"Arrow" sign: a rapid microscopic diagnosis of hair change associated with epidermal growth factor receptor inhibitors.

To the Editor: Epidermal growth factor receptor (EGFR) inhibitors have been used more and more frequently to treat advanced malignancies in recent years. The most well-known cutaneous adverse effects include acneiform eruption, paronychia, and xerosis.1Hu J.C. Sadeghi P. Pinter-Brown L.C. Yashar S. Chiu M.W. Cutaneous side effects of epidermal growth factor receptor inhibitors: clinical presentation, pathogenesis, and management.J Am Acad Dermatol. 2007; 56: 317-326Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 2Agero A.L. Dusza S.W. Benvenuto-Andrade C. Busam K.J. Myskowski P. Halpern A.C. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors.J Am Acad Dermatol. 2006; 55: 657-670Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar Others such as hyperpigmentation, telangiectasia, hair change, and alopecia are less commonly seen.3Graves J.E. Jones B.F. Lind A.C. Heffernan M.P. Nonscarring inflammatory alopecia associated with the epidermal growth factor receptor inhibitor gefitinib.J Am Acad Dermatol. 2006; 55: 349-353Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 4Pongpudpunth M. Demierre M.F. Goldberg L.J. A case report of inflammatory nonscarring alopecia associated with the epidermal growth factor receptor inhibitor erlotinib.J Cutan Pathol. 2009; 36: 1303-1307Crossref PubMed Scopus (22) Google Scholar, 5Lin S.S. Tsai T.H. Yang H.H. Rare cutaneous side-effect of gefitinib masquerading as superficial dermatophytosis.Clin Exp Dermatol. 2009; 34: 528-530Crossref PubMed Scopus (4) Google Scholar We report a new and rapid diagnostic method using microscopic examination in plucked hairs from patients having hair change and hair loss with or without pustule formation under the treatment of EGFR inhibitors. Altogether there were 13 patients with stage IV lung cancer, 6 female and 7 male, ages 32 to 78 years, under the treatment of gefitinib or erlotinib (clinical summary in Table I, and patient 1 in Fig 1, A). In normal control of a well-plucked anagen hair, a large caliber of hair root with a pigmented bulb and firmly attached inner and outer root sheaths can be seen. In these 13 cases summarized in Table I, plucked anagen hairs all showed similar degeneration of the distal part of root sheaths (Fig 1, B, red arrow) and a distal split of the remaining proximal part (Fig 1, B, blue arrowhead), giving an “arrow” appearance microscopically. This arrow sign can be found not only in patents reporting hair or scalp change, but also in those patients having no detectable hair loss or scalp change (patients 12 and 13). The histopathology (Fig 1, C, patient 3) showed an atrophic outer root sheath with more obvious change in the distal third part. There is a cleftlike area over the outer root sheath (Fig 1, C, arrowheads), and the distal part from the cleft showed an obvious atrophy of the outer root sheath (Fig 1, C, arrows), which is compatible with the findings in Fig 1, B (red arrow).Table IClinical summary of patients under treatment of epidermal growth factor receptor inhibitorsPatient no.Age, y/sexCancer type and stageMedication and dosageTime interval from starting treatment to having hair and scalp changeScalp change∗Severe = multiple erythematous papules, pustules, and crusts; moderate = multiple erythematous papules, and sometimes pustules; mild = some erythematous papules intermittently. (erythematous papules, pustules, and crusts)Hair lossTypical “arrow” sign149/FAdenocarcinoma of lung, stage IVGefitinib 250 mg/d2 moSevere+, Vertex+273/FBronchoalveolar cancer of lung, stage IVErlotinib 150 mg/d3 moSevere+, Diffuse, especially over vertex+378/FAdenocarcinoma of lung, stage IVGefitinib 250 mg/d7 moSevere+, Diffuse, especially over vertex+463/MAdenocarcinoma of lung, stage IVErlotinib 150 mg/d2 moModerate+, Occiput+532/MAdenocarcinoma of lung, stage IVGefitinib 250 mg/d1 moMild+, Diffuse, especially over vertex+656/MAdenocarcinoma of lung, stage IVGefitinib 250 mg/d3 moMild+, Diffuse, especially over vertex+771/MAdenocarcinoma of lung, stage IVGefitinib 250 mg/d3 moMild+, Mild, diffuse+871/MAdenocarcinoma of lung, stage IVErlotinib 150 mg/d2 moNo lesions on presentation, but with previous scalp change+, Diffuse, especially over vertex+967/FAdenocarcinoma of lung, stage IVGefitinib 250 mg/d3 moNo lesions on presentation, but with previous scalp change+, Diffuse, especially over vertex and occiput+1057/MAdenocarcinoma of lung, stage IVGefitinib 250 mg/d6 moNo lesions on presentation, but with previous scalp change+, Mild, diffuse+1162/FAdenocarcinoma of lung, stage IVErlotinib 150 mg/d3 moNo lesions on presentation, but with previous scalp change+, Mild, vertex+1276/MAdenocarcinoma of lung, stage IVGefitinib 250 mg/dDenied having hair or scalp change after 12 moNo lesions noted before and at presentation–+1355/FAdenocarcinoma of lung, stage IVGefitinib 250 mg/dDenied having hair or scalp change after 6.5 moNo lesions noted before and at presentation–+F, Female; M, male.∗ Severe = multiple erythematous papules, pustules, and crusts; moderate = multiple erythematous papules, and sometimes pustules; mild = some erythematous papules intermittently. Open table in a new tab F, Female; M, male. To do a microscopic examination, hairs should be obtained from the scalp by forcibly plucking the hair shafts. Put the hairs on the slides, and cover with a cover glass. To facilitate the examination, add a few drops of potassium hydroxide solution, then press the cover glass gently to squeeze out the air and fully immerse the hair in the potassium hydroxide solution. If a telogen is plucked, because of the shrinkage of telogen hair bulb, it does not have diagnostic value. Because a mixture of anagen and telogen hairs will be plucked and the process of plucking anagen hairs may lead to artificial distortion with one or both of the root sheaths missing from the bulbs, at least 5 hairs should be obtained from a single patient for a proper diagnosis. Because EGFR is overexpressed in many solid tumors, its therapeutic blockade is beneficial by the effects on cancer growth and spread.2Agero A.L. Dusza S.W. Benvenuto-Andrade C. Busam K.J. Myskowski P. Halpern A.C. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors.J Am Acad Dermatol. 2006; 55: 657-670Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar EGFRs are also expressed on epidermal keratinocytes, hair follicle epithelium (especially outer root sheath), and the sweat gland apparatus,2Agero A.L. Dusza S.W. Benvenuto-Andrade C. Busam K.J. Myskowski P. Halpern A.C. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors.J Am Acad Dermatol. 2006; 55: 657-670Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar so cutaneous adverse effects are commonly seen. However, hair change and alopecia with or without pustular eruptions on the scalp that occur after an average of 7 to 10 weeks of treatment are less commonly reported.3Graves J.E. Jones B.F. Lind A.C. Heffernan M.P. Nonscarring inflammatory alopecia associated with the epidermal growth factor receptor inhibitor gefitinib.J Am Acad Dermatol. 2006; 55: 349-353Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 4Pongpudpunth M. Demierre M.F. Goldberg L.J. A case report of inflammatory nonscarring alopecia associated with the epidermal growth factor receptor inhibitor erlotinib.J Cutan Pathol. 2009; 36: 1303-1307Crossref PubMed Scopus (22) Google Scholar, 5Lin S.S. Tsai T.H. Yang H.H. Rare cutaneous side-effect of gefitinib masquerading as superficial dermatophytosis.Clin Exp Dermatol. 2009; 34: 528-530Crossref PubMed Scopus (4) Google Scholar In this report, we find a characteristic arrow appearance hair change microscopically that has never been reported before to our knowledge. A possible mechanism is that the targeted EGFR on the hair follicle epithelium leads to the degeneration and fragility of root sheaths. In summary, this characteristic microscopic arrow sign can be used to make the rapid diagnosis of EGFR inhibitor–related hair change, and to rule out the possibility of fungal infection at the same time because the clinical presentation may sometimes be masquerading as tinea capitis.