Pattern-Specific Loss of Desmoplakin I and II Immunoreactivity in Erythema Multiforme and its Variants: A Possible Aid in Histologic Diagnosis

Abstract

Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) comprise a family of mucocutaneous diseases associated with significant morbidity and mortality. Previous studies have confirmed the presence of autoantibodies to desmoplakin (Dp) I and II in patients with EM, SJS, and TEN. Truncated Dp production leads to characteristic changes visible on light microscopy: perinuclear clumping of keratin filaments and dyskeratotic keratinocyte. Based on these observations, the question arises as to whether a loss of Dp immunoreactivity in skin biopsies could serve as a diagnostic marker of EM, SJS, and TEN. This study analyzed Dp immunostaining patterns in 20 patients with EM or SJS/TEN. To assess the specificity of this approach, Dp immunostaining was also performed on specimens from patients with 5 potential histologic mimics of EM, SJS, and TEN. All of the samples from patients with EM, SJS, and TEN demonstrated absent or markedly diminished staining for Dp. A χ2 test demonstrated a statistically significant difference between the staining patterns in EM, SJS, and TEN and each of the other diagnostic groups that were investigated. This is the first report demonstrating statistically significant specificity of Dp staining patterns in EM/SJS/TEN as compared with other interface dermatitides.

Desmoplakin I/II immunohistochemical staining may be a helpful tool in differentiating cutaneous graft versus host disease from the erythema multiforme, Stevens–Johnson syndrome, and toxic epidermal necrolysis spectrum disorders

“…Our finding of a significant decrease in Dp I/II staining in EM/SJS/TEN compared to all grades of cGVHD confirms the work of Forrester et al 9 Having the largest retrospective cohort to date, our sample size allowed us to further analyze subgroups of cGVHD by histopathologic grade, where we found a significant difference between EM/SJS/TEN and Grades 2 + 3 cGVHD, but not between EM/SJS/TEN and Grade 4 cGVHD. The inability of Dp I/II to differentiate Grade 4 cGVHD from TEN in particular is notable, given the considerable morphologic overlap 32 .…”

“…Immunohistochemical staining was performed on 4‐μm thick formalin‐fixed, paraffin‐embedded tissue sections at a dilution of 1:50 using an automated platform (Leica Bond III Immunostainer; Leica Microsystems). High‐power (×40) microscopic fields from each biopsy specimen were compared and assigned a value of 1–3 based on the intensity of staining for Dp I/II in the epidermis by two pathologists independently 9 . A value of 1 indicated loss of staining across the span of one ×40 field; 2 was indicative of faint, diffuse staining or focal loss of staining (less than ×40 field); 3 was assigned to biopsy specimens with strong, diffuse staining.…”

“…Desmoplakin (Dp) I and II are intracellular, desmosomal plaque proteins responsible for the assembly of intermediate keratin filaments and subsequent attachment to other structural components of desmosomes 3–7 . Prior studies have demonstrated Dp I and II autoantibodies in patients with EM/SJS/TEN, with some proposing that these antibodies may play a pathogenic role via disruption of Dp 3–9 . Loss of Dp I/II immunoreactivity may distinguish EM/SJS/TEN from other histopathologic mimickers, including cGVHD 9 .…”

“…[3][4][5][6][7] Prior studies have demonstrated Dp I and II autoantibodies in patients with EM/SJS/TEN, with some proposing that these antibodies may play a pathogenic role via disruption of Dp. [3][4][5][6][7][8][9] Loss of Dp I/II immunoreactivity may distinguish EM/SJS/TEN from other histopathologic mimickers, including cGVHD. 9 We aimed to further assess the use of Dp I/II immunohistochemical stain in discriminating skin biopsy specimens from patients with EM/SJS/TEN from those with cGVHD.…”

“…[3][4][5][6][7][8][9] Loss of Dp I/II immunoreactivity may distinguish EM/SJS/TEN from other histopathologic mimickers, including cGVHD. 9 We aimed to further assess the use of Dp I/II immunohistochemical stain in discriminating skin biopsy specimens from patients with EM/SJS/TEN from those with cGVHD.…”