Skin signs associated with epidermal growth factor inhibitors

BACKGROUND: Inhibitors of epidermal growth factor receptors (EGFR) constitute a new alternative treatment for patients presenting certain advanced stage solid cancers (bowel, breast, ovary). Adverse cutaneous effects of these drugs are now starting to be described. OBSERVATIONS: Our study involved 2 men and 2 women with no previous history of acne included in a treatment protocol comprising EGFR inhibitors. Mean age was 52 years. The primary cancers were breast, ovary, bowel and unidentified. The EGFR inhibitors used were gefitinib (ZD1839) (2 cases), carnetinib (Cl1033) and cetuximab (IMC-C225). Skin lesions appeared after 7 days and included erythematous papules and follicular pustules of the face, back and upper chest. No comedons were seen, and there were no nodules or cysts. The severity of the rash resulted in discontinuation of treatment in 2 patients with complete disappearance of skin lesions in both cases. In one patient, reduction of the dosage of gefitinib (IMC-C225) led to gradual resolution of the rash. Histological examination of papules and pustules concluded on an acute suppurative folliculitis. Smears and cultures ofa nasal lesion and pustules revealed coagulase-positive Staphylococcus aureus in 2 patients. Combined doxycycline 100 mg daily and benzoyl peroxide was prescribed for 3 months and a favourable outcome was achieved after a mean 2 weeks. DISCUSSION: EGFR inhibitors act by inhibiting mechanisms oftumour proliferation in certain cancers at advanced stages or refractory to other treatments. Our findings in these four patients are similar to the published cases in terms of rapid onset of monomorphous, papulopustular, follicular eruption without comedons. Rapid response to cyclines and benzoyl peroxide is also reported in literature. This treatment must be instituted rapidly and patients must be informed about the cutaneous side-effects of EGFR inhibitors before the start of therapy. The pathophysiology of these eruptions is still unknown. Skin signs are probably due to interaction with EGFR functions, including overexpression of EGFR in keratinocytes and hair follicles.     

Acneiform eruptions associated with epidermal growth factor receptor-targeted chemotherapy

A relatively newer class of chemotherapy agents, known as the epidermal growth factor receptor inhibitors (EGF-RIs), is being used to treat advanced stages of solid tumors. Acneiform eruptions are a frequent adverse effect and one which has been associated with increased survival in some studies. We describe 3 patients who presented shortly after initiation of EGF-RI therapy. Characteristics included an absence of comedones, facial and truncal involvement, and a perifollicular lymphoneutrophilic infiltrate detected on biopsy. Lesion counts were reduced with topical adapalene and oral tetracyclines in two patients. Patient 3 had dramatic clearance with low-dose isotretinoin (20 mg daily) until completion of EGF-RI therapy. Acneiform eruptions are a common adverse reaction to EGF-RI therapy and can be treated with traditional acne therapy. This should not be considered a drug hypersensitivity eruption or allergy, and patients should continue therapy. For patients with severe eruptions, oral isotretinoin is a consideration.     

Dermatologic side effects associated with the epidermal growth factor receptor inhibitors

Epidermal growth factor receptor (EGFR) inhibitors are associated with unique and dramatic dermatologic side effects. Cetuximab, erlotinib, and gefitinib have been approved for patients with colorectal and non-small cell lung cancer refractory or intolerant to chemotherapy. Our aim was to describe key clinical features of common dermatologic adverse reactions among EGFR inhibitors, focusing mainly on skin toxicity, as well as to discuss the pathology, possible causes, and suggested treatments for these reactions. The most commonly encountered adverse effect was a mild skin toxicity characterized by a sterile follicular and pustular rash that may be treated empirically and usually does not require treatment modification. Although the precise mechanism for development of rash is not well defined, it is related to inhibition of EGFR-signaling pathways in the skin, and may serve as visible markers of anti-tumor activity and therapeutic efficacy. Secondary adverse reactions seen with anti-EGFR therapy include xerosis, pruritus, paronychia, hair abnormality, and mucositis.     

Regulation of epidermal growth factor receptor expression in human melanocytes

The epidermal growth factor receptor (EGFR) and its ligand, transforming growth factor alpha (TGFalpha), are reportedly involved in autocrine growth of melanoma cells. The signal pathway has also been implicated in early events of transformation, suggesting a function for EGFR in normal cells. This study reports the presence of EGFR in cultured melanocytes and examines some cellular responses to TGFalpha. Western analysis revealed 170 kDa bands in extracts of cultured neonatal human melanocytes, corresponding to the receptor Mr. Protein expression was more pronounced in cells during active growth. EGFR were less evident in cultures populated predominantly by melanized cells, indicating that receptor expression became reduced in differentiating cells. Immunocytochemistry confirmed these observations and also showed that EGFR reactivity was predominantly localized in the cell body but absent from dendrites. Addition of TGFalpha to early cultures induced a rapid increase in phosphotyrosine signal of the 170 kDa protein. Longer treatment (24-48 h) increased the intensity of the EGFR signal, suggesting that receptors had been upregulated. However, inclusion of TGFalpha in cultures did not result in an increase in cell numbers when compared to controls. The observations provide evidence of the existence of a receptor-mediated pathway in melanocytes which has transforming potential in vivo.     

Neonatal cutaneous inflammatory syndrome associated with homozygous epidermal growth factor receptor mutation

The epidermal growth factor receptor (EGFR) is a transmembrane protein with tyrosine kinase signaling activity regulating many essential cellular functions, and loss of function mutations in EGFR result in a life-threatening neonatal syndrome. We present the case of a preterm boy born with intrauterine growth restriction who developed multisystem disease due to a homozygous mutation in the EGFR gene. He experienced a tumultuous and complex clinical course with recurrent skin infections and sepsis, nephrocalcinosis, failure to thrive, severe electrolyte imbalances, rectal perforation, and thrombus formation, and died after 11 months due to renal failure. This case report builds on work recently published in 2020 describing a case series of 18 similar patients and adds to the growing literature describing the severe phenotype and multisystem disease associated with loss of EGFR mutation in the Roma population.     

Nonscarring inflammatory alopecia associated with the epidermal growth factor receptor inhibitor gefitinib

Gefitinib (ZD1839, Iressa, AstraZeneca, Wilmington, Del) is a novel oral anticancer agent that acts by blocking the function of the epidermal growth factor receptor. Gefitinib and other drugs that block epidermal growth factor receptor function have been associated with a similar and interesting pattern of cutaneous adverse effects, including follicular acneiform eruptions, xerosis, desquamation, seborrheic dermatitis, chronic paronychia, and hair texture changes. These effects appear to reflect the significance of epidermal growth factor receptor signaling in the skin. Here we present a case of a woman who developed an extensive nonscarring inflammatory alopecia after 2 years of gefitinib therapy.     

The expression levels and the differential expression of transforming growth factor-beta receptors in dermatofibroma and dermatofibrosarcoma protuberans

BACKGROUND: Dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFSP) are benign and intermediate malignant fibrotic dermal tumours, respectively. The contribution of transforming growth factor (TGF)-beta has been implicated in the progression of sclerosis in fibrotic diseases. OBJECTIVES: To investigate the expression of TGF-beta receptors in these fibrotic tumours. METHODS: We examined the expression levels of TGF-beta type I and type II receptors (TGFbeta-RI and TGFbeta-RII) in DF and DFSP using in situ hybridization and immunohistochemical analysis. We also examined the expression of TGF-beta1 and collagen type I using immunohistochemical analysis. RESULTS: We detected strong expression of TGFbeta-RI and TGFbeta-RII on epidermis and epidermal appendages, moderate expression in vascular endothelial cells, smooth muscle cells and neural tissues, and weak expression in fibroblasts in normal skin sections. The expression levels of TGFbeta-RI and TGFbeta-RII were elevated in the tissue sections of DF in comparison with normal dermal sections using in situ hybridization and immunohistochemical staining. Furthermore, the expression of TGFbeta-RI and TGFbeta-RII was strong in spindle-shaped cells around DF. The expression of TGFbeta-RI and TGFbeta-RII was decreased in DFSP in comparison with DF, and their expression was found to be homogeneous in each DFSP tumour cell. The staining for TGF-beta1 was found prominently on matrix and spindle-shaped tumour cells of DF, and peripheral regions of DFSP. Weak expression of TGF-beta1 was found on normal skin or tumour cells in the central part of DFSP. Type I collagen expression was found on spindle-shaped tumour cells in DF, but not in tumour cells of DFSP. CONCLUSIONS: These results suggest the possibility that TGF-beta signalling may contribute to the fibrosis around DF, and that TGF-beta receptors may play important roles in TGF-beta signalling. The expression patterns of TGFbeta-RI and TGFbeta-RII may be helpful in distinguishing these diseases.     

Increased cutaneous immunoreactive stem cell factor expression and serum stem cell factor level in systemic scleroderma.

Skin hyperpigmentation and itching are characteristic findings in systemic sclerosis (SSC) patients. Stem cell factor (SCF, c-kit ligand) is a multifunctional cytokine which can promote melanocyte and mast cell development. We investigated the SCF expression histopathologically in normal and SSC skin, and compared the expression with the serum SCF levels measured with a specific enzyme-linked immunosorbent assay. The epidermal and dermal immunoreactive SCF expression was markedly higher in the forearm skin of edematous phase SSC patients than in that of normal subjects. Tissue SCF expression declined from the sclerotic phase to the atrophic phase, where it was close to the normal level. In contrast, the elevated serum SCF level seen in the edematous phase samples was further increased in the sclerotic phase samples. The serum SCF level decreased in the atrophic phase, but it still remained at a level higher than that of the normal controls. Itching and increase of dermal mast cell number are characteristic of edematous phase SSC, and are in bears a parallel to the presently observed dermal SCF expression profile. Pigmentation is significant in sclerotic phase SSC and lasts to the atrophic phase, which may correspond to the serum SCF level observed here. These results indicate a contribution of the fibroblast membrane integral SCF in dermal mast cell development, and of the soluble serum SCF to melanocyte activation in SSC.     

体外培养人角质形成细胞周期与表皮生长因子受体表达检测

[摘 要] 目的 比较人角质形成细胞（KC）在角质形成细胞无血清培养基（K-SFM）和限制性角质形成细胞无血清培养基（DK-SFM）中的生长、增殖、传代和细胞性状变化的情况。方法 取健康男性包皮,将KC用K-SFM和DK-SFM培养,倒置显微镜下观察两组的细胞形态、数量、传代情况;用流式细胞仪检测细胞周期和细胞表皮生长因子受体（EGFR）的含量。结果 原代培养天12天,K-SFM培养基KC的细胞数量(304.70±83.08)明显多于DK-SFM(75.30±26.08),有统计学差异（P＜0.01）,K-SFM培养基KC细胞集落数(2.20±1.23)明显多于DK-SFM(0.00±0.00),有统计学差异（P＜0.01）。K-SFM组细胞可以传4代,DK-SFM组无法传代。K-SFM组G0-G1期细胞比例65.40%, DK-SFM组G0-G1期细胞比例84.10%;K-SFM组G2-M期细胞比例17.02%,DK-SFM组G2-M期细胞比例0.07%; K-SFM组S期细胞比例17.57%,D K-SFM组S期细胞比例组15.82%;K-SFM组细胞凋亡率1.04%,D-SFM组细胞凋亡率18.69%。K-SFM组细胞EGFR表达率为33.73%;DK-SFM组细胞EGFR表达率为3.19%。结论K-SFM培养基中KC细胞生长性状、增殖活性、细胞集落数、传代次数、EGFR表达量等指标均优于DK-SFM培养基。     

Regulation of epidermal growth factor receptor expression in normal and transformed keratinocytes

Summary Transformed keratinocytes (SCC-4, SCC-15, SCC-12F2, SVK14) or normal keratinocytes which differ in their differentiation programme were used to study the regulation of EGF-receptor expression. The capacity of the cells to differentiate was modulated by changing the extracellular calcium concentration. We were able to demonstrate that EGF-receptor expression in normal and transformed keratinocytes depends upon the cell type and one or more levels of regulatory control. At the DNA level, EGF-receptor gene amplification occurred in poorly differentiating cells. At the mRNA level, cells showing EGF-receptor gene amplification expressed elevated mRNA and protein levels when cultured under low Ca²⁺ conditions. Cells not exhibiting EGF-receptor gene amplification showed equal mRNA expression, regardless the Ca²⁺ concentration in the culture medium. At the protein level, EGF-receptor protein was decreased in cells exhibiting EGF-receptor gene amplification when extracellular Ca²⁺ was increased (to 1.6 mM) to stimulate differentiation, the decrease in protein being comparable to mRNA expression. Cells not exhibiting EGF-receptor gene amplification showed equal protein expression, regardless of the Ca²⁺ concentration in the culture medium. Under the same conditions, SV40 transformed keratinocytes showed equal mRNA but elevated protein expression in cells grown under low Ca²⁺ conditions. At the membrane level, normal keratinocytes and SCC-12F2 cells showed elevated numbers of cell surface exposed EGF-receptors in cells grown under low Ca²⁺ conditions, but equal mRNA and protein expression. These and previous findings demonstrate that EGF-receptor expression is regulated at the levels of DNA, mRNA and protein as well as by the plasma membrane composition, depending upon the cell type.