Pathophysiology

Structure of Skin and Hair Follicle

The outer layer of the skin is the epidermis, which overlies the dermis and the hypodermis. The epidermis is composed primarily of Keratinocytes (approximately 90% of the cells), which express the highest concentrations of EGFR in the basal and suprabasal layers.1 The EGFR is involved in the regulation of the differentiation, migration and survival of Keratinocytes.1 The EGFR is expressed on normal epidermal and Follicular Keratinocytes, Sebaceous Epithelium, Eccrine Epithelium, dendritic Antigen-presenting cells, and various connective tissue cells.1 As a consequence, the EGFR plays a role in the normal development and physiology of the epidermis and the outer layers of the hair Follicle.1

Structure of skin and hair Follicle. Adapted from: Lacouture ME. Nat Rev Cancer 2006; 6: 803-812.

Structure of skin and hair Follicle. Adapted from: Lacouture ME. Nat Rev Cancer 2006; 6: 803-812.

 

Effects of EGFRI in skin

Inhibition of EGFR signalling is thought to affect basal Keratinocytes, leading to the development of the cutaneous side effects seen with all EGFRI treatments. In brief, inhibition of the EGFR-mediated signalling pathways induces growth arrest and Apoptosis, decreased cell migration, increased cell attachment and differentiation, and eventually stimulates inflammation, all of which result in distinctive cutaneous manifestations.1,2 The clinical findings are reflected by the histological findings, ie premature differentiation of basal Keratinocytes, leukocyte infiltration, apoptosis and tissue damage, and a decrease in epidermal thickness.1

Effects of EGFRIs in skin. Adapted from: Lacouture ME. Nat Rev Cancer 2006; 6: 803-812.

Effects of EGFRIs in skin. Adapted from: Lacouture ME. Nat Rev Cancer 2006; 6: 803-812.

 

Mechanism of EGFRI Action

The mechanism of EGFRI-induced skin toxicity is not completely understood.1,3,4 Currently, inhibition of EGFR signalling in the basal Keratinocytes is believed to immediately cause growth and migratory abnormalities and inflammatory changes, which result in sensory disturbance and a Papulopustular rash within the first few days or weeks of therapy. Keratinocyte maturation and differentiation are also impaired, and these changes become clinically evident later on, when Xerosis and nail and hair growth disturbances predominate.

References

1Lacouture ME. Nat Rev Cancer 2006; 6: 803-812.
2Kari C et al. Cancer Res 2003; 63: 1-5.
3Peréz-Soler R et al. Oncologist 2005; 10: 345-356.
4Peréz-Soler R & Saltz L. J Clin Oncol 2005; 23: 5235-5246.

Last update: 14 May 2009