The Journal of Practical Medicine >
Advances in pancreatic adenosquamous carcinoma: Histopathological characteristics, molecular mechanisms, and therapeutic perspectives
Received date: 2025-09-02
Online published: 2026-01-22
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.
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 . DOI: 10.3969/j.issn.1006-5725.2026.02.001
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [9] | SOMERVILLE T D, BIFFI G, DA?LER-PLENKER J, et al. Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation[J]. eLife, 2020, 9: e53381. 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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [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 . |
| [40] | GLAPI?SKI F, ZAJ?C 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 . |
| [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 . |
| [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 . |
| [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 . |
/
| 〈 |
|
〉 |