Letters to the Editor
4 Oetting WS, Handoko HY, Mentink MM, Paller AS, White JG, King RA. Molecular analysis of an extended family with type IA (tyrosinase-negative) oculocutaneous albinism. J Invest Dermatol 1991; 97: 15–19. 5 Inagaki K, Suzuki T, Ito S et al. OCA4: evidence for a founder effect for the p.D157N mutation of the MATP gene in Japanese and Korean. Pigment Cell Res 2005; 18: 385–388.
SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Figure S1. Methods for reverse transcriptase-PCR analysis.
Reversible hair depigmentation in a Japanese female treated with pazopanib Dear Editor, Soft tissue sarcoma (STS) comprises a heterogeneous group of rare tumors that require multidisciplinary medical treatment, including surgery, chemotherapy and radiotherapy. With respect to chemotherapy for STS, doxorubicin and ifosfamide have been shown to have activity against STS and are used as first-line chemotherapy. However, progress in the development of new therapeutic options for treating STS has been limited within the past few decades. Pazopanib is a novel oral multi-targeted tyrosine kinase inhibitor (TKI) that acts via various receptors, including vascular endothelial growth factor receptor (VEGFR) types 1, 2 and 3, platelet-derived factor receptor (PDGFR) a and b and stem-cell factor receptor (c-Kit). This drug was approved as a new treatment agent for patients with metastatic STS that fails to respond to first-line chemotherapy following a recent randomized phase III clinical trial.1 Although pazopanib exhibits efficacy in patients with metastatic STS, it is associated with various adverse events, including cutaneous complications, with hair depigmentation being one of the most common symptoms. We herein report the case of a Japanese female with metastatic sarcoma who experienced reversible hair depigmentation under pazopanib therapy. A 32-year-old Japanese female was diagnosed with intermediate-grade myofibroblastic sarcoma arising from the right hip in 2005. Despite wide resection with the placement of a hip prosthesis and pedicled abdominal flap, multiple lung, lymph node and subcutaneous metastases developed 2 years after the operation. Although the behavior of the tumor was indolent, she started treatment with pazopanib (starting dose, 800 mg daily orally, continuously) in February 2013 after the failure of three cycles of standard chemotherapy. Two months after the initial treatment with pazopanib, she noticed depigmentation of her hair, although no other adverse events associated with pazopanib were observed. In October 2013, the pazopanib therapy was discontinued due to the need for another operation to treat a deep infection associated with necrosis of the subcutaneous metastasis on the patient’s right knee. Surprisingly, she noticed hair repigmentation as early as 2 months after the discontinuation of pazopanib therapy (Fig. 1).
Figure 1. Hair depigmentation was observed 2 months after the initial treatment with pazopanib, and hair darkened remarkably 2 months after pazopanib discontinuation. The use of multi-targeted TKI as cancer therapy is increasing. One of the adverse events of multi-targeted TKI treatment is hair depigmentation, likely due to the inhibition of c-Kit, which plays a critical role in melanocyte proliferation, differentiation and migration.2 Imatinib, sunitinib, sorafenib, dasatinib and pazopanib all inhibit c-Kit and have previously been reported to promote hair depigmentation.1,3–5 However, the rate of depigmentation varies and the quantifiable degree of depigmentation has not been assessed. Nevertheless, one study reported hair depigmentation in 38% of patients treated with pazopanib, compared to 2% of patients treated with a placebo.1 Hair depigmentation thus occurs more frequently in association with pazopanib therapy than with other TKIs. Therefore, further studies to evaluate the incidence of hair depigmentation among TKIs in context with the genetic background factors of patients with hair depigmentation would contribute to understanding the mechanisms underlying hair
Correspondence: Eisuke Kobayashi, M.D., Ph.D., Division of Musculoskeletal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Email: [email protected]
© 2014 Japanese Dermatological Association
1021
Letters to the Editor
depigmentation. Moreover, evaluation is desirable for the possibility of hair depigmentation being a hallmark of efficacy of TKI.
CONFLICT OF INTEREST:
The authors have no conflict of
interest to declare.
Eisuke KOBAYASHI,1 Taro KOYAMA,2,3 Kazuhiro KOBAYASHI,2,3 Nokitaka SETSU,1 Makoto KAWASHIMA,2,4 Akira KAWAI1 1
2
Division of Musculoskeletal Oncology, National Cancer Center Hospital, NPO Future Medical Laboratory, 3Men’s Health Clinic, and 4Department of Dermatology, Tokyo Women’s Medical University, Tokyo, Japan
REFERENCES 1 Van der Graaf WT, Blay JY, Chawla SP et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012; 379: 1879–1886. 2 Tobin DJ. Human hair pigmentation–biological aspects. Int J Cosmet Sci 2008; 30: 233–257. 3 Brzezniak C, Szabo E. Images in clinical medicine. Sunitinibassociated hair depigmentation. N Engl J Med 2014; 24: e27. 4 Brazzelli V, Grasso V, Barbaccia V et al. Hair depigmentation and vitiligo-like lesions in a leukaemic paediatric patient during chemotherapy with dasatinib. Acta Derm Venereol 2012; 92: 218–219. 5 Yun SK, Song KH, Hwang SR et al. Hair graying and loss induced by imatinib mesylate. J Dermatol 2014; 41: 107–108.
doi: 10.1111/1346-8138.12654
Pazopanib-induced leg ulcer in a patient with malignant fibrous histiocytoma Dear Editor, Pazopanib is an oral, multi-targeted, tyrosine kinase inhibitor that has recently been approved for advanced soft tissue sarcoma. We herein report a patient with malignant fibrous histiocytoma treated with pazopanib who developed severe leg ulcers without progression of lung metastasis. An 84-year-old Japanese woman noticed a red nodule on her right forearm and visited a clinic in March 2012. Histopathological findings of the skin biopsy specimen were suggestive of soft tissue sarcoma and she was referred to our hospital. A firm, immobile, red tumor measuring 45 mm 9 35 mm in diameter was noted (Fig. 1a). Additional radiological examinations revealed no metastasis. Surgical local excision was performed and positive deep margins were evident histologically. Atypical spindle cells with bizarre nuclei increased in vague intricate pattern. Immunohistochemical results were not positive for S100, CD34, CD68, smooth muscle actin or desmin. Therefore, diagnosis was pleomorphic malignant fibrous histiocytoma with pT1aN0M0 (stage IA). Five months later, the red nodule recurred at the same site, and computed tomography revealed a new nodule in the right lung suggestive of distant metastasis. Surgical excision again revealed positive deep margins. She declined to undergo radiotherapy, multi-agent chemotherapy as an inpatient or radical excision that might have resulted in dysfunction because of her advanced age and dementia. We therefore started pazopanib (800 mg) on an outpatient basis. Because of serious adverse reactions (grade 3), such as hypertension, fatigue and anorexia, pazopanib was immediately discontinued. After the patient completely recovered from these adverse events, pazopanib was restarted at 400 mg. However, small skin erosions developed on both lower legs that were
associated with stasis dermatitis (Fig. 1b), and severe leg ulcers developed 2 weeks after the second administration of pazopanib (Fig. 1c). Ultrasonogram, enhanced computed tomography and laboratory data ruled out the thrombosis and
(a)
(b)
(c)
(d)
Figure 1. Clinical appearance of (a) a tumor on the right forearm at the first visit, (b) the skin ulcers on the left lower leg before the second pazopanib treatment, (c) 2 weeks after treatment with pazopanib 400 mg and (d) 8 weeks after cessation of pazopanib.
Correspondence: Hiroyuki Fujita, M.D., Ph.D., Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa, Yokohama 236-0004, Japan. Email: [email protected]
1022
© 2014 Japanese Dermatological Association
4 Oetting WS, Handoko HY, Mentink MM, Paller AS, White JG, King RA. Molecular analysis of an extended family with type IA (tyrosinase-negative) oculocutaneous albinism. J Invest Dermatol 1991; 97: 15–19. 5 Inagaki K, Suzuki T, Ito S et al. OCA4: evidence for a founder effect for the p.D157N mutation of the MATP gene in Japanese and Korean. Pigment Cell Res 2005; 18: 385–388.
SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Figure S1. Methods for reverse transcriptase-PCR analysis.
Reversible hair depigmentation in a Japanese female treated with pazopanib Dear Editor, Soft tissue sarcoma (STS) comprises a heterogeneous group of rare tumors that require multidisciplinary medical treatment, including surgery, chemotherapy and radiotherapy. With respect to chemotherapy for STS, doxorubicin and ifosfamide have been shown to have activity against STS and are used as first-line chemotherapy. However, progress in the development of new therapeutic options for treating STS has been limited within the past few decades. Pazopanib is a novel oral multi-targeted tyrosine kinase inhibitor (TKI) that acts via various receptors, including vascular endothelial growth factor receptor (VEGFR) types 1, 2 and 3, platelet-derived factor receptor (PDGFR) a and b and stem-cell factor receptor (c-Kit). This drug was approved as a new treatment agent for patients with metastatic STS that fails to respond to first-line chemotherapy following a recent randomized phase III clinical trial.1 Although pazopanib exhibits efficacy in patients with metastatic STS, it is associated with various adverse events, including cutaneous complications, with hair depigmentation being one of the most common symptoms. We herein report the case of a Japanese female with metastatic sarcoma who experienced reversible hair depigmentation under pazopanib therapy. A 32-year-old Japanese female was diagnosed with intermediate-grade myofibroblastic sarcoma arising from the right hip in 2005. Despite wide resection with the placement of a hip prosthesis and pedicled abdominal flap, multiple lung, lymph node and subcutaneous metastases developed 2 years after the operation. Although the behavior of the tumor was indolent, she started treatment with pazopanib (starting dose, 800 mg daily orally, continuously) in February 2013 after the failure of three cycles of standard chemotherapy. Two months after the initial treatment with pazopanib, she noticed depigmentation of her hair, although no other adverse events associated with pazopanib were observed. In October 2013, the pazopanib therapy was discontinued due to the need for another operation to treat a deep infection associated with necrosis of the subcutaneous metastasis on the patient’s right knee. Surprisingly, she noticed hair repigmentation as early as 2 months after the discontinuation of pazopanib therapy (Fig. 1).
Figure 1. Hair depigmentation was observed 2 months after the initial treatment with pazopanib, and hair darkened remarkably 2 months after pazopanib discontinuation. The use of multi-targeted TKI as cancer therapy is increasing. One of the adverse events of multi-targeted TKI treatment is hair depigmentation, likely due to the inhibition of c-Kit, which plays a critical role in melanocyte proliferation, differentiation and migration.2 Imatinib, sunitinib, sorafenib, dasatinib and pazopanib all inhibit c-Kit and have previously been reported to promote hair depigmentation.1,3–5 However, the rate of depigmentation varies and the quantifiable degree of depigmentation has not been assessed. Nevertheless, one study reported hair depigmentation in 38% of patients treated with pazopanib, compared to 2% of patients treated with a placebo.1 Hair depigmentation thus occurs more frequently in association with pazopanib therapy than with other TKIs. Therefore, further studies to evaluate the incidence of hair depigmentation among TKIs in context with the genetic background factors of patients with hair depigmentation would contribute to understanding the mechanisms underlying hair
Correspondence: Eisuke Kobayashi, M.D., Ph.D., Division of Musculoskeletal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Email: [email protected]
© 2014 Japanese Dermatological Association
1021
Letters to the Editor
depigmentation. Moreover, evaluation is desirable for the possibility of hair depigmentation being a hallmark of efficacy of TKI.
CONFLICT OF INTEREST:
The authors have no conflict of
interest to declare.
Eisuke KOBAYASHI,1 Taro KOYAMA,2,3 Kazuhiro KOBAYASHI,2,3 Nokitaka SETSU,1 Makoto KAWASHIMA,2,4 Akira KAWAI1 1
2
Division of Musculoskeletal Oncology, National Cancer Center Hospital, NPO Future Medical Laboratory, 3Men’s Health Clinic, and 4Department of Dermatology, Tokyo Women’s Medical University, Tokyo, Japan
REFERENCES 1 Van der Graaf WT, Blay JY, Chawla SP et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012; 379: 1879–1886. 2 Tobin DJ. Human hair pigmentation–biological aspects. Int J Cosmet Sci 2008; 30: 233–257. 3 Brzezniak C, Szabo E. Images in clinical medicine. Sunitinibassociated hair depigmentation. N Engl J Med 2014; 24: e27. 4 Brazzelli V, Grasso V, Barbaccia V et al. Hair depigmentation and vitiligo-like lesions in a leukaemic paediatric patient during chemotherapy with dasatinib. Acta Derm Venereol 2012; 92: 218–219. 5 Yun SK, Song KH, Hwang SR et al. Hair graying and loss induced by imatinib mesylate. J Dermatol 2014; 41: 107–108.
doi: 10.1111/1346-8138.12654
Pazopanib-induced leg ulcer in a patient with malignant fibrous histiocytoma Dear Editor, Pazopanib is an oral, multi-targeted, tyrosine kinase inhibitor that has recently been approved for advanced soft tissue sarcoma. We herein report a patient with malignant fibrous histiocytoma treated with pazopanib who developed severe leg ulcers without progression of lung metastasis. An 84-year-old Japanese woman noticed a red nodule on her right forearm and visited a clinic in March 2012. Histopathological findings of the skin biopsy specimen were suggestive of soft tissue sarcoma and she was referred to our hospital. A firm, immobile, red tumor measuring 45 mm 9 35 mm in diameter was noted (Fig. 1a). Additional radiological examinations revealed no metastasis. Surgical local excision was performed and positive deep margins were evident histologically. Atypical spindle cells with bizarre nuclei increased in vague intricate pattern. Immunohistochemical results were not positive for S100, CD34, CD68, smooth muscle actin or desmin. Therefore, diagnosis was pleomorphic malignant fibrous histiocytoma with pT1aN0M0 (stage IA). Five months later, the red nodule recurred at the same site, and computed tomography revealed a new nodule in the right lung suggestive of distant metastasis. Surgical excision again revealed positive deep margins. She declined to undergo radiotherapy, multi-agent chemotherapy as an inpatient or radical excision that might have resulted in dysfunction because of her advanced age and dementia. We therefore started pazopanib (800 mg) on an outpatient basis. Because of serious adverse reactions (grade 3), such as hypertension, fatigue and anorexia, pazopanib was immediately discontinued. After the patient completely recovered from these adverse events, pazopanib was restarted at 400 mg. However, small skin erosions developed on both lower legs that were
associated with stasis dermatitis (Fig. 1b), and severe leg ulcers developed 2 weeks after the second administration of pazopanib (Fig. 1c). Ultrasonogram, enhanced computed tomography and laboratory data ruled out the thrombosis and
(a)
(b)
(c)
(d)
Figure 1. Clinical appearance of (a) a tumor on the right forearm at the first visit, (b) the skin ulcers on the left lower leg before the second pazopanib treatment, (c) 2 weeks after treatment with pazopanib 400 mg and (d) 8 weeks after cessation of pazopanib.
Correspondence: Hiroyuki Fujita, M.D., Ph.D., Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa, Yokohama 236-0004, Japan. Email: [email protected]
1022
© 2014 Japanese Dermatological Association
