Neuropathies Associated With Malignancy

Slide 1 · Neuropathies Associated With Malignancy

Mechanisms • nerve-injury patterns • clinicopathologic localization

Peripheral nerve pathology

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Classify cancer-associated neuropathies by mechanism rather than tumor label alone.

Localize symptoms to nerve, plexus, root, or sensory neuron.

Explain immune and paraprotein-associated axonal or myelin injury.

Distinguish direct tumor effects from toxicity associated with cancer treatment.

Slide 3 · Four principal mechanisms

Cancer-associated peripheral neuropathy

Local tumor effect

Nerve or root compression and infiltration

Paraneoplastic

Immune injury remote from the tumor

Paraprotein-mediated

Tumor-derived immunoglobulins or light chains

Treatment-related

Drug-related nerve injury

Slide 4 · What part of the peripheral nerve is injured?

Axon

Disrupted axon

Primary degeneration; Lower action-potential amplitude

Myelin / Schwann cell

Myelin gaps

Segmental myelin injury; Slowed conduction

Neuron cell body

Cell body loss

Loss of neuron; Distal processes degenerate

Slide 5 · A phenotype is not a mechanism

Pattern → localization → mechanism

The same clinical pattern can arise through different pathogenic routes.

Cancer can affect axons, Schwann-cell myelin, or neuronal cell bodies.

Begin with anatomic localization, then assess plausible malignant mechanisms.

Slide 6 · From anatomy to a cancer-related hypothesis

Distribution

Injury compartment

Cancer relationship

Mechanism

A focal palsy and a generalized polyneuropathy need different localization.

The mechanism may be direct, paraneoplastic, paraprotein-mediated, or toxic.

Slide 7 · Mononeuropathy: A single-nerve deficit

ONE NERVE → RESTRICTED DEFICIT

A focal deficit follows the anatomy of the involved nerve.

Direct tumor infiltration or compression commonly causes axonal mononeuropathy.

A focal neuropathy may be the presenting symptom of a malignancy.

Slide 8 · Polyneuropathy: Multiple nerves

MULTIPLE NERVES → OFTEN SYMMETRIC

Classic length-dependent patterns begin distally and progress proximally.

Axonal sensorimotor neuropathy is a common paraneoplastic phenotype.

A treatment-related injury can also affect multiple peripheral nerves.

Slide 9 · Axonopathy versus neuronopathy

Axonal neuropathy

Primary injury occurs in the axonal process.

In many settings the longest axons are most susceptible.

Axonal dropout produces reduced response amplitudes.

Sensory neuronopathy

Primary injury occurs at neuronal cell bodies.

Affected distal and proximal processes degenerate secondarily.

A non–length-dependent pattern is possible.

Slide 10 · Axonal versus demyelinating physiology

Axonal injury

Loss of functioning axons lowers recorded signal amplitude.

Conduction velocity may be relatively preserved.

Demyelinating injury

Loss of myelin disrupts saltatory conduction.

Slowed conduction velocity is a hallmark.

Slide 11 · Direct effects: Malignant injury at the nerve

Localized pathology can produce a localized neurologic syndrome.

Tumor cells may infiltrate a nerve or adjacent tissue may compress it.

The resulting deficit often follows a single nerve or plexus distribution.

Some patients first present with a neuropathy before cancer is recognized.

Slide 12 · Conceptual anatomy of tumor-related nerve injury

Illustrative direct-effect anatomy (not a specimen)

Peripheral nerve fibers

Tumor

Infiltration or compression may disrupt axons in a restricted distribution.

Slide 13 · Lung apex: Brachial plexopathy

APICAL LUNG TUMOR ↓ BRACHIAL PLEXUS

A neoplasm at the lung apex can affect the nearby brachial plexus.

The syndrome is a plexopathy rather than a generalized polyneuropathy.

The exact clinical distribution depends on the injured plexus components.

Slide 14 · Pelvic malignancy: Obturator nerve palsy

PELVIC TUMOR ↓ OBTURATOR NERVE

Pelvic malignant neoplasms may compromise the obturator nerve.

The resulting focal palsy maps to the anatomy of this nerve.

Localization is a stronger first clue than assuming a diffuse toxic process.

Slide 15 · Cranial neuropathy and skull-base disease

INTRACRANIAL / SKULL-BASE TUMOR ↓ CRANIAL NERVE

Tumors in the cranial cavity or at the skull base may cause cranial nerve palsies.

A focal cranial neuropathy warrants assessment of anatomic tumor effects.

Cancer-associated cranial nerve findings do not automatically establish paraneoplasia.

Slide 16 · Meningeal carcinomatosis and cauda equina

Meningeal carcinomatosis

Cauda equina involvement

Multiple lower roots

Lower-extremity polyradiculopathy

Root-level involvement differs anatomically from a solitary peripheral-nerve lesion.

Slide 17 · Direct effects: Anatomic localization

Malignant setting

Affected structure

Neuropathy pattern

Apical lung neoplasm

Brachial plexus

Plexopathy

Pelvic malignancy

Obturator nerve

Focal nerve palsy

Intracranial / skull-base tumor

Cranial nerve

Cranial nerve palsy

Meningeal carcinomatosis

Cauda equina roots

Lower-extremity polyradiculopathy

Slide 18 · Neurolymphomatosis: A specific infiltrative entity

LYMPHOMA CELLS INFILTRATE PERIPHERAL NERVES

Neurolymphomatosis is tumor-cell infiltration of peripheral nerves.

It is an example of direct malignant nerve injury, not a paraneoplastic syndrome.

The disease need not present with a known systemic lymphoma.

Slide 19 · Neurolymphomatosis: Tumor association

Peripheral nerve infiltration is part of the neoplastic process.

Most cases arise in association with non-Hodgkin B-cell lymphoma.

The pathologic principle is direct nerve infiltration by neoplastic cells.

The infiltrative mechanism distinguishes it from an antibody-mediated neuropathy.

Slide 20 · Neurolymphomatosis may precede lymphoma recognition

NO KNOWN SYSTEMIC LYMPHOMA AT PRESENTATION

Approximately half have no recognized systemic lymphoma at diagnosis.

An unexplained neuropathy therefore does not exclude nerve-infiltrating lymphoma.

This frequency is specific to neurolymphomatosis in the cited textbook.

Slide 21 · Local neoplastic neuropathies: Two mechanisms

Compression

Tumor imposes pressure on neural structures.

Localization reflects the compressed nerve, plexus, or root.

Infiltration

Tumor cells enter nerve tissue itself.

Neurolymphomatosis is a specific example.

Slide 22 · What makes a neuropathy paraneoplastic?

Neoplasm

Shared antigen recognition

Immune response

Peripheral nerve injury

Neuropathy arises at a distance from direct tumor infiltration or compression.

Slide 23 · Paraneoplastic neuropathy may be an early clue

NEUROPATHY CAN PRECEDE CANCER DIAGNOSIS

A paraneoplastic neuropathy may arise at any point in the cancer course.

It often appears before the underlying tumor is diagnosed.

A negative prior cancer history therefore does not rule out a paraneoplastic process.

Slide 24 · Paraneoplastic clinical spectrum

Immune-related neuropathy

Axonal

Sensorimotor axonal neuropathy

Sensory neuronopathy

Pure sensory neuronal injury

Demyelinating

CIDP-like polyneuropathy

Other localizations

Plexopathy or autonomic neuropathy

Slide 25 · Sensorimotor axonal neuropathy

Most frequent paraneoplastic phenotype: Sensorimotor axonal.

It is the most common paraneoplastic neuropathy form.

Both sensory and motor functions may be affected.

Axonal injury is the pathologic classification; It is not proof of one tumor type.

Slide 26 · Pure sensory neuronopathy

SENSORY NEURON CELL BODY INJURY

The primary target is the sensory neuronal cell body, not merely distal myelin.

Secondary damage extends to axonal processes.

This localization can explain a multifocal, asymmetric sensory presentation.

Slide 27 · Paraneoplastic sensory neuronopathy: Cellular target

Schematic: Neuronal body injury propagates into its peripheral process

Sensory neuron (DRG)

Sensory axon

Paraneoplastic sensory neuronopathy: CD8⁺ T-cell attack directed at DRG cells.

CD8⁺ T-cell injury

Slide 28 · Anti-Hu: Tumor–neuron antigen overlap

Cancer cell expresses antigen

Neuron expresses related antigen

Anti-Hu / ANNA-1 may be detected

Sensory-neuron injury

Anti-Hu is a recognized associated autoantibody, not necessarily the direct effector of injury.

Slide 29 · Anti-Hu: Terminology and meaning

Antibody association ≠ proven antibody-mediated cytotoxicity.

Anti-Hu is also called antineuronal nuclear antibody type 1 (ANNA-1).

It recognizes antigenic proteins expressed in both tumor cells and normal neurons.

It is often found in paraneoplastic sensory neuronopathy but should not be equated with the full injury mechanism.

Slide 30 · Proposed effector: CD8⁺ cytotoxic T cells

Antigen-recognizing immune response

CD8⁺ T-cell attack

Dorsal root ganglion neurons

Sensory neuronopathy

Injury as appearing to be mediated by cytotoxic T cells.

Slide 31 · Small cell lung carcinoma association

SENSORY NEURONOPATHY ↔ SMALL CELL LUNG CANCER

Paraneoplastic sensory neuronopathy is most commonly associated with small cell lung cancer.

The association is not a claim that all sensory neuropathies indicate this cancer.

Clinical pattern and tumor search must still be interpreted together.

Slide 32 · Sensory symptom distribution

Distal onset does not guarantee symmetric dying-back axonopathy.

Sensory symptoms often begin distally.

The early pattern may be asymmetric and multifocal.

Such a pattern differs from a stereotypical symmetric length-dependent polyneuropathy.

Slide 33 · Anti-CV2 targets CRMP5

ANTI-CV2 RECOGNIZES CRMP5

CRMP5 is described as an intracellular signaling protein.

Anti-CV2 is a distinct paraneoplastic antibody association from anti-Hu.

The associated neuropathy phenotype matters when interpreting the antibody.

Slide 34 · Anti-CV2-associated neuropathy phenotype

Painful + asymmetric + sensorimotor + axonal.

The typical presentation described is painful and asymmetric.

Sensory and motor involvement coexist.

Axonal damage characterizes the peripheral-nerve injury pattern.

Slide 35 · Anti-Hu and anti-CV2: Compare the associations

Characteristic

Anti-Hu / ANNA-1

Anti-CV2 / CRMP5

Antigen association

Shared tumor / neuronal proteins

CRMP5 intracellular signaling protein

Reported phenotype

Often sensory neuronopathy

Painful asymmetric sensorimotor axonopathy

Injury explanation

CD8⁺ T-cell injury appears important

Autoantibody association described; precise mechanism not specified

Slide 36 · Paraneoplastic phenotypes beyond axonopathy

CIDP-like demyelination

Chronic inflammatory demyelinating polyneuropathy may be paraneoplastic.

Demyelination affects Schwann-cell myelin.

Plexus or autonomic injury

Plexopathy may occur without direct tumor invasion.

Autonomic neuropathy is also recognized.

Slide 37 · What a paraneoplastic antibody can—and cannot—say

Separate disease association, antigen recognition, and tissue injury.

An associated neuronal antibody can support a cancer-linked immune hypothesis.

Anti-Hu detection alone does not show antibody-driven destruction of dorsal root ganglia.

The neuropathy phenotype and temporal cancer relationship remain essential.

Slide 38 · Monoclonal gammopathy: The causal chain

Neoplastic B-cell clone

Intact IgM

Some IgM antibodies bind myelin antigens

IgG / IgA

Associated neuropathies also occur

Light chains

Amyloid formation can injure axons

Slide 39 · What is a paraprotein in this setting?

The tumor product, not necessarily the tumor mass, injures nerve.

Neoplastic B cells can secrete monoclonal immunoglobulins or immunoglobulin fragments.

These tumor-derived products are termed paraproteins.

Nerve injury may follow antigen binding, deposition, amyloid effects, or multiple pathways.

Slide 40 · IgM paraprotein: Myelin-directed injury

B-cell neoplasm

IgM monoclonal protein

Binding to myelin antigen

Demyelinating neuropathy

Robbins gives myelin-associated glycoprotein as a myelin antigen.

Slide 41 · Myelin-associated glycoprotein as a target

IgM–myelin recognition links clone biology to myelin pathology.

Some pathogenic IgM paraproteins are thought to bind myelin-associated antigens.

Myelin-associated glycoprotein (MAG) is a specified example.

Binding to a myelin antigen provides a mechanistic explanation for demyelinating disease.

Slide 42 · IgM deposition: Myelin lamellae schematic

Schematic illustration — layer relationships only; Not electron microscopy

Myelin membranes / lamellae

Paraprotein deposition between layers

Slide 43 · Interpreting a demyelinating IgM neuropathy

Electron-microscopic location: Between myelin membrane layers.

The dominant lesion is associated with myelin rather than primary axonal dropout.

IgM deposition can be seen between layers of the myelin sheath ultrastructurally.

The textbook’s observation is a morphologic association, not an image provided in this deck.

Slide 44 · Other immunoglobulin classes

IgG OR IgA PARAPROTEINS

IgG and IgA monoclonal proteins may also be associated with peripheral neuropathy.

The textbook does not assign every such case one uniform mechanism.

Do not assume the IgM–MAG model automatically applies to all classes.

Slide 45 · POEMS: The named multisystem syndrome

POEMS syndrome

P

Polyneuropathy

O

Organomegaly

E

Endocrinopathy

M

Monoclonal gammopathy

S

Skin changes

Slide 46 · POEMS neuropathy

Distinctive pairing: Systemic features + demyelinating neuropathy.

POEMS includes a demyelinating peripheral neuropathy.

Paraprotein deposition occurs between noncompacted myelin lamellae.

The neuropathy is part of a multisystem syndrome, not an isolated electrophysiologic label.

Slide 47 · Two paraprotein–myelin associations

Feature

IgM / MAG model

POEMS description

Associated product

IgM paraprotein

Paraprotein in monoclonal gammopathy

Reported morphology

IgM between myelin membrane layers

Deposition between noncompacted lamellae

Clinical framing

Demyelinating peripheral neuropathy

Demyelinating neuropathy + multisystem features

Slide 48 · Free light chains can create amyloid

Excess light chains

Amyloid deposition

Vascular or direct toxic effect

Axonal peripheral neuropathy

This is a different downstream lesion from paraprotein-associated demyelination.

Slide 49 · Light-chain amyloid: Two routes to nerve injury

Light-chain excess

Amyloid deposition within nerve

Vascular insufficiency

Reduced support to nerve fibers

Direct toxic effect

Deposited material injures nerve

Slide 50 · Amyloid mechanism: Vascular insufficiency

AMYLOID → VASCULAR INSUFFICIENCY

Deposited light-chain amyloid may impair the vascular support of peripheral nerve.

Reduced vascular supply is one route to axonal injury.

This does not establish that every amyloid neuropathy is exclusively ischemic.

Slide 51 · Amyloid mechanism: Direct neurotoxicity

AMYLOID → DIRECT TOXIC EFFECT

The textbook gives direct toxicity as another pathway to neuropathy.

The ultimate peripheral-nerve injury is described as axonal.

The vascular and toxic explanations are alternatives that may coexist.

Slide 52 · Paraprotein neuropathies: Mechanism comparison

Product / syndrome

Proposed lesion

Typical pathology pattern

IgM paraprotein

Myelin antigen binding / deposition

Demyelinating neuropathy

POEMS

Deposition in noncompacted myelin

Demyelinating neuropathy

Light-chain amyloid

Vascular insufficiency or toxic injury

Axonal neuropathy

Slide 53 · Treatment-related neuropathy is a separate category

Cancer association alone does not identify causation.

Peripheral neuropathy can be a complication of anticancer treatment.

Drug injury should be distinguished from tumor compression and paraneoplastic immune disease.

Robbins specifically discusses cytotoxic chemotherapy and immune checkpoint inhibitors.

Slide 54 · Vinca alkaloids and taxanes: Axonal transport

Microtubule-inhibiting drug

Impaired axonal transport

Distal axonal dysfunction

Toxic neuropathy

Interference with axonal transport is the mechanism emphasized by Robbins.

Slide 55 · Platinum-related neuropathy

Cisplatin is identified among chemotherapeutic causes of peripheral neuropathy.

The parent section recognizes platinum compounds among potential sensory neuron–injuring toxins.

Do not automatically attribute a neuropathy in a cancer patient to paraneoplastic immunity.

Slide 56 · Immune checkpoint inhibitor–related injury

Checkpoint inhibitor therapy

Immune dysregulation

Peripheral nerve injury

Diverse phenotypes

The clinical pattern is not restricted to a distal symmetric axonal neuropathy.

Slide 57 · Checkpoint inhibitor neuropathy: Phenotypic range

Recognized pattern

Anatomic emphasis

Non–length-dependent polyradiculopathy

Root / nerve involvement, potentially proximal and distal

Axonal or demyelinating features

Different injury compartments can be affected

Cranial neuropathy

Cranial nerve localization

Sensory neuronopathy

Sensory neuronal cell-body pattern

Slide 58 · Cancer-associated neuropathy: Integrating the mechanisms

Etiologic group

Distinctive clue

Typical injury logic

Direct local effect

Restricted nerve / plexus / root distribution

Compression or infiltration

Paraneoplastic

May precede tumor diagnosis; diverse immune phenotypes

Immune-related axonal / neuronal / myelin injury

Paraprotein-mediated

Monoclonal immunoglobulin or light chains

Myelin binding / deposition / amyloid

Treatment-related

Neuropathy arising in therapy context

Axonal transport toxicity or immune toxicity

Slide 59 · Practical clinicopathologic reasoning

Describe deficit pattern

Localize affected structure

Identify exposure / protein / tumor

Select likely mechanism

A definitive attribution requires more than finding a malignancy alongside neuropathy.

Slide 60 · Application I: Focal deficit and lung apex

HYPOTHETICAL TEACHING VIGNETTE

A patient is found to have an apical pulmonary neoplasm and a new focal upper-limb neurologic deficit. The deficit follows a plexus distribution.

Which malignancy-associated mechanism is most directly suggested?

Slide 61 · Application I: Interpretation

Finding

Focal upper-limb findings localize to the brachial plexus.

Interpretation

Direct tumor-related brachial plexopathy is the leading mechanistic category.

Mechanistic rationale

Robbins explicitly associates tumors of the lung apex with brachial plexopathy.

Slide 62 · Application II: Sensory syndrome before tumor recognition

HYPOTHETICAL TEACHING VIGNETTE

A patient develops distal sensory symptoms in an asymmetric, multifocal pattern. A cancer diagnosis has not yet been established.

Which paraneoplastic syndrome and cancer association should be considered?

Slide 63 · Application II: Interpretation

Finding

Asymmetric, multifocal sensory onset suggests a sensory neuronopathy pattern.

Interpretation

A paraneoplastic sensory neuronopathy is a possible explanation; Small cell lung cancer is a major association.

Mechanistic rationale

Anti-Hu / ANNA-1 may be present; DRG damage appears to involve CD8⁺ cytotoxic T cells.

Slide 64 · Application III: Monoclonal IgM and slow conduction

HYPOTHETICAL TEACHING VIGNETTE

A B-cell neoplasm produces a monoclonal IgM protein. Peripheral nerve conduction studies indicate a demyelinating process.

What antibody–target relationship fits the source description?

Slide 65 · Application III: Interpretation

Finding

Demyelination identifies the myelin compartment as a major injury site.

Interpretation

The IgM paraprotein may bind myelin-associated glycoprotein or another myelin antigen.

Mechanistic rationale

IgM may accumulate between myelin membrane layers, as described ultrastructurally.

Slide 66 · Application IV: Lymphoma without a prior systemic diagnosis

HYPOTHETICAL TEACHING VIGNETTE

A patient presents with peripheral nerve dysfunction. Tissue evaluation establishes infiltrating lymphoma cells within the involved nerve, although no systemic lymphoma was previously recognized.

What is the diagnosis and why is the timing plausible?

Slide 67 · Application IV: Interpretation

Finding

Neoplastic cells infiltrate peripheral nerve tissue.

Interpretation

This defines neurolymphomatosis, most often associated with non-Hodgkin B-cell lymphoma.

Mechanistic rationale

Roughly half lack a known systemic lymphoma at diagnosis.

Slide 68 · High-yield synthesis: Mechanism drives explanation

Cancer and peripheral-nerve injury

Direct

Nerve, plexus or root infiltration / compression

Immune

Paraneoplastic antibodies, T cells and diverse phenotypes

Protein

IgM, POEMS and light-chain amyloid

Iatrogenic

Cytotoxic drugs and checkpoint inhibitors

Slide 69 · Primary source and scope

Robbins, Cotran & Kumar: Pathologic Basis of Disease

11th edition (2026) · Chapter 27 · Peripheral Nerves and Skeletal Muscles

Primary topic: Neuropathies Associated With Malignancy (printed p. 1113)

Additional parent context: general nerve injury, anatomic patterns and toxic neuropathies (pp. 1106–1113)

Original diagrams and teaching vignettes; no textbook figures or patient specimens reproduced.