Clinical and histopathologic features of cutaneous adverse reactions associated with checkpoint inhibitor immunotherapy

CAE category	Cutaneous eruption	Time to onset	Clinical findings	Histopathology
Inflammatory	Maculopapular (morbilliform)	3 to 6 weeks	Erythematous macules and flat papules on trunk and dorsal aspect of extremities	Superficial, perivascular, lymphohistiocytic infiltrate +/– eosinophils.
	Eczematous	0 to 3 weeks	Pruritic, erythematous papules coalescing into plaques predominantly on trunk and extremities	Spongiotic dermatitis with superficial, perivascular, lymphohistiocytic infiltrate +/– eosinophils.
	Psoriasiform	0 to 3 weeks	Well-demarcated, erythematous papules or plaques with adherent scale of the trunk and extremities (most common); palmoplantar, pustular, inverse, or guttate variations	Regular acanthosis with hypogranulosis; confluent parakeratosis; and superficial, perivascular dermatitis with lymphocytes, histiocytes, and neutrophils.
	Lichenoid	6 to 12 weeks	Flat-topped, violaceous papules with adherent scale	Lichenoid and vacuolar dermatitis with lymphocytes and histiocytes, hyperorthokeratosis, wedge-shaped hypergranulosis, and saw-tooth rete ridges.
	Granulomatous	3 weeks or later	Red-brown papules or nodules on the head, trunk, or extremities	Nodular, histiocytic dermatitis with minimal surrounding lymphocytes or other inflammatory cells, negative special stains for organisms.
	Vitiligo	7 to 16 weeks or later	Depigmented macules and patches	Decreased or absent melanocytes at the dermal-epidermal junction.
Neoplastic	Cutaneous squamous cell carcinoma/keratoacanthoma	12 to 18 weeks or later	Hyperkeratotic papules and nodules	Full-thickness epidermal atypia with a crateriform architecture in the case of keratoacanthoma.
Severe cutaneous reactions	SJS/TEN	1 to 4 weeks (may be shorter on re-exposure)	Dusky red, coalescent, macular eruption, with atypical target lesions with central vesiculation and mucosal involvement	Full-thickness epidermal necrosis with a sparse, superficial, perivascular, lymphohistiocytic infiltrate and possible vacuolar degeneration.
	DRESS	2 to 8 weeks	Erythematous macules and papules (nonspecific cutaneous findings) Facial edema and lymphadenopathy	Interface dermatitis with basal vacuolization; spongiosis; perivascular, lymphocytic infiltrate; vascular damage.
	AGEP	<1 week	Widespread erythema with numerous tiny, pinpoint pustules	Spongiotic psoriasiform dermatitis with subcorneal pustules and numerous dermal eosinophils.
Connective tissue disease	Dermatomyositis	>12 weeks	Erythematous or violaceous papules in photodistribution "heliotrope eruption" (pink-violaceous erythema and edema of the eyelids)	Sparse interface dermatitis with focal dyskeratosis and increased dermal mucin.
Connective tissue disease	Lupus erythematosus	≥6 weeks	Features of acute lupus erythematosus (eg, malar rash), subacute lupus erythematosus (erythematous papules and plaques; annular, polycyclic plaques on upper trunk, neck, and arms), or discoid lupus erythematosus (papulosquamous, photodistributed eruption)	Superficial and deep, perivascular and periadnexal dermatitis with overlying interface dermatitis and increased dermal mucin.
Antibody mediated	Bullous pemphigoid	13 to 16 weeks or later	Prodromal pruritus followed by formation of tense vesicles	Subepidermal, vesicular dermatitis with superficial, perivascular, and intravesicular eosinophils. Direct immunofluorescence positive for IgG and C3 at the dermal-epidermal junction.
Hair	Alopecia areata	13 to 16 weeks or later	Round, alopecic patches on the scalp without scale or erythema	Nonscarring alopecia with lymphocytic infiltrate at the base of the hair follicles.
Rare, including possible exacerbation of pre-existing disease	Acneiform	1 to 8 weeks or later	Erythematous, follicular papules and pustules	Acute neutrophilic folliculitis with disturbance of the follicular epithelium.
	Sweet syndrome	≥4 weeks	Erythematous, edematous, and tender plaques and nodules on face, upper extremities, and trunk	Papillary dermal edema with minimal epidermal change and underlying, neutrophilic dermatitis without vasculitis.
	Pyoderma gangrenosum	16 weeks(?)	Inflammatory papule, pustule, or nodule that subsequently enlarges and ulcerates with undermined, violaceous borders	Diffuse, neutrophilic, dermal infiltrate often with fibrosis, granulation tissue, and negative tissue cultures and/or special stains for organisms.

AGEP: acute generalized exanthematous pustulosis; C3: complement component 3; CAE: cutaneous adverse event; DRESS: drug reaction with eosinophilia and systemic symptoms; IgG: immunoglobulin G; SJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysis.

Graphic 131015 Version 3.0

خرید پکیج

Clinical and histopathologic features of cutaneous adverse reactions associated with checkpoint inhibitor immunotherapy