Clinical presentations, histopathological diagnoses, and grade of rash
Diagnoses were rendered via clinicopathological correlation. Of the 42 cutaneous irAEs identified via skin biopsy, the most common rash type was maculopapular rash (33/42, 78.6%), namely scattered edematous macules and/or red papules. The diagnosis of maculopapular rah was also renderd in cases with scattered papules, even there was a possibility of a fused taget lesion forming an erythematous plaque. The irAE of maculopapular rash was similar to typical exanthematous drug eruptions secondary to antibiotics, nonsteroidal anti-inflammatory drugs, and other treatments. The distribution of maculopapular rash was trunk-predominant (n = 14), extremity-predominant (n = 8), trunk alone (n = 6), or extremities alone (n = 5). Histopathologically, vacuolar degeneration at the dermal-epidermal junction and perivascular infiltration of lymphocytes were observed. Eosinophilic infiltration was not evident in some cases (n = 6). Other rash types included erythema multiforme (2/42, 4.8%), lichenoid reaction (3/42, 7.1%), psoriasiform reaction (1/42, 2.4%), bullous pemphigoid (1/42, 2.4%), scleroderma-like reaction (1/42, 2.4%), and SJS (1/42, 2.4%). Histopathologically, erythema multiforme shared similar features as maculopapular rashes (vacuolar degeneration at the dermal-epidermal junction, perivascular infiltration of lymphocytes, and infiltration of eosinophils). Lichenoid reactions had lichen planus-like clinical features, including pink-to-violaceous scaly papules. Oral ulcers and leukoplakia were observed in one case, and nail dystrophy were not evident in our patients. Psoriasiform reactions were similar to typical psoriasis vulgaris, including plaque psoriasis with well-defined, reddish-pink papules and plaques with silvery scales. Histopathologically, we observed epidermal hyperkeratotic parakeratosis and acanthosis without a granular layer, elongation of rete ridges, and dermal papilla. Perivascular infiltration of lymphocytes, eosinophils, and neutrophils at the upper dermis was also observed. In cases of bullous pemphigoid, broken bullae with erythematous macules appeared together with histopathological subepidermal bullae and eosinophilic infiltrate. An additional direct immunofluorescence test was performed, and linear deposits of IgG and C3 were identified. Overall, cutaneous irAEs shared clinical and histopathological features with classical inflammatory eruptions. Clinical presentations and histopathological features are summarized in Table 2, and examples of typical findings are presented in Figure 1.
Of the 42 rashes, 27 (64.3%) were grade 1, 12 (28.6%) were grade 2, and 3 (7.1%) were grade 3, and no grade 4 rash was observed. The grade 3 rashes included maculopapular rashes and SJS. No patients died of cutaneous irAEs.