原发皮肤恶性黑色素瘤细胞分子遗传学研究进展

本文综述了原发皮肤恶性黑色素细胞分子遗传学改变，染色体上的非随机改变主要发生在1、6、9、7及10号染色体上。     

BRAF V600E mutation as a prognostic factor in cutaneous melanoma patients

The prognostic significance of BRAF mutations in the natural course of melanoma is controversial. The aim of study was to assess the prognostic significance of BRAF V600E mutation in cutaneous melanoma patients. A total of 151 melanomas were included in the study. BRAF V600E mutation was detected using the real‐time PCR. BRAF V600E mutation rate was 51%. BRAF mutation rate was higher for young patients (61.4%) and upper limbs (63.2%), trunk (59.3%) and head and neck (59.2%) were the most frequently afflicted sites in BRAF‐mutant patients, whereas lower limbs were mostly affected in BRAF‐wild patients (77.8%). Likewise, acral melanomas rarely harbored BRAF mutation (17.1%). The disease‐free survivals regarding the entire and Stage III cohorts were longer in the BRAF‐mutant group than in the BRAF‐wild group (p = .006 and p = .004, respectively), whereas Stage I–II patients had no survival differences between BRAF statuses (p = .2). Likewise, BRAF‐mutant patients had better overall survival (OS) time compared to BRAF‐wild patients in all stages (p = .01), in Stage III (p = .01), and in Stage IV patients (p = .001). However, no differences between BRAF statuses were observed in Stage I–II melanomas (p = .3). In conclusion, BRAF V600E‐mutant melanomas show favorable prognostic impact on both disease‐free and OSs in all staged melanomas except local disease.     

Awareness and early detection of cutaneous melanoma: an analysis of factors related to delay in treatment

Factors associated with the detection of cutaneous melanomas and reasons for delay in diagnosis were investigated in 429 patients with histologically proven melanoma operated on between January 1993 and June 1996. Patients were interviewed using a standardized questionnaire. In 25% of patients, treatment was delayed for more than 1 year from the time they first noticed a suspicious pigmented lesion. Melanoma was detected by the patients themselves in 67% of women and 45% of men. The three predominant clinical symptoms of melanoma were change in colour (darker), increase in size and increase in elevation of a pigmented lesion. The role of sun exposure and of naevi as risk factors for melanoma, as well as the potential benefit of early treatment, were known by 87%, 66% and 82% of the patients, respectively. However, melanoma awareness had no impact on the time period between first observation of skin changes and treatment. Among the factors associated with delay in melanoma diagnosis, an initial incorrect diagnosis as a benign lesion by the physician first visited (in 18% of all cases) had the highest significance. Patients detecting their lesions themselves were treated significantly later than patients in whom others had remarked on changes in a naevus. Furthermore, melanomas of the head and neck were treated later than melanomas at other body sites. Further efforts to educate both the public and the medical profession are essential to ensure earlier treatment for cutaneous melanomas.     

Local cryosurgery and imiquimod: A successful combination for the treatment of locoregional cutaneous metastasis of melanoma: A case series

Locoregional cutaneous metastases of melanoma (LCMM) represent a therapeutic challenge. Many treatment options are available with varying results. The combination of cryotherapy and imiquimod, two treatments with a possible synergistic effect, has not yet been described for treating this disease. In this paper, we aimed to show the response of LCMM to cryotherapy combined with topical imiquimod 5%. A retrospective review of 20 patients diagnosed with LCMM and treated with cryotherapy combined with topical imiquimod 5% between November 2000 and May 2014 at three institutions was performed. The locoregional cutaneous response was evaluated. After a mean of five sessions, 13 patients (65%) responded to treatment, eight (40%) of these completely and five (25%) partially. Systemic disease progressed in 16 (80%) patients. Cryotherapy followed by topical imiquimod 5% is simple to apply, has minimal adverse effects and provides response rates similar to other, more complex treatment options.     

皮肤黑色素瘤诊治的误区

目的揭示皮肤黑色素瘤诊断和治疗的误区，探讨合理诊断和治疗黑色素瘤的方法。方法结合有关文献，并对15例足部皮肤黑色素瘤的病程和治疗进行分析。结果大多数患者没有及时就医以及医疗单位病检取材不合理。结论正确取材活检，明确切除范围，及时手术以及一期修复组织缺损是有效防止癌肿扩散，提高生存率的关键。     

Frequent brain metastases during treatment with BRAF/MEK inhibitors: A retrospective single institutional study

Recent clinical trials revealed that both immune checkpoint inhibitors (ICI) and BRAF/MEK inhibitors significantly prolonged survival in melanoma patients when used for both advanced stage disease and postoperative adjuvant therapy. Although BRAF/MEK inhibitors are associated with a higher objective response rate than ICI, most patients relapse during treatment. However, progression patterns during treatment with BRAF/MEK inhibitors have not been extensively investigated. Here, we retrospectively collected the data of melanoma patients initially treated with BRAF/MEK inhibitors or anti-programmed death 1 (PD-1) antibody monotherapy at the University of Tsukuba Hospital and compared their results. The χ²-test revealed that frequency of brain metastasis (BM) development was significantly higher in cases treated with BRAF/MEK inhibitors compared with those with anti-PD-1 antibody monotherapy. In addition, BM-free survival in cases treated with BRAF/MEK inhibitors was significantly shorter than those treated with anti-PD-1 antibody monotherapy. Our results indicate that BM development during treatment with BRAF/MEK inhibitors may be more frequent than anti-PD-1 antibody monotherapy, even though the extracranial metastases are well controlled. Therefore, we recommend frequent brain examinations during treatment with BRAF/MEK inhibitors to detect BM at an early stage and to promptly administrate ICI with local radiation therapy.     

Diffuse melanosis cutis in the setting of BRAFV600E mutant melanoma and treatment with targeted therapies

Diffuse melanosis cutis (DMC) is a rare presentation of metastatic melanoma associated with a particularly guarded prognosis. We report a case of a 35‐year‐old man with BRAF^V600E metastatic melanoma treated with dabrafenib (as well as ipilimumab and whole brain radiotherapy), who is alive, 25 months after the onset of his DMC. This is significantly longer than the reported mean survival of 4 months, highlighting the importance of BRAF mutation testing and the promising survival advantage of using targeted therapies compared with conventional chemotherapeutic regimens.     

Desmoplastic melanoma may mimic a cutaneous peripheral nerve sheath tumor: Report of 3 challenging cases

Desmoplastic melanoma (DM) and cutaneous malignant peripheral nerve sheath tumors (MPNST) reveal histological and immunohistochemical similarities, including S100 positivity and negative staining for conventional melanocytic markers. We present 3 cases of cutaneous S100‐positive spindle cell tumors in elderly patients, in which first findings led to initial misdiagnoses as cutaneous MPNST and benign peripheral sheath nerve tumor (neurofibroma). The identification of adjacent atypical melanocytic hyperplasia in the overlying skin along with tumor cell proliferation, also in the superficial dermis, the neurotropic component and the absence of any relationship between the tumor and a major nerve, pre‐existing neural benign tumor or the existence of stigmata suggestive of neurofibromatosis raised consideration of a DM. Careful attention should be paid to the presence of a firm dermal nodule and atypical scar lesions especially in sun‐exposed areas (mainly head and neck region) in elderly patients associated with S100‐positive spindle cell proliferation, solar elastosis and adjacent atypical melanocytic proliferation. In such cases, the possibility of a DM should be excluded with caution, especially if the tumor reveals a paucicellular morphology resembling various non‐melanocytic neoplasms including malignant or benign peripheral sheath nerve tumors.     

A profile of invasive cutaneous malignant melanoma in Malta: 1993–2002

BACKGROUND: The incidence of malignant melanoma of the skin has risen in every part of the world where reliable cancer registration data are found. OBJECTIVE: Our study aims to describe the changing incidence of and survival from invasive cutaneous malignant melanoma in Malta, by analysing the data from the 211 cases that were registered at the Malta National Cancer Registry between 1993 and 2002. RESULTS: The age standardized incidence rates for invasive cutaneous malignant melanoma rose from 3.7 per 100,000 population per year for males and 5.1 for females in the first 5-year period, to 8.0 per 100,000 population per year for males and 5.9 for females in the second 5-year period. In both sexes, numbers of thin (< or = 1.0 mm) invasive melanomas increased significantly between 1993 and 2002; males also registered a significant increase in intermediate-thickness (1.01-4.0 mm) melanomas. The increase in numbers of thin and intermediate-thickness melanomas between the two 5-year periods was greatest in patients aged 60 years and over. The overall absolute 5-year survival rate for the first period was 74% and for the second period 92%. CONCLUSION: Numbers of reported cases of invasive cutaneous malignant melanoma in Malta have more than doubled during the 10-year study period. This is mostly due to a marked rise in the diagnosis of thin melanomas in both sexes, occurring mainly in patients aged 60 years and over. As thin melanomas are of low metastasizing potential, this has resulted in an increase in survival between the two 5-year study periods.     

Recent advances in cytokines in cutaneous and systemic lupus erythematosus

Lupus erythematosus (LE) includes a broad spectrum of diseases from a cutaneous‐limited type to a systemic type. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease which affects multiple organs. Cutaneous lupus erythematosus (CLE) includes skin symptoms seen in SLE and cutaneous‐limited LE. Although immune abnormalities, as well as heritable, hormonal and environmental factors, are involved in the pathology of LE, the actual pathogenesis is still unclear. Recently, the involvement of various cytokines has been shown in the pathogenesis of LE. Moreover, some trials with biological agents targeted specific cytokines are also ongoing for SLE. In this article, we review the contributions of major cytokines such as interferon, tumor necrosis factor‐α and interleukin‐18 to LE, especially SLE and CLE.     

Oncogenic BRAF signalling increases Mcl‐1 expression in cutaneous metastatic melanoma

The Bcl‐2 family member Mcl‐1 is essential for melanoma survival; however, the influence of oncogenic BRAF signalling remains elusive. In this study, Mcl‐1 splice variant expression was determined in a panel of melanoma cell lines in relation to BRAF mutational status. Mcl‐1L mRNA expression was increased in melanoma cells compared with primary melanocytes with significantly increased mRNA and protein expression observed in BRAF^V600E mutant melanoma cells. Although no change in Mcl‐1S mRNA was observed, Mcl‐1S protein expression also increased in BRAF mutant melanoma cells. Additionally, while over‐expression of mutant BRAF^V600E increased both Mcl‐1L and Mcl‐1S expression, inhibition of hyperactive BRAF signalling resulted in decreased Mcl‐1L expression. These studies suggest that the regulation of Mcl‐1 expression by BRAF signalling is increased by oncogenic activation of BRAF, revealing a mechanism of apoptotic resistance which may be overcome by the use of more specifically targeted Mcl‐1 inhibitors.     

恶性黑素瘤的诊治进展

皮肤恶性黑素瘤(cutaneous malignant melanoma,CMM)是黑色素细胞的恶性肿瘤,本文对CMM的发病情况、临床分期及目前的治疗方法进行了综述。     

皮肤黑素瘤中囊泡胺转运蛋白1的免疫浸润景观和预后价值的鉴定

 目的 评估囊泡胺转运蛋白1(VAT1)在皮肤黑素瘤（SKCM）中的免疫浸润景观和预后价值。方法采用基因表达谱交互分析(GEPIA)方法分析VAT1在SKCM中的mRNA表达,利用人类蛋白图谱(HPA)进行蛋白质水平的验证。通过GEPIA的生存模块评估VAT1对SKCM患者生存的影响,并利用GSE98394数据集进行验证。从TCGA下载SKCM的数据集,采用单因素Cox分析评估VAT1与生存率的关系,利用GSE98394数据集进行验证。利用肿瘤免疫评估资源(TIMER)检测SKCM中免疫浸润水平与VAT1表达以及SKCM累积存活率的相关性。使用CIBERSORT的相关模块进一步探讨VAT1与肿瘤免疫浸润的相关性。结果在SKCM中,VAT1的mRNA和蛋白质表达水平较正常人高。生存曲线和单因素Cox分析显示VAT1表达上调是预后不良的因素。VAT1的表达水平与SKCM中CD8+T细胞、巨噬细胞、中性粒细胞和树突状细胞的浸润水平呈负相关（P均<0.01）。此外,VAT1高表达组与低表达组相比,驻留记忆CD4+T细胞、活化的记忆CD4+T细胞、M1巨噬细胞、驻留肥大细胞、调节性T细胞、活化的NK细胞、浆细胞等免疫细胞组成比例上差异均有统计学意义（P均<0.05）。结论VAT1是SKCM潜在的预后生物标志物,且与免疫浸润有关。     

Diagnosis of cutaneous melanoma: accuracy of a computerized image analysis system (Skin View)

Background/aims: Early diagnosis is essential for reducing the high mortality of CM (cutaneous melanoma). An expert dermatologist has a diagnostic accuracy of 85% but, in performing mass screening, the problem is to transfer the experience of a specialized centre to peripheral health clinics. Therefore, some computerized analysis systems were made. The aim of this paper is to compare the diagnostic accuracy of one such system, the Skin View System (SVS), to the accuracy of a well trained dermatologist in order to establish the real usefulness of the instrument and to verify how much it can help the diagnostic accuracy of the clinician in a dermatology setting.
Method: During a campaign for the early diagnosis of CM, 176 patients with small and flat pigmentary lesions underwent clinical diagnosis, computerized analysis with SVS and skin biopsy. For clinical and computerized diagnosis, we evaluated sensitivity, specificity, true and negative predictive value.
Results: The statistical evaluation, in our study, reveals that the computerized system has a diagnostic accuracy lower than that of a trained dermatologist.
Conclusions: This computerized system does not help the clinician in the diagnosis of pigmented lesions.