Can melanoma cause paraneoplastic syndrome?

Can Melanoma Cause Paraneoplastic Syndrome?

Yes, melanoma definitively causes paraneoplastic syndromes, though they are rare complications occurring in less than 1% of melanoma patients. 1, 2

Types of Paraneoplastic Syndromes Associated with Melanoma

Melanoma triggers multiple distinct paraneoplastic syndromes through autoimmune mechanisms, where the immune response against tumor antigens cross-reacts with normal tissue:

Ocular Manifestations

• Melanoma-associated retinopathy (MAR) is the most frequently reported paraneoplastic syndrome in melanoma patients 1, 2
• Bilateral diffuse uveal melanocytic proliferation (BDUMP) presents with multiple elevated pigmented bilateral uveal lesions, progressive cataracts, and RPE changes, typically associated with non-ocular tumors but can occur with melanoma 3
• Paraneoplastic vitelliform maculopathy has a direct relationship with both cutaneous and uveal melanoma, characterized by vitelliform lesions and anti-RPE/anti-retinal autoantibodies in serum 3

Neurological Manifestations

• Paraneoplastic encephalitis and cerebellar degeneration are among the most frequently reported neurological syndromes 1, 2
• Acute paraneoplastic neurological syndrome can present with progressive ataxia and dysdiadochokinesia, even with negative paraneoplastic antibodies on initial testing 4
• These syndromes result from autoantibodies against neuronal or tumor antigens causing immune-mediated damage 1

Dermatological Manifestations

• Paraneoplastic psoriasiform dermatosis can occur, requiring differentiation from checkpoint inhibitor-related immune adverse events in patients receiving immunotherapy 5
• Skin biopsy is necessary to establish histopathologic diagnosis and rule out cutaneous metastases 5

Hematological Manifestations

• Paraneoplastic granulocytosis from ectopic G-CSF production by melanoma tumors is rare but well-documented 6
• Serum G-CSF levels directly correlate with absolute neutrophil count, and this diagnosis should be considered after ruling out infection 6

Diagnostic Approach

When evaluating suspected paraneoplastic syndrome in melanoma patients:

• Document target organ inflammation through biopsy when diagnosis is unclear 5
• Obtain serum paraneoplastic antibodies, though approximately one-third of patients will have negative antibodies despite true paraneoplastic syndrome 2
• Use advanced imaging (CT, MRI, or PET-CT) to distinguish between metastases and paraneoplastic manifestations 5
• Rule out checkpoint inhibitor-related immune adverse events if patient is receiving immunotherapy 5
• Consider lumbar puncture for neurological presentations, which may show elevated protein with normal cell count 4

Management Strategy

The primary treatment for melanoma-associated paraneoplastic syndromes is aggressive treatment of the underlying malignancy, which may lead to resolution or improvement of paraneoplastic manifestations. 1

Specific Treatment Approaches:

• Immune-modulating therapies including corticosteroids, intravenous immunoglobulins, and plasmapheresis may ameliorate symptoms and suppress autoimmune response in selected cases 1, 4
• BRAF-targeted therapy (dabrafenib and trametinib) has shown efficacy in BRAF-mutant melanoma with paraneoplastic neurological syndrome 4
• Plasmapheresis and plasma exchange are recommended for BDUMP 3
• High-dose corticosteroids combined with IVIG can stabilize progressive neurological symptoms 4

Critical Clinical Pitfalls

• Paraneoplastic syndromes often develop before the cancer becomes clinically overt, so neurological or systemic symptoms may precede melanoma diagnosis 2
• Negative paraneoplastic antibodies do not exclude the diagnosis—approximately one-third of patients lack detectable antibodies 2
• Do not delay cancer treatment while pursuing paraneoplastic workup, as treating the underlying malignancy is the most effective intervention 1
• In patients on immunotherapy, distinguish between paraneoplastic syndrome and immune-related adverse events, as management differs 5