- Email: [email protected]
Scarring alopecia associated with the epidermal growth factor receptor inhibitor erlotinib
J AM ACAD DERMATOL
996 Letters
MAY 2011
homing molecules may play a role in the pathogenesis of pigmentation of cutaneous metastases.5 In addition, metastatic infiltrates within the epidermis may lead to a blockade of the normal transfer of melanin to keratinocytes. Phagocytosis of melanin from melanocytes by the epithelial cells of the carcinoma has been shown (most notably in pigmented adenocarcinoma of the rectum). To our knowledge, we present one of the most extensive and destructive cases recorded in the literature of an underlying breast carcinoma presenting as ulcerated and pigmented metastatic nodules. Adam Friedman, MD,a Marc Jacobson, MD,a,b and Ranon Mann, MDa Division of Dermatology, Department of Medicinea and the Department of Pathology,b Albert Einstein College of Medicine, Bronx, New York Funding sources: None. Conflicts of interest: None declared. Correspondence to: Adam Friedman, MD, Division of Dermatology, Department of Medicine, Albert Einstein College of Medicine, 3411 Wayne Ave, 2nd floor, Bronx, NY 10461 E-mail: [email protected] REFERENCES 1. Krathen RA, Orengo IF, Rosen T. Cutaneous metastasis: a metaanalysis of data. South Med J 2003;96:164-7. 2. Jacoby R, Roses DF, Valensi Q. Carcinoma of the breast metastatic to the skin and simulating malignant melanoma. In: Ackerman AB, editor. Pathology of malignant melanoma. Chicago: Masson; 1981. pp. 263-7. 3. Wyatt AJ, Agero AL, Delgado R, Busam KJ, Marghoob AA. Cutaneous metastatic breast carcinoma with melanocyte colonization: a clinical and dermoscopic mimic of malignant melanoma. Dermatol Surg 2006;32:949-54. ~ez C, White CR Jr, Sangueza OP. 4. Requena L, Sanchez Yus E, N un Epidermotropically metastatic breast carcinomas: rare histopathologic variants mimicking melanoma and Paget’s disease. Am J Dermatopathol 1996;18:385-95. 5. Konomi K, Imayama S, Nagae S, Terasaka R, Chijiiwa K, Yashima Y. Melanocyte chemotactic factor produced by skin metastases of a breast carcinoma. J Surg Oncol 1992;50:62-6.
doi:10.1016/j.jaad.2009.08.010
Scarring alopecia associated with the epidermal growth factor receptor inhibitor erlotinib To the Editor: Erlotinib (Tarceva; Genentech, South San Francisco, CA) is an oral anticancer agent that blocks the function of the epidermal growth factor
Fig 1. A and B, Patient at presentation, with scalp erythema, pustules, and alopecia.
receptor (EGFR) and has been approved by the US Food and Drug Administration for the treatment of nonesmall cell lung and pancreatic cancers. Therapy is frequently complicated by multiple cutaneous adverse effects ranging from follicular papulopustular (‘‘acneiform’’) eruptions, xerosis, nail changes (including paronychia and pyogenic granulomas in the lateral nail folds), and hair texture changes.1 Previous reports exist of both nonscarring and scarring alopecia with gefitinib (Iressa; AstraZeneca, Wilmington, DE), another EGFR inhibitor; however, to date there are no reports of scarring alopecia with erlotinib. A 77-year-old white female with metastatic nonsmall cell lung cancer was referred to our department by her oncologist for the evaluation of scalp erythema, pustules, and alopecia (Fig 1). The scalp eruption started 18 months before the referral and within 2 weeks of initiating therapy with erlotinib 100 mg daily for progressive metastatic disease. She
J AM ACAD DERMATOL VOLUME 64, NUMBER 5
was initially treated by her oncologist with minocycline 50 mg twice daily. This was discontinued because of intolerable dizziness. She presented to the dermatology clinic with diffuse scalp erythema, many pustules, altered hair texture, alopecia, and a loss of follicular orifices at the vertex of the scalp. The patient described moderate pruritus. No other significant cutaneous findings or symptoms were present. The patient denied scalp pruritus or hair loss before beginning erlotinib therapy. Cultures for superinfection taken when the patient had been off oral antibiotics for longer than 8 months were negative. Two 4-mm punch biopsy specimens were obtained from an erythematous scaly alopecic patch on the scalp at the initial visit (Fig 2). Sections of the vertically oriented punch biopsy show chronic folliculitis and perifolliculitis with abundant plasma cells and lymphocytes and rare neutrophils and eosinophils. There was associated perifollicular fibrosis of the lower infundibular and upper isthmus portions of the hair follicles. Histiocytic and foreign body giant cell reactions around residual follicular structures were seen. Horizontally sectioned tissue showed an increased number of telogen and catagen hairs with perifollicular chronic inflammation and fibrosis consistent with a scarring alopecia. Topical clobetasol solution and oral acitretin 25 mg daily were started, given the reports of successful treatment of erlotinib-induced cutaneous side effects with low dose acitretin.2,3 Acitretin (and subsequent low dose isotretinoin at 30 mg/day) therapy led to intolerable dryness of the skin and lips and was discontinued. Because of the patient’s scalp discomfort and progressive erythema and alopecia, erlotinib therapy was held for 3 weeks. This led to marked improvement of the scalp eruption and symptoms. When erlotinib was reinitiated at a reduced dose of 50 mg daily, the patient experienced another scalp flare. Alopecia is a rare side effect of EGFR inhibitors when compared to the far more prevalent papulopustular eruption on the face and trunk. EGFR null mice have been shown to develop alopecia.4,5 Graves et al6 first described a nonscarring inflammatory alopecia in a patient soon after starting gefitinib therapy. Scarring was not present, and hair regrowth occurred after treatment was discontinued.6 Donovan et al7 described a patient who developed scarring alopecia after 8 months of gefitinib therapy. Similar histopathologic changes were reported, including chronic follicular inflammatory infiltrate, consisting mainly of plasma cells and lymphocytes, and fibrosis consistent with scarring in the upper portion of hair follicles. In the case published by
Letters 997
Fig 2. Punch biopsy specimens showing an increased number of telogen and catagen hairs with perifollicular chronic inflammation and perifollicular fibrosis consistent with a scarring alopecia. (Original magnifications: A, 340; B, 3100.)
Donovan et al,7 the authors were unable to evaluate the effect of discontinuing gefitinib treatment because their patient died shortly thereafter of widespread metastatic disease. In our case, erlotinib was discontinued for 3 weeks with significant improvement of the scalp erythema, scaling, and pustules, but without significant hair regrowth. Retrial with erlotinib, despite a dose reduction, caused a recurrence of the scalp eruption. To our knowledge, this is the first case of scarring alopecia from erlotinib that was confirmed by histopathology with a recurrence or eruption upon the reinitiation of erlotinib. We report the present case to show the possible association of scarring alopecia with not only the EGFR inhibitor gefitinib, but also another member of this class, erlotinib. We believe that this is likely a class effect—although rare—with all systemic EGFR antagonists. We thank Dr Anne Lind and Dr Omar Jassim for histopathological evaluation and photos.
Donna M. Hepper, MD, Peggy Wu, MD, and Milan J. Anadkat, MD Division of Dermatology, Washington University Saint Louis, Saint Louis, Missouri
J AM ACAD DERMATOL
998 Letters
MAY 2011
Funding sources: None. Conflicts of interest: Dr Anadkat is a speaker for ImClone and Eisai and an investigator for Hana Biosciences. The other authors have no conflicts of interest to disclose. Correspondence and reprint requests: Milan J. Anadkat, MD, Division of Dermatology, Washington University Saint Louis, Campus Box 8123, 600 S Euclid Ave, Saint Louis, MO 63108. E-mail: [email protected] REFERENCES 1. Jacot W, Bessis D, Jorda E, Ychou M, Fabbro M, Pujo JL, et al. Acneiform eruption induced by epidermal growth factor receptor inhibitors in patients with solid tumors. Br J Dermatol 2004;151:238-41. 2. Pomerantz RG, Chirinos RE, Falo LD, Geskin LJ. Acitretin for treatment of EGFR inhibitor-induced cutaneous toxic effects. Arch Dermatol 2008;144:949-50. 3. Gutzmer R, Werfel T, Mao R, Kapp A, Elsner J. Successful treatment with oral isotretinoin of acneiform skin lesions associated with cetuximab therapy. Br J Dermatol 2005;153:849-51. 4. Murillas R, Larcher F, Conti CJ, Santos M, Ullrich A, Jorcano JL. Expression of dominant negative mutant of epidermal growth factor receptor in the epidermis of transgenic mice elicits striking alterations in hair follicle development and skin structure. EMBO J 1995;14:5216-23. 5. Hansen LA, Alexander N, Hogan ME, Sundberg JP, Dlugosz A, Threadgill DW, et al. Genetically null mice reveal a central role for the epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development. Am J Pathol 1997;150:1959-75. 6. Graves JE, Jones BF, Lind AC, Heffernan MP. Nonscarring alopecia associated with the epidermal growth factor inhibitor gefitinib. J Am Acad Dermatol 2006;55:349-53. 7. Donovan JC, Ghazarian DM, Shaw JC. Scarring alopecia associated with the use of the epidermal growth factor receptor inhibitor gefitinib. Arch Dermatol 2008;144:1524-5. doi:10.1016/j.jaad.2009.08.024
Inoculation of Mycobacteria chelonae from a tattoo To the Editor: A healthy 41-year-old man presented with a 2-week history of a lower extremity rash within his 2-month-old gray tattoos (Fig 1). He reported leg pain, myalgia, fatigue, and night sweats. A clinical examination revealed tender erythematous plaques and pustules confined to the tattoos with fever and lymphadenopathy. A white blood cell count was 1200 L (normal, 3.28-9.29). He denied a similar reaction with previous tattoos. He denied a history of travel, drug use, or high-risk sexual activity. He responded poorly to a 2-week course of doxycycline. A skin biopsy specimen revealed a mixed granulomatous infiltrate with acute and chronic inflammation composed of histiocytes, lymphocytes, neutrophils, and giant cells (Fig 2). Tissue
Fig 1. Clinical presentation of scaly plaques within the margins of a gray-colored tattoo.
Fig 2. Hematoxylineeosin staining (low magnification) revealed a mixed granulomatous infiltrate with histiocytes, lymphocytes, neutrophils, and giant cells.
culture grew Mycobacterium chelonae after 2 weeks. Chest radiograph was unremarkable. HIV and viral hepatitis serologies were negative. He responded with significant improvement to dual therapy with oral clarithromycin 500 mg and levofloxacin 500 mg twice daily for 6 months. Tattoo inoculation of M chelonae has increased in frequency on a worldwide scale, with several reported cases in France, Australia, and the United States. The reported cases share the following common findings: lesions confined to gray-colored tattoos, onset within 10 days to 5 months after tattooing (average, 10.5 weeks), infection in healthy individuals, and response to macrolide and quinolone antibiotic therapy.1-4 It has been proposed that infection results from colonized tap water used to dilute the black tattoo ink to the desired gray color. The current case adds to the growing evidence that tattoo-associated mycobacterial infection is becoming a worldwide epidemic.
996 Letters
MAY 2011
homing molecules may play a role in the pathogenesis of pigmentation of cutaneous metastases.5 In addition, metastatic infiltrates within the epidermis may lead to a blockade of the normal transfer of melanin to keratinocytes. Phagocytosis of melanin from melanocytes by the epithelial cells of the carcinoma has been shown (most notably in pigmented adenocarcinoma of the rectum). To our knowledge, we present one of the most extensive and destructive cases recorded in the literature of an underlying breast carcinoma presenting as ulcerated and pigmented metastatic nodules. Adam Friedman, MD,a Marc Jacobson, MD,a,b and Ranon Mann, MDa Division of Dermatology, Department of Medicinea and the Department of Pathology,b Albert Einstein College of Medicine, Bronx, New York Funding sources: None. Conflicts of interest: None declared. Correspondence to: Adam Friedman, MD, Division of Dermatology, Department of Medicine, Albert Einstein College of Medicine, 3411 Wayne Ave, 2nd floor, Bronx, NY 10461 E-mail: [email protected] REFERENCES 1. Krathen RA, Orengo IF, Rosen T. Cutaneous metastasis: a metaanalysis of data. South Med J 2003;96:164-7. 2. Jacoby R, Roses DF, Valensi Q. Carcinoma of the breast metastatic to the skin and simulating malignant melanoma. In: Ackerman AB, editor. Pathology of malignant melanoma. Chicago: Masson; 1981. pp. 263-7. 3. Wyatt AJ, Agero AL, Delgado R, Busam KJ, Marghoob AA. Cutaneous metastatic breast carcinoma with melanocyte colonization: a clinical and dermoscopic mimic of malignant melanoma. Dermatol Surg 2006;32:949-54. ~ez C, White CR Jr, Sangueza OP. 4. Requena L, Sanchez Yus E, N un Epidermotropically metastatic breast carcinomas: rare histopathologic variants mimicking melanoma and Paget’s disease. Am J Dermatopathol 1996;18:385-95. 5. Konomi K, Imayama S, Nagae S, Terasaka R, Chijiiwa K, Yashima Y. Melanocyte chemotactic factor produced by skin metastases of a breast carcinoma. J Surg Oncol 1992;50:62-6.
doi:10.1016/j.jaad.2009.08.010
Scarring alopecia associated with the epidermal growth factor receptor inhibitor erlotinib To the Editor: Erlotinib (Tarceva; Genentech, South San Francisco, CA) is an oral anticancer agent that blocks the function of the epidermal growth factor
Fig 1. A and B, Patient at presentation, with scalp erythema, pustules, and alopecia.
receptor (EGFR) and has been approved by the US Food and Drug Administration for the treatment of nonesmall cell lung and pancreatic cancers. Therapy is frequently complicated by multiple cutaneous adverse effects ranging from follicular papulopustular (‘‘acneiform’’) eruptions, xerosis, nail changes (including paronychia and pyogenic granulomas in the lateral nail folds), and hair texture changes.1 Previous reports exist of both nonscarring and scarring alopecia with gefitinib (Iressa; AstraZeneca, Wilmington, DE), another EGFR inhibitor; however, to date there are no reports of scarring alopecia with erlotinib. A 77-year-old white female with metastatic nonsmall cell lung cancer was referred to our department by her oncologist for the evaluation of scalp erythema, pustules, and alopecia (Fig 1). The scalp eruption started 18 months before the referral and within 2 weeks of initiating therapy with erlotinib 100 mg daily for progressive metastatic disease. She
J AM ACAD DERMATOL VOLUME 64, NUMBER 5
was initially treated by her oncologist with minocycline 50 mg twice daily. This was discontinued because of intolerable dizziness. She presented to the dermatology clinic with diffuse scalp erythema, many pustules, altered hair texture, alopecia, and a loss of follicular orifices at the vertex of the scalp. The patient described moderate pruritus. No other significant cutaneous findings or symptoms were present. The patient denied scalp pruritus or hair loss before beginning erlotinib therapy. Cultures for superinfection taken when the patient had been off oral antibiotics for longer than 8 months were negative. Two 4-mm punch biopsy specimens were obtained from an erythematous scaly alopecic patch on the scalp at the initial visit (Fig 2). Sections of the vertically oriented punch biopsy show chronic folliculitis and perifolliculitis with abundant plasma cells and lymphocytes and rare neutrophils and eosinophils. There was associated perifollicular fibrosis of the lower infundibular and upper isthmus portions of the hair follicles. Histiocytic and foreign body giant cell reactions around residual follicular structures were seen. Horizontally sectioned tissue showed an increased number of telogen and catagen hairs with perifollicular chronic inflammation and fibrosis consistent with a scarring alopecia. Topical clobetasol solution and oral acitretin 25 mg daily were started, given the reports of successful treatment of erlotinib-induced cutaneous side effects with low dose acitretin.2,3 Acitretin (and subsequent low dose isotretinoin at 30 mg/day) therapy led to intolerable dryness of the skin and lips and was discontinued. Because of the patient’s scalp discomfort and progressive erythema and alopecia, erlotinib therapy was held for 3 weeks. This led to marked improvement of the scalp eruption and symptoms. When erlotinib was reinitiated at a reduced dose of 50 mg daily, the patient experienced another scalp flare. Alopecia is a rare side effect of EGFR inhibitors when compared to the far more prevalent papulopustular eruption on the face and trunk. EGFR null mice have been shown to develop alopecia.4,5 Graves et al6 first described a nonscarring inflammatory alopecia in a patient soon after starting gefitinib therapy. Scarring was not present, and hair regrowth occurred after treatment was discontinued.6 Donovan et al7 described a patient who developed scarring alopecia after 8 months of gefitinib therapy. Similar histopathologic changes were reported, including chronic follicular inflammatory infiltrate, consisting mainly of plasma cells and lymphocytes, and fibrosis consistent with scarring in the upper portion of hair follicles. In the case published by
Letters 997
Fig 2. Punch biopsy specimens showing an increased number of telogen and catagen hairs with perifollicular chronic inflammation and perifollicular fibrosis consistent with a scarring alopecia. (Original magnifications: A, 340; B, 3100.)
Donovan et al,7 the authors were unable to evaluate the effect of discontinuing gefitinib treatment because their patient died shortly thereafter of widespread metastatic disease. In our case, erlotinib was discontinued for 3 weeks with significant improvement of the scalp erythema, scaling, and pustules, but without significant hair regrowth. Retrial with erlotinib, despite a dose reduction, caused a recurrence of the scalp eruption. To our knowledge, this is the first case of scarring alopecia from erlotinib that was confirmed by histopathology with a recurrence or eruption upon the reinitiation of erlotinib. We report the present case to show the possible association of scarring alopecia with not only the EGFR inhibitor gefitinib, but also another member of this class, erlotinib. We believe that this is likely a class effect—although rare—with all systemic EGFR antagonists. We thank Dr Anne Lind and Dr Omar Jassim for histopathological evaluation and photos.
Donna M. Hepper, MD, Peggy Wu, MD, and Milan J. Anadkat, MD Division of Dermatology, Washington University Saint Louis, Saint Louis, Missouri
J AM ACAD DERMATOL
998 Letters
MAY 2011
Funding sources: None. Conflicts of interest: Dr Anadkat is a speaker for ImClone and Eisai and an investigator for Hana Biosciences. The other authors have no conflicts of interest to disclose. Correspondence and reprint requests: Milan J. Anadkat, MD, Division of Dermatology, Washington University Saint Louis, Campus Box 8123, 600 S Euclid Ave, Saint Louis, MO 63108. E-mail: [email protected] REFERENCES 1. Jacot W, Bessis D, Jorda E, Ychou M, Fabbro M, Pujo JL, et al. Acneiform eruption induced by epidermal growth factor receptor inhibitors in patients with solid tumors. Br J Dermatol 2004;151:238-41. 2. Pomerantz RG, Chirinos RE, Falo LD, Geskin LJ. Acitretin for treatment of EGFR inhibitor-induced cutaneous toxic effects. Arch Dermatol 2008;144:949-50. 3. Gutzmer R, Werfel T, Mao R, Kapp A, Elsner J. Successful treatment with oral isotretinoin of acneiform skin lesions associated with cetuximab therapy. Br J Dermatol 2005;153:849-51. 4. Murillas R, Larcher F, Conti CJ, Santos M, Ullrich A, Jorcano JL. Expression of dominant negative mutant of epidermal growth factor receptor in the epidermis of transgenic mice elicits striking alterations in hair follicle development and skin structure. EMBO J 1995;14:5216-23. 5. Hansen LA, Alexander N, Hogan ME, Sundberg JP, Dlugosz A, Threadgill DW, et al. Genetically null mice reveal a central role for the epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development. Am J Pathol 1997;150:1959-75. 6. Graves JE, Jones BF, Lind AC, Heffernan MP. Nonscarring alopecia associated with the epidermal growth factor inhibitor gefitinib. J Am Acad Dermatol 2006;55:349-53. 7. Donovan JC, Ghazarian DM, Shaw JC. Scarring alopecia associated with the use of the epidermal growth factor receptor inhibitor gefitinib. Arch Dermatol 2008;144:1524-5. doi:10.1016/j.jaad.2009.08.024
Inoculation of Mycobacteria chelonae from a tattoo To the Editor: A healthy 41-year-old man presented with a 2-week history of a lower extremity rash within his 2-month-old gray tattoos (Fig 1). He reported leg pain, myalgia, fatigue, and night sweats. A clinical examination revealed tender erythematous plaques and pustules confined to the tattoos with fever and lymphadenopathy. A white blood cell count was 1200 L (normal, 3.28-9.29). He denied a similar reaction with previous tattoos. He denied a history of travel, drug use, or high-risk sexual activity. He responded poorly to a 2-week course of doxycycline. A skin biopsy specimen revealed a mixed granulomatous infiltrate with acute and chronic inflammation composed of histiocytes, lymphocytes, neutrophils, and giant cells (Fig 2). Tissue
Fig 1. Clinical presentation of scaly plaques within the margins of a gray-colored tattoo.
Fig 2. Hematoxylineeosin staining (low magnification) revealed a mixed granulomatous infiltrate with histiocytes, lymphocytes, neutrophils, and giant cells.
culture grew Mycobacterium chelonae after 2 weeks. Chest radiograph was unremarkable. HIV and viral hepatitis serologies were negative. He responded with significant improvement to dual therapy with oral clarithromycin 500 mg and levofloxacin 500 mg twice daily for 6 months. Tattoo inoculation of M chelonae has increased in frequency on a worldwide scale, with several reported cases in France, Australia, and the United States. The reported cases share the following common findings: lesions confined to gray-colored tattoos, onset within 10 days to 5 months after tattooing (average, 10.5 weeks), infection in healthy individuals, and response to macrolide and quinolone antibiotic therapy.1-4 It has been proposed that infection results from colonized tap water used to dilute the black tattoo ink to the desired gray color. The current case adds to the growing evidence that tattoo-associated mycobacterial infection is becoming a worldwide epidemic.