近5年单中心肢端型及皮肤型黑色素瘤外科治疗患者的预后因素分析

doi:10.19401/j.cnki.1007-3639.2022.12.003

中国癌症杂志 ›› 2022, Vol. 32 ›› Issue (12): 1158-1167.doi: 10.19401/j.cnki.1007-3639.2022.12.003

近5年单中心肢端型及皮肤型黑色素瘤外科治疗患者的预后因素分析

林馨怡¹(), 孙伟¹, 胡涂¹, 王春萌¹, 严望军¹, 罗志国², 刘欣³, 钟景钦¹, 邹孜瑊¹, 徐宇¹, 陈勇¹()

1.复旦大学附属肿瘤医院骨软组织外科，复旦大学上海医学院肿瘤学系，上海 200032
2.复旦大学附属肿瘤医院消化肿瘤内科，复旦大学上海医学院肿瘤学系，上海 200032
3.复旦大学附属肿瘤医院头颈及神经内分泌肿瘤内科，复旦大学上海医学院肿瘤学系，上海 200032

收稿日期:2022-11-01 修回日期:2022-12-12 出版日期:2022-12-30 发布日期:2023-02-02
通信作者: 陈勇（ORCID: 0000-0002-7188-4566），主任医师，复旦大学附属肿瘤医院骨软组织外科副主任。
作者简介:林馨怡（ORCID: 0000-0001-9872-2842），博士。
陈勇，主任医师，副教授，硕士研究生导师。现任复旦大学附属肿瘤医院骨软组织外科副主任，复旦大学附属肿瘤医院恶性黑色素瘤诊治中心主任。现任中国抗癌协会黑色素瘤专业委员会副主任委员，上海市抗癌协会黑色素瘤专业委员会主任委员，中国抗癌协会肉瘤专业委员会常委，中国抗癌协会肉瘤专业委员会脊柱肿瘤学组委员，中国修复重建外科专业委员会骨肿瘤学组委员，中国中医药研究促进会骨伤科分会骨肿瘤专业委员会委员，上海市抗癌协会肉瘤专业委员会常委兼秘书长。从事肿瘤外科临床和科研工作20余年，擅长骨与软组织肿瘤、恶性黑色素瘤的综合治疗。先后承担国家自然科学基金和行业协会等10余项重要课题，主要负责恶性黑色素瘤、肉瘤等相关临床试验10余项，以第一作者及通信作者身份发表论文30余篇，2021年以第一完成人获“中国抗癌协会科技奖二等奖”；2017年获“上海市卫健委杰出青年”称号，2018年获“复旦大学十佳医务青年”称号。
基金资助:
国家自然科学基金(82272857);国家自然科学基金(81802636);临港实验室基金(LG-QS-202205-11);上海市科学技术委员会科研计划(19411951700)

Multivariable prognostic analyses of Chinese acral and cutaneous melanoma after surgical treatment for the past five years in a single cancer center

LIN Xinyi¹(), SUN Wei¹, HU Tu¹, WANG Chunmeng¹, YAN Wangjun¹, LUO Zhiguo², LIU Xin³, ZHONG Jingqin¹, ZOU Zijian¹, XU Yu¹, CHEN Yong¹()

1. Department of Musculoskeletal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
2. Department of Gastrointestinal Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
3. Department of Head and Neck and Neuroendocrine Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China

Received:2022-11-01 Revised:2022-12-12 Published:2022-12-30 Online:2023-02-02
Contact: CHEN Yong

摘要/Abstract

摘要：

背景与目的：中国及亚洲部分国家和地区的恶性黑色素瘤（malignant melanoma，MM）患者的预后显著低于欧美人群，主要是因为肢端型黑色素瘤（acral melanoma，AM）无论是在生物学行为、临床特征、预后以及药物的疗效（主要是免疫治疗）上都差于皮肤型黑色素瘤（cutaneous melanoma，CM）。近5年在MM外科治疗和药物辅助治疗选择方面发生了一定的变化。本文回顾性分析近5年单中心经手术治疗的AM及CM患者的生存变化和相关的独立预后因素。方法：对2017—2021年在复旦大学肿瘤医院黑色素瘤诊治中心接受外科治疗的MM患者进行回顾性研究。通过病史回顾和随访收集患者完整的基本信息、原发灶特点、淋巴灶转移特征和生存状态，剔除黏膜型、原发不明、随访时间短于6个月的病例。通过生存分析和多因素分析，探讨患者生存的差异和相关预后因素。结果：本研究共入组585例黑色素瘤患者，其中AM 397例，CM 188例。中位年龄59（19~89）岁，女性占54%。AM和CM在性别、年龄、原发灶位置、基因突变分布和辅助治疗等方面存在差异，但在Breslow深度、溃疡、淋巴结转移等肿瘤负荷因素上差异无统计学意义。中位随访时间为24个月，中位无疾病生存期为36个月，1、2年无复发生存期（relapse-free survival，RFS）分别为75.6%和61.2%。但两亚型的预后差异无统计学意义。AM中RFS的独立风险因素包括：原发灶溃疡（HR=2.265，95% CI：1.257~4.080），NRAS基因突变（HR=1.816，95% CI：1.211~2.725），较晚的N分期（N₁、N₂、N₃相较N₀的HR分别为1.850、4.085、4.191）；保护因素为女性（HR=0.636，95% CI：0.433~0.933）和上肢原发灶（HR=0.259，95% CI：0.105~0.639）。CM中RFS的独立风险因素包括：原发灶溃疡（HR=4.073，95% CI：1.718~9.654），较晚的N分期（其中N₃期的HR=5.482，95% CI：2.385~12.601）。结论：预后分析发现，原发灶的肿瘤负荷仍旧与CM和AM患者的预后密切相关，而NRAS基因的突变状态则提示AM预后更差。

关键词: 黑色素瘤, 肢端型, 皮肤型, 预后分析, 外科治疗

Abstract:

Background and purpose: The prognosis of malignant melanoma (MM) in China and Asia is significantly worse than that of European and American populations, mainly because acral melanoma (AM) is inferior to cutaneous melanoma (CM) in terms of biological behavior, clinical features, prognosis, and efficacy of drugs (mainly immunotherapy). Certain changes have occurred in the last 5 years in the choice of surgical and drug-adjuvant treatment for MM. This study retrospectively analyzed the survival outcomes of Chinese CM and AM patients after surgical treatment in a single cancer center for the past five years. Methods:Data of melanoma patients undergoing surgical treatment were retrospectively collected from 2017 to 2021 in Fudan University Shanghai Cancer Center. The basic clinical characteristics, pathological features, lymph node tumor burden and survival information were carefully collected from medical document. Patients with mucosal subtype, unknown primary sites, or follow-up less than 6 months were excluded. Survival analysis and multivariable Cox regression analysis were performed to explore prognosis and associated risk factors. Results:Totally 585 patients were enrolled, including 397 AM and 188 CM patients. The median age was 59 (19-89) years, and 54% were female. AM and CM patients differed in gender, age, primary tumor location, gene mutation distribution and adjuvant therapy, but not in tumor burden associated factors including the Breslow thickness, ulceration and lymph node involvment. The median follow-up time was 24 months, and the median relapse-free survival (mRFS) was 36 months, with 1-year and 2-year RFS of 75.6% and 61.2%, respectively. However, there was no statistically significant difference in prognosis between the two subtypes. Primary ulceration (HR=2.265, 95% CI: 1.257-4.080), NRAS mutation (HR=1.816, 95% CI: 1.211-2.725) and advanced N stage (HR of N₁, N₂ and N₃ versus N₀ were 1.850, 4.085 and 4.191, respectively) were independent prognostic risk factors for RFS in AM; while the protective factors were female (HR=0.636, 95% CI: 0.433-0.933) and upper extremity primary lesions (HR=0.259, 95% CI: 0.105-0.639). Independent risk factors for RFS in CM included primary ulceration (HR=4.073, 95% CI: 1.718-9.654), and later N stage (HR=5.482, 95% CI: 2.385-12.601 for N₃ stage). Conclusion: High tumor burden of primay lesion still deteriorates overall outcomes for both AM and CM, while harboring NRAS mutation might suggest even worse outcome for AM.

Key words: Melanoma, Acral, Cutaneous, Prognostic analysis, Surgical treatment

中图分类号:

R739.5

林馨怡, 孙伟, 胡涂, 王春萌, 严望军, 罗志国, 刘欣, 钟景钦, 邹孜瑊, 徐宇, 陈勇. 近5年单中心肢端型及皮肤型黑色素瘤外科治疗患者的预后因素分析[J]. 中国癌症杂志, 2022, 32(12): 1158-1167.

LIN Xinyi, SUN Wei, HU Tu, WANG Chunmeng, YAN Wangjun, LUO Zhiguo, LIU Xin, ZHONG Jingqin, ZOU Zijian, XU Yu, CHEN Yong. Multivariable prognostic analyses of Chinese acral and cutaneous melanoma after surgical treatment for the past five years in a single cancer center[J]. China Oncology, 2022, 32(12): 1158-1167.

图/表 5

表1

表2

图1

表3

表4

参考文献 21

[1]	ARNOLD M, SINGH D, LAVERSANNE M, et al. Global burden of cutaneous melanoma in 2020 and projections to 2040[J]. JAMA Dermatol, 2022, 158(5): 495-503. doi: 10.1001/jamadermatol.2022.0160
[2]	ZHENG R S, et al. Cancer incidence and mortality in China, 2016[J]. J Natl Cancer Cent, 2022, 2(1): 1-9.
[3]	BRADFORD P T, GOLDSTEIN A M, MCMASTER M L, et al. Acral lentiginous melanoma: incidence and survival patterns in the United States, 1986-2005[J]. Arch Dermatol, 2009, 145(4): 427-434. doi: 10.1001/archdermatol.2008.609 pmid: 19380664
[4]	WEN X Z, LI D D, ZHAO J J, et al. Time-varying pattern of recurrence risk for localized melanoma in China[J]. World J Surg Oncol, 2020, 18(1): 6. doi: 10.1186/s12957-019-1775-5 pmid: 31901239
[5]	NAGORE E, PEREDA C, BOTELLA-ESTRADA R, et al. Acral lentiginous melanoma presents distinct clinical profile with high cancer susceptibility[J]. Cancer Causes Control, 2009, 20(1): 115-119. doi: 10.1007/s10552-008-9221-y
[6]	DUARTE C A, FLÓREZ J P, LÓPEZ H G, et al. Survival of acral lentiginous melanoma in the national cancer institute of Colombia[J]. J Eur Acad Dermatol Venereol, 2017, 31(3): 438-442. doi: 10.1111/jdv.13913 pmid: 27518480
[7]	LIAN B, et al. The natural history and patterns of metastases from mucosal melanoma: an analysis of 706 prospectively-followed patients[J]. Ann Oncol, 2017, 28(4): 868-873. doi: 10.1093/annonc/mdw694 pmid: 28039178
[8]	FARIES M B, THOMPSON J F, COCHRAN A J, et al. Completion dissection or observation for sentinel-node metastasis in melanoma[J]. N Engl J Med, 2017, 376(23): 2211-2222. doi: 10.1056/NEJMoa1613210
[9]	CURTI B D, FARIES M B. Recent advances in the treatment of melanoma[J]. N Engl J Med, 2021, 384(23): 2229-2240. doi: 10.1056/NEJMra2034861
[10]	WEI X T, WU D, LI H, et al. The clinicopathological and survival profiles comparison across primary sites in acral melanoma[J]. Ann Surg Oncol, 2020, 27(9): 3478-3485. doi: 10.1245/s10434-020-08418-5 pmid: 32253677
[11]	HUANG K, XU Y, GABRIEL E M, et al. Comparative analysis of acral melanoma in Chinese and Caucasian patients[J]. J Skin Cancer, 2020, 2020: 5169051.
[12]	FRANKE V, VAN AKKOOI A C J. The extent of surgery for stage Ⅲ melanoma: how much is appropriate?[J]. Lancet Oncol, 2019, 20(3): e167-e174. doi: 10.1016/S1470-2045(19)30099-3
[13]	LEITER U, STADLER R, MAUCH C, et al. Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial[J]. Lancet Oncol, 2016, 17(6): 757-767. doi: S1470-2045(16)00141-8 pmid: 27161539
[14]	LEITER U, STADLER R, MAUCH C, et al. Final analysis of DeCOG-SLT trial: no survival benefit for complete lymph node dissection in patients with melanoma with positive sentinel node[J]. J Clin Oncol, 2019, 37(32): 3000-3008. doi: 10.1200/JCO.18.02306 pmid: 31557067
[15]	WEI X T, WU D, CHEN Y, et al. Prognostic value of ulceration varies across Breslow thicknesses and clinical stages in acral melanoma: a retrospective study[J]. Br J Dermatol, 2022, 186(6): 977-987. doi: 10.1111/bjd.21026 pmid: 35042273
[16]	RANDIC T, KOZAR I, MARGUE C, et al. NRAS mutant melanoma: towards better therapies[J]. Cancer Treat Rev, 2021, 99: 102238.
[17]	WHITE R M, ZON L I. Melanocytes in development, regeneration, and cancer[J]. Cell Stem Cell, 2008, 3(3): 242-252. doi: 10.1016/j.stem.2008.08.005 pmid: 18786412
[18]	ALEXANDROV L B, NIK-ZAINAL S, WEDGE D C, et al. Signatures of mutational processes in human cancer[J]. Nature, 2013, 500(7463): 415-421. doi: 10.1038/nature12477
[19]	CHALMERS Z R, CONNELLY C F, FABRIZIO D, et al. Analysis of 100 000 human cancer genomes reveals the landscape of tumor mutational burden[J]. Genome Med, 2017, 9(1): 34. doi: 10.1186/s13073-017-0424-2
[20]	HUANG K, FAN J, MISRA S. Acral lentiginous melanoma: incidence and survival in the United States, 2006-2015, an analysis of the SEER registry[J]. J Surg Res, 2020, 251: 329-339. doi: S0022-4804(20)30097-4 pmid: 32208196
[21]	MANDALÀ M, RUTKOWSKI P, GALLI F, et al. Acral lentiginous melanoma histotype predicts outcome in clinical stage Ⅰ-Ⅱ melanoma patients: an international multicenter study[J]. ESMO Open, 2022, 7(3): 100469.

Characteristics	All	AM	CM	P value
Case n	585	397	188
Gender				0.017
Female	316 (54.0)	201 (50.6)	115 (61.2)
Male	269 (46.0)	196 (49.4)	73 (38.8)
Age/year				< 0.001
Median (range)	59 (19-89)	61 (19-89)	54 (19-82)
<60	303 (51.8)	178 (44.8)	125 (66.5)
≥60	282 (48.2)	219 (55.2)	63 (33.5)
Primary site				< 0.001
Head and neck	4 (0.7)	N/A	4 (2.1)
Trunk	90 (15.4)	N/A	90 (47.9)
Upper extremity	80 (13.7)	52 (13.1)	28 (14.9)
Lower extremity	411 (70.3)	345 (86.9)	66 (35.1)
Breslow thickness/mm				0.576
≤1	61 (11.2)	48 (12.8)	13 (7.7)
>1-2	107 (19.7)	73 (19.5)	34 (20.2)
>2-4	182 (33.5)	119 (31.7)	63 (37.5)
>4	193 (35.5)	135 (36.0)	58 (34.5)
Clark level				0.177
Ⅰ-Ⅲ	61 (12.0)	45 (12.7)	16 (10.5)
Ⅳ-Ⅴ	444 (88.0)	308 (87.3)	136 (89.5)
Ulceration				0.689
Present	350 (64.1)	238 (64.7)	112 (62.9)
Absent	196 (35.9)	130 (35.3)	66 (37.1)
N stage				0.075
N₀	277 (47.4)	198 (49.9)	79 (42.0)
N₁	121 (20.7)	81 (20.4)	40 (21.3)
N₂	95 (16.2)	58 (14.6)	37 (19.7)
N₃	92 (15.7)	60 (15.1)	32 (17.0)
LN station				0.297
N₁	241 (78.2)	152 (76.4)	89 (81.7)
N-ITT	10 (3.2)	7 (3.5)	17 (15.6)
N₂	57 (18.5)	40 (20.1)	3 (2.8)
LN involvement				0.089
Negative	277 (47.4)	198 (49.9)	79 (42.0)
Micrometastasis	137 (23.4)	89 (22.4)	48 (25.5)
Macrometastasis	171 (29.2)	110 (27.7)	61 (32.4)
Gene mutation				< 0.001
WT	226 (46.6)	177 (55.7)	49 (29.3)
KIT	34 (7.0)	33 (10.4)	1 (0.6)
BRAF	144 (29.7)	37 (11.6)	107 (64.1)
NRAS	81 (16.7)	71 (22.3)	10 (6.0)
Stage				0.096
Ⅰ	97 (16.6)	69 (17.4)	28 (14.9)
Ⅱ	180 (30.8)	129 (32.5)	51 (27.1)
Ⅲ	308 (52.6)	199 (50.1)	109 (58.0)
Adjuvant therapy				0.004
IFN, OBS	284 (48.5)	209 (52.6)	75 (39.9)
C, IO, TT	301 (51.5)	188 (47.4)	113 (60.1)

Item	Mediant/month	1-year/%	2-year/%
RFS	36.0	75.6	61.2
Ⅰ	NR	100.0	98.8
Ⅱ	39.0	86.6	68.4
Ⅲ	18.0	61.5	46.2
OS	NR	97.2	91.2
LRFS	NR	80.5	69.0
DMFS	NR	88.4	79.1

Factors	Risk	OS					RFS
		Univariable			Multivariable		Univariable			Multivariable
		P value	HR	95% CI	Adjusted P value	Adjusted HR	P value	HR	95% CI	Adjusted P value	Adjusted HR
Age	≥60 vs < 60	0.011	2.386	1.217-4.679	0.013	3.014
Gender	Female vs male	0.017	0.463	0.246-0.871			0.013	0.658	0.473-0.916	0.021	0.636
Primary site	Upper extremity vs others						0.008	0.420	0.221-0.800	0.003	0.259
NRAS mutation	Present vs absent	0.013	2.473	1.215-5.035			0.001	1.937	1.329-2.823	0.004	1.816
Breslow thickness	> 2 mm vs ≤ 2 mm	0.002	6.737	2.057-22.065			<0.001	4.322	2.635-7.087
Ulceration	Present vs absent	<0.001	6.611	2.340-18.679	0.091	5.924	<0.001	4.355	2.761-6.868	0.006	2.265
N stage	N₀	<0.001	1.000	-	0.063	1.000	<0.001	1.000	-	<0.001	1.000
	N₁	0.009	3.308	1.341-8.163	0.452	1.563	<0.001	2.705	1.688-4.337	0.030	1.850
	N₂	0.003	3.805	1.583-9.147	0.074	2.560	<0.001	4.458	2.829-7.025	<0.001	4.085
	N₃	<0.001	8.017	3.395-18.931	0.011	3.955	<0.001	6.560	4.133-10.414	<0.001	4.191

Factors		OS					RFS
		Univariable			Multivariable		Univariable			Multivariable
		P value	HR	95% CI	Adjusted P	Adjusted HR	P value	HR	95% CI	Adjusted P value	Adjusted HR
NRAS mutation	Present vs absent						0.035	2.504	1.069-5.867
Breslow thickness	> 2 mm vs ≤ 2 mm	0.094	5.658	0.743-43. 064			0.001	4.941	1.964-12.427
Ulceration	Present vs absent	0.031	9.351	1.229-71.146	0.070	7.082	<0.001	5.402	2.550-11.446	0.001	4.073
N stage	N₀						<0.001	1.000	-	0.001	1.000
	N₁						0.036	2.213	1.054-4.647	0.293	1.594
	N₂						0.002	3.024	1.488-6.148	0.310	1.542
	N₃						<0.001	6.743	3.322-13.684	<0.001	5.482

近5年单中心肢端型及皮肤型黑色素瘤外科治疗患者的预后因素分析

Multivariable prognostic analyses of Chinese acral and cutaneous melanoma after surgical treatment for the past five years in a single cancer center

RichHTML

PDF

可视化

摘要/Abstract

引用本文

使用本文

图/表 5

参考文献 21

相关文章 15

编辑推荐

Metrics

本文评价

[1]	杨梓怡, 李盼丽, 顾丙新, 刘成, 宋少莉, 许晓平. ⁶⁸Ga-DOTA-PDL1P的设计合成及其在黑色素瘤小鼠模型中的应用研究[J]. 中国癌症杂志, 2023, 33(4): 354-360.
[2]	邹淳缘, 许晓峰, 卢仁泉, 郭林. 肺癌组织和外周血中p53、PGP9.5、SOX2、GAGE7、GBU4-5和MAGE A1蛋白水平检测及其临床价值探讨[J]. 中国癌症杂志, 2023, 33(1): 36-44.
[3]	王先泽, 吴文铭. 胰腺神经内分泌肿瘤外科治疗理念的四种转变[J]. 中国癌症杂志, 2022, 32(9): 765-771.
[4]	江健韵, 应红梅. BRAF V600突变阳性的晚期黑色素瘤治疗的临床研究进展[J]. 中国癌症杂志, 2022, 32(5): 445-450.
[5]	王子茂, 曹原, 王琪影. 皮肤梭形细胞黑色素瘤患者生存预测模型的构建及验证[J]. 中国癌症杂志, 2022, 32(3): 234-242.
[6]	徐宇, 陈勇, 杨吉龙, 朱冠男. Ⅲ期黑色素瘤围手术期治疗的现状与展望[J]. 中国癌症杂志, 2022, 32(12): 1133-1146.
[7]	李婷, 徐宇, 贾东东, 廖智超, 孙伟, 吴海啸, 任志午, 赵军, 邢汝维, 滕胜, 杨蕴, 陈勇, 李涛, 杨吉龙. Ⅲ期恶性黑色素瘤患者术后辅助抗PD-1 vs 靶向治疗：中国多中心真实世界数据分析[J]. 中国癌症杂志, 2022, 32(12): 1147-1157.
[8]	邹孜瑊, 孙伟, 胡涂, 王春萌, 严望军, 罗志国, 刘欣, 钟景钦, 林馨怡, 徐宇, 陈勇. 前哨淋巴结活检在皮肤型和肢端型黑色素瘤临床诊疗中的价值[J]. 中国癌症杂志, 2022, 32(12): 1168-1177.
[9]	贾东东, 李涛. 达拉非尼联合曲美替尼用于24例恶性黑色素瘤辅助治疗的回顾性分析[J]. 中国癌症杂志, 2022, 32(12): 1178-1183.
[10]	韩如雪, 梁翔, 马旭辉, 郭伟, 吴云腾, 任国欣. 口腔黏膜恶性黑色素瘤肺转移特征及预后分析[J]. 中国癌症杂志, 2022, 32(12): 1184-1189.
[11]	胡冠男, 陈　雷, 周良平, 周正荣 . 肺恶性黑色素瘤合并肺腺癌1例并文献复习[J]. 中国癌症杂志, 2021, 31(7): 647-650.
[12]	梁　翔 , 吴云腾 . 伴复发转移的口腔黏膜黑色素瘤长期生存患者的临床特征及预后分析[J]. 中国癌症杂志, 2020, 30(7): 531-537.
[13]	杨晓玲, 斯璐, 毛丽丽, 王轩, 崔传亮, 迟志宏, 盛锡楠, 郭军. 帕博丽珠单抗治疗晚期黑色素瘤的不良事件及相关性分析[J]. 中国癌症杂志, 2020, 30(5): 362-368.
[14]	朱晓东, 陈思元. 免疫检查点抑制剂联合治疗：从机制到临床[J]. 中国癌症杂志, 2020, 30(12): 969-976.
[15]	周宏宇, 陈丽华, 李浩然, 程　玺. c-kit在原发性女性生殖道恶性黑色素瘤治疗及预后中的作用：现状与展望[J]. 中国癌症杂志, 2020, 30(10): 834-840.