Is membranous glomerulonephritis associated with malignancy?

Is Membranous Glomerulonephritis Associated with Malignancy?

Yes, membranous nephropathy is definitively associated with malignancy, with approximately 10% of cases presenting with cancer within one year of diagnosis, and this association is particularly strong in patients over 60 years of age. 1

Magnitude of the Association

The relationship between membranous nephropathy and malignancy is well-established and clinically significant:

• Approximately 10% of membranous nephropathy cases have an associated malignancy detected within the first year of diagnosis. 2
• The malignancy rate in patients with membranous nephropathy is five times greater than the baseline population incidence. 3
• The risk is highest in elderly patients, particularly those over 60 years of age. 1, 3

Clinical Presentation Pattern

The temporal relationship between membranous nephropathy and malignancy follows a predictable pattern:

• In approximately 80% of cases, proteinuria manifests prior to or concomitantly with the diagnosis of the neoplasm. 4
• Membranous nephropathy may antedate the detection of malignancy, serving as a potential early warning sign. 5
• Patients typically present with nephrotic-range proteinuria. 4

Types of Associated Malignancies

Membranous nephropathy has been documented with both solid tumors and hematologic malignancies:

• Solid tumors include lung, stomach, colon, and gastric cancers. 1, 5
• Hematologic malignancies are also associated with membranous nephropathy. 4
• The association occurs across various tumor types, not limited to specific organ systems. 4

Pathophysiologic Markers

Specific antigenic patterns may indicate higher malignancy risk:

• Thrombospondin type 1 domain-containing 7A (THSD7A) and neural epidermal growth factor-like-1 (NELL-1) antigens are often reported in patients with underlying malignancies. 2
• However, even when these antigens are expressed, the risk of concurrent malignancy does not exceed 25-30%. 2
• Patients who are anti-phospholipase A2 receptor (PLA2R) negative may represent secondary forms of disease and warrant further investigation for malignancy. 1

Histopathologic Features Suggesting Secondary Disease

Certain kidney biopsy findings should trigger more intensive cancer screening:

• Subendothelial or mesangial deposits (rather than purely subepithelial deposits). 1
• Greater than 8 white blood cells per glomerulus. 1
• Non-IgG4 subtype immunoglobulin deposition. 1

Recommended Cancer Screening Approach

All patients with membranous nephropathy, particularly those older than 60 years, should be considered for cancer screening following age-appropriate guidelines. 1

Standard Screening Protocol:

• Limit malignancy workup to age-appropriate cancer screening unless specific risk factors or symptoms suggest the need for additional testing. 1
• Age-appropriate screening includes routine tests recommended for the general population based on age and sex. 1

Intensified Screening Indications:

Patients with histopathologic features of secondary membranous nephropathy (subendothelial/mesangial deposits, >8 WBCs per glomerulus, non-IgG4 subtype) should be more intensively screened for underlying malignancy. 1

Re-screening Considerations:

• Refractoriness to initial therapy may indicate an occult primary malignancy not diagnosed during initial screening. 2
• Re-screening is sensible for relapsing patients who carry higher cancer risks, including older age and smoking history. 2

Treatment Response and Prognosis

The response of membranous nephropathy to cancer treatment provides evidence of causality:

• Complete remission of proteinuria can occur with successful treatment of the underlying tumor. 4
• Persistent proteinuria is associated with tumor recurrence or metastasis. 4
• Relapse of malignancy may result in recurrence of glomerulonephritis. 2
• Treatment is usually directed toward the underlying malignancy with combinations of surgery, chemotherapy, and/or radiotherapy. 2

Critical Pitfalls to Avoid

• Do not assume all membranous nephropathy is idiopathic without appropriate cancer screening, especially in patients over 60. 1
• Do not perform exhaustive cancer screening in all patients; balance the approach based on age, risk factors, and biopsy findings. 1
• Do not overlook the possibility that conditions listed as "secondary causes" may be coincidental rather than causal. 1
• Do not ignore persistent or worsening proteinuria despite immunosuppressive therapy, as this may indicate occult malignancy. 2