In a patient with biopsy‑proven membranous nephropathy positive for both phospholipase A2 receptor (PLA2R) and thrombospondin type‑1 domain‑containing 7A (THSD7A), what is the risk of associated malignancy and what cancer screening approach should be undertaken?

Risk of Malignancy in PLA2R and THSD7A Positive Membranous Nephropathy

A patient with membranous nephropathy positive for both PLA2R and THSD7A on biopsy should undergo age-appropriate cancer screening, as dual positivity is extremely rare and THSD7A positivity carries higher malignancy risk than PLA2R alone, though the presence of PLA2R antibodies does not exclude cancer-associated disease. 1, 2

Understanding the Unusual Dual Positivity

• Dual positivity for both PLA2R and THSD7A is exceptionally rare, occurring in less than 1% of membranous nephropathy cases 3
• This unusual finding warrants heightened clinical suspicion, as it may represent:
  • Coincidental primary MN with unrelated malignancy 4
  • Malignancy-induced autoantibody formation 4
  • Evolution of disease etiology during the clinical course 2

Malignancy Risk Stratification

THSD7A-Associated Risk

• THSD7A-positive MN has a higher prevalence of comorbid malignancy compared to PLA2R-positive MN 1, 2
• Case reports document THSD7A-positive bladder cancer, colon cancer, and other solid tumors 2, 5
• The presence of THSD7A should trigger more intensive cancer screening regardless of PLA2R status 1

PLA2R Does Not Exclude Malignancy

• Anti-PLA2R antibodies can coexist with active malignancy, including esophageal adenocarcinoma and renal cell carcinoma 4
• The traditional classification that PLA2R-positive disease is "primary" and malignancy-associated disease is "secondary" oversimplifies the relationship 4
• Age-appropriate cancer screening remains mandatory even with positive anti-PLA2R antibodies 4

Recommended Cancer Screening Approach

Immediate Evaluation

• Perform age-appropriate cancer screening at minimum, including colonoscopy, mammography, PSA, and chest imaging as indicated by age and risk factors 1
• Do not limit screening to age-appropriate measures alone when THSD7A is positive—consider expanded evaluation 1

Specific Screening Based on THSD7A Positivity

• Urological evaluation including cystoscopy and renal imaging (given bladder cancer association) 2
• Gastrointestinal evaluation including upper and lower endoscopy (given colon cancer association) 5
• CT chest/abdomen/pelvis to screen for occult solid tumors 1

Clinical Monitoring Strategy

• Serial monitoring of both PLA2R and THSD7A antibody titers to detect changes that may precede clinical progression 1
• Unexpected recurrence of proteinuria or change in therapy response should trigger repeat malignancy screening 2
• Consider repeat kidney biopsy if disease behavior changes, as the dominant antigen may shift during the clinical course 2

Critical Pitfalls to Avoid

• Do not assume PLA2R positivity excludes secondary causes—evaluate for malignancy, lupus, hepatitis, and medications regardless of antibody status 1, 6, 7
• Do not rely on standard age-appropriate screening alone when THSD7A is present—this marker warrants enhanced surveillance 1
• Do not dismiss new symptoms or proteinuria recurrence as simple disease relapse without reconsidering malignancy 2
• Do not assume the etiology is fixed—MN can evolve from idiopathic to malignancy-associated during follow-up 2

Prognostic Implications

• THSD7A-positive MN demonstrates worse composite remission rates compared to THSD7A-negative disease 5
• The presence of both antibodies may indicate more aggressive disease requiring closer monitoring 5
• If malignancy is identified and treated, proteinuria may spontaneously remit, confirming the secondary nature 2