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course controlled by a slow taper of prednisone with onset of symptoms around the time of her CD diagnosis. As in our patient, cPAN is generally responsive to corticosteroids.3,4 Nonsteroidal anti-inflammatory medications may be useful for prevention and treatment of mild flares and were successfully employed in our patient. We present an instructive case of cPAN presenting as a solitary blue toe to make clinicians aware of this unusual presentation in order to facilitate initiation of appropriate work-up and therapy. Amanda Joy Tschetter, MD,a Vincent Liu, MD,a,b and Karolyn A. Wanat, MDa,b Department of Dermatologya and Department of Pathologyb at the University of Iowa Hospitals and Clinics, Iowa City Funding sources: None. Conflicts of interest: None declared. Correspondence to: Amanda Joy Tschetter, MD, 200 Hawkins Drive, Iowa City, Iowa 52242 E-mail: [email protected] REFERENCES 1. Hirschmann JV, Raugi GJ. Blue (or purple) toe syndrome. J Am Acad Dermatol 2009;60:1-22. 2. Begon E, Bouilly P, Cheysson E, Cohen P, Bachmeyer C. Isolated blue toe syndrome as the initial sign of Wegener granulomatosis. Am J Med 2010;123:e7-8. 3. Daoud MS, Hutton KP, Gibson LE. Cutaneous periarteritis nodosa: a clinicopathological study of 79 cases. Br J Dermatol 1997;136:706-13. 4. Komatsuda A, Kinoshita K, Togashi M, Maki N, Masai R, Niitsu H, et al. Cutaneous polyarteritis nodosa in a patient with Crohn’s disease. Mod Rheumatol 2008;18:639-42. 5. Magnant J, Lhommet C, Machet L, Machet MC, Guilmot JL, Diot E. [Cutaneous polyarteritis nodosa and Crohn’s disease: an association not to be ignored]. Rev Med Interne 2009;30: 345-8. http://dx.doi.org/10.1016/j.jaad.2014.03.037
Major response to vemurafenib in patient with severe cutaneous Langerhans cell histiocytosis harboring BRAF V600E mutation To the Editor: We report the case of a female patient in her 90s with a history of age-related macular degeneration and pulmonary embolism. In 2011, she presented with pruritic, erythematous, confluent, maculopapular skin lesions located on the trunk, inframammary fold, groin, and genital and perianal areas. Histology of a skin biopsy revealed a mononuclear cell infiltrate that was morphologically and phenotypically consistent with Langerhans cell
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histiocytosis (LCH) expressing CD1a and S100protein by immunohistochemistry. A body computed tomography scan showed no visceral involvement, the patient had no exophthalmos or diabetes insipidus, and laboratory tests related to LCH secondary localizations were normal (eg, inflammatory and hepatic markers, hemogram). Subsequently, a diagnosis of single system cutaneous LCH was established. Topical and systemic corticosteroid treatments failed to elicit any clinical improvement as first-line treatment, and the patient was suffering from chronic and severe pruritus and pain, affecting her quality of life that declined significantly. A second line of systemic treatment with thalidomide was initiated but was quickly discontinued because the patient experienced minor clinical response with major side effects such as dizziness, asthenia, and impaired coordination. Recently, she experienced a severe new flare of her disease with multiple papulonodular lesions in the same skin areas (Fig 1, before). The patient complained of major pain and had suicidal ideation related to her intolerable skin discomfort. No extracutaneous involvement was found, and a new biopsy confirmed the diagnosis of widespread single system cutaneous LCH (Fig 2, A-C). In conjunction with this finding, the DNA from the biopsy was extracted and a pyrosequencing analysis revealed a BRAF V600E mutation, as expected for up to 57% of LCH cases.1 After a multidisciplinary consultation, she was started on a third-line vemurafenib treatment, (960 mg orally twice a day) immediately after obtaining written informed consent. Vemurafenib induced a major clinical improvement in the first days of treatment. The patient was seen for follow-up 3 weeks after vemurafenib introduction and showed indisputable regression of her cutaneous lesions. Moreover, histopathologic and immunohistochemical studies confirmed the clinical response, in that a new biopsy revealed the absence of remaining cells expressing LCH markers (Fig 2, D and E). After the third month of treatment, the clinical response remained stable and after 6 months of vemurafenib, only scar tissue was noticeable (Fig 1, after). Vemurafenib is an anti-BRAF targeted therapy approved for the treatment of metastatic unresectable melanoma with V600 mutations; sensitivity to this molecule was recently demonstrated for BRAF mutated non-LCH (ie, CD1- negative ErdheimChester disease).2 Here we report a major clinical response to vemurafenib for refractory, widespread, skin-limited, pure LCH carrying the BRAF V600E
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Fig 1. Langerhans cell histiocytosis and vemurafenib response. Inframammary folds (upper images) and left groin area (lower images) before and after a 6-months period of vemurafenib treatment.
mutation. According to other frequent localizations of LCH, it would also be important to evaluate whether vemurafenib can diffuse and be effective in bones and brain. The rapid response and remarkable efficacy of vemurafenib in this case should encourage practitioners to perform systematic BRAF gene mutation testing for LCH patients. These results also suggest that this strategy could become a new gold standard first-line treatment for BRAF V600E LCH after further validation in prospective multicenter trials. We thank Dr Lucie Sancey, PhD, for expert graphical artwork and Dr Stratton Beatrous, MD, for manuscript revision.
Julie Charles, MD, PhD,a Jean-Claude Beani, MD,a Giacomo Fiandrino, MD,c and Benoit Busser, PharmD, PhDb Dermatology Unita and Cancer Clinical b Laboratory, Univ. Grenoble Alpes, IAB, CHU de Grenoble, and Department of Pathology, CHU de Grenoble,c F-38000 Grenoble, France Funding sources: None. Conflicts of interest: None declared. Correspondence to: Julie Charles, MD, PhD, Dermatology Unit, CHU de Grenoble, CS 10217 F-38043, Grenoble cedex 09 E-mail: [email protected]
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VOLUME 71, NUMBER 3
Fig 2. Histologic and immunohistologic pictures of Langerhans cell histiocytosis. A, Histologically, tumor cells were medium-sized, with grooved or indented nuclei and abundant eosinophilic cytoplasms. Moderate cellular pleomorphism was also a feature. Mitoses were not exceptional, with absence of overtly atypical forms. B, Low-power view of the biopsy specimen before treatment. C, Tumor cells were uniformly stained by the CD1a antibody, which also highlighted epidermotropic tumor cells. D, After 3 weeks of vemurafenib treatment, the dermal infiltrate had entirely disappeared, being replaced by mixed inflammatory cells. E, After treatment, immunostaining for CD1a was restricted to skin-resident Langerhans cells. (A, B, and D, Hematoxylin-eosin stain; original magnifications: A, 340; B, 32.5; D, 32.5. C and E, SABC; original magnifications: C, 310; E, 35.) REFERENCES 1. Badalian-Very G, Vergilio JA, Degar BA, MacConaill LE, Brandner B, Calicchio ML, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 2010;116:1919-23. 2. Haroche J, Cohen-Aubart F, Emile JF, Arnaud L, Maksud P, Charlotte F, et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 2013;121:1495-500. http://dx.doi.org/10.1016/j.jaad.2014.03.038
Extensive scleredema adultorum with loss of eccrine glands To the Editor: Scleredema adultorum is a disease characterized by woody induration of the skin,1 in which the skin appendages are usually preserved. Here, we report a case of scleredema adultorum with loss of eccrine glands leading to frequent heat strokes. A 50-year-old Taiwanese woman visited us for hardened and thickened skin extending from the nape to the lower aspect of her back over the past 5
years. Her back became anhidrotic and the front of her trunk seemed hyperhidrotic. In the meantime, she became progressively intolerant to heat and experienced several episodes of heat strokes. She refrained from outdoor activities to avoid heat strokes. She had a 20-year history of type 2 diabetes mellitus under insulin treatment over the past 10 years. She denied previous radiotherapy, topical medications, toxin exposure, or family history of similar skin changes. Neither photosensitivity nor arthritis was present. Examination revealed the skin from her nape to the lower aspect of her back was hardened and thickened, except the side aspects. The overlying skin was slightly erythematous with preservation of the hair follicles. Starch-iodine test showed the lesional skin was anhidrotic (Fig 1). Her blood tests were negative for antinuclear antibody, anti-Scl-70 antibody, and rheumatoid factor and pulmonary function test result was within normal limits. Fasting glucose level was 234 mg/dL and hemoglobin A1c (HbA1c) was 9.6%.
course controlled by a slow taper of prednisone with onset of symptoms around the time of her CD diagnosis. As in our patient, cPAN is generally responsive to corticosteroids.3,4 Nonsteroidal anti-inflammatory medications may be useful for prevention and treatment of mild flares and were successfully employed in our patient. We present an instructive case of cPAN presenting as a solitary blue toe to make clinicians aware of this unusual presentation in order to facilitate initiation of appropriate work-up and therapy. Amanda Joy Tschetter, MD,a Vincent Liu, MD,a,b and Karolyn A. Wanat, MDa,b Department of Dermatologya and Department of Pathologyb at the University of Iowa Hospitals and Clinics, Iowa City Funding sources: None. Conflicts of interest: None declared. Correspondence to: Amanda Joy Tschetter, MD, 200 Hawkins Drive, Iowa City, Iowa 52242 E-mail: [email protected] REFERENCES 1. Hirschmann JV, Raugi GJ. Blue (or purple) toe syndrome. J Am Acad Dermatol 2009;60:1-22. 2. Begon E, Bouilly P, Cheysson E, Cohen P, Bachmeyer C. Isolated blue toe syndrome as the initial sign of Wegener granulomatosis. Am J Med 2010;123:e7-8. 3. Daoud MS, Hutton KP, Gibson LE. Cutaneous periarteritis nodosa: a clinicopathological study of 79 cases. Br J Dermatol 1997;136:706-13. 4. Komatsuda A, Kinoshita K, Togashi M, Maki N, Masai R, Niitsu H, et al. Cutaneous polyarteritis nodosa in a patient with Crohn’s disease. Mod Rheumatol 2008;18:639-42. 5. Magnant J, Lhommet C, Machet L, Machet MC, Guilmot JL, Diot E. [Cutaneous polyarteritis nodosa and Crohn’s disease: an association not to be ignored]. Rev Med Interne 2009;30: 345-8. http://dx.doi.org/10.1016/j.jaad.2014.03.037
Major response to vemurafenib in patient with severe cutaneous Langerhans cell histiocytosis harboring BRAF V600E mutation To the Editor: We report the case of a female patient in her 90s with a history of age-related macular degeneration and pulmonary embolism. In 2011, she presented with pruritic, erythematous, confluent, maculopapular skin lesions located on the trunk, inframammary fold, groin, and genital and perianal areas. Histology of a skin biopsy revealed a mononuclear cell infiltrate that was morphologically and phenotypically consistent with Langerhans cell
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histiocytosis (LCH) expressing CD1a and S100protein by immunohistochemistry. A body computed tomography scan showed no visceral involvement, the patient had no exophthalmos or diabetes insipidus, and laboratory tests related to LCH secondary localizations were normal (eg, inflammatory and hepatic markers, hemogram). Subsequently, a diagnosis of single system cutaneous LCH was established. Topical and systemic corticosteroid treatments failed to elicit any clinical improvement as first-line treatment, and the patient was suffering from chronic and severe pruritus and pain, affecting her quality of life that declined significantly. A second line of systemic treatment with thalidomide was initiated but was quickly discontinued because the patient experienced minor clinical response with major side effects such as dizziness, asthenia, and impaired coordination. Recently, she experienced a severe new flare of her disease with multiple papulonodular lesions in the same skin areas (Fig 1, before). The patient complained of major pain and had suicidal ideation related to her intolerable skin discomfort. No extracutaneous involvement was found, and a new biopsy confirmed the diagnosis of widespread single system cutaneous LCH (Fig 2, A-C). In conjunction with this finding, the DNA from the biopsy was extracted and a pyrosequencing analysis revealed a BRAF V600E mutation, as expected for up to 57% of LCH cases.1 After a multidisciplinary consultation, she was started on a third-line vemurafenib treatment, (960 mg orally twice a day) immediately after obtaining written informed consent. Vemurafenib induced a major clinical improvement in the first days of treatment. The patient was seen for follow-up 3 weeks after vemurafenib introduction and showed indisputable regression of her cutaneous lesions. Moreover, histopathologic and immunohistochemical studies confirmed the clinical response, in that a new biopsy revealed the absence of remaining cells expressing LCH markers (Fig 2, D and E). After the third month of treatment, the clinical response remained stable and after 6 months of vemurafenib, only scar tissue was noticeable (Fig 1, after). Vemurafenib is an anti-BRAF targeted therapy approved for the treatment of metastatic unresectable melanoma with V600 mutations; sensitivity to this molecule was recently demonstrated for BRAF mutated non-LCH (ie, CD1- negative ErdheimChester disease).2 Here we report a major clinical response to vemurafenib for refractory, widespread, skin-limited, pure LCH carrying the BRAF V600E
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SEPTEMBER 2014
Fig 1. Langerhans cell histiocytosis and vemurafenib response. Inframammary folds (upper images) and left groin area (lower images) before and after a 6-months period of vemurafenib treatment.
mutation. According to other frequent localizations of LCH, it would also be important to evaluate whether vemurafenib can diffuse and be effective in bones and brain. The rapid response and remarkable efficacy of vemurafenib in this case should encourage practitioners to perform systematic BRAF gene mutation testing for LCH patients. These results also suggest that this strategy could become a new gold standard first-line treatment for BRAF V600E LCH after further validation in prospective multicenter trials. We thank Dr Lucie Sancey, PhD, for expert graphical artwork and Dr Stratton Beatrous, MD, for manuscript revision.
Julie Charles, MD, PhD,a Jean-Claude Beani, MD,a Giacomo Fiandrino, MD,c and Benoit Busser, PharmD, PhDb Dermatology Unita and Cancer Clinical b Laboratory, Univ. Grenoble Alpes, IAB, CHU de Grenoble, and Department of Pathology, CHU de Grenoble,c F-38000 Grenoble, France Funding sources: None. Conflicts of interest: None declared. Correspondence to: Julie Charles, MD, PhD, Dermatology Unit, CHU de Grenoble, CS 10217 F-38043, Grenoble cedex 09 E-mail: [email protected]
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Fig 2. Histologic and immunohistologic pictures of Langerhans cell histiocytosis. A, Histologically, tumor cells were medium-sized, with grooved or indented nuclei and abundant eosinophilic cytoplasms. Moderate cellular pleomorphism was also a feature. Mitoses were not exceptional, with absence of overtly atypical forms. B, Low-power view of the biopsy specimen before treatment. C, Tumor cells were uniformly stained by the CD1a antibody, which also highlighted epidermotropic tumor cells. D, After 3 weeks of vemurafenib treatment, the dermal infiltrate had entirely disappeared, being replaced by mixed inflammatory cells. E, After treatment, immunostaining for CD1a was restricted to skin-resident Langerhans cells. (A, B, and D, Hematoxylin-eosin stain; original magnifications: A, 340; B, 32.5; D, 32.5. C and E, SABC; original magnifications: C, 310; E, 35.) REFERENCES 1. Badalian-Very G, Vergilio JA, Degar BA, MacConaill LE, Brandner B, Calicchio ML, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 2010;116:1919-23. 2. Haroche J, Cohen-Aubart F, Emile JF, Arnaud L, Maksud P, Charlotte F, et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 2013;121:1495-500. http://dx.doi.org/10.1016/j.jaad.2014.03.038
Extensive scleredema adultorum with loss of eccrine glands To the Editor: Scleredema adultorum is a disease characterized by woody induration of the skin,1 in which the skin appendages are usually preserved. Here, we report a case of scleredema adultorum with loss of eccrine glands leading to frequent heat strokes. A 50-year-old Taiwanese woman visited us for hardened and thickened skin extending from the nape to the lower aspect of her back over the past 5
years. Her back became anhidrotic and the front of her trunk seemed hyperhidrotic. In the meantime, she became progressively intolerant to heat and experienced several episodes of heat strokes. She refrained from outdoor activities to avoid heat strokes. She had a 20-year history of type 2 diabetes mellitus under insulin treatment over the past 10 years. She denied previous radiotherapy, topical medications, toxin exposure, or family history of similar skin changes. Neither photosensitivity nor arthritis was present. Examination revealed the skin from her nape to the lower aspect of her back was hardened and thickened, except the side aspects. The overlying skin was slightly erythematous with preservation of the hair follicles. Starch-iodine test showed the lesional skin was anhidrotic (Fig 1). Her blood tests were negative for antinuclear antibody, anti-Scl-70 antibody, and rheumatoid factor and pulmonary function test result was within normal limits. Fasting glucose level was 234 mg/dL and hemoglobin A1c (HbA1c) was 9.6%.
