A 62-year-old man with metastatic colorectal cancer is started on cetuximab. Two weeks after initiating therapy, he develops an eruption predominantly affecting the face, scalp, and upper trunk comprised of crusted papules and pustules. He denies fevers or systemic symptoms.

Which of the following best explains the pathogenesis of his skin eruption?

A. Immune complex deposition in dermal vessels

B. Neutrophil-driven inflammation secondary to altered follicular keratinization

C. Type I immediate hypersensitivity reaction to cetuximab

D. Phototoxic injury induced by ultraviolet radiation and cetuximab interaction

E. Drug-induced sebaceous gland hyperplasia leading to follicular occlusion

Rationale:

This patient has developed the classic papulopustular (acneiform) eruption associated with EGFR inhibitors like cetuximab, erlotinib, and gefitinib. This eruption is not true acne because it lacks comedones. The severity of rash may correlate with better tumor response to EGFR therapy. Treatment typically includes oral antibiotics such as doxycycline and topical steroids which are sometimes used prophylactically when starting EGFR inhibitors to prevent this eruption. Most patients do not need to discontinue the EGFR inhibitor unless the eruption is severe.

Correct answer: B. Neutrophil-driven inflammation secondary to altered follicular keratinization

EGFR is highly expressed in the basal layer of the epidermis and pilosebaceous units and EGFR signaling regulates keratinocyte proliferation, differentiation, and survival. Inhibition leads to abnormal keratinization of the follicular infundibulum, promoting follicular rupture and neutrophilic inflammation, resulting in the papulopustular eruption. Secondary infection may occur and culture can be helpful.

Incorrect answer choices:

A. Immune complex deposition in dermal vessels describes leukocytoclastic vasculitis, which presents with palpable purpura, not a pustular eruption.

C. Type I immediate hypersensitivity reaction to cetuximab typically present as any other type I reaction with urticaria, angioedema, or anaphylaxis.

D. Phototoxic injury induced by ultraviolet radiation and cetuximab interaction. Phototoxic reactions cause diffuse erythema and blistering in sun-exposed areas, not localized papulopustular eruptions.

E. Drug-induced sebaceous gland hyperplasia leading to follicular occlusion can occur with long-term androgen stimulation or cyclosporine, but is not the mechanism for EGFR-inhibitor eruptions.

Additional reading at Fitzpatrick's Dermatology Chapter 194: Molecular Targeted Therapies