中国抗癌协会多原发和不明原发肿瘤诊治指南（2023年版）

doi:10.19401/j.cnki.1007-3639.2023.04.011

摘要/Abstract

摘要：

原发灶不明肿瘤（cancer of unknown primary，CUP）和多原发肿瘤（cancer of multiple primaries，CMP），因其临床异质性高、发病率低、循证医学证据的相对匮乏及临床疾病认识的相对局限，目前诊疗仍面临巨大挑战。随着对疾病影像学、病理学、基因特点等认识的不断深入，多学科的协作和发展，以及分子靶向治疗和免疫治疗的针对性探索正在不断地更新对这部分患者治疗的理念和手段。本指南的制定旨在为临床工作者提供CUP和CMP患者诊疗的原则和纲要，为患者提供从诊断、治疗到康复的全流程规范化指导。

关键词: 原发灶不明肿瘤, 多原发肿瘤, 诊断, 治疗, 指南

Abstract:

Cancer of unknown primary (CUP) and cancer of multiple primaries (CMP) are two groups of neoplasm with high heterogeneity, low incidence, limited clinical knowledge and evidence. The diagnosis and treatment of patients with CUP and CMP is challenging. With the progress in the radiology, pathology and genetic features of these diseases, the cooperation and development of multi-disciplinary treatment, along with the investigation of targeted and immunology treatment have updated the treatment of these patients. We intended to guide the diagnosis and treatment of patients with CUP and CMP through this guideline, providing standard guidance for the overall management of patients.

Key words: Cancer of unknown primary, Cancer of multiple primaries, Diagnosis, Treatment, Guideline

中图分类号:

R730

中国抗癌协会多原发和不明原发肿瘤专业委员会. 中国抗癌协会多原发和不明原发肿瘤诊治指南（2023年版）[J]. 中国癌症杂志, 2023, 33(4): 403-422.

Society of Cancer of Multiple and Unknown Primary of China Anti-Cancer Association Yuguang . China Anti-Cancer Association guideline for diagnosis and treatment of cancer of multiple and unknown primaries (2023 edition)[J]. China Oncology, 2023, 33(4): 403-422.

图/表 6

表1

表 2

表3

肿瘤特异性标志物及其染色模式"

标志物	肿瘤类型	染色模式
Arginase-1	肝细胞癌	细胞核
Calretinin	间皮瘤、性索间质肿瘤、肾上腺皮质癌	细胞质
CDX2	结直肠癌、胃癌、胰胆管癌	细胞核
D2-40	间皮瘤	细胞膜
EBV	鼻咽癌	细胞核
ER/PR	乳腺癌、卵巢癌、子宫内膜癌	细胞核
GATA3	乳腺癌、膀胱癌、唾液腺癌	细胞核
GCDFP-15	乳腺癌、汗腺癌、唾液腺癌	细胞质
Glypican-3	肝细胞癌、生殖细胞肿瘤	细胞质
HepPar-1	肝细胞癌	细胞质
HPV	子宫颈癌、外阴癌、阴道癌、阴茎癌、肛管癌、口咽癌	细胞核（DNA ISH）；细胞核/细胞质（RNA ISH）
Inhibin	性索间质肿瘤、肾上腺皮质癌	细胞质
Mammaglobin	乳腺癌、唾液腺癌	细胞质
Melan-A	肾上腺皮质癌、黑色素瘤	细胞核
Napsin A	肺腺癌	细胞质
NKX3.1	前列腺癌	细胞核
P16	子宫颈癌、外阴癌、阴道癌、阴茎癌、肛管癌、口咽癌	细胞核/细胞质（如果阳性，行HPV ISH）
PSAP	前列腺癌	细胞膜
PAX8	甲状腺癌、肾癌、卵巢癌、子宫内膜癌、子宫颈癌、胸腺癌	细胞核
PSA	前列腺癌	细胞质
SF-1	肾上腺皮质癌、性索间质肿瘤	细胞核
SATB2	结直肠癌	细胞核
Thyroglobulin	甲状腺癌（乳头/滤泡）	细胞质
TTF1	肺腺癌、甲状腺癌	细胞核
Uroplakin Ⅲ	尿路上皮癌	细胞膜
Villin	胃癌、结直肠癌	细胞质
WT1	卵巢癌、间皮瘤、Wilms瘤	细胞核
HER2	乳腺癌	细胞膜
MITF	黑色素瘤	细胞核
PNL2	黑色素瘤	细胞质/细胞膜
SOX10	黑色素瘤	细胞核
DOG1	胃肠道间质瘤	细胞质/细胞膜
Syn	神经内分泌肿瘤	细胞质
CgA	神经内分泌肿瘤	细胞质
CD56	神经内分泌肿瘤	细胞膜
INSM1	神经内分泌肿瘤	细胞核
SMAD4（表达缺失）	胰腺癌、胆管癌	细胞质
ERG	前列腺癌、血管肿瘤	细胞核
Fli1	血管肿瘤	细胞核
CD34	血管肿瘤、胃肠道间质瘤	细胞质
PSMA	前列腺癌	细胞质/细胞膜
SALL4	生殖细胞肿瘤	细胞核
HMB45	黑色素瘤	细胞质
OCT3/4	生殖细胞肿瘤	细胞核
CD138	浆细胞瘤	细胞质
Calcitonin	甲状腺髓样癌	细胞质
S100	黑色素瘤、脂肪肿瘤	细胞核
CD117	胃肠道间质瘤	细胞质
CD30	生殖细胞肿瘤	细胞质/细胞膜

表3

表4

表5

表1

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	常规项目	特殊项目
初始评估	① 完整的病史和体检：包括乳腺、泌尿生殖道、盆腔检查及肛检，特别关注：过去活检史或恶性肿瘤史、曾切除的病变（必要时再次行免疫组织化学检测）、自发退缩的病变、已有的影像学检查、肿瘤家族史 ② 血常规、肝肾功能、电解质；尿常规、粪常规+隐血；肿瘤标志物检测 ③ 胸腹盆腔增强CT，颈部增强CT或MRI；或PET/CT	临床导向的内镜检查，乳腺X线/MRI检查
常规和分子病理学检查	活检：粗针活检（首选）或细针穿刺细胞团块或胸腹水细胞团块；与病理科专家沟通标本是否符合要求和用于免疫组织化学的抗体选择等	TMB NTRK MSI/MMR检测可推荐肿瘤组织起源基因检测
病理学检查结果	① 上皮源性，非特定部位→按CUP处理 ② 非上皮源性，如淋巴瘤、黑色素瘤、肉瘤、生殖细胞肿瘤等→按相应指南处理 ③ 非恶性→进一步评估和合适随访

怀疑肿瘤类型	推荐肿瘤指标
肝细胞肝癌	AFP
前列腺癌	PSA
生殖细胞肿瘤	β-HCG、AFP
卵巢癌	CA12-5
垂体肿瘤	β-HCG、ACTH、催乳素
鼻咽肿瘤	EBV
甲状腺癌	TG、降钙素
肺肿瘤	CYFRA21-1、SCC、CEA、CA15-3、TPA
神经内分泌癌	NSE、ProGRP
乳腺肿瘤	CA15-3 、CEA、HER2/neu（血清）、CA12-5
胃肠肿瘤	CEA、CA72-4、CA19-9、CA242、CA50、EGFR
结直肠肿瘤	CEA、Ras（粪）、MSI（粪）
胆胰肿瘤	CA19-9、CEA
肾上腺肿瘤	ACTH、DHEA-S、皮质醇、醛固酮
膀胱肿瘤	CYFRA21-1、TPA、NMP22（尿）
子宫颈癌	HPV、SCC、CEA
卵巢肿瘤	CA12-5、HE4、CEA、HER2/neu（血清）、TPA
睾丸肿瘤	AFP、β-HCG
类癌	5-羟色胺、5-羟吲哚乙酸（尿）

标志物	最有可能的细胞谱系
Pan-keratin（AE1/AE3、CAM5.2）	癌
CK7、CK19、CK20	腺癌
CK5/6、p63、p40	鳞状细胞癌
HMB45、SOX10	黑色素瘤
LCA、CD20、CD3	淋巴瘤
SALL4、OCT3/4	生殖细胞肿瘤
Calretinin、WT1、D2-40	间皮瘤
Vimentin	肉瘤

CK7和CK20	肿瘤部位或类型	肿瘤特异性指标
CK7⁺/CK20^-	乳腺癌	ER⁺/PR⁺、GATA3⁺、GCDFP15⁺、mammagloblin⁺
	卵巢浆液性癌	PAX8⁺、ER⁺、WT1⁺
	卵巢透明细胞癌	PAX8⁺、HNF-1β⁺、napsin A⁺
	子宫内膜癌	ER⁺、PAX8⁺、vimentin⁺
	子宫颈腺癌	p16⁺、HPV⁺、CEA⁺
	肺腺癌	TTF1⁺、napsin A⁺
	甲状腺癌（滤泡性癌或乳头状癌）	TTF1⁺、thyroglobulin⁺、PAX8⁺
	甲状腺癌（髓样癌）	TTF1⁺、calcitonin⁺、CEA⁺、Syn⁺、CgA⁺
	胃癌	CEA⁺、CDX2⁺、CK19⁺
	胰腺癌、胆管癌及胆囊癌	CK19⁺、SMAD4^-
	胸腺癌	CD5⁺、p63⁺、PAX8⁺、CD117⁺
	唾液腺癌	GATA3⁺、AR⁺、GCDFP-15⁺
	肾癌（嫌色细胞肾癌或部分乳头状肾癌）	PAX8⁺、vimentin⁺、CA9⁺
	膀胱癌	GATA3⁺、p63⁺、CK5/6⁺、p40⁺、uroplakin Ⅲ⁺
	间皮瘤	Calretinin⁺、WT1⁺、CK5/6⁺、MOC31^-
CK7⁺/CK20⁺	胰腺癌、胆管癌及胆囊癌	CK19⁺、SMAD4^-
	胃癌	CEA⁺、CDX2⁺、CK19⁺
	膀胱癌	GATA3⁺、p63⁺、CK5/6⁺、p40⁺、uroplakin Ⅲ⁺
	结直肠癌	CDX2⁺、villin⁺、SATB2⁺
	小肠癌	CDX2⁺、villin⁺
	阑尾腺癌	CDX2⁺、villin⁺、SATB2⁺
CK7^-/CK20⁺	结直肠癌	CDX2⁺、villin⁺、SATB2⁺
	阑尾腺癌	CDX2⁺、villin⁺、SATB2⁺
	小肠癌	CDX2⁺、villin⁺
	皮肤Merkel细胞癌	CgA⁺、Syn⁺、CD5/6⁺、INSM1⁺
CK7^-/CK20^-	鳞状细胞癌	CK5/6⁺、p63⁺、p40⁺、P16⁺
	前列腺癌	PSA⁺、NKX3.1⁺、PSAP⁺、PSMA⁺、P504S⁺、ERG⁺、AR⁺
	肾癌（透明细胞肾癌或部分乳头状肾癌）	PAX8⁺、vimentin⁺、CA9⁺
	肝癌	HepPar1⁺、AFP⁺、glypican-3⁺、arginase-1⁺
	肾上腺皮质癌	Melan A⁺、inhibin⁺、synaptophysin⁺、SF1⁺
	生殖细胞肿瘤	SALL4⁺、OCT3/4⁺、CD30⁺、glypican-3⁺、PLAP⁺
	黑色素瘤	MITF⁺、PNL2⁺、SOX10⁺、HMB45⁺、S100⁺、melan A⁺

免疫组织化学标志物	肿瘤类型
GCDFPl5、mammaglobin	乳腺癌
TTF1（CK7⁺、CK20^-情况下）	肺癌
HepPar1	肝癌
RCC	肾癌
TG、TTF1	甲状腺肿瘤
PLAP/OCT4	生殖细胞肿瘤
CDX2（CK7^-、CK20⁺情况下）	结直肠癌
WT1、PAX8	卵巢癌
CgA、syn	神经内分泌肿瘤
LCA	淋巴瘤或白血病
p53、p16、p27和HER2在肺癌病灶的差异表达	鉴别CMP与肺内转移
EBER	鼻咽癌或EB病毒相关淋巴瘤
P16	口咽部肿瘤或宫颈癌