, patients with HIV and lymphoma may develop neuropathy associated with tumor infiltration of the nerves.42,140HIV infections can be associated with an increased incidence of lymphoma and increased virulence.40

Rarer causes of mononeuropathy and asymmetric neuropathy syndrome in lymphoma are vasculitis16,98and cryoglobulinemia,37the latter often associated with monoclonal antibodies (types III cryoglobulinemia).37Also, in the setting of a monoclonal paraprotein, amyloidosis may cause neuropathy15Generalized neuropathy:NHLchronic lymphocytic leukemia Waldenstrm's macroglobulinemiaosteosclerotic myeloma

Others

Lymphoma cells can affect peripheral nerves remotely, causing generalized neuropathies.57,58,96,132Examples include NHL, chronic lymphocytic leukemia, Waldenstrm's macroglobulinemia, and osteosclerotic myeloma.67These may be due to circulating anti-nerve monoclonal antibodies secreted by the tumor cells or other factors as yet unknown, as in the case of osteosclerotic myeloma. In some cases, the monoclonal anti-nerve antibodies, usually immunoglobulin-M paraproteins, are directed at specific antigens such as myelin-associated glycoprotein and the ganglioside GM1.57,58,66,76,9616Nonmalignant 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).

OthersNonmalignant lymphopoliferative disorders, such as Castleman's disease (angiofollicular lymph node hyperplasia), may cause neuropathy,26,140sometimes associated with CrowFukase syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes; POEMS syndrome).66,91Although not a focus of this review, they often feature in the differential diagnosis of lymphomatous neuropathies. These disorders may be associated with a monoclonal gammopathy, which is likely not the cause of nerve damage but can be a diagnostic clue.Frequently, neuropathies occur in lymphoma without clear explanation, as in all malignancies. They are usually mild, mostly sensory and axonal in type. The cause is not known but metabolic and toxic mechanisms are generally suspected, some undoubtedly related to treatment.140Known viral infections such as herpes zoster virus (VZV) can directly affect nerves and nerve roots.2,55In addition, it is possible that EBV or other viruses may lead to a lymphoproliferative state similar to Marek's disease80,87or focal inflammatory disorders such as lymphomatoid granulomatosis.81

17Case 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.In 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 presentation1- Pain radiate to the lower ectremitites than assending sensory motor polyradiculopathy result in symetric paresis quadri or para Needs month but can be acute mimicking GBS2- in 20 % of pt 3- sensory loss precedes weakness, 4- motor more imp than pain syndrom31Needs 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 MRI pictureEnlarge and enhance with gadolinium Chonic or acute inflamatory radiculopathy Peripheral neruve sheath tumor33PET pictureInsert table Treatment 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 When NL is not diagnosed in pt with csf disseminated NHL only intrathecal chemo and radiation is provided, progression outside dura happen MRI CT ABD CHEST BX slit lamp

36Systemic 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

Reference