胰腺腺鳞癌研究进展：组织学特征、分子机制与治疗前景

doi:10.3969/j.issn.1006-5725.2026.02.001

摘要/Abstract

摘要：

近年来，胰腺腺鳞癌（pancreatic adenosquamous carcinoma， PASC）因其罕见性与高度恶性逐渐受到关注。作为一种同时包含腺癌与鳞癌成分的特殊亚型，其临床预后显著差于胰腺导管腺癌，中位生存期仅6个月。该文综述PASC的主要分子机制，包括TP53/NOTCH通路失活、具有转录调控功能的ΔNp63和转录因子SRY-box转录因子2（SRY-box transcription factor 2，SOX2）的上调，以及Zeste增强子同源物2（enhancer of zeste homolog 2，EZH2）介导的表观遗传重塑，探讨其在谱系转分化和肿瘤可塑性中的作用。同时，结合高通量测序与单细胞多组学的研究，介绍PASC免疫微环境的抑制性特征及其对治疗反应的影响。文章还分析了当前研究中存在的不足，如病例数量有限、临床循证证据缺乏、机制研究与转化脱节等，最后展望通过多中心临床研究和分子分型，探索表观遗传抑制剂联合免疫治疗等新策略，以期改善患者的诊疗结局。

关键词: 胰腺腺鳞癌, 组织学特征, 分子机制, 肿瘤微环境, 治疗前景

Abstract:

In recent years， pancreatic adenosquamous carcinoma （PASC） has drawn growing attention owing to its rarity and highly aggressive characteristics. As a distinct subtype defined by the co-existence of adenocarcinoma and squamous carcinoma components， PASC is linked to substantially worse prognoses compared to pancreatic ductal adenocarcinoma， with a median survival period of merely six months. This review outlines the key molecular mechanisms underlying PASC， such as the inactivation of the TP53/NOTCH pathways， the up-regulation of the transcriptional regulator ΔNp63 and the transcription factor SRY-box transcription factor 2 （SOX2）， along with enhancer of zeste homolog 2 （EZH2）-mediated epigenetic remodeling， and deliberates on their functions in lineage transdifferentiation and tumor plasticity. We further synthesize findings from high-throughput sequencing and single-cell multi-omics studies to depict the immunosuppressive traits of the PASC tumor microenvironment and their implications for therapeutic resistance. Current challenges are also addressed， including the scarce number of reported cases， the absence of high-level clinical evidence， and the disparity between mechanistic studies and clinical translation. Finally， we suggest that future research ought to concentrate on establishing multicenter clinical cohorts and molecular stratification approaches， and on exploring novel therapeutic strategies like combining epigenetic inhibitors with immunotherapy， with the ultimate aim of enhancing patient outcomes.

Key words: pancreatic adenosquamous carcinoma, histological features, molecular mechanisms, tumor microenvironment, therapeutic prospects

中图分类号:

R735.9

安建虹,宋美慧,黄长文. 胰腺腺鳞癌研究进展：组织学特征、分子机制与治疗前景[J]. 实用医学杂志, 2026, 42(2): 169-175.

Jianhong AN,Meihui SONG,Changwen HUANG. Advances in pancreatic adenosquamous carcinoma： Histopathological characteristics， molecular mechanisms， and therapeutic perspectives[J]. The Journal of Practical Medicine, 2026, 42(2): 169-175.

图/表 2

参考文献 43

[1]	MOSLIM M A， LEFTON M D， ROSS E A， et al. Clinical and histological basis of adenosquamous carcinoma of the pancreas： A 30-year experience［J］. J Surg Res， 2021， 259： 350-356. doi：10.1016/j.jss.2020.09.024 . doi: 10.1016/j.jss.2020.09.024
[2]	WARD J D， FOWLER M， ROBLEDO-GOMEZ A， et al. PD-L1 expression in pancreaticobiliary adenosquamous carcinoma： A single-institution case series［J］. J Gastrointest Oncol， 2024， 15（2）： 768-779. doi：10.21037/jgo-24-9 . doi: 10.21037/jgo-24-9
[3]	AN J， JIANG T， QI L， et al. Acinar cells and the development of pancreatic fibrosis［J］. Cytokine Growth Factor Rev， 2023， 71-72： 40-53. doi：10.1016/j.cytogfr.2023.05.003 . doi: 10.1016/j.cytogfr.2023.05.003
[4]	HUANG Z， WANG J， ZHANG R， et al. Pancreatic adenosquamous carcinoma： A population level analysis of epidemiological trends and prognosis［J］. Cancer Med， 2023， 12（8）： 9926-9936. doi：10.1002/cam4.5700 . doi: 10.1002/cam4.5700
[5]	TOSHIMA F， INOUE D， YOSHIDA K， et al. Adenosquamous carcinoma of pancreas： CT and MR imaging features in eight patients， with pathologic correlations and comparison with adenocarcinoma of pancreas［J］. Abdom Radiol， 2016， 41（3）： 508-520. doi：10.1007/s00261-015-0616-4 . doi: 10.1007/s00261-015-0616-4
[6]	郑立春，张欢，顾程，等. 18F-FDG PET/CT联合血清CA19-9、CEA、NSE鉴别胰腺导管腺癌与胰腺神经内分泌肿瘤［J］. 实用医学杂志， 2023， 39（18）： 2395-2400. doi：10.3969/j.issn.1006-5725.2023.18.019 . doi: 10.3969/j.issn.1006-5725.2023.18.019
[7]	MARCUS R， MAITRA A， ROSZIK J. Recent advances in genomic profiling of adenosquamous carcinoma of the pancreas［J］. J Pathol， 2017， 243（3）： 271-272. doi：10.1002/path.4959 . doi: 10.1002/path.4959
[8]	RAJBHANDARI N， HAMILTON M， QUINTERO C M， et al. Single-cell mapping identifies MSI（+） cells as a common origin for diverse subtypes of pancreatic cancer［J］. Cancer Cell， 2023， 41（11）： 1989-2005.e9. doi：10.1016/j.ccell.2023.09.008 . doi: 10.1016/j.ccell.2023.09.008
[9]	SOMERVILLE T D， BIFFI G， DAßLER-PLENKER J， et al. Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation［J］. eLife， 2020， 9： e53381. doi：10.7554/eLife.53381 . doi: 10.7554/eLife.53381
[10]	AHMED M， LARSON B K， OSIPOV A， et al. A case of adenosquamous pancreatic cancer with a KRAS G¹²C mutation with an exceptional response to immunotherapy［J］. Oncotarget， 2024， 15： 741-747. doi：10.18632/oncotarget.28659 . doi: 10.18632/oncotarget.28659
[11]	BURDZIAK C， ALONSO-CURBELO D， WALLE T， et al. Epigenetic plasticity cooperates with cell-cell interactions to direct pancreatic tumorigenesis［J］. Science， 2023， 380（6645）： eadd5327. doi：10.1126/science.add5327 . doi: 10.1126/science.add5327
[12]	MUELLER S， ENGLEITNER T， MARESCH R， et al. Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes［J］. Nature， 2018， 554（7690）： 62-68. doi：10.1038/nature25459 . doi: 10.1038/nature25459
[13]	XIONG Q， ZHANG Z， XU Y， et al. Pancreatic adenosquamous carcinoma： A rare pathological subtype of pancreatic cancer［J］. J Clin Med， 2022， 11（24）： 7401. doi：10.3390/jcm11247401 . doi: 10.3390/jcm11247401
[14]	BASTURK O， KHANANI F， SARKAR F， et al. DeltaNp63 expression in pancreas and pancreatic neoplasia［J］. Mod Pathol， 2005， 18（9）： 1193-1198. doi：10.1038/modpathol.3800401 . doi: 10.1038/modpathol.3800401
[15]	HAUGK B， HORTON D， OPPONG K， et al. Morphological and p40 immunohistochemical analysis of squamous differentiation in endoscopic ultrasound guided fine needle biopsies of pancreatic ductal adenocarcinoma［J］. Sci Rep， 2021， 11（1）： 21290. doi：10.1038/s41598-021-00652-5 . doi: 10.1038/s41598-021-00652-5
[16]	SOMERVILLE T D D， XU Y， MIYABAYASHI K， et al. TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma［J］. Cell Rep， 2018， 25（7）： 1741-1755.e7. doi：10.1016/j.celrep.2018.10.051 . doi: 10.1016/j.celrep.2018.10.051
[17]	HERREROS-VILLANUEVA M， ZHANG J S， KOENIG A， et al. SOX2 promotes dedifferentiation and imparts stem cell-like features to pancreatic cancer cells［J］. Oncogenesis， 2013， 2（8）： e61. doi：10.1038/oncsis.2013.23 . doi: 10.1038/oncsis.2013.23
[18]	ROY S， DUKIC T， KEEPERS Z， et al. SOX2 and OCT4 mediate radiation and drug resistance in pancreatic tumor organoids［J］. Cell Death Discov， 2024， 10（1）： 106. doi：10.1038/s41420-024-01871-1 . doi: 10.1038/s41420-024-01871-1
[19]	WUEBBEN E L， WILDER P J， COX J L， et al. SOX2 functions as a molecular rheostat to control the growth， tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells［J］. Oncotarget， 2016， 7（23）： 34890-34906. doi：10.18632/oncotarget.8994 . doi: 10.18632/oncotarget.8994
[20]	HSIEH M H， CHOE J H， GADHVI J， et al. p63 and SOX2 dictate glucose reliance and metabolic vulnerabilities in squamous cell carcinomas［J］. Cell Rep， 2019， 28（7）： 1860-1878.e9. doi：10.1016/j.celrep.2019.07.027 . doi: 10.1016/j.celrep.2019.07.027
[21]	OOIZUMI Y， KOJIMA K， IGARASHI K， et al. Comprehensive exploration to identify predictive DNA markers of ΔNp63/SOX2 in drug resistance in human esophageal squamous cell carcinoma［J］. Ann Surg Oncol， 2019， 26（13）： 4814-4825. doi：10.1245/s10434-019-07795-w . doi: 10.1245/s10434-019-07795-w
[22]	HAYASHI A， FAN J， CHEN R， et al. A unifying paradigm for transcriptional heterogeneity and squamous features in pancreatic ductal adenocarcinoma［J］. Nat Cancer， 2020， 1（1）： 59-74. doi：10.1038/s43018-019-0010-1 . doi: 10.1038/s43018-019-0010-1
[23]	BAILEY P， CHANG D K， NONES K， et al. Genomic analyses identify molecular subtypes of pancreatic cancer［J］. Nature， 2016， 531（7592）： 47-52. doi：10.1038/nature16965 . doi: 10.1038/nature16965
[24]	BRAY S J. Notch signalling in context［J］. Nat Rev Mol Cell Biol， 2016， 17（11）： 722-735. doi：10.1038/nrm.2016.94 . doi: 10.1038/nrm.2016.94
[25]	ZHOU B， LIN W， LONG Y， et al. Notch signaling pathway： Architecture， disease， and therapeutics［J］. Signal Transduct Target Ther， 2022， 7（1）： 95. doi：10.1038/s41392-022-00934-y . doi: 10.1038/s41392-022-00934-y
[26]	HANLON L， AVILA J L， DEMAREST R M， et al. Notch1 functions as a tumor suppressor in a model of K-ras-induced pancreatic ductal adenocarcinoma［J］. Cancer Res， 2010， 70（11）： 4280-4286. doi：10.1158/0008-5472.CAN-09-4645 . doi: 10.1158/0008-5472.CAN-09-4645
[27]	MEANS A L， MESZOELY I M， SUZUKI K， et al. Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates［J］. Development， 2005， 132（16）： 3767-3776. doi：10.1242/dev.01925 . doi: 10.1242/dev.01925
[28]	ANDRICOVICH J， PERKAIL S， KAI Y， et al. Loss of KDM6A activates super-enhancers to induce gender-specific squamous-like pancreatic cancer and confers sensitivity to BET inhibitors［J］. Cancer Cell， 2018， 33（3）： 512-526.e8. doi：10.1016/j.ccell. 2018.02.003 . doi: 10.1016/j.ccell. 2018.02.003
[29]	BORAZANCI E， MILLIS S Z， KORN R， et al. Adenosquamous carcinoma of the pancreas： Molecular characterization of 23 patients along with a literature review［J］. World J Gastrointest Oncol， 2015， 7（9）： 132-140. doi：10.4251/wjgo.v7.i9.132 . doi: 10.4251/wjgo.v7.i9.132
[30]	DAVID C J， HUANG Y H， CHEN M， et al. TGF-β tumor suppression through a lethal EMT［J］. Cell， 2016， 164（5）： 1015-1030. doi：10.1016/j.cell.2016.01.009 . doi: 10.1016/j.cell.2016.01.009
[31]	FEIG C， JONES J O， KRAMAN M， et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer［J］. Proc Natl Acad Sci USA， 2013， 110（50）： 20212-20217. doi：10.1073/ pnas. 1320318110 . doi: 10.1073/ pnas. 1320318110
[32]	TAKAHASHI R， MACCHINI M， SUNAGAWA M， et al. Interleukin-1β-induced pancreatitis promotes pancreatic ductal adenocarcinoma via B lymphocyte-mediated immune suppression［J］. Gut， 2021， 70（2）： 330-341. doi：10.1136/gutjnl-2019-319912 . doi: 10.1136/gutjnl-2019-319912
[33]	O′KANE G M， GRÜNWALD B T， JANG G H， et al. GATA6 expression distinguishes classical and basal-like subtypes in advanced pancreatic cancer［J］. Clin Cancer Res， 2020， 26（18）： 4901-4910. doi：10.1158/1078-0432.CCR-19-3724 . doi: 10.1158/1078-0432.CCR-19-3724
[34]	张习杰，李昕，周文策. 转移性胰腺癌的联合免疫治疗研究进展［J］. 实用医学杂志， 2023， 39（6）： 655-659. doi：10.3969/j.issn.1006-5725.2023.06.001 . doi: 10.3969/j.issn.1006-5725.2023.06.001
[35]	MOFFITT R A， MARAYATI R， FLATE E L， et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma［J］. Nat Genet， 2015， 47（10）： 1168-1178. doi：10.1038/ng.3398 . doi: 10.1038/ng.3398
[36]	MONCADA R， BARKLEY D， WAGNER F， et al. Integrating microarray-based spatial transcriptomics and single-cell RNA-seq reveals tissue architecture in pancreatic ductal adenocarcinomas［J］. Nat Biotechnol， 2020， 38（3）： 333-342. doi：10.1038/s41587-019-0392-8 . doi: 10.1038/s41587-019-0392-8
[37]	HALDAR S D， SAJ F， PAVLICK D， et al. Pancreatic adenosquamous carcinoma （PASC）： A comparative genomic landscape study［J］. J Clin Oncol， 2025， 43（）： 4153. doi：10.1200/ jco.2025.43.16_suppl.4153 . doi: 10.1200/ jco.2025.43.16_suppl.4153
[38]	ZHANG D， WU S， PAN S， et al. Single-cell sequencing reveals heterogeneity between pancreatic adenosquamous carcinoma and pancreatic ductal adenocarcinoma with prognostic value［J］. Front Immunol， 2022， 13： 972298. doi：10.3389/fimmu.2022.972298 . doi: 10.3389/fimmu.2022.972298
[39]	ULLMAN N A， BURCHARD P R， DUNNE R F， et al. Immunologic strategies in pancreatic cancer： Making cold tumors hot［J］. J Clin Oncol， 2022， 40（24）： 2789-2805. doi：10.1200/JCO. 21. 02616 . doi: 10.1200/JCO. 21. 02616
[40]	GLAPIŃSKI F， ZAJĄC W， FUDALEJ M， et al. The role of the tumor microenvironment in pancreatic ductal adenocarcinoma： Recent advancements and emerging therapeutic strategies［J］. Cancers， 2025， 17（10）： 1599. doi：10.3390/cancers17101599 . doi: 10.3390/cancers17101599
[41]	ROE J S， HWANG C I， SOMERVILLE T D D， et al. Enhancer reprogramming promotes pancreatic cancer metastasis［J］. Cell， 2017， 170（5）： 875-888.e20. doi：10.1016/j.cell.2017.07.007 . doi: 10.1016/j.cell.2017.07.007
[42]	PAN Y， ZHAO S， CAO Z. Organoid models of gastrointestinal Neoplasms： Origin， current status and future applications in personalized medicine［J］. Genes Dis， 2018， 5（4）： 323-330. doi：10.1016/j.gendis.2018.09.002 . doi: 10.1016/j.gendis.2018.09.002
[43]	CHAN-SENG-YUE M， KIM J C， WILSON G W， et al. Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution［J］. Nat Genet， 2020， 52（2）： 231-240. doi：10.1038/s41588-019-0566-9 . doi: 10.1038/s41588-019-0566-9