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.