Lymphoma and peripheral

neuropathy
a literature review
Jack El Sawda
University of Illinois at Peoria/OSF
Neurology rotation

Outlines

Case report
Introduction to Lymphoma
Pathogenesis of lymphomatous neuropathy
Neurological syndromes in individual
lymphomas
Clinical presentation
Neurolymphomatosis

Diagnosis
Management
Treatment
Outcome

Case Report

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.

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 NeuroOncology. All rights reserved. For permissions, please e-mail:
journals.permissions@oxfordjournals.org.

Case report
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active treatment was withdrawn because of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.

Outlines

Case report
Introduction to Lymphoma
Pathogenesis of lymphomatous neuropathy
Neurological syndromes in individual
lymphomas
Clinical presentation
Neurolymphomatosis

Diagnosis
Management
Treatment
Outcome

Lymphoma
Lymphomas are hematopoietic neoplasms
originating from immunocompetent cells
The lymphocytes, spread to other lymphoid
and nonlymphoid tissues either by direct
infiltration or hematogenous dissemination.

Classification of lymphoma

Further divided into B

and T
Assd with EBV HTLV-1
immunosupression
HIV
More common to
cause disease outside
lymphoreticular
system.

NHL

Has reed sternberg

Young pt,
immunocompetent
2 age peaks
Better prognosis

HL

Classification of lymphoma

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

Lymph proliferative disorders

Castelman syndrome
Lymphoid granulomatosis

Outlines

Case report
Introduction to Lymphoma
Pathogenesis of lymphomatous neuropathy
Neurological syndromes in individual
lymphomas
Clinical presentation
Neurolymphomatosis

Diagnosis
Management
Treatment
Outcome

Pathogenesis of lymphomatous
neuropathy
Direct
compression

infiltration

Remote
effect

Direct access
CNS directly access cranial nerves or nerve
root
PNS lymphocytes need to cross the BBB
usually at spinal or dorsal root ganglion (epi
and endoneurium!)
Most are B cells

Inflammatory, dysimmune
neuropathies

Looks like GBS, CIDP, multifocal neuropathy,

anti-hu neuropathy, neuromyotonia.

Relies on molecular mimickery

Hematogenous metastases

Local intravascular proliferation or direct

pressure, hence nerve infarct.

Patient present with vasculitic like

mononeuropathy multiplex syndrome

Others

Patients 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

Others

Generalized neuropathy:

NHL
chronic lymphocytic leukemia
Waldenstrm's macroglobulinemia
osteosclerotic myeloma

Others

Nonmalignant 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).

Outlines

Case report
Introduction to Lymphoma
Pathogenesis of lymphomatous neuropathy
Neurological syndromes in individual
lymphomas
Clinical presentation
Neurolymphomatosis

Diagnosis
Management
Treatment
Outcome

NHL

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 neuropathy

Neurolymphomatosis
NHL 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 autopsy
Can cause mononeuropathy, asymmetric
regional polyneuropathy,
polyraducolopathy, cauda equina syndrome

HL
Mainly autoimmune rarely infiltrative

Miscelaneous

Intravascular 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 granulomatosis
Chronic 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.

Clinical presentation
Cranial Nerve disease
Spinal Nerve root disease
Plexopathy
Mononeuropathies
Polyneuropathy
Motor neuron disease and motor
neuropathy

Mononeuropathies
Rarest
Assd with NHL rather than NL or IVL
Mechanism: NL, Herpes infection,
Cryglobulenimia, Infarct with IVL, vasculitis.
Often confused with plexopathy
EMG: Mixed axonal and demyelinating
process

Outlines

Case report
Introduction to Lymphoma
Pathogenesis of lymphomatous neuropathy
Neurological syndromes in individual
lymphomas
Clinical presentation
Neurolymphomatosis

Diagnosis
Management
Treatment
Outcome

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

Pathogenesis

Mainly B cells

Similar to primary CNS lymphoma Assd

with autoimmune disease

Follows similar rule of lymphocytic spread

Clinical presentation

Painful polyneuropathy or polyradiculopathy

(Lumbosacral roots >thoracic roots)

Cranial neuropathy

Painless polyneuropathy

Peripheral mononeuropathy (sciatic Nerve)

Diagnosis
Needs integration of multiple data
Uncommonly response to empiric Tx
MRI: most sensitive and specific non
invasive tool
Fluorodeoxyglucose PET: for possible Bx
sites
BX is gold standard
CSF analysis

MRI picture

PET picture

Treatment

Insert table

Treatment
Treatment principle similar to primary CNS
lymphoma hence systemic chemo +/intrathecal chemo, or external beam
radiation.
Needs ACCURATE STAGING
Biggest challenge is to distinguish between
NL and meningeal lymphomatosis, or
coexistance.
Primary NL complete staging should be
followed

Treatment

Systemic chemo: 82% response rate, but its

not durable
Intraathecal MTX when CNS involved
Clinical and radiologic improvement after 6 cycles
Polychemo for patients with concomitant
lymphoma

Myoablative chemotherapy with autologous

stem cell transplant for NL pt with complete
remission with conventional chemotherapy
should be considered.

Treatement

Ritiuximab: significant improve in survival

Radiation therapy: curative or palliation

Chemosensitive tumor: unclear benefit
Localized Bulky disease in systemic NHL: Reports
Salvage therapy of drug refractory localized
lymphomatous aggregates: Indicated

HOWEVER
Patient relapse rate is high

Prognosis
In 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

Conclusion
NL is an aggressive tumor with poor
prognosis
Mainly NHL, B cell type
Have diverse presentations
Mutiple modalities for diagnosis
Tx involes Chemo, radio, rituximab, steroids
High relapse rate despite tx

Reference
1.

Neurolymphomatosis: diagnosis, management, and outcomes

in patients treated with rituximab

2.

Diagnoses and management of neurolymphomatosis

3.

Lymphoma and peripheral neuropathy a clinical review

4.

Lymphoma presenting as a mononeuritis mutiplex

5.

Mononeuropathy multiplex due to infiltration of lymphoma in

hematologic remission

6.

Neurolymphomatosis an international primary CNS lymphoma

collaborative group report

7.

Neurolymphomatosis the challenge of diagnoses and treatment

8.

Neurolymphomatosis mimicking guillaume barre

9.

Neurolymphomatosis an atypical presentation