Yota Sato

Dermoscopy Findings of Hidroacanthoma Simplex

Hidroacanthoma simplex (HAS), also known as intraepidermal eccrine poroma, is a rare eccrine adnexal tumor that tends to be misdiagnosed as other types of benign skin tumor, including clonal seborrheic keratosis. Notably, HAS is sometimes misdiagnosed and treated by cryosurgery as seborrheic keratosis, which could trigger the later development of porocarcinoma. Therefore, accurate diagnosis of HAS is indispensable for dermatologists to avoid the development of malignant tumors by an unsuitable treatment. In this report, we present the characteristic dermoscopy findings of HAS. Indeed, the dermoscopy findings might be related to the melanin-rich necrotic cells in the epidermis, which are quite different from dermoscopy findings of clonal seborrheic keratosis. As a previous report suggested, it is difficult for a dermatologist to differentiate HAS from clonal seborrheic keratosis by the naked eye. Our findings might be supportive for the early diagnosis of HAS.

Cytotoxic anti‐melanoma drugs suppress the activation of M2 macrophages

Together with regulatory T cells (Tregs), tumor‐associated macrophages (TAMs) play roles in maintaining the tumor microenvironment. Although cytotoxic antimelanoma drugs such as dacarbazine (DTIC), nimustine hydrochloride (ACNU) and vincristine (VCR) have been used for the treatment of malignant melanoma as adjuvant therapy in Japan, the detailed mechanisms of their immunomodulatory effects are not fully understood. As the majority of TAMs are alternatively activated M2 macrophages that favour tumor development, the aim of this study was to elucidate the immunomodulatory effects of these reagents on human monocyte‐derived M2 macrophages. First, mRNA expressions and protein production of immune checkpoint molecules, PD‐L1 and chemokines by CD163+ CD206+ M2 macrophages derived from peripheral blood mononuclear cells were investigated to determine the immunomodulatory effects of DTIC, ACNU, and VCR. DTIC and VCR significantly decreased PD‐L1 mRNA expression, which was confirmed by flow cytometry. Moreover, the mRNA expression and production of CCL22 were significantly decreased by DTIC, which suggested that DTIC might suppress the recruitment of Tregs in the tumor site. Furthermore, the decreased expression of PD‐L1 and production of CCL22 were validated in vivo, using the B16F10 mouse melanoma model, leading to abrogation of the suppressive function of T‐cell proliferation. The present report suggests one of the possible antimelanoma mechanisms of DAV combination chemotherapy for melanoma patients.

Keratoacanthoma, palmoplantar keratoderma developing in an advanced melanoma patient treated with vemurafenib regressed by blockade of mitogen-activated protein kinase kinase signaling

Dear Editor, Although the inhibition of BRAF signaling is one of the most effective therapies for advanced melanoma with BRAF mutation, severe adverse events (AE), such as keratotic disorders, occasionally develop. A 56-year-old Japanese woman visited our outpatient clinic after resection of a subcutaneous nodule on the chest by private surgery. The histological diagnosis was malignant melanoma (Fig. S1). We performed radical excision, and 4 months after, magnetic resonance imaging (MRI) revealed an 8-mm nodule on the parietal cortex. We diagnosed this patient as having brain metastasis of melanoma. Because a THxID kit (BioM erieux, Marcy-l’ Etoile, France) for BRAF mutation revealed that her primary tumor possessed the BRAF mutation, we administrated vemurafenib 1920 mg/day. Ten days after commencing administration of vemurafenib, she developed a papuloerythematous eruption (Fig. 1a) with reduced renal function and lymphopenia. We reduced vemurafenib to a dose of 1440 mg/day and administrated oral prednisolone 30, 25 and 20 mg/day for 3 days each. After 7 days of oral administration of prednisolone, the patient developed multiple, dome-shaped, skin-colored tumors with point keratosis on the face and scalp (Fig. 1b) and hyperkeratosis on the bilateral soles and palms (Fig. 1c). A biopsy specimen from the right temple revealed a cup-shaped, symmetrical, well-differentiated squamous epithelium with individual cell keratinization and keratin pearls, suggesting keratoacanthoma (Fig. 1d). A biopsy specimen from the right sole revealed prominent hyperkeratosis with mild lymphocyte infiltration in the dermis (Fig. 1e). Although follow-up MRI 2 months after the administration of vemurafenib revealed stable disease, we changed vemurafenib to dabrafenib (150 mg/day) and trametinib (2 mg/ day) because the patient complained of difficulty in walking from the severe pain on her soles. Surprisingly, 2 weeks after we started dabrafenib and trametinib, all of the keratotic tumors (Fig. 1f) and palmoplantar keratoderma (Fig. 1g) had disappeared. Although targeting therapies are one of the most optimal therapies for the treatment of advanced melanoma, monotherapy of BRAF inhibitors, such as vemurafenib,

Successful treatment of multiple in‐transit melanomas on the leg with intensity‐modulated radiotherapy and immune checkpoint inhibitors: Report of two cases

Because the efficacy rates of monotherapy with immune checkpoint inhibitors such as nivolumab or ipilimumab are not sufficient, to enhance the antitumor effects of these reagents is of great interest among dermato‐oncologists. In this report, we describe two cases of multiple in‐transit metastatic melanomas on the leg successfully treated with intensity‐modulated radiotherapy (IMRT) using a CyberKnife in combination with ipilimumab or nivolumab. Our cases suggested that IMRT could enhance the antitumor effects of immune checkpoint inhibitors in patients with multiple in‐transit melanomas.

Serum levels of soluble CD163 and CXCL5 may be predictive markers for immune-related adverse events in patients with advanced melanoma treated with nivolumab: A pilot study

Antibodies against PD-1, such as nivolumab and pembrolizumab, are widely used in the treatment of various cancers including advanced melanoma. The anti-PD-1 Ab significantly prolongs survival in patients with metastatic melanoma, and its administration in combination with local or systemic therapy may also lead to improved outcomes. Although anti-PD-1 Ab-based combined therapy might be effective for the treatment of advanced melanoma, the associated risk of irAEs is an important consideration. Therefore, being able to predict irAEs is of great interest to oncologists. The purpose of this study was to evaluate the value of using serum levels of sCD163 and CXCL5 to predict irAEs in patients with advanced melanoma who were administered nivolumab. To this end, we analyzed these serum levels in 46 cases of advanced melanoma treated with nivolumab. In addition, the tumor stroma was evaluated by immunohistochemistry and immunofluorescence. We measured the serum levels of sCD163 and CXCL5 on day 0 (immediately before nivolumab administration) and day 42. The serum absolute levels of sCD163 were significantly increased in patients who developed AEs (p = 0.0018). Although there was no significant difference in serum levels of CXCL5, the absolute value of CXCL5 could at least be a supportive marker for the increased absolute levels of serum sCD163. This study suggests that sCD163 and CXCL5 may serve as possible prognostic biomarkers for irAEs in patients with advanced melanoma treated with nivolumab.

HLA-DRB1*04:05 in two cases of Vogt-Koyanagi-Harada disease-like uveitis developing from an advanced melanoma patient treated by sequential administration of nivolumab and dabrafenib/trametinib therapy

Although uveitis is reported as a rare adverse event (AE) associated with dabrafenib/trametinib therapy or nivolumab, the occurrence of severe uveitis is extremely rare. We describe two cases of Vogt–Koyanagi–Harada (VKH)‐like uveitis developing after the sequential administration of nivolumab and dabrafenib/trametinib therapy. Interestingly, both cases had HLA‐DRB1*04:05, which is strongly associated with VKH disease, and achieved biologically complete remission after the treatment for uveitis. Our cases suggest a possible correlation between VKH‐like uveitis as an AE and the clinical outcomes of sequential administration of nivolumab and dabrafenib/trametinib therapy for the treatment of advanced melanoma.

Successful Treatment of Nivolumab-Resistant Multiple In-Transit Melanomas with Ipilimumab and Topical Imiquimod

Simultaneous or sequential, planned administration of ipilimumab could significantly enhance the antitumor effects of nivolumab in advanced melanoma patients. On the other hand, the efficacy of ipilimumab for nivolumab-resistant advanced melanoma is extremely poor. Therefore, additional supportive therapy for anti-PD-1 antibody therapy-resistant advanced melanoma has been widely investigated. In this report, we describe a case of multiple in-transit melanomas developing in a nivolumab-resistant patient successfully treated with ipilimumab in combination with imiquimod. Our present case suggested a possible therapy for nivolumab-resistant multiple in-transit melanomas using ipilimumab in combination with topical imiquimod.

Successful Treatment of Primary Cutaneous Peripheral T-Cell Lymphoma Presenting Acquired Ichthyosis with Oral Bexarotene Monotherapy

Acquired ichthyosis (AI) is a reactive cutaneous manifestation that can be associated with malignant hematological disease, including cutaneous T-cell lymphoma (CTCL). Since it is difficult to distinguish AI from ichthyosiform mycosis fungoides, to select the treatment for CTCL with ichthyosis-like appearance and to evaluate its efficacy is sometimes challenging. In this report, we describe a case of primary cutaneous peripheral T-cell lymphoma not otherwise specified presenting AI successfully treated with oral bexarotene. In the present case, the administration of oral bexarotene was not only effective for lymphoma cells infiltrating ulcers and nodules, but it also eliminated AI.

Eruptive keratoacanthoma with spontaneous regression arising from a cervical squamous cell carcinoma patient treated with nivolumab

Dear Editor, Multiple eruptive keratoacanthoma is a rare adverse event (AE) of nivolumab. A 73-year-old Japanese man visited our outpatient clinic with a 1-month history of multiple asymptomatic hyperkeratotic nodules on the upper arm. He had been treated for cervical squamous cell carcinoma (SCC) with nivolumab (3 mg/kg b.i.d) for 2 months. One month before the initial visit, he developed a grade 3 fever and skin eruption, and was administrated methylprednisolone 2 mg/kg. At his initial visit, physical examination revealed multiple infiltrated hyperkeratotic plaques and nodules surrounded by erythematous macules on the dorsal hand

Successful control of phototherapy‐resistant lymphomatoid papulosis with oral bexarotene

Dear Editor, Although lymphomatoid papulosis (LyP) undergoes spontaneous regression after weeks or months, LyP easily develops in other regions, and it is difficult to achieve complete remission (CR). A 48-year-old Japanese woman visited our outpatient clinic with recurrent, disseminated papules on her legs that spontaneously regressed. On her initial visit, physical examination revealed asymmetrical, skin-colored papules disseminated on her left lower extremity (Fig. 1a). A biopsy specimen from the left lower leg revealed atypical lymphoid cells densely infiltrated throughout the dermis (Fig. 1b,c) with large atypical cells (Fig. 1c). In addition, band-like infiltration of smaller atypical lymphocytes with epidermotropism was observed in the dermoepidermal junction (Fig. 1b,e). Immunohistochemical staining revealed that these atypical lymphocytes, which were distributed throughout the dermis, were positive for CD2, CD3, CD4, CD30 (Fig. 1f,g) and CD45, and negative for CD5, CD7 and CD8. We screened for possible metastatic lesions with positron emission tomography and found no evidence of lymph node swelling or visceral lesions. From the above findings, we diagnosed this patient as having type A LyP mixed with type B. We treated her with psoralen plus ultraviolet (UV)-A therapy and a 308-nm excimer light, but there was no therapeutic effect on the development of papules at other sites. Then, we administrated oral bexarotene 300 mg/m per day. The papules diminished 2 weeks after the administration of bexarotene (Fig. 1d). Half a year after the remission of the disseminated papules, LyP was still under remission. Lymphomatoid papulosis is characterized by a chronic course of years to decades of recurrent papulonodular lesions, each of which undergoes spontaneous regression after weeks or months. Indeed, a recent report suggested that although UV light phototherapy is commonly used for LyP, sustained CR is rarely achieved. Therefore, other useful therapies for LyP are needed. Bexarotene is a third-generation retinoid X receptor-selective retinoid that is administrated for the treatment of cutaneous T-cell lymphoma (CTCL). The mechanisms of its antitumor effects are diverse. Bexarotene reduces the expression of chemokine receptors to suppress the migration of CTCL cells in skin lesions. On the other hand, bexarotene also induces a dose-dependent apoptosis of CTCL cells. Although the efficacy of bexarotene on LyP has been reported previously, reported cases are still limited. Among them, Krathen et al. reported three cases of LyP treated with oral (a) (b)