Department of Dermatologic Oncology

Naoya Yamazaki, Kenjiro Namikawa, Dai Ogata, Eiji Nakano

Introduction

The Department of Dermatologic Oncology has consistently served as the core hospital for the establishment of treatment strategies for malignant skin tumors since the National Cancer Center opened in 1962, and over 4,000 cases of malignant melanoma have been accumulated thus far, an impressive number for a hospital or research institution in Japan. Today, patients are referred from throughout Japan. Most of the patients are examined and treated for skin cancer including malignant melanoma. Surgery is the main treatment modality for skin cancer, and multi-disciplinary treatments, consisting of immunotherapy, targeted therapy, chemotherapy, and radiotherapy, are also routinely carried out. But these days, especially, the importance of immunotherapy is increasing. Melanoma is at the center of development of immune therapy. This department plays an active role in multicenter trials for new agents for skin cancer all over Japan.

The Team and What We Do

The department has four staff dermatologic oncologists, one chief resident and seven residents. We are also engaged in routine outpatient activities on Wednesdays and Thursdays in the National Cancer Center East.

Our department is a high-volume center, where we have seen an average of 180 patients with malignant melanoma annually in the last 5 years (Table 1). This is the result of the creation of a national network to develop treatment for malignant skin tumors, and nivolumab, an anti- PD-1 antibody, was approved as a therapeutic agent for malignant melanoma in Japan for the first time in the world as a result of vigorous development of new drugs.

Table 1. Number of New Patients 

For first-line systemic therapy of unresectable or metastatic melanoma, recommended treatment options include checkpoint immunotherapy, BRAF-targeted therapy for patients with BRAF-mutated disease, or clinical trials.

Checkpoint immunotherapy options in this setting include anti-PD-1 monotherapy or a combination of ipilimumab and nivolumab.

At all times, about 14 patients are hospitalized to undergo surgery, chemotherapy, or radiation therapy. In 2021, 292 operations were performed including 153 operations under general anesthesia (Table 2).

Treatment of non-melanoma skin cancer is primarily surgery. On the other hand, radiotherapy plus paclitaxel is often the first line therapy for angiosarcoma.

Rounds are made and case presentations are held every morning. A dermatologic oncology conference is held every Monday to discuss the therapeutic principles for outpatients and inpatients. A clinicopathological conference that focuses on surgically removed skin specimens is held with pathologists once a month.

In addition, we have treated advanced cases of mucosal melanoma patients in the nasal cavity, genital lesions, perianal lesions, and uveal melanoma even though our origins are “dermatologic”.

In addition, we have treated advanced cases of mucosal melanoma in the nasal cavity, genital lesions, perianal lesions, and uveal melanoma even if the origins are “dermatologic”.

This year, our hospital was affected by COVID 19 and the number of patients was affected. Nevertheless, the number of patients with sweat gland carcinoma and extramammary Paget’s disease is increasing year by year in our department.

Research activities

In recent years, several new drugs have been developed rapidly overseas for the treatment of malignant melanoma, and our department is conducting many clinical studies and trials for all skin cancers; the major ones are described below.

• A study of the prognosis of malignant melanoma and the relevant gene expressions in the tumor.
• Investigation of the effects of aldehyde dehydrogenase 2 (ALDH2) gene polymorphism on the onset, prognosis, and therapeutic efficacy in malignant melanoma.
• Confirmatory trial of non-amputative digit preservation surgery for subungal melanoma. (JCOG1602; J-NAIL study)
• A single-arm confirmatory trial of pazopanib in patients with paclitaxel-pretreated primary cutaneous angiosarcoma. (JCOG1605)
• Real-world efficacy of anti-PD-1 antibodies in advanced acral melanoma patients: a retrospective, multicenter study. (JAMP study)
• A multicenter retrospective study on the effects of first-line nivolumab + ipilimumab combination therapy and first-line anti-PD-1 antibody monotherapy in mucosal/acral lentiginous melanoma.
• Analysis of circulating tumor DNA by blood screening of malignant melanoma patients.
• Confirmatory trial of narrower side margins for basal cell carcinoma in Japanese population. (JCOG2005)
• Study on RB1 gene mutation as a predictor of Merkel cell carcinoma.
• Prognosis of melanoma patients with a complete response to anti-PD-1 therapy.
• A retrospective study on the efficacy of chemotherapy for sweat gland carcinoma.

Table 2. Operative Procedures (total number) in 2021/3 – 2022/4

Clinical trials

Table 3 presents the summary of our clinical trials.

Table 3. New Agent Studies in 2021

Education

Currently, training in routine clinical practice under skilled guidance is ongoing for one chief resident and seven resident physicians. In addition, conferences with the departments of oncology, radiotherapy and pathology are held on a regular basis. The trainees made a total of 17 presentations in domestic academic conferences, and published five papers; in particular, seven of them were international academic papers in English.

Future prospects

With continuous progress in drug therapy for advanced cutaneous malignant melanoma, we are now facing an era where the indications of drug therapy for rare types of malignant melanoma are being expanded to include combination and neoadjuvant therapies based on international multicenter studies.

In addition to these, the Department of Radiation Oncology is developing a linear accelerator for the hospital-based boron neutron capture therapy (BNCT) as a new radiotherapy. We are participating in this trial for angiosarcoma and melanoma.

Meanwhile, we are developing treatments for advanced squamous cell carcinoma and angiosarcoma with immune checkpoint inhibitors.

List of papers published

Journal

1. Gogas H, Dummer R, Ascierto PA, Arance A, Mandalà M, Liszkay G, Garbe C, Schadendorf D, Krajsová I, Gutzmer R, Chiarion Sileni V, Dutriaux C, Yamazaki N, Loquai C, Queirolo P, de Willem GJ, Sellier AT, Suissa J, Murris J, Gollerkeri A, Robert C, Flaherty KT . Corrigendum to 'Quality of life in patients with BRAF-mutant melanoma receiving the combination encorafenib plus binimetinib: Results from a multicentre, open-label, randomised, phase III study (COLUMBUS)' European Journal of Cancer 152: 116-128, 2021

2. Tsutsui K, Kikuchi K, Nozawa K, Takashima A, Tsuchiyama K, Namikawa K, Aiba S, Yamazaki N. Efficacy and safety of topical benzoyl peroxide for prolonged acneiform eruptions induced by cetuximab and panitumumab: A multicenter, phase II trial. The Journal of dermatology, 48:1077-1080, 2021

3. Mizuta H, Nakano E, Yamazaki N. Primary Cutaneous Rosai-Dorfman Disease of the Scalp. Dermatology practical & conceptual, 11:e2020086, 2021

4. Mizuta H, Namikawa K, Takahashi A, Ogata D, Muto Y, Jinnai S, Nakama K, Tsutsui K, Yamazaki N. The first case of a collision tumor of melanotrichoblastoma and seborrheic keratosis. International journal of dermatology, 60:e54-e56, 2021

5. Ding Z, Ogata D, Roszik J, Qin Y, Kim SH, Tetzlaff MT, Lazar AJ, Davies MA, Ekmekcioglu S, Grimm EA. iNOS Associates With Poor Survival in Melanoma: A Role for Nitric Oxide in the PI3K-AKT Pathway Stimulation and PTEN S-Nitrosylation. Frontiers in oncology, 11:631766, 2021

6. Mizuta H, Namikawa K, Nakama K, Yamazaki N. Intramedullary spinal cord metastasis of malignant melanoma:Two cases with rim signs in contrast-enhanced magnetic resonance imaging: A case report. Molecular and clinical oncology, 14時47分, 2021

7. Ogata D, Haydu LE, Glitza IC, Patel SP, Tawbi HA, McQuade JL, Diab A, Ekmekcioglu S, Wong MK, Davies MA, Amaria RN. The efficacy of anti-programmed cell death protein 1 therapy among patients with metastatic acral and metastatic mucosal melanoma. Cancer medicine, 10時22分93-2299, 2021

8. Uhara H, Kiyohara Y, Uehara J, Fujisawa Y, Takenouchi T, Otsuka M, Uchi H, Fukushima S, Minami H, Hatsumichi M, Yamazaki N. Five-year survival with nivolumab in previously untreated Japanese patients with advanced or recurrent malignant melanoma. The Journal of dermatology, 48:592-599, 2021

9. Ogata D, Namikawa K, Takahashi A, Yamazaki N. A review of the AJCC melanoma staging system in the TNM classification (eighth edition). Japanese journal of clinical oncology, 51:671-674, 2021

10.  Bottomley A, Coens C, Mierzynska J, Blank CU, Mandalà M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Puig S, Ascierto PA, Larkin J, Lorigan PC, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C, Eggermont AMM . Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial. The Lancet. Oncology, 22:655-664, 2021

11. Eggermont AMM, Blank CU, Mandalà M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C . Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. The Lancet. Oncology, 22:643-654, 2021

12. Muto Y, Ryo E, Namikawa K, Takahashi A, Ogata D, Fujimura T, Yatabe Y, Aiba S, Yamazaki N, Mori T. RB1 gene mutations are a distinct predictive factor in Merkel cell carcinoma. Pathology international, 71:337-347, 2021

13. Yamazaki N, Takenouchi T, Nakamura Y, Takahashi A, Namikawa K, Kitano S, Fujita T, Kubota K, Yamanaka T, Kawakami Y. Prospective observational study of the efficacy of nivolumab in Japanese patients with advanced melanoma (CREATIVE study). Japanese journal of clinical oncology, 51:1232-1241, 2021

14. Gogas H, Dummer R, Ascierto PA, Arance A, Mandalà M, Liszkay G, Garbe C, Schadendorf D, Krajsová I, Gutzmer R, Sileni VC, Dutriaux C, Yamazaki N, Loquai C, Queirolo P, Jan de Willem G, Sellier AT, Suissa J, Murris J, Gollerkeri A, Robert C, Flaherty KT . Quality of life in patients with BRAF-mutant melanoma receiving the combination encorafenib plus binimetinib: Results from a multicentre, open-label, randomised, phase III study (COLUMBUS). European journal of cancer (Oxford, England: 1990), 152:116-128, 2021

15. Nakama K, Ogata D, Nakano E, Tsutsui K, Jinnai S, Namikawa K, Takahashi A, Yamazaki N. Clinical response to a MEK inhibitor in a patient with metastatic melanoma harboring an RAF1 gene rearrangement detected by cancer gene panel testing. The Journal of dermatology, 48:e256-e257, 2021

16. Ishiguro A, Ogata D, Namikawa K, Takahashi A, Yamazaki N. Two cases of advanced cutaneous squamous cell carcinoma lesions on the head and neck successfully treated with nivolumab. The Journal of dermatology, 48:e434-e435, 2021

17. Takai E, Omata W, Totoki Y, Nakamura H, Shiba S, Takahashi A, Namikawa K, Mori T, Yamazaki N, Shibata T, Yachida S. Clonal dynamics of circulating tumor DNA during immune checkpoint blockade therapy for melanoma. Cancer science, 112時47分48-4757, 2021

18. Umeda Y, Yoshikawa S, Kiniwa Y, Maekawa T, Yamasaki O, Isei T, Matsushita S, Nomura M, Nakai Y, Fukushima S, Saito S, Takenouchi T, Tanaka R, Kato H, Otsuka A, Matsuya T, Baba N, Nagase K, Inozume T, Onuma T, Kuwatsuka Y, Fujimoto N, Kaneko T, Onishi M, Namikawa K, Yamazaki N, Nakamura Y. Real-world efficacy of anti-PD-1 antibody or combined anti-PD-1 plus anti-CTLA-4 antibodies, with or without radiotherapy, in advanced mucosal melanoma patients: A retrospective, multicenter study. European journal of cancer (Oxford, England: 1990), 157:361-372, 2021

19. Ogata D, Tanese K, Nakamura Y, Otsuka M, Namikawa K, Funakoshi T, Yoshikawa S, Tsutsui K, Nakama K, Jinnai S, Kiyohara Y, Takahashi A, Yamazaki N. Impact of the changes in the completion lymph node dissection criteria and approval of adjuvant therapies on the real-world outcomes of Japanese stage III melanoma patients. International journal of clinical oncology, 26:2338-2346, 2021

20. Eggermont AM, Meshcheryakov A, Atkinson V, Blank CU, Mandala M, Long GV, Barrow C, Di Giacomo AM, Fisher R, Sandhu S, Kudchadkar R, Ortiz Romero PL, Svane IM, Larkin J, Puig S, Hersey P, Quaglino P, Queirolo P, Stroyakovskiy D, Bastholt L, Mohr P, Hernberg M, Chiarion-Sileni V, Strother M, Hauschild A, Yamazaki N, van Akkooi AC, Lorigan P, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C. Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase III trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma. European journal of cancer (Oxford, England: 1990), 158:156-168, 2021

21. Nishimura Y, Ryo E, Yamazaki N, Yatabe Y, Mori T. Cutaneous Primary NUT Carcinoma With BRD3-NUTM1 Fusion. The American journal of surgical pathology, 45:1582-1584, 2021

22. Nakamura Y, Namikawa K, Yoshikawa S, Kiniwa Y, Maekawa T, Yamasaki O, Isei T, Matsushita S, Nomura M, Nakai Y, Fukushima S, Saito S, Takenouchi T, Tanaka R, Kato H, Otsuka A, Matsuya T, Baba N, Nagase K, Inozume T, Fujimoto N, Kuwatsuka Y, Onishi M, Kaneko T, Onuma T, Umeda Y, Ogata D, Takahashi A, Otsuka M, Teramoto Y, Yamazaki N. Anti-PD-1 antibody monotherapy versus anti-PD-1 plus anti-CTLA-4 combination therapy as first-line immunotherapy in unresectable or metastatic mucosal melanoma: a retrospective, multicenter study of 329 Japanese cases (JMAC study). ESMO open, 6時10分0325, 2021

23. Nishino K, Fujiwara Y, Ohe Y, Saito R, Miyauchi E, Kobayashi T, Nakai Y, Takahashi T, Shibata T, Hamaguchi T, Kikuchi K, Yamazaki N, Fukuda H, Nozawa K, Kiyohara Y. Results of the non-small cell lung cancer part of a phase III, open-label, randomized trial evaluating topical corticosteroid therapy for facial acneiform dermatitis induced by EGFR inhibitors: stepwise rank down from potent corticosteroid (FAEISS study, NCCH-1512). Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer, 29:2327-2334, 2021

24. Tsutsui K, Namikawa K, Mori T, Kato K, Jinnai S, Nakama K, Ogata D, Takahashi A, Yamazaki N. Case of acquired reactive perforating collagenosis induced by panitumumab for colon cancer. The Journal of dermatology, 48:e114-e115, 2021

25. Kitajima K, Watabe T, Nakajo M, Ishibashi M, Daisaki H, Soeda F, Tanemura A, Kanekura T, Yamazaki N, Ito K. Tumor response evaluation in patients with malignant melanoma undergoing immune checkpoint inhibitor therapy and prognosis prediction using 18 F-FDG PET/CT: multicenter study for comparison of EORTC, PERCIST, and imPERCIST. Jpn J Radiol. Jpn J Radiol.40(1):75-85. 2022 Jan

26. Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin YT, Togashi Y, Kamada T, Irie T, Okumura G, Kono H, Ito D, Fujii R, Watanabe S, Sai A, Fukuoka S, Sugiyama E, Watanabe G, Owari T, Nishinakamura H, Sugiyama D, Maeda Y, Kawazoe A, Yukami H, Chida K, Ohara Y, Yoshida T, Shinno Y, Takeyasu Y, Shirasawa M, Nakama K, Aokage K, Suzuki J, Ishii G, Kuwata T, Sakamoto N, Kawazu M, Ueno T, Mori T, Yamazaki N, Tsuboi M, Yatabe Y, Kinoshita T, Doi T, Shitara K, Mano H, Nishikawa H. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell. 2022 Feb 14;40(2):201-218.e9.

27. Ogata D, Tsutsui K, Namikawa K, Moritani K, Nakama K, Jinnai S, Takahashi A, Tsukamoto S, Kanemitsu Y, Yamazaki N. Treatment outcomes and prognostic factors in 47 patients with primary anorectal malignant melanoma in the immune therapy era. J Cancer Res Clin Oncol. 2022 Feb 3. Online ahead of print.

28. Tsutsui K, Ogata S, Tsukamoto S, Moritani K, Mori T, Namikawa K, Takahashi A, Kanemitu Y, Yamazaki N. Post-Immunotherapy Robotic-Assisted Resection for Primary Anorectal Melanoma: A Case Report. Case Rep Oncol. 2022 Feb 7;15(1):56-61.

29. Igaki H, Murakami N, Nakamura S, Yamazaki N, Kashihara T, Takahashi A, Namikawa K, Takemori M, Okamoto H, Iijima K, Chiba T, Nakayama H, Takahashi A, Kaneda T, Takahashi K, Inaba K, Okuma K, Nakayama Y, Shimada K, Nakagama H, Itami J. Scalp angiosarcoma treated with linear accelerator-based boron neutron capture therapy: A report of two patients. Clin Transl Radiat Oncol. 2022 Feb 18;33:128-133.

30. Kashihara T, Igaki H, Ogata D, Nakayama H, Nakamura S, Okuma K, Mori T, Yamakawa K, Takahashi A, Namikawa K, Takahashi A, Takahashi K, Kaneda T, Inaba K, Murakami N, Nakayama Y, Okamoto H, Yamazaki N, Itami J. Prognostic factor analysis of definitive radiotherapy using intensity-modulated radiation therapy and volumetric modulated arc therapy with boluses for scalp angiosarcomas. Sci Rep. 2022 Mar 14;12(1):4355.