What is the malignancy risk for a 62‑year‑old asymptomatic patient with biopsy‑proven membranous nephropathy diagnosed three years ago, dual positive for anti‑phospholipase A2 receptor (anti‑PLA2R) and anti‑thrombospondin type‑1 domain‑containing 7A (anti‑THSD7A) antibodies, who has relapsed twice and responded to rituximab?

Malignancy Risk in Dual PLA2R/THSD7A-Positive Membranous Nephropathy

This 62-year-old patient with dual positivity for anti-PLA2R and anti-THSD7A antibodies faces a markedly elevated malignancy risk that mandates intensive cancer screening beyond routine age-appropriate measures. 1

Understanding the Unique Risk Profile

Dual positivity for both PLA2R and THSD7A antibodies is exceedingly uncommon and fundamentally changes the risk assessment. 1 While PLA2R positivity alone typically indicates primary (idiopathic) membranous nephropathy with low malignancy risk, the presence of THSD7A antibodies signals a substantially higher cancer association. 1

Key Evidence on Dual Positivity

• Dual autoimmune responses with both antibodies present simultaneously have been documented in Chinese cohorts, representing approximately 2% of all membranous nephropathy cases and suggesting enhanced autoimmune activity. 2
• The presence of PLA2R antibodies does not exclude cancer-associated disease—case reports document very high anti-PLA2R titers in patients with synchronous esophageal adenocarcinoma and renal cell carcinoma. 3
• THSD7A-positive membranous nephropathy demonstrates a greater prevalence of concurrent malignancies compared with PLA2R-positive disease alone. 1

Mandatory Cancer Screening Protocol

Baseline Age-Appropriate Screening

All membranous nephropathy patients require standard cancer screening regardless of antibody status, including colonoscopy, mammography (if applicable), prostate-specific antigen testing, and chest imaging. 4, 1

Enhanced THSD7A-Specific Surveillance

Because THSD7A positivity is present, screening must extend beyond standard measures: 1

• Contrast-enhanced CT chest/abdomen/pelvis to detect occult solid tumors 1
• Urological assessment including cystoscopy and dedicated renal imaging (THSD7A associates with bladder and renal cancers) 1
• Gastrointestinal endoscopy beyond screening colonoscopy (THSD7A associates with colon and rectal cancers) 1, 5
• Lymph node evaluation as lymph node metastasis may be a specific risk factor for THSD7A-associated cancer-related membranous nephropathy 5

Serial Antibody Monitoring

Measure both anti-PLA2R and anti-THSD7A antibody titers at 3-6 month intervals to identify serologic shifts that may precede clinical changes or signal emerging malignancy. 4, 1 Changes in antibody levels can predict disease trajectory by 6 or more months. 6

Critical Clinical Context

The Relapsing Course Matters

This patient has relapsed twice despite rituximab responses. Each relapse with rising antibody titers increases concern for:

• Persistent autoimmune activity that may be paraneoplastic in origin 7
• Occult malignancy driving antibody production 3
• The need for repeat comprehensive cancer screening with each relapse 1

Age-Specific Considerations

At 62 years old, this patient falls into the higher-risk age group where membranous nephropathy patients with cancer demonstrate significantly older age and worse kidney function compared to those without malignancy. 8

Common Pitfalls to Avoid

• Do not assume PLA2R positivity excludes secondary causes—evaluation for malignancy must proceed regardless of PLA2R antibody status. 1, 6, 3
• Do not rely solely on routine age-appropriate screening when THSD7A is present—enhanced surveillance protocols are mandatory. 1
• Do not perform single antibody measurements—serial measurements showing trajectory are more informative than isolated values. 9, 1
• Do not ignore clinical context with dual positivity—this rare finding demands heightened vigilance for occult malignancy. 1, 2

Quantifying the Risk

While precise numerical risk stratification for dual-positive patients is not established in guidelines, the available evidence indicates:

• THSD7A-positive membranous nephropathy alone carries approximately 10-20% malignancy prevalence in reported series 5, 2
• Dual positivity represents an even rarer and potentially higher-risk subset 2
• The relapsing course despite rituximab may indicate paraneoplastic antibody production 3, 7

The practical recommendation is to treat this patient as high-risk for occult malignancy requiring comprehensive enhanced screening now and with each subsequent relapse. 1