Is IgG4 Disease Cancer? Key Facts and Insights.

IgG4-related disease (IgG4-RD) is a chronic inflammatory condition affecting multiple organs, often resembling cancer. Its ability to form masses and cause tissue enlargement leads to frequent misdiagnoses. Understanding whether IgG4-RD is a form of cancer or increases malignancy risk is essential for accurate diagnosis and treatment.

Pathology And Classification

IgG4-RD is characterized by fibroinflammatory processes, leading to tissue infiltration by IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. Classified as an immune-mediated disorder, it often mimics neoplastic processes due to its mass-forming nature. Histologically, affected tissues exhibit dense lymphoplasmacytic infiltrates, with IgG4-positive plasma cells exceeding diagnostic thresholds based on organ involvement. The storiform fibrosis pattern can resemble desmoplastic reactions seen in cancers like pancreatic adenocarcinoma, complicating differentiation.

Classification relies on organ involvement and histopathological features rather than a single unifying mechanism. It is divided into systemic and organ-specific forms, with systemic cases affecting multiple sites and organ-specific cases confined to a single organ. The American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) criteria emphasize histology, serum IgG4 levels, and radiological patterns. While elevated IgG4 levels are a hallmark, they are neither universally present nor specific, as some malignancies and inflammatory conditions also show increased IgG4 expression.

Mass-forming lesions in IgG4-RD closely resemble malignancies on imaging, leading to diagnostic uncertainty. IgG4-related sclerosing pancreatitis, for instance, can be mistaken for pancreatic cancer, while retroperitoneal fibrosis may resemble lymphoma or sarcoma. Progressive fibrosis can cause irreversible organ damage, similar to untreated malignancies. However, unlike cancer, IgG4-RD lacks uncontrolled cellular proliferation and genetic mutations.

Common Sites Involvement

IgG4-RD affects various organs, often forming mass-like lesions that complicate diagnosis. The pancreas is a common site, with IgG4-related autoimmune pancreatitis (AIP) often mimicking pancreatic adenocarcinoma. This condition presents with diffuse or focal pancreatic enlargement and pancreatic duct narrowing, leading to frequent misdiagnoses. Histological analysis reveals hallmark features like dense lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis, distinguishing it from malignancy.

The biliary system is another frequent site, where IgG4-related sclerosing cholangitis (IgG4-SC) can resemble primary sclerosing cholangitis (PSC) or cholangiocarcinoma. Patients present with biliary strictures, elevated liver enzymes, and jaundice, complicating differentiation. Unlike PSC, which is linked to inflammatory bowel disease, IgG4-SC typically responds to corticosteroids. Imaging often shows long, smooth strictures, unlike the irregular nodular strictures of cholangiocarcinoma. In some cases, liver biopsy or endoscopic ultrasound-guided fine-needle aspiration is needed to confirm the diagnosis.

Lacrimal and salivary gland involvement is also common, with IgG4-related dacryoadenitis and sialadenitis causing painless swelling that can be mistaken for Sjögren’s syndrome or lymphoproliferative disorders. Unlike Sjögren’s syndrome, which primarily affects exocrine function, IgG4-RD leads to glandular hypertrophy and fibrosis. Histopathological analysis reveals dense IgG4-positive plasma cell infiltration and fibrosis, helping differentiate it from other conditions.

Retroperitoneal and renal involvement is frequent, with IgG4-related retroperitoneal fibrosis causing ureteral obstruction and hydronephrosis, often confused with malignant retroperitoneal tumors. In renal cases, IgG4-related tubulointerstitial nephritis leads to diffuse renal enlargement and impaired kidney function. Imaging shows cortical hypodensities, while biopsy findings include interstitial fibrosis, tubular atrophy, and dense IgG4-positive plasma cell infiltrates. Unlike malignancies, IgG4-RD lacks cellular atypia and invasive growth.

Malignancy Incidence

The link between IgG4-RD and cancer remains under investigation. While IgG4-RD itself is not neoplastic, some studies suggest a modestly increased malignancy risk. A Rheumatology study found higher cancer incidence in IgG4-RD patients, particularly within the first year of diagnosis. This suggests possible misdiagnosis rather than a direct oncogenic effect.

Chronic inflammation in IgG4-RD may create a tumorigenic environment. Persistent inflammation and fibrosis have been linked to malignancies in conditions like chronic pancreatitis and primary sclerosing cholangitis. Given the pathological overlap, researchers have explored whether IgG4-RD shares similar risks, though no causal link has been established. The observed malignancy rates may stem from diagnostic misclassification or underlying predisposition.

Immunosuppressive treatments used in IgG4-RD management, particularly corticosteroids, have been associated with increased infection risk and, in rare cases, secondary malignancies. However, current evidence does not strongly support a direct connection between IgG4-RD therapy and cancer. Some patients with IgG4-RD also have prior malignancies, raising the possibility of a paraneoplastic phenomenon rather than direct progression from IgG4-RD to cancer. Careful clinical evaluation is necessary to distinguish between true malignancy risk and coincidental associations.

Diagnostic Tools

Diagnosing IgG4-RD requires clinical assessment, imaging, histopathology, and laboratory tests. Given its tendency to mimic malignancies, a structured approach is essential. Serum IgG4 measurement is commonly used, though elevated levels lack specificity, as they can also be seen in pancreatic cancer and primary sclerosing cholangitis. Thus, IgG4 levels must be interpreted alongside other findings.

Imaging plays a key role in identifying organ involvement and distinguishing IgG4-RD from malignancies. CT and MRI often reveal diffuse organ enlargement, soft tissue masses, or thickened structures. PET scans using fluorodeoxyglucose (FDG) highlight metabolically active lesions, though increased uptake is not exclusive to IgG4-RD and occurs in cancers as well. Endoscopic ultrasound with fine-needle aspiration (EUS-FNA) is particularly useful for pancreatic and biliary involvement, enabling targeted tissue sampling for histological confirmation.

Treatment Options

Treatment aims to reduce inflammation and prevent organ damage. Corticosteroids are the first-line therapy, with prednisone typically prescribed at an initial dose of 30-40 mg per day, followed by gradual tapering. Most patients experience symptom relief within weeks, though relapse rates are high, necessitating ongoing monitoring.

For recurrent or refractory cases, steroid-sparing immunosuppressants like azathioprine, mycophenolate mofetil, and methotrexate help maintain remission. Rituximab, a monoclonal antibody targeting CD20-positive B cells, has shown efficacy in patients unresponsive to corticosteroids. It works by depleting B cells, reducing IgG4-producing plasma cells. While generally well-tolerated, rituximab carries risks, including infusion reactions and increased infection susceptibility. In cases where fibrosis has caused significant organ dysfunction, surgical interventions may be required.

Differences Between IgG4-Related Disease And Cancer

Despite its ability to mimic malignancies, IgG4-RD differs fundamentally from cancer. The key distinction lies in its immune-mediated nature, whereas cancer involves uncontrolled cellular proliferation driven by genetic mutations. Histopathology is the most definitive differentiator—IgG4-RD features dense lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis, while malignancies exhibit cellular atypia, mitotic activity, and invasive growth.

Response to treatment also sets IgG4-RD apart. While cancer often requires surgery, chemotherapy, or radiation, IgG4-RD responds well to immunosuppressive therapies. Additionally, IgG4-RD lesions are generally reversible with early intervention, unlike cancerous growths, which tend to progress without treatment. Imaging can sometimes aid differentiation, as IgG4-RD lesions typically show homogenous enhancement and smooth margins, while malignancies exhibit irregular borders and heterogeneous enhancement. Given the clinical overlap, thorough evaluation is critical to avoid misdiagnosis and inappropriate treatment.