原发灶不明肿瘤诊断与治疗研究进展

赵婷; 张晓伟; 刘欣; 王奇峰; 胡夕春; 罗志国

doi:10.19401/j.cnki.1007-3639.2024.12.008

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原发灶不明肿瘤诊断与治疗研究进展

综述 | 更新时间：2025-12-31

- 原发灶不明肿瘤诊断与治疗研究进展
- Cancer of unknown primary: recent advancements in the diagnosis and treatment
- 中国癌症杂志 2024年34卷第12期页码：1134-1143
- 作者机构：
  
  1. 复旦大学附属肿瘤医院肿瘤内科，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病理科，复旦大学上海医学院肿瘤学系，上海 200032
- 作者简介：
  
  [ "赵婷（ORCID：0000-0002-1352-3113），博士，住院医师。" ]
  罗志国（ORCID：0000-0003-0389-2350），主任医师，教授。
- 基金信息：
  
  上海市抗癌协会翱翔计划(SACA-AX202206);上海市青年科技英才扬帆计划(23YF1406800)
- DOI：10.19401/j.cnki.1007-3639.2024.12.008
  中图分类号：
- 收稿：2024-09-18，
  
  纸质出版：2024-12-30
- 稿件说明：
移动端阅览
赵婷, 张晓伟, 刘欣, 等. 原发灶不明肿瘤诊断与治疗研究进展[J]. 中国癌症杂志, 2024,34(12):1134-1143.

Ting ZHAO, Xiaowei ZHANG, Xin LIU, et al. Cancer of unknown primary: recent advancements in the diagnosis and treatment[J]. China Oncology, 2024, 34(12): 1134-1143.
赵婷, 张晓伟, 刘欣, 等. 原发灶不明肿瘤诊断与治疗研究进展[J]. 中国癌症杂志, 2024,34(12):1134-1143. DOI： 10.19401/j.cnki.1007-3639.2024.12.008.

Ting ZHAO, Xiaowei ZHANG, Xin LIU, et al. Cancer of unknown primary: recent advancements in the diagnosis and treatment[J]. China Oncology, 2024, 34(12): 1134-1143. DOI： 10.19401/j.cnki.1007-3639.2024.12.008.

摘要

原发灶不明肿瘤（cancer of unknown primary，CUP）是一类经组织病理学确认为转移，但经系统性检查仍然无法明确原发灶的转移性肿瘤的统称，约占全球所有癌症新发病例的3%~5%，其总生存期（overall survival，OS）仅2.7~16.0个月。CUP因原发灶的隐匿性及异质性导致其诊断成为长期困扰临床医师的关键问题，也是CUP精准治疗最大的阻碍。在诊断方面，在免疫组织化学时代，两轮标志物的诊断可以让大约70%的CUP明确原发灶，然而，免疫组织化学对于原发不明未分化癌的诊断价值极其有限，且结果易受实验因素及人为因素干扰。近年来，随着肿瘤诊断进入分子检测时代，基于细胞学、组织学、基因表达谱（gene expression profiling，GEP）、基因组及表观基因组分析等技术已经能够准确地检出90%的原发灶。目前，国内可帮基因公司研发的90基因肿瘤组织起源检测已被证实诊断CUP原发灶的准确率高达94.4%，为CUP的精准治疗奠定了基础。在治疗方面，CUP既往的治疗是采用铂类药物和紫杉类药物的经验性化疗方案，患者的生存及预后并没有得到显著改善。自2008年以来，全球范围内陆续开展了分子检测指导的CUP器官特异性治疗的临床研究，但因研究设计缺陷以及结果争议等问题，尚未在国际范围内达成共识。器官特异性治疗相较于经验性化疗可改善患者的无进展生存期（progression-free survival，PFS）和OS。有鉴于此，2017年，复旦大学附属肿瘤医院多原发与不明原发肿瘤诊治中心开展了全球首个Ⅲ期临床研究，结果证实，90基因检测指导的器官特异性治疗可显著地改善患者的PFS，且OS有获益的趋势，两组患者在不良反应方面的差异无统计学意义，由此奠定了器官特异性治疗在CUP一线治疗中的地位。本文综述CUP的流行病学、发病机制、临床特征及CUP诊断从免疫组织化学时代到分子检测时代的进步，也将介绍CUP治疗从经验性化疗到分子检测指导的器官特异性治疗的进展。此外，本文详述二线治疗方案的探索以及临床分层管理模式的建立是未来CUP研究领域的两个重要方向。本综述旨在总结CUP诊断与治疗的进展，进一步明确CUP的研究方向，以最大程度地改善CUP患者的生存及预后。

Abstract

Cancer of unknown primary (CUP) refers to a group of histopathologically confirmed malignancies that cannot be identified in terms of their primary origin despite thorough investigations. CUP accounts for approximately 3%-5% of all newly diagnosed cancers worldwide

with an overall survival (OS) ranging from 2.7 to 16.0 months. CUP has long been a significant scientific challenge due to the elusive nature and heterogeneity of the primary sites. In the era of immunohistochemistry (IHC)

IHC has been applied to identify the primary site in approximately 70% of CUP cases. However

IHC also has limitations for undifferentiated cancers of unknown primary

and results can be influenced by experimental and human factors. In recent years

with the development of molecular tumor profiling (MTP)

techniques such as cytology

histology

gene expression profiling (GEP)

genomics and epigenomics have been able to accurately detect the primary site in 90% of cases. Currently

the 90-gene tumor tissue origin test has been proven to have an accuracy rate of 94.4% in diagnosing the primary site of CUP

laying the foundation for precision treatment. In the past

platinum and taxane-based empirical chemotherapy was commonly used for treating CUP. However

these treatments did not yield significant improvements in patient survival and prognosis. Since 2008

there has been a global emergence of clinical studies on MTP-guided first-line therapy for CUP. However

due to study design flaws and result controversies

there is no international consensus on the superiority of organ-specific treatment over empirical chemotherapy in terms of improving progression-free survival (PFS) and OS for CUP. Based on this

our center conducted the world's first phase Ⅲ clinical trial in 2017

and demonstrated improved PFS and favorable OS by GEP-guided site-specific therapy of CUP

which established the primacy of site-specific first-line therapy for CUP. In this review

we detailed the epidemiology

pathogenesis

clinical characteristics and the progression of CUP diagnosis from the era of IHC to MTP. Furthermore

we reviewed the advancements in CUP treatment from empirical chemotherapy to MTP-guided organ-specific treatment. Additionally

this review delved into the exploration of second-line treatment options and the establishment of a clinical stratified management model

which are two topics in future research of CUP. This review aimed to summarize the progress in the diagnosis and treatment of CUP

further explore future research directions for CUP

and improve the survival and prognosis of patients with CUP.

关键词

Keywords

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