The role of macrophage migration inhibitory factor family and CD74 in the pathogenesis of melanoma.

Melanoma is an aggressive tumour with poor prognosis that arises from the malignant transformation of melanocytes. Over the past few decades, intense research into the pathogenesis of melanoma has led to the development of BRAF and immune checkpoint inhibitors, including antibodies against programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which have shown clinically significant efficacy. However, some tumours do not respond to these therapies initially or become treatment resistant. Most melanoma tissues appear to possess biological characteristics that allow them to evade these treatments, and identifying these characteristics is one of the major challenges facing cancer researchers. One such characteristic that has recently gained attention is the role of macrophage migration inhibitory factor (MIF) and its receptor CD74. This review outlines the cellular and molecular functions of CD74, MIF and their family of proteins. We then review their roles in tumours based on previous reports, highlight their pathological significance in melanoma and discuss their potential as therapeutic targets.

Recent treatment and prognosis in 643 patients with extramammary Paget's disease.

Information about extramammary Paget's (EMPD) treatment is limited because of the rarity of the disease. The prognosis differs between in situ EMPD and invasive EMPD; therefore, therapy should be planned according to the disease stage. We collected data on 643 EMPD cases treated between 2015 and 2019 in Japan and assessed recent trends in EMPD treatment and prognosis based on the EMPD-oriented TNM staging. Among the 643 patients, 317 had stage 0 (49.3%), 185 had stage I (28.8%), 51 had stage II (7.9%), 18 had stage IIIA (2.8%), 48 had stage IIIB (7.5%) and 24 had stage IV (3.7%) disease. Each stage showed a distinct survival curve, with the exception of stages II and IIIA. Curative surgery was most common in patients with stage 0-III disease. Chemotherapy was the first-line therapy, mainly in patients with stage IIIB and IV disease, most commonly with docetaxel (DTX), followed by DTX + tegafur gimeracil oteracil potassium (TS-1) and TS-1. Patients with local disease exhibited a 4.4% recurrence rate. Univariate analysis revealed no prognostic differences according to age, sex or primary tumour site. SLNB was not related to disease-specific survival. In multivariate analysis, female sex significantly predicted local relapse in stage 0-I (HR 3.09; 95% CI, 1.13-8.43), and initial treatment with curative surgery was significantly protective in terms of disease-specific survival in stage II-IIIA (HR, 0.17; 95% CI, 0.04-0.71) and stage IIIB-IV (HR 0.16; 95% CI, 0.05-0.51). Further clinical studies are needed to improve the prognosis of patients with stage II-IV EMPD.

Epidemiology of skin cancer based on Japan's National Cancer Registry 2016-2017.

Skin cancer is most frequently diagnosed in the White population. However, its subtypes and epidemiology in Japan are understudied. We aimed to elucidate skin cancer incidence in Japan based on the National Cancer Registry, a new nationwide integrated population-based registry. Data from patients diagnosed with skin cancer in 2016 and 2017 were extracted and classified by cancer subtypes. Data were analyzed using the World Health Organization and General Rules tumor classifications. Tumor incidence was calculated as the number of new cases divided by the corresponding total person-years. Overall, 67,867 patients with skin cancer were included. The percentage of each subtype was as follows: basal cell carcinoma, 37.2%; squamous cell carcinoma, 43.9% (18.3% of which, in situ); malignant melanoma, 7.2% (22.1% of which, in situ); extramammary Paget's disease, 3.1% (24.9% of which, in situ); adnexal carcinoma, 2.9%; dermatofibrosarcoma protuberans, 0.9%; Merkel cell carcinoma, 0.6%; angiosarcoma, 0.5%; and hematologic malignancies, 3.8%. The overall age-adjusted incidence of skin cancer was 27.89 for the Japanese population model and 9.28 for the World Health Organization (WHO) model. The incidences of basal cell carcinoma and squamous cell carcinoma were the highest (3.63 and 3.40 per 100,000 persons, respectively, in the WHO model) among skin cancers, whereas the incidences of angiosarcoma and Merkel cell carcinoma were the lowest (0.026 and 0.038 per 100,000 persons, respectively, in the WHO model). This is the first report to provide comprehensive information on the epidemiological status of skin cancers in Japan using population-based NCR data.

Functional preservation benefits of minimal surgery for extramammary Paget's disease.

As extramammary Paget's disease (EMPD) sometimes invades and metastasizes from the skin to the mucosa, radical surgical resection of these lesions is often difficult. The purpose of this study was to analyse the association between surgical margins and survival as well as the benefit of functional preservation over complete resection, in patients with EMPD. We retrospectively analysed 230 patients diagnosed with EMPD between 1969 and 2020. Patient and treatment characteristics were recorded. Since our centre is a specialized hospital and almost all patients were referred from other hospitals, we reviewed their referral letters. Prognostic factors and survival time were also analysed. Among 230 patients, 78 (33.9%) had positive margins. The presence of margin positive lesions increased the local recurrence rate but was not significantly correlated with survival. Of all the patients who had received a thorough explanation about the surgical procedure in the referring hospital, 43.8% were scheduled for surgeries that would result in functional impairment, and all of them had function-preserving surgeries at our hospital with a 10-year survival rate of 100%. Our result suggest that less invasive surgery preserves anogenital and urethral function may be an acceptable option for EMPD treatment.

Merkel cell carcinoma: a review of clinical management with focus on Asian patients.

Merkel cell carcinoma is a highly aggressive skin cancer characterized by neuroendocrine differentiation. This review aimed to present updates on the knowledge and current trends of clinical management of Merkel cell carcinoma. Additionally, we focused on Asian reports of Merkel cell carcinoma because most skin cancers differ substantially between Caucasians and Asians, and researchers have reported differences in Merkel cell carcinoma in racial and ethnic groups. Owing to its rarity, there is limited evidence for the epidemiology, pathogenesis, diagnosis and Merkel cell carcinoma treatment. The development of a nationwide survey or cancer registry, the identification of Merkel cell polyomavirus and the use of immune checkpoint inhibitors allowed a better understanding of its characteristics and biology and have revolutionized the clinical management of patients with Merkel cell carcinoma. Its incidence has gradually increased worldwide; however, it depends on the geographic location, race and ethnicity. No randomized prospective studies have evaluated the significance of sentinel lymph node biopsy, complete lymph node dissection and adjuvant radiation therapy; however, most patients with localized Merkel cell carcinoma are treated surgically or with post-operative radiation. Patients with distant Merkel cell carcinoma are administered immune checkpoint inhibitors as the first-line therapy; however, there is no established second-line therapy for refractory Merkel cell carcinoma. Furthermore, it is necessary to validate the favorable results of clinical studies performed in Western countries in the patients in Asia.

Clinical outcomes of head and neck mucosal melanoma treated with surgery: a single-center study in Japan.

BACKGROUND: Head and neck mucosal melanomas are rare malignancies. Although the prognosis is poor owing to the high incidence of distant metastases, locoregional control remains important. It is difficult to obtain results in a large cohort because of its rarity. This study aimed to elucidate the survival outcomes of patients with head and neck mucosal melanoma treated with surgery in Japan. METHODS: Patients with head and neck mucosal melanoma who were surgically treated between 2007 and 2021 at the National Cancer Center Hospital were retrospectively analyzed. RESULTS: A total of 47 patients were included in this study. The 5-year overall survival, disease-specific survival, locoregional control and relapse-free survival rates were 42%, 50%, 79% and 13%, respectively. The disease-specific survival of the oral mucosal melanoma group was significantly better than that of the sinonasal mucosal melanoma group (5-year disease-specific survival rate: 70% versus 37%, respectively; P = 0.04). Multivariate analyses revealed that sinonasal mucosal melanoma were independently significant adverse prognostic factor, for overall survival and disease-specific survival. Patients with oral mucosal melanoma patients had a higher incidence of lymph node metastasis than those with sinonasal mucosal melanoma patients (P < 0.0001). CONCLUSION: This study demonstrated the survival outcomes of the largest cohort of patients with head and neck mucosal melanomas treated surgically at a single institution within the past 20 years in Japan. We found that survival outcomes and incidence of nodal metastases varied by site.

Efficacy of chemotherapies for unresectable extramammary Paget disease: a single-centre retrospective study.

BACKGROUND: Extramammary Paget disease (EMPD) is a cutaneous neoplasm that can metastasize to the lymph nodes and distant organs, resulting in a poor prognosis. For unresectable distant metastases of EMPD, no consensus has been reached regarding optimal chemotherapy owing to a lack of data. OBJECTIVES: To evaluate the efficacy of three regimens: docetaxel (DTX) monotherapy; combination therapy with 5-fluorouracil, epirubicin, carboplatin, vincristine and mitomycin C (FECOM); and tegafur (S-1) monotherapy. METHODS: This single-centre retrospective study included 32 patients diagnosed with unresectable EMPD and treated with chemotherapy between 2002 and 2022 at the National Cancer Center Hospital in Japan. Patient characteristics, responses to treatment and survival data were evaluated for each of the first-line therapies. RESULTS: Among the 17 patients who received DTX monotherapy, the response rate (RR) and disease control rate (DCR) were 47% and 77%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 12.3 months [95% confidence interval (CI) 6.1-26.6] and 19.2 months (95% CI 8.5-not reached), respectively. Among the 11 patients who received combination FECOM chemotherapy, the RR and DCR were 55% and 64%, respectively. The median PFS and OS were 6.8 months (95% CI 3.5-not reached) and 13.4 months (95% CI 8.6-21.3), respectively. Among the four patients who received S-1 monotherapy, the RR and DCR were 0% and 25%, respectively. The median PFS and OS were 5.4 months (95% CI 2.3-not reached) and 12.5 (95% CI 2.3-not reached) months, respectively. CONCLUSIONS: Further investigations with prospective analysis are required to confirm these findings.

Prognostic factors in cutaneous apocrine carcinoma: a single-institution retrospective study of 32 patients.

BACKGROUND: Cutaneous apocrine carcinoma (CAC) is a rare adnexal carcinoma. Limited data exists on the demographics and overall survival (OS) of patients with CAC; thus, there is no consensus on surgical management. This study aimed to examine demographic and survival data of patients with CAC to determine optimal surgical management. METHODS: A single-center retrospective cohort study was conducted at the National Cancer Center Hospital in Tokyo between 2005 and 2022. Patients with a histologically-confirmed CAC diagnosis were identified and data on patient demographics, OS, and lymph node (LN) status were gathered. RESULTS: Thirty-two patients were included (median age, 65.5 years; male-female ratio, 15:1). The most common involvement site was the axilla (87.5%). Of the nine patients in the clinical local stage, pathological LN metastases were found in five patients. Either pathological LN or distant metastases were present in 75% of the patients at initial diagnosis. The most common initial surgical treatments included wide local excision and complete LN dissection. Across cohorts, the median OS was 39 months. Patients with ≥ 4 LN metastases had reduced recurrence-free survival and OS compared to those with ≤ 3 LN metastases (p = 0.042, p = 0.041, respectively). The OS was not remarkably different between patients who did and did not receive postoperative radiation therapy. CONCLUSIONS: Since CAC has a high rate of LN metastasis-and the number of LN metastases is a significant prognostic factor-LN evaluation should be considered for patients with CAC as initial treatment. Nonetheless, ≥ 4 LN metastases can be a poor prognostic factor for CAC.

Clinical significance of local control of primary tumour in definitive radiotherapy for scalp angiosarcomas.

INTRODUCTION: Scalp angiosarcoma is a rare and aggressive cancer. Definitive radiotherapy is a treatment option for localised scalp angiosarcoma patients. Although definitive surgical resection reportedly prolongs overall survival (OS), whether initial local treatment effect affects OS when definitive radiotherapy is administered is unclear. Therefore, this study analysed whether local recurrence within 6 months of irradiation correlates with OS and cancer-specific survival (CSS). Furthermore, how local control affects patients' quality of life was investigated. MATERIALS AND METHODS: Thirty-one localised scalp angiosarcoma patients who had received definitive radiotherapy at our institution between October 2010 and July 2021 were analysed retrospectively. The most commonly used dose fractionation was 70 Gy in 35 fractions (83.9%). Local recurrence within 6 months of radiotherapy and other clinical factors were examined in univariate and subsequent multivariate analyses for correlation with OS and CSS. RESULTS: The median follow-up period was 16 months (range, 6-45 months). Local recurrence was detected in 16 patients (51.6%), 12 of whom had recurrence within 6 months. In multivariate analyses, the presence of local recurrence within 6 months of radiotherapy was significantly associated with OS and CSS (p = 0.003, 0.0001, respectively). Ten of the 16 patients with local recurrence had severe symptoms such as bleeding, pain, difficulty opening the eye and malodour. CONCLUSIONS: The initial local treatment effect was significantly associated with OS and CSS after definitive radiotherapy. Furthermore, local recurrence after radiotherapy resulted in a variety of symptoms, including bleeding and pain, which reduced the patient's quality of life.

Dermatoscopic and clinical features of congenital or congenital-type nail matrix nevi: A multicenter prospective cohort study by the International Dermoscopy Society.

BACKGROUND: Congenital nail matrix nevi (NMN) are difficult to diagnose because they feature clinical characteristics suggestive of adult subungual melanoma. Nail matrix biopsy is difficult to perform, especially in children. OBJECTIVE: To describe the initial clinical and dermatoscopic features of NMN appearing at birth (congenital) or after birth but before the age of 5 years (congenital-type). METHODS: We conducted a prospective, international, and consecutive data collection in 102 hospitals or private medical offices across 30 countries from 2009 to 2019. RESULTS: There were 69 congenital and 161 congenital-type NMNs. Congenital and congenital-type NMN predominantly displayed an irregular pattern of longitudinal microlines (n = 146, 64%), reminiscent of subungual melanoma in adults. The distal fibrillar ("brush-like") pattern, present in 63 patients (27.8%), was more frequently encountered in congenital NMN than in congenital-type NMN (P = .012). Moreover, congenital NMN more frequently displayed a periungual pigmentation (P = .029) and Hutchinson's sign (P = .027) than did congenital-type NMN. LIMITATIONS: Lack of systematic biopsy-proven diagnosis and heterogeneity of clinical and dermatoscopic photographs. CONCLUSION: Congenital and congenital-type NMN showed worrisome clinical and dermatoscopic features similar to those observed in adulthood subungual melanoma. The distal fibrillar ("brush-like") pattern is a suggestive feature of congenital and congenital-type NMN.

A review of the AJCC melanoma staging system in the TNM classification (eighth edition).

In the eighth edition of the American Joint Committee on Cancer Staging Manual, several modifications were made for melanoma. These modifications were aimed at improving the prognosis prediction accuracy of the staging system. The main modifications are as follows: the cutoff value of the T1 category has been changed, and there are new classifications of stage IIID and of M1d (metastasis of the central nervous system). These changes will allow for more accurate stratification of melanoma prognosis. However, it is necessary to validate the new modifications through future clinical research.

RB1 gene mutations are a distinct predictive factor in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma that tends to show local recurrence and metastasis. Typically, MCC is polyomavirus (MCPyV)-associated and cytokeratin 20 (CK20) positive. However, little is known about this tumor and its origins. Here, we aimed to determine the developmental origins of MCC and to identify prognostic clinicopathologic factors. Initial examinations revealed that CK20 and MCPyV expression (CK20+, MCPyV+ (60%); CK20+, MCPyV- (10%); CK20-, and MCPyV- (30%)) did not affect overall survival. With RB1 gene sequencing of FFPE specimens, which covered an entire exon, all RB1 mutation-positive cases showed positive regional lymph node and/or distant metastases (8/8 cases, 100%), whereas the frequency of the metastasis was statistically significantly lower in RB1 mutation-negative cases, (10/16 cases, 62%, P = 0.033). The results were also confirmed with immunohistochemistry, and either RB1 alterations, entire exon sequencing, or immunohistochemistry was associated with the metastasis (P = 0.007). RB1 alterations may be used to access the aggressive clinical course of MCC.

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.

BACKGROUND: Completion lymph node dissection (CLND) has long been the standard treatment for stage III melanomas identified as metastasis on the sentinel node (SN-positive). Two major changes occurred in 2017 and 2018, the change in the CLND criteria for SN-positive patients and the approval of several adjuvant therapies could revolutionize such management approach. However, their effects have not been fully investigated on the real-world outcomes of stage III melanoma patients. Therefore, we investigated the impact of these changes on the prognosis of Japanese stage III melanoma patients. METHODS: Totally, 119 stage III, SN-positive melanoma patients were included. They were categorized into those diagnosed as SN-positive between January 2015 and June 2017 (pre-June 2017 group) and between July 2017 and December 2019 (post-July 2017 group). Recurrence-free survival (RFS), overall survival, and prognostic factors were analyzed. RESULTS: The frequency of patients who received CLND was significantly higher in the pre-June 2017 group (p = 0.001), and those who received adjuvant therapy were significantly higher in the post-July 2017 group (p < 0.001). The 2-year RFS was 50.1% and 68.5% in the pre-June and post-July 2017 groups, respectively (p = 0.049). Cox proportional hazards model analysis for RFS showed that adjuvant therapies reduce the risk of recurrence (hazard ratio 0.37; 95% confidence interval 0.14-0.99; p = 0.047). CONCLUSION: Changes in the CLND criteria in SN-positive patients and the approval of adjuvant therapies for stage III melanomas have significantly impacted Japanese melanoma medicine. Adjuvant therapy tended to prolong patient's RFS while omitting immediate CLND had no significant negative influence on it.

Association between prognosis and complete resection in primary cutaneous myoepithelial carcinoma: two case presentations and literature review.

Myoepithelial carcinoma is a rare tumor that occurs in the salivary glands. Therefore, primary cutaneous myoepithelial carcinoma is extremely rare. The malignancy of this tumor is due to its aggressive nature and high metastatic potential. Despite the general consideration that primary cutaneous myoepithelial carcinoma has a poor prognosis, there are few available prognostic data. Herein, we report two cases of primary cutaneous myoepithelial carcinoma to expand the literature on the clinical and pathological characteristics of this disease. In case 1, the tumor was completely resected and sentinel lymph node biopsy was performed, resulting in long-term survival. In contrast, case 2 progressed aggressively with multiple bone metastases despite treatment with docetaxel chemotherapy, and the patient ultimately died of the disease. Only 14 cases, including the present two cases, of primary cutaneous myoepithelial carcinoma have been reported to date. Overall, patients with clinical regional or distant metastases show a severe clinical course. Nevertheless, even in cases of inappropriate resection or local recurrence, if complete resection is ultimately achieved prior to clinical metastasis, the prognosis is good and survival is prolonged. Therefore, obtaining complete resection appears to be the most important treatment strategy for primary cutaneous myoepithelial carcinoma.

Systemic Immunotherapy for Advanced Cutaneous Squamous Cell Carcinoma.

OPINION STATEMENT: Advanced (i.e., unresectable) cutaneous squamous cell carcinoma (cSCC) is a rare condition with a dismal prognosis. Although less than 5% of cSCC patients develop metastases or local recurrence after complete excision, advanced cSCC is difficult to treat. These conditions tend to develop in elderly patients, although, at times, metastases are noted in middle-aged patients. Once metastasis occurs in cSCC, the 10-year survival rates fall to less than 20% for patients with regional lymph node involvement and less than 10% for patients with distant metastases, indicating that cSCC can be difficult to treat effectively when it is advanced. Traditionally, platinum-based therapy has been considered as a conventional option for advanced cSCC. It is efficacious to some degree, but the toxic effects of the combination treatments often prohibit their use in elderly patients. It has been a decade since the development of epidermal growth factor receptor (EGFR) inhibitors as agents that are less toxic. However, evidence regarding systemic therapy for advanced cSCC is limited because of a lack of high-quality prospective studies. Remarkably, the US Food and Drug Administration (FDA) approved an anti-PD-1 antibody treatment (cemiplimab) for the treatment of patients who are not candidates for curative surgery or curative radiation. It will be a promising treatment option for these types of rare conditions.

Randomized phase III trial of adjuvant therapy with locoregional interferon beta versus surgery alone in stage II/III cutaneous melanoma: Japan Clinical Oncology Group Study (JCOG1309, J-FERON).

The Dermatologic Oncology Group of Japan Clinical Oncology Group has started a randomized phase III trial to confirm the superiority of adjuvant therapy with locoregional interferon beta in overall survival over surgery alone for patients with pathological stage II/III cutaneous melanoma (JCOG1309). Patients in the interferon beta arm receive intra- or subcutaneous injections of interferon beta directly into the surgical site at a flat dose of 3 million units once per day. Treatment is repeated for 10 consecutive days every 8 weeks for a total of 3 courses during the induction phase, then 1-day injection every 4 weeks for 2.5 years. A total of 240 patients will be accrued from 17 Japanese institutions within 6.5 years. Primary endpoint is overall survival. Secondary endpoints are relapse-free survival, distant metastasis-free survival, pattern of recurrence, and adverse events. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000017494 [http://www.umin.ac.jp/ctr/index.htm].

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.