Letters to the Editor
cal examination of the vertex of the scalp revealed a 2.0-cm yellowish plaque. A 1.3-cm red nodule with a hemorrhagic crust and 0.4-cm black papule arose within the plaque. Complete excision of the entire plaque was performed, and histopathology revealed NS in association with three distinct lesions: syringocystadenoma papilliferum, sebaceoma and trichoblastoma (Fig. 1a). Case 2 was a 61-year-old Japanese man who had a 2-year history of rapid growth in a previously asymptomatic plaque on his scalp since birth. There was no family history of malignancy. A physical examination of the left side of the scalp revealed a 1.0 cm 9 3.0 cm brown, verrucous plaque. A 3.0cm red nodule and 0.8-cm black papule arose within the plaque. Complete excision of the entire plaque was performed, and histopathology revealed NS in association with three distinct lesions: trichoblastoma, trichoepithelioma and squamous cell carcinoma (Fig. 1b). We performed an immunohistochemical study to elucidate bKlotho expression in NS. A paraffin-embedded tissue section was immunostained with 1:1000 diluted anti-bKlotho antibody (Aviva Systems Biology, San Diego, CA, USA). bKlotho was expressed in the epidermis of the NS lesion as well as in the normal epidermis (Fig. 1c). It was expressed in skin appendages of the NS lesion; the sebaceous duct (Fig. 1d), sebaceous cells (Fig. 1d) and most of the ectopic apocrine gland (Fig. 1e). In contrast, bKlotho expression was suppressed in the secondary tumors of NS; syringocystadenoma papilliferum (Fig. 1f), trichoblastoma (Fig. 1g), trichoepithelioma (Fig. 1h), sebaceoma (Fig. 1i) and squamous cell carcinoma (Fig. 1j). bKlotho regulates the function of FGF19 by forming a complex with fibroblast growth factor receptor (FGFR)4 to suppress the expression of the CYP7A1 gene, which encodes the ratelimiting enzyme for bile acid synthesis in hepatocytes.2 Additionally, anti-tumorigenic effects of bKlotho in hepatocellular carcinoma was reported.3 Although bKlotho and FGFR4 are expressed in skin,2,4 to our knowledge, there has been no report about the expression of bKlotho in skin diseases. A
recent study reported postzygotic HRAS or KRAS mutations that resulted in constitutive activation of Ras–Raf–MAPK and PI3K–Akt signaling pathways in NS and its secondary tumors.5 Because the interaction of bKlotho with FGFR4 suppresses Akt signaling and proliferation of tumor cells,3 it is possible that the reduction of bKlotho expression synergistically enhances the HRAS- or KRAS-related Akt signaling in the epidermis of NS developing secondary tumors. However, further studies are required to clarify the roles of bKlotho in skin diseases including secondary tumors arising in NS.
CONFLICT OF INTEREST:
None.
Kozo NAKAI,1 Kozo YONEDA,1 Reiji HABA,2 Yoshio KUSHIDA,2 Naomi KATSUKI,2 Junko MORIUE,1 Tetsuya MORIUE,1 Emiko ISHIKAWA,1 Shigeaki INOUE,3 Yasuo KUBOTA1 1
Departments of Dermatology, 2Diagnostic Pathology, Kagawa University, Kagawa, and 3Institute of Innovative Science and Technology, Tokai University, Kanagawa, Japan doi: 10.1111/1346-8138.12371
REFERENCES 1 Cribier B, Scrivener Y, Grosshans E. Tumors arising in nevus sebaceus: a study of 596 cases. J Am Acad Dermatol 2000; 42 (Pt 1): 263– 268. 2 Kuro-o M. Klotho and the aging process. Korean J Intern Med 2011; 26: 113–122. 3 Ye X, Guo Y, Zhang Q et al. bKlotho suppresses tumor growth in hepatocellular carcinoma by regulating Akt/GSK-3b/cyclin D1 signaling pathway. PLoS One 2013; 8: e55615. 4 Takenaka H, Yasuno H, Kishimoto S. Immunolocalization of fibroblast growth factor receptors in normal and wounded human skin. Arch Dermatol Res 2002; 294: 331–338. 5 Groesser L, Herschberger E, Ruetten A et al. Postzygotic HRAS and KRAS mutations cause nevus sebaceus and Schimmelpenning syndrome. Nat Genet 2012; 44: 783–787.
Successful treatment of oral squamous cell carcinoma with intra-arterial cisplatin and concurrent radiotherapy Dear Editor, The standard treatment for oral squamous cell carcinoma (OSCC) is surgery with/without adjunct radiotherapy. Selective intra-arterial cisplatin infusion with concurrent radiotherapy for head and neck squamous cell carcinoma (HNSCC) has been reported as a promising treatment.1 Here, we report OSCC treated with intra-arterial cisplatin chemotherapy and concurrent radiotherapy.
A 72-year-old Japanese female presented with a nodule that had been increasing in size for 10 years on the right corner of the mouth that connected to a white plaque on the right buccal mucosa. She had been suffered from Candida-related bilateral angular cheilitis before the nodule appeared. Physical examination revealed that the nodule on the right corner of mouth measured 8 mm 9 8 mm (Fig. 1a) and the white plaque on right cheek mucosa measured 20 mm 9 13 mm (Fig. 1b) without
Correspondence: Shinichi Koba, M.D., Ph.D., Division of Dermatology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan. Email: [email protected]
172
© 2014 Japanese Dermatological Association
Letters to the Editor
(a)
(b)
(e)
(c)
(d)
(f)
Figure 1. (a,b) Before treatment, the clinical appearance was compatible with a diagnosis of squamous cell carcinoma. (c,d) Six months after the treatment, the tumor had disappeared. (e,f) Results of the biopsy revealing downward proliferation of squamous epithelial cells with mild atypia and pushing border, histologically compatible with low-grade squamous cell carcinoma (hematoxylin–eosin, original magnifications: [e] 940; [f] 9200). lymphadenopathy. Biopsy showed an exophytic and endophytic tumor with extensive hyperkeratosis and parakeratosis and a pushing deep border. The basement membrane was almost intact. These histological and clinical aspects revealed well-differentiated OSCC (Fig. 1e,f). Although we initially recommended surgical treatment, she refused because cosmetic and functional disability. Therefore, selective intra-arterial cisplatin chemotherapy with concurrent radiotherapy was administrated. Rapid infusions of cisplatin (100 mg/m2) were delivered through a transfemoral microcatheter inserted into the right facial artery subsequent to branching the submental artery supplying the primary lesion four times per week. Additionally, sodium thiosulfate was administrated i.v. to provide effective cisplatin neutralization. The radiotherapy was 66 Gy in 33 fractions. The patient developed acute toxicity with grade II oral pain and grade I skin reactions, but grade III–IV was not observed according to the National Cancer Institute Common Terminology Criteria for Adverse Events. Following 6 months of the treatment, the OSCC completely disappeared (Fig. 1c,d) and was not detected by re-biopsy. Furthermore, there was no recurrence within 2 years after the treatment. The treatment of OSCC usually involves surgery and nonsurgical modalities (radiotherapy and chemotherapy). Surgery may offer greater tumor control, but can result in cosmetic and functional disabilities. In this case, as the OSCC was present in the corner of mouth connecting to the cheek mucosa, an advanced surgical technique was required. Radiotherapy is considered acceptable in cases where surgery is unfeasible;
© 2014 Japanese Dermatological Association
however, it frequently results in poorer local control than surgery and concurrent chemoradiotherapy.2,3 Concurrent chemoradiotherapy for advanced HNSCC is beneficial for local control and survival compared to radiotherapy alone.4 Moreover, selective high-dose intra-arterial cisplatin with sodium thiosulfate and concurrent radiotherapy for advanced OSCC can be performed safely with a relatively low complication rate, compared to standard i.v. chemotherapy.5 Robbins et al.1 reported administrating 150 mg/m2 cisplatin intra-arterial infusion for stage IV HNSCC. By contrast, Fuwa et al.5 indicated 20–30 mg/m2 instead of longer infusion than Robbins et al.’s procedure.1 We adopted 100 mg/m2 cisplatin, because the present case was stage II and well-differentiated OSCC. Although intra-arterial cisplatin with sodium thiosulfate therapy minimizes the side-effects systemically, catheter operation-related cranial nerve disorders may occur (2–4%). In this case, the OSCC disappeared clinically and histopathologically without any disabilities or serious sideeffects. We conclude that selective high-dose intra-arterial cisplatin and concurrent radiotherapy is a potential treatment modality for OSCC.
CONFLICT OF INTEREST:
All authors of this manuscript have no financial or personal relationships to disclose.
Shinichi KOBA,1 Noriyuki MISAGO,1 Reiko SHIRAI,1 Sunao TOKUMARU,2 Tomoyuki NOGUCHI,2 Yutaka NARISAWA1 1
Division of Dermatology, Department of Internal Medicine, and 2Department of Radiology, Faculty of Medicine, Saga University, Saga, Japan doi: 10.1111/1346-8138.12355
REFERENCES 1 Robbins KT, Kumar P, Harris J et al. Supradose intra-arterial cisplatin and concurrent radiation therapy for the treatment of stage IV head and neck squamous cell carcinoma is feasible and efficacious in a multi-institutional setting: results of Radiation Therapy Oncology Group Trial 9615. J Clin Oncol 2005; 23: 1447–1454. 2 Denis F, Garaud P, Bardet E et al. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 2004; 22: 69– 76. 3 Brizel DM, Esclamado R. Concurrent chemoradiotherapy for locally advanced, nonmetastatic, squamous carcinoma of the head and neck: consensus, controversy, and conundrum. J Clin Oncol 2006; 24: 2612–2617. 4 Al-Sarraf M, Pajak TF, Byhardt RW et al. Postoperative radiotherapy with concurrent cisplatin appears to improve locoregional control of advanced, resectable head and neck cancers: RTOG 88-24. Int J Radiat Oncol Biol Phys 1997; 37: 777–782. 5 Fuwa N, Kodaira T, Furutani K et al. Intra-arterial chemoradiotherapy for locally advanced oral cavity cancer: analysis of therapeutic results in 134 cases. Br J Cancer 2008; 98: 1039–1045.
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cal examination of the vertex of the scalp revealed a 2.0-cm yellowish plaque. A 1.3-cm red nodule with a hemorrhagic crust and 0.4-cm black papule arose within the plaque. Complete excision of the entire plaque was performed, and histopathology revealed NS in association with three distinct lesions: syringocystadenoma papilliferum, sebaceoma and trichoblastoma (Fig. 1a). Case 2 was a 61-year-old Japanese man who had a 2-year history of rapid growth in a previously asymptomatic plaque on his scalp since birth. There was no family history of malignancy. A physical examination of the left side of the scalp revealed a 1.0 cm 9 3.0 cm brown, verrucous plaque. A 3.0cm red nodule and 0.8-cm black papule arose within the plaque. Complete excision of the entire plaque was performed, and histopathology revealed NS in association with three distinct lesions: trichoblastoma, trichoepithelioma and squamous cell carcinoma (Fig. 1b). We performed an immunohistochemical study to elucidate bKlotho expression in NS. A paraffin-embedded tissue section was immunostained with 1:1000 diluted anti-bKlotho antibody (Aviva Systems Biology, San Diego, CA, USA). bKlotho was expressed in the epidermis of the NS lesion as well as in the normal epidermis (Fig. 1c). It was expressed in skin appendages of the NS lesion; the sebaceous duct (Fig. 1d), sebaceous cells (Fig. 1d) and most of the ectopic apocrine gland (Fig. 1e). In contrast, bKlotho expression was suppressed in the secondary tumors of NS; syringocystadenoma papilliferum (Fig. 1f), trichoblastoma (Fig. 1g), trichoepithelioma (Fig. 1h), sebaceoma (Fig. 1i) and squamous cell carcinoma (Fig. 1j). bKlotho regulates the function of FGF19 by forming a complex with fibroblast growth factor receptor (FGFR)4 to suppress the expression of the CYP7A1 gene, which encodes the ratelimiting enzyme for bile acid synthesis in hepatocytes.2 Additionally, anti-tumorigenic effects of bKlotho in hepatocellular carcinoma was reported.3 Although bKlotho and FGFR4 are expressed in skin,2,4 to our knowledge, there has been no report about the expression of bKlotho in skin diseases. A
recent study reported postzygotic HRAS or KRAS mutations that resulted in constitutive activation of Ras–Raf–MAPK and PI3K–Akt signaling pathways in NS and its secondary tumors.5 Because the interaction of bKlotho with FGFR4 suppresses Akt signaling and proliferation of tumor cells,3 it is possible that the reduction of bKlotho expression synergistically enhances the HRAS- or KRAS-related Akt signaling in the epidermis of NS developing secondary tumors. However, further studies are required to clarify the roles of bKlotho in skin diseases including secondary tumors arising in NS.
CONFLICT OF INTEREST:
None.
Kozo NAKAI,1 Kozo YONEDA,1 Reiji HABA,2 Yoshio KUSHIDA,2 Naomi KATSUKI,2 Junko MORIUE,1 Tetsuya MORIUE,1 Emiko ISHIKAWA,1 Shigeaki INOUE,3 Yasuo KUBOTA1 1
Departments of Dermatology, 2Diagnostic Pathology, Kagawa University, Kagawa, and 3Institute of Innovative Science and Technology, Tokai University, Kanagawa, Japan doi: 10.1111/1346-8138.12371
REFERENCES 1 Cribier B, Scrivener Y, Grosshans E. Tumors arising in nevus sebaceus: a study of 596 cases. J Am Acad Dermatol 2000; 42 (Pt 1): 263– 268. 2 Kuro-o M. Klotho and the aging process. Korean J Intern Med 2011; 26: 113–122. 3 Ye X, Guo Y, Zhang Q et al. bKlotho suppresses tumor growth in hepatocellular carcinoma by regulating Akt/GSK-3b/cyclin D1 signaling pathway. PLoS One 2013; 8: e55615. 4 Takenaka H, Yasuno H, Kishimoto S. Immunolocalization of fibroblast growth factor receptors in normal and wounded human skin. Arch Dermatol Res 2002; 294: 331–338. 5 Groesser L, Herschberger E, Ruetten A et al. Postzygotic HRAS and KRAS mutations cause nevus sebaceus and Schimmelpenning syndrome. Nat Genet 2012; 44: 783–787.
Successful treatment of oral squamous cell carcinoma with intra-arterial cisplatin and concurrent radiotherapy Dear Editor, The standard treatment for oral squamous cell carcinoma (OSCC) is surgery with/without adjunct radiotherapy. Selective intra-arterial cisplatin infusion with concurrent radiotherapy for head and neck squamous cell carcinoma (HNSCC) has been reported as a promising treatment.1 Here, we report OSCC treated with intra-arterial cisplatin chemotherapy and concurrent radiotherapy.
A 72-year-old Japanese female presented with a nodule that had been increasing in size for 10 years on the right corner of the mouth that connected to a white plaque on the right buccal mucosa. She had been suffered from Candida-related bilateral angular cheilitis before the nodule appeared. Physical examination revealed that the nodule on the right corner of mouth measured 8 mm 9 8 mm (Fig. 1a) and the white plaque on right cheek mucosa measured 20 mm 9 13 mm (Fig. 1b) without
Correspondence: Shinichi Koba, M.D., Ph.D., Division of Dermatology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan. Email: [email protected]
172
© 2014 Japanese Dermatological Association
Letters to the Editor
(a)
(b)
(e)
(c)
(d)
(f)
Figure 1. (a,b) Before treatment, the clinical appearance was compatible with a diagnosis of squamous cell carcinoma. (c,d) Six months after the treatment, the tumor had disappeared. (e,f) Results of the biopsy revealing downward proliferation of squamous epithelial cells with mild atypia and pushing border, histologically compatible with low-grade squamous cell carcinoma (hematoxylin–eosin, original magnifications: [e] 940; [f] 9200). lymphadenopathy. Biopsy showed an exophytic and endophytic tumor with extensive hyperkeratosis and parakeratosis and a pushing deep border. The basement membrane was almost intact. These histological and clinical aspects revealed well-differentiated OSCC (Fig. 1e,f). Although we initially recommended surgical treatment, she refused because cosmetic and functional disability. Therefore, selective intra-arterial cisplatin chemotherapy with concurrent radiotherapy was administrated. Rapid infusions of cisplatin (100 mg/m2) were delivered through a transfemoral microcatheter inserted into the right facial artery subsequent to branching the submental artery supplying the primary lesion four times per week. Additionally, sodium thiosulfate was administrated i.v. to provide effective cisplatin neutralization. The radiotherapy was 66 Gy in 33 fractions. The patient developed acute toxicity with grade II oral pain and grade I skin reactions, but grade III–IV was not observed according to the National Cancer Institute Common Terminology Criteria for Adverse Events. Following 6 months of the treatment, the OSCC completely disappeared (Fig. 1c,d) and was not detected by re-biopsy. Furthermore, there was no recurrence within 2 years after the treatment. The treatment of OSCC usually involves surgery and nonsurgical modalities (radiotherapy and chemotherapy). Surgery may offer greater tumor control, but can result in cosmetic and functional disabilities. In this case, as the OSCC was present in the corner of mouth connecting to the cheek mucosa, an advanced surgical technique was required. Radiotherapy is considered acceptable in cases where surgery is unfeasible;
© 2014 Japanese Dermatological Association
however, it frequently results in poorer local control than surgery and concurrent chemoradiotherapy.2,3 Concurrent chemoradiotherapy for advanced HNSCC is beneficial for local control and survival compared to radiotherapy alone.4 Moreover, selective high-dose intra-arterial cisplatin with sodium thiosulfate and concurrent radiotherapy for advanced OSCC can be performed safely with a relatively low complication rate, compared to standard i.v. chemotherapy.5 Robbins et al.1 reported administrating 150 mg/m2 cisplatin intra-arterial infusion for stage IV HNSCC. By contrast, Fuwa et al.5 indicated 20–30 mg/m2 instead of longer infusion than Robbins et al.’s procedure.1 We adopted 100 mg/m2 cisplatin, because the present case was stage II and well-differentiated OSCC. Although intra-arterial cisplatin with sodium thiosulfate therapy minimizes the side-effects systemically, catheter operation-related cranial nerve disorders may occur (2–4%). In this case, the OSCC disappeared clinically and histopathologically without any disabilities or serious sideeffects. We conclude that selective high-dose intra-arterial cisplatin and concurrent radiotherapy is a potential treatment modality for OSCC.
CONFLICT OF INTEREST:
All authors of this manuscript have no financial or personal relationships to disclose.
Shinichi KOBA,1 Noriyuki MISAGO,1 Reiko SHIRAI,1 Sunao TOKUMARU,2 Tomoyuki NOGUCHI,2 Yutaka NARISAWA1 1
Division of Dermatology, Department of Internal Medicine, and 2Department of Radiology, Faculty of Medicine, Saga University, Saga, Japan doi: 10.1111/1346-8138.12355
REFERENCES 1 Robbins KT, Kumar P, Harris J et al. Supradose intra-arterial cisplatin and concurrent radiation therapy for the treatment of stage IV head and neck squamous cell carcinoma is feasible and efficacious in a multi-institutional setting: results of Radiation Therapy Oncology Group Trial 9615. J Clin Oncol 2005; 23: 1447–1454. 2 Denis F, Garaud P, Bardet E et al. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 2004; 22: 69– 76. 3 Brizel DM, Esclamado R. Concurrent chemoradiotherapy for locally advanced, nonmetastatic, squamous carcinoma of the head and neck: consensus, controversy, and conundrum. J Clin Oncol 2006; 24: 2612–2617. 4 Al-Sarraf M, Pajak TF, Byhardt RW et al. Postoperative radiotherapy with concurrent cisplatin appears to improve locoregional control of advanced, resectable head and neck cancers: RTOG 88-24. Int J Radiat Oncol Biol Phys 1997; 37: 777–782. 5 Fuwa N, Kodaira T, Furutani K et al. Intra-arterial chemoradiotherapy for locally advanced oral cavity cancer: analysis of therapeutic results in 134 cases. Br J Cancer 2008; 98: 1039–1045.
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