Immune checkpoint inhibitor-based therapy for advanced acral and mucosal melanoma.

Acral melanoma (AM) and mucosal melanomas (MM) are rare clinical subtypes of melanoma. AM and MM are etiologically, biologically, and molecularly distinct from cutaneous melanoma (CM). Despite the recent development of immune checkpoint inhibitors (ICIs) for the treatment of advanced CMs, the true therapeutic efficacy of ICIs for these rare subtypes remains unclear. Since these subtypes are rare, especially in the Caucasian population, their biological features and corresponding novel therapies are underexplored than those of CM. Even in the larger phase III clinical trials for ICIs, the sample size of patients with AM and MM is limited. Consequently, establishment of standard of care for advanced AM and MM has been challenging. This review covers current update and overview on clinical efficacy of ICIs and ICI-based therapy for advanced AM and MM, based mainly on the reported clinical trials, prospective observational studies, and retrospective studies, to provide a better understanding of the current landscape of this field. In addition, we discuss the future direction of treatment for those rare clinical subtypes, focusing on issues relevant to dermatology and medical oncology.

Evaluation of prognostic prediction ability of the novel Japanese risk factor scoring system in a Japanese cohort of resectable cutaneous squamous cell carcinoma: A retrospective cross-sectional study.

Japanese patients with very high-risk cutaneous squamous cell carcinomas (cSCCs), based on the National Comprehensive Cancer Network guidelines, have been reported to display a higher cumulative incidence of relapse and disease-specific death (DSD) than those with high-risk cSCC. Therefore, prognosis prediction is crucial for Japanese patients with very high-risk cSCCs. Herein, we aimed to evaluate the prognostic prediction ability of our novel Japanese Risk Factor Scoring Systems (JARF scoring) in a Japanese cohort of cSSC patients. Data of 424 Japanese patients with resectable very high-risk cSCCs were analysed. We compared the prognostic ability of the following three staging systems: Brigham and Women's Hospital (BWH) tumour staging, number of NCCN very high-risk factors, and JARF scoring, including recurrent tumour, high-risk histological features, deep tumour invasion and lymphatic or vascular involvement as risk factors. The prognostic ability of these staging systems was evaluated according to the cumulative incidence of local recurrence (LR), regional lymph node metastasis (RLNM), DSD, and overall survival (OS). When BWH staging was used, high T stage led to significantly poor outcomes only in the cumulative incidence of RLNM (p = 0.01). The presence of very high-risk NCCN factors led to significantly poor outcomes in terms of RLNM (p = 0.03) and OS (p = 0.02). Meanwhile, a high number of risk factors in the JARF scoring system clearly led to poor outcomes in terms of LR (p = 0.01), RLNM (p < 0.01), DSD (p = 0.03), and OS (p < 0.01). The JARF scoring system may accurately predict the risk of recurrence and death in very high-risk cSCC patients in Japan.

Narrower clinical margin in high or very high-risk squamous cell carcinoma: a retrospective, multicenter study of 1,000 patients.

BACKGROUND AND OBJECTIVES: In cutaneous squamous cell carcinoma (cSCC), adherence to guideline-recommended fixed surgical margins is often difficult, and narrower margins are preferable. This study aimed to evaluate relapse and disease-specific death with narrower margins for high or very high-risk cSCC. PATIENTS/METHODS: We retrospectively investigated high or very high-risk cSCC patients who underwent tumor excision. Patients were divided into guideline-recommended standard margin group (SMG) and narrower-margin group (NMG). Co-primary outcomes were local relapse, SCC relapse, and SCC death. Cumulative incidence function (CIF) was used to describe SCC death probability and competing risk mortality. Gray's test was used to compare differences in CIF between the groups. RESULTS: In total, 1,000 patients with cSCC (high-risk, 570; very high-risk, 430) were included. In the high-risk cohort, there were no significant differences in incomplete excision rate (IER) between SMG and NMG (2.6 % vs. 3.0 %, P > 0.99). However, in the very high-risk cohort, IER in SMG was significantly lower than in NMG (8.9 % vs. 16.2 %, P = 0.03). No significant differences were observed between SMG and NMG for local relapse (high-risk, P = 0.56; very high-risk, P = 0.70), SCC relapse (high-risk, P = 0.30; very high-risk, P = 0.47), and SCC death (high-risk, P = 0.23; very high-risk, P = 0.83). CONCLUSIONS: Surgical margin size has limited impact on margin control, relapse, and disease-specific death in high-risk cSCC.

Knapperer Resektionsrand bei Plattenepithelkarzinomen mit hohem oder sehr hohem Risiko: eine retrospektive multizentrische Studie mit 1000 Patienten.

HINTERGRUND UND ZIELE: Bei kutanen Plattenepithelkarzinomen (PEK) ist die Einhaltung der in Leitlinien empfohlenen festen Resektionsränder oft schwierig und knappere Ränder sind wünschenswert. Ziel dieser Studie war die Bewertung des Auftretens von Rezidiven und krankheitsspezifischen Todesfällen bei knapperen Resektionsrändern für PEK mit hohem oder sehr hohem Risiko. PATIENTEN/METHODEN: PEK-Patienten mit hohem oder sehr hohem Risiko, bei denen eine Tumorexzision durchgeführt wurde, wurden retrospektiv untersucht. Die Patienten wurden in eine Gruppe mit Standardrand gemäß Leitlinienempfehlung (standard margin group, SMG) und eine Gruppe mit knapperen Rändern (narrower-margin group, NMG) eingeteilt. Gemeinsame primäre Endpunkte waren lokales Rezidiv, PEK-Rezidiv und PEK-bedingter Tod. Die Wahrscheinlichkeit eines PEK-bedingten Tods und konkurrierender Mortalitätsrisiken wurde mittels kumulativer Inzidenzfunktion (CIF) beschrieben. Unterschiede bei der CIF zwischen den Gruppen wurden mit dem Test nach Gray verglichen. ERGEBNISSE: Insgesamt wurden 1.000 Patienten mit PEK (hohes Risiko, 570; sehr hohes Risiko, 430) eingeschlossen. In der Kohorte mit hohem Risiko gab es keine signifikanten Unterschiede bei der unvollständigen Exzisionsrate (IER) zwischen SMG und NMG (2,6 % vs. 3,0 %, P > 0,99). In der Kohorte mit sehr hohem Risiko war die IER in der SMG jedoch signifikant geringer als in der NMG (8.9 % vs. 16.2 %, P = 0,03). Keine signifikanten Unterschiede zwischen SMG und NMG wurden für Lokalrezidiv (hohes Risiko, P = 0.56; sehr hohes Risiko, P = 0,70), PEK-Rezidiv (hohes Risiko, P = 0,30; sehr hohes Risiko, P = 0,47) und PEK-bedingtem Tod (hohes Risiko, P = 0,23; sehr hohes Risiko, P = 0,83) beobachtet. SCHLUSSFOLGERUNGEN: Die Größe des Resektionsrands hat einen begrenzten Einfluss auf Randkontrolle, Rezidive und krankheitsspezifischen Tod bei PEK mit hohem Risiko.

A single-arm confirmatory trial of pazopanib in patients with paclitaxel-pretreated primary cutaneous angiosarcoma: Japan Clinical Oncology Group study (JCOG1605, JCOG-PCAS protocol).

BACKGROUND: Paclitaxel is a standard of care for patients with primary cutaneous angiosarcoma of the scalp and face. However, no standard second-line treatment for paclitaxel-resistant patients has ever been established. Since primary cutaneous angiosarcoma expresses a high level of vascular endothelial growth factor receptor, the multitargeted tyrosine kinase inhibitor pazopanib seemed to be the most promising agent, and several retrospective studies have demonstrated its activity against this disease. However, the efficacy and safety of pazopanib in paclitaxel-resistant patients with primary cutaneous angiosarcoma have never been evaluated in a clinical trial. METHODS: In February 2018 the Dermatologic Oncology Group of Japan Clinical Oncology Group started a single-arm confirmatory trial to evaluate the efficacy and safety of pazopanib as a second-line treatment for patients with primary cutaneous angiosarcoma whose disease was resistant to paclitaxel or who were unable to tolerate paclitaxel (JCOG1605, JCOG-PCAS). Patients with primary cutaneous angiosarcoma not associated with lymphedema or radiation, progressing despite first-line paclitaxel monotherapy are included in the study. No prior systemic chemotherapy other than paclitaxel is permitted. Pazopanib is administered orally at an initial dosage of 800 mg once daily. Dose modifications for adverse events are made according to the dose reduction criteria described in the protocol. Treatment is continued until recurrence, disease progression, unacceptable toxic effects, patient refusal, or death. The primary endpoint is progression-free survival, secondary endpoints include overall survival, response rate, disease control rate, adverse events, and serious adverse events. We plan to recruit 30 participants in 5.5 years from 23 Japanese institutions. The follow-up period is set as 1 year after completion of accrual. The study protocol was approved by the Japan Clinical Oncology Group Protocol Review Committee in December 2017. Ethical approval for this study was granted by Ethics Committee of each institute. DISCUSSION: If the primary endpoint is met, pazopanib will be regarded as a standard of care for paclitaxel-resistant patients for whom no standard second-line treatment is established. TRIALS REGISTRATION: Registry number: UMIN000031438 [ http://www.umin.ac.jp/ctr/index.htm ]. Date of Registration: 23/Feb/2018. Date of First Participant Enrollment: 8/Mar/2018.

The rate of facial nerve dysfunction and time to recovery after intraparotid and extraparotid facial nerve exposure and protection in head and neck cutaneous tumor surgery.

BACKGROUND: Most patients with head and neck skin tumors present with normal facial nerve function. A common treatment strategy for these patients is facial nerve preservation surgery, although the degree to which the nerve is successfully preserved is still unclear. Data on the incidence and recovery of facial nerve dysfunction are woefully lacking in the field of dermato-oncology. METHODS: In 23 patients with normal preoperative facial nerve function, we retrospectively reviewed twenty-six head and neck surgical interventions that included facial nerve exposure and protection, focusing particularly on the differences in outcome between intraparotid and extraparotid exposure of the facial nerve branches. RESULTS: Eleven of the 26 cases (42.4%) developed transient paresis, but only one (3.8%) developed permanent paresis. Of 41 dissected facial nerve branches, 14 developed transient paresis (34.1%) and one, a marginal mandibular branch, developed permanent paresis (2.4%). The branches most susceptible to developing paresis were the temporal (4/6 branches, 66.7%) and marginal mandibular branches (8/17 branches, 47.1%). Although the rate of paresis was higher, and ensuing recovery period slightly longer in the extraparotid dissection group compared to the intraparotid dissection group, there were no statistically significant differences between the two groups. The extraparotid and intraparotid rates of paresis were 48% (11/23 branches) and 21.1% (4/19 branches), respectively, P = 0.139; and the average recovery periods were 10.3 and 9.3 weeks, respectively, P = 0.64. CONCLUSIONS: The functional outcome, regardless of the different sites of facial nerve exposure, was almost always either complete facial nerve sparing or transient dysfunction that resolved within 6 months.

A Rare Case of a Primary Cutaneous Desmoplastic Atypical Granular Cell Tumor.

Granular cell tumors are uncommon neoplasms and a small number of these neoplasms have been reported as showing malignant behavior. Here, we report a rare case of a solitary granular cell tumor that exhibited atypical histology, including an extensive desmoplastic stroma, in a 69-year-old woman. The surgical specimen revealed localized areas of spindling cells, areas of cellular pleomorphism, and p53 overexpression. Based on previously published criteria, we classified this lesion as an atypical granular cell tumor. To date, only very few case reports have documented this desmoplastic variant of granular cell tumor. However, the classifications of benign, atypical, and malignant granular cell tumors are still controversial, owing to an overlap of morphological and immunohistochemical profiles and lack of consistent histological criteria. Additionally, it is unknown whether the histology of the desmoplastic variant in the present case is significant for the classification of granular cell tumors and prediction of patient prognosis. Regardless of these issues, awareness, and close follow-up are required because of potential recurrences of this rare variant of granular cell tumor.

Frequency of level II and III axillary nodes metastases in patients with positive sentinel lymph nodes in melanoma: a multi-institutional study in Japan.

BACKGROUND: Axillary lymph node dissection (ALND) has been recommended to include levels I-III for melanoma patients who have evidence of metastasis in the axillary sentinel lymph node (SLN). The extent of the subsequent axillary dissection is in debate. The objective of this study was to determine the frequency of metastasis of level III nodes in addition to that of level II nodes in this setting. METHODS: A multi-institutional retrospective study was undertaken in 14 melanoma treatment centers in Japan. RESULTS: Between 2007 and 2012, 69 patients with involved axillary SLNs underwent a subsequent ALND and 55 underwent level I and II dissections. Level III metastatic nodes, which is our primary endpoint, were seen in only 1 patient (1.5 %). The level II metastatic rate was 4.4 %. CONCLUSIONS: Our study sample size was small, but melanoma patients with positive SLN rarely had level III disease, suggesting that level III dissection may be unnecessary. We also found that level II metastasis was not so frequent. More evidence is needed to standardize the extent of ALND and to identify the patients who would have the most benefit with undergoing level II dissection for positive axillary SLNs.

[Immune Checkpoint Inhibitors for Advanced Melanoma - Evidences and Future Perspectives].

Recently developed immune checkpoint inhibitors, such as anti-PD-1 antibodies, have shown a clear improvement in clinical efficacy compared with conventional cytotoxic chemotherapy in the treatment of patients with advanced melanoma. Treatment with anti-PD-1 antibodies has resulted in improved objective response rates, longer durations of response, and longer overall survival rates. Although the incidence rate of adverse events associated with anti-PD-1 antibodies is lower than that associated with cytotoxic agents, characteristic severe adverse events such as pneumonia, endocrinopathy, and colitis can occur. A recent clinical trial that evaluated the utility of an anti-PD-1 antibody in combination with an anti-CTLA-4 antibody reported that the treatment enhanced clinical efficacy in terms of response rate and progression-free survival. However, the incidence of adverse events and treatment discontinuation also increased. For optimal selection of immune checkpoint inhibitors for treating patients with advanced melanoma, biomarkers capable of predicting clinical efficacy, prognosis, and adverse events in each patient need to be identified. In addition, novel combination therapies, including immune checkpoint inhibitors and MAP kinase pathway-targeting agents, should result in more favorable clinical responses and prolonged overall survival rates.

A novel approach for inguinal lymph node dissection without inguinal skin incision for invasive extramammary Paget disease.

Inguinal lymph node dissection (ILND) for skin cancer is associated with a high incidence of wound complications. The traditional skin approaches are associated with a high risk of wound/flap necrosis of the inguinal skin, which leads to wound dehiscence and wound infection. We report a novel approach for ILND without inguinal skin incision for patients with invasive extramammary Paget disease (EMPD) to minimize the wound complications inherent in conventional ILND. We totally performed this procedure in 3 patients with invasive EMPD with inguinal nodal metastases. No patient had complications, including flap necrosis, wound dehiscence, or wound infection. Our novel surgical approach would retain the vascular supply because there was no inguinal skin incision, preventing postoperative wound complications. In addition, ILND was easily performed with satisfactory exposure of the surgical field. However, the number of patients was small and the follow-up period was short. Further evaluation of a larger case series with longer follow-up is essential to investigate the effect, safety, and indications for this novel approach.

Favorable efficacy of S-1 treatment for locoregionally advanced cutaneous squamous cell carcinoma in the head and neck region.

Cutaneous squamous cell carcinoma is usually treated with surgery; however, locoregionally advanced cutaneous squamous cell carcinoma can be difficult to resect. Although recent guidelines from Western countries recommend using anti-programmed cell death protein 1 (PD-1) antibodies, including cemiplimab and pembrolizumab, there are no approved anti-PD-1 antibodies for locoregional cutaneous squamous cell carcinoma in Asian countries. S-1 is an oral drug with a low incidence of severe toxicity that can be used for head and neck cancers, including head and neck locoregional cutaneous squamous cell carcinoma, in Japan. We retrospectively evaluated patients with head and neck locoregional cutaneous squamous cell carcinoma treated with S-1 at two Japanese institutions (2008-2022). The initial dosage was determined by the body surface area (<1.25 m2 : 80 mg/day, 1.25-1.5 m2 : 100 mg/day, ≥1.5 m2: 120 mg/day) for 28 consecutive days. The outcome measures were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Fourteen patients were included. The ORR was 78%, and the complete response (CR) rate was 64.3%. The median PFS and OS were not reached (NR) (95% confidence interval [CI], 5.9 months-NR) and NR (95% CI, 13.8 months-NR), respectively. The 12-month PFS and OS rates were 51% and 85%, respectively. Six of the nine patients who achieved CR showed no recurrence during the follow-up period (median follow-up, 24.7 months). After CR, three patients experienced recurrence. Among these, two resumed S-1 treatment and subsequently underwent salvage surgery, resulting in a sustained absence of recurrence. One patient developed lung metastasis and died, although S-1 therapy was resumed. Only one patient (7.1%) developed grade 3 anemia. S-1 showed favorable efficacy and low toxicity in patients with head and neck locoregionally advanced cutaneous squamous cell carcinoma. S-1 may be a good alternative to the anti-PD-1 antibody for treating head and neck locoregionally advanced squamous cell carcinoma.

Comparison of surgical morbidities between LigaSure™ and conventional techniques in inguinal or ilioinguinal lymph node dissection for skin cancer: A single center retrospective study.

Skin cancer patients with clinical nodal disease or whose positive sentinel nodes had great tumor burden remain candidates for regional lymph node dissections. Among these patients, inguinal or ilioinguinal lymph node dissection is frequently required in clinical practice, which is associated with significant postoperative morbidity-including lymphatic leakage. The aim of this retrospective study was to evaluate the efficacy of LigaSure™, an electrothermal bipolar vessel sealing system, in reducing lymphatic leakage in inguinal or ilioinguinal lymph node dissection. In total, 58 patients who received inguinal or ilioinguinal lymph node dissection (conventional group, 48; LigaSure™ group, 10) and shared similar characteristics were included in this study. Lymphatic leakage after drain removal was significantly lower in the LigaSure™ group than that in the conventional group (present ratio, 0% vs. 37%; p = 0.02). The daily lymphatic drainage volume also tended to be lower in the LigaSure™ than that in the conventional group, with significant differences on postoperative day 1 (p = 0.02). Other perioperative outcomes including the operating time, intraoperative blood loss, time to drain removal, duration of hospital stay, flap necrosis, and wound infection showed no significant differences between the two groups. The use of the LigaSure™ in inguinal or ilioinguinal lymph node dissection for the treatment of skin cancer could reduce the incidence of postoperative lymphatic leakage after drain removal.

Glucose-6-phosphate dehydrogenase correlates with tumor immune activity and programmed death ligand-1 expression in Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and highly malignant skin cancer. Some cases have a good prognosis and spontaneous regression can occur. Reported prognostic markers, such as Merkel cell polyoma virus infection or programmed death ligand-1 (PD-L1) expression, remain insufficient for precisely estimating the vastly different patient outcomes. We performed RNA sequencing to evaluate the immune response and comprehensively estimate prognostic values of immunogenic factors in patients with MCC. METHODS: We collected 90 specimens from 71 patients and 53 blood serum samples from 21 patients with MCC at 10 facilities. The mRNA was extracted from formalin-fixed paraffin-embedded tissues. Next-generation sequencing, immunohistochemical staining and blood serum tests were performed. RESULTS: Next-generation sequencing results classified MCC samples into two types: the 'immune active type' was associated with better clinical outcomes than the 'cell division type'. Expression of the glucose-6-phosphate dehydrogenase (G6PD) gene was highly significantly upregulated in the 'cell division type'. Among 395 genes, G6PD expression correlated with the presence of lymph node or distant metastases during the disease course and significantly negatively correlated with PD-L1 expression. Immunohistochemical staining of G6PD also correlated with disease-specific survival and exhibited less heterogeneity compared with PD-L1 expression. G6PD activity could be measured by a blood serum test. The detection values significantly increased as the cancer stage progressed and significantly decreased after treatment. CONCLUSIONS: G6PD expression was an immunohistochemically and serum-detectable prognostic marker that negatively correlated with immune activity and PD-L1 levels, and could be used to predict the immunotherapy response.

Prediction of the invasive level of basal cell carcinomas in the facial area: Analysis of 718 Japanese cases.

BACKGROUND: Basal cell carcinoma (BCC) is the most common skin cancer. While Mohs micrographic surgery is commonly accepted for BCC treatment, surgical excision with free margins is widely considered the best treatment modality for BCCs in Japan. However, little is known about the predictors of the invasion levels of BCCs. OBJECTIVE: To investigate the optimization of deep surgical margins by identifying factors significantly influencing the invasion levels of facial BCCs. METHODS: The tumor invasion level was defined as the deepest part of a tumor. Tumor thickness was measured from the top of the granular layer to the deepest extension of the tumor or from the ulcer base overlying the deepest point of invasion in ulcerated lesions. Factors independently associated with tumor thickness and invasion level were identified by multivariate analysis. Six variables were tested: age, sex, anatomical region (nose, orbit, others), histologic pattern (aggressive, non-aggressive), presence of pigmentation, and diameter. RESULTS: We included 718 cases of facial BCCs involving 705 Japanese patients. The most frequent anatomical region and histologic pattern were the nose and nodular pattern, respectively. Only tumor diameter showed a correlation with tumor thickness (ß = 0.377, P < 0.001). Tumor diameter (AOR = 71.189, 95 % CI: 11.420-430.931, P = 0.01) and the following anatomical regions showed correlations with the invasion level: nose/others: AOR=2.769, 95 % CI: 1.235-6.493, P = 0.01; orbit/others: AOR=6.369, 95 % CI: 2.728-15.429, P < 0.001; orbit/nose: AOR=2.300, 95 % CI: 1.056-4.984, P = 0.04. CONCLUSIONS: This study serves as a guide for optimizing deep surgical margins and planning surgery for facial BCCs considering independently associated factors.

Vitiligo expansion and extent correlate with durable response in anti-programmed death 1 antibody treatment for advanced melanoma: A multi-institutional retrospective study.

Vitiligo is an autoimmune disorder resulting from the destruction of melanocytes. Several reports indicate the association between vitiligo and treatment response in advanced melanoma during immunotherapy. It has not been investigated, however, if an increase of vitiligo while on treatment with anti-programmed death 1 (PD-1) antibodies is associated with more durable responses. The aim of this study is to evaluate the correlation between the vitiligo dynamics and clinical efficacy of anti-PD-1 antibodies. This study included advanced melanoma patients who were treated with nivolumab or pembrolizumab and developed vitiligo thereafter. Correlation between vitiligo expansion (defined as an increase of lesion size at two separate time points at least 4 weeks apart) as well as vitiligo extent (body surface area [BSA] affected) and clinical efficacy based on response rate, progression-free survival and overall survival was assessed. We retrospectively reviewed 29 patients. The median time from the initiation of anti-PD-1 antibody to vitiligo onset was 4.3 months in patients who showed a response and 5.5 months in patients who showed no response (P = 0.31). Twelve patients showed vitiligo expansion, and in nine of these patients, vitiligo increased to grade 2 (covering ≥ 10% BSA). Vitiligo expansion and grade 2 vitiligo showed no improvement in treatment response (P = 0.59 and 0.25) but were associated with prolonged progression-free survival (P = 0.019 and 0.04). Grade 2 vitiligo also showed a trend for prolonged overall survival (P = 0.07). Trend of expansion and larger vitiligo extent may be predictive factors of prolonged survival during anti-PD-1 antibody in melanoma patients.