What are the pathological features seen in non-bullous bullous pemphigoid?

Pathological Features of Non-Bullous Bullous Pemphigoid

In non-bullous bullous pemphigoid, histopathology is commonly nonspecific, showing mild superficial perivascular lymphocytic infiltration with eosinophils arranged along the basement membrane zone, but the diagnosis critically depends on direct immunofluorescence demonstrating linear IgG and/or C3 deposits at the dermoepidermal junction. 1, 2, 3

Histopathological Findings

The histopathological features in non-bullous bullous pemphigoid differ significantly from classic bullous pemphigoid and are often diagnostically challenging:

Light Microscopy Features

• Moderate eosinophilic infiltrate arranged along the basement membrane zone, with focal invasion into the epidermis 4
• Dermal infiltrate composed of eosinophils and/or neutrophils, though this may be subtle 1
• Marginalization of eosinophils along the dermoepidermal junction when present 1
• Mild superficial perivascular lymphocytic infiltration with mild papillary edema, representing early or non-bullous disease 5
• Nonspecific findings are the rule rather than the exception—histopathology alone is insufficient for diagnosis 2, 3

Key Distinction from Classic Bullous Pemphigoid

• Absence of subepidermal bullae containing eosinophils and/or neutrophils, which are the hallmark of classic bullous pemphigoid 1
• The lack of frank blister formation means the characteristic subepidermal split is not visualized 4, 3

Essential Immunopathological Features

Direct immunofluorescence (DIF) is absolutely essential and diagnostic, as histopathology is unreliable in non-bullous forms:

Direct Immunofluorescence (DIF)

• Linear deposits of IgG and/or C3 along the dermoepidermal junction in 93.2% of cases 3
• Sometimes IgA and IgE deposits with similar linear pattern 1
• N-serrated pattern of deposition when present 1
• DIF must be performed on perilesional skin (not from a blister, as none may be present) 6
• Positive DIF is essential for diagnosis of bullous pemphigoid, including non-bullous variants 1, 5

Immunoelectron Microscopy

• When performed, deposits are localized within the lamina lucida and over the hemidesmosomal plaques 4

Serological Features

Indirect Immunofluorescence and ELISA

• Indirect immunofluorescence on salt-split skin is positive in 90.2% of cases, with IgG binding to the epidermal side of the split 3
• Anti-BP180 (BPAG2) antibodies detected by ELISA 6, 4
• Anti-BP230 (BPAG1) antibodies may be present, sometimes as the sole autoantibody 4
• Positive indirect immunofluorescence is associated with eventual blister formation (p=0.014) 2

Clinical Correlation and Diagnostic Pitfalls

Common Pitfall

The mean diagnostic delay is 22.6-30.4 months because histopathology shows nonspecific findings and clinicians fail to consider bullous pemphigoid in the absence of blisters 2, 3, 7. Do not rely on histopathology alone—always obtain DIF from perilesional skin when bullous pemphigoid is suspected in elderly patients with refractory pruritus 1, 5.

Evolution to Bullous Disease

• Only 9.8-17% of non-bullous pemphigoid patients eventually develop blisters during follow-up 2, 3
• 71% never develop blisters despite having the same autoimmune pathophysiology 7
• Positive BP180 immunoblot (p=0.032) predicts blister formation 2

Diagnostic Algorithm

When evaluating suspected non-bullous bullous pemphigoid:

1. Obtain DIF from perilesional skin—this is the single most important diagnostic test 1, 5, 6
2. Perform serum ELISA for anti-BP180 and anti-BP230 antibodies 6
3. Indirect immunofluorescence on salt-split skin if ELISA unavailable 1, 3
4. Do not exclude the diagnosis based on nonspecific histopathology alone 2, 3