Reviews

Research progress of perineural invasion in gynecological malignant tumors

  • Yekun HE ,
  • Ying LONG ,
  • Lizhang CEN ,
  • Desheng. YAO
Expand
  • Department of Gynecologic Oncology,Affiliated Tumor Hospital of Guangxi Medical University,Nanning 530021,Guangxi,China

Received date: 2025-01-13

  Online published: 2025-07-02

Abstract

As a distinct pathological factor and metastatic route of malignant tumors, perineural invasion (PNI) exhibits a close association with the prognosis of several cancer types. In recent years, the clinical significance and underlying mechanisms of PNI in gynecological malignant tumors have increasingly drawn research attention. Currently, it is recognized that PNI is clinicopathologically and prognostically linked to cervical cancer and vulvar cancer. The exploration of its mechanisms encompasses multiple gynecological tumors and numerous molecular pathways, including the CCL2/CCR2 axis, NGF/TrkA pathway, GluR2, among others. Nevertheless, the existing research models are fragmented, lacking systematicity and in-depth analysis, thus necessitating integration. This paper presents a comprehensive review of the occurrence of PNI in gynecologic malignancies, its correlations with clinicopathology and prognosis, its implications for surgical approaches and postoperative adjuvant therapies, as well as the potential molecular mechanisms. By synthesizing the advancements in both clinical and basic research, this review aims to offer a solid theoretical foundation for further exploration of the mechanisms underlying PNI in gynecologic malignancies and for the optimization of clinical therapeutic strategies.

Cite this article

Yekun HE , Ying LONG , Lizhang CEN , Desheng. YAO . Research progress of perineural invasion in gynecological malignant tumors[J]. The Journal of Practical Medicine, 2025 , 41(12) : 1929 -1935 . DOI: 10.3969/j.issn.1006-5725.2025.12.023

References

1 LIEBIG C, AYALA G, WILKS J A, et al. Perineural invasion in cancer: A review of the literature. Cancer. 2009,115(15): 3379-3391. doi:10.1002/cncr.24396
2 BRAY F, LAVERSANNE M, SUNG H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024,74(3):229-263. doi:10.3322/caac.21834
3 张国楠, 阳燕, 朱熠,等. 嗜神经侵袭对早期子宫颈癌患者预后的影响[J]. 中华妇产科杂志,2015,50(9):673-678. doi:10.3760/cma.j.issn.0529-567x.2015.09.007
4 VURAL C, BAYRAK B Y, MUEZZ?NOGLU B, et al. Perineural invasion is a valuable prognostic factor in advanced stage and/or Node (+) cervical cancer[J]. Indian J Pathol Microbiol, 2017,60(1):27-32. doi:10.4103/0377-4929.200021
5 ZHU Y, ZHANG G, YANG Y, et al. Perineural invasion in early-stage cervical cancer and its relevance following surgery[J]. Oncol Lett, 2018,15(5):6555-6561. doi:info:doi/10.3892/ol.2018.8116
6 刘涛, 周黎, 陈雅,等. 神经侵袭与宫颈癌临床病理特征及预后的关系[J]. 中国妇产科临床杂志,2020,21(1):3-5. doi:10.13390/j.issn.1672-1861.2020.01.002
7 GAO X, WANG Q, HUANG T, et al. Cervical cancer-produced neuromedin-B reprograms Schwann cells to initiate perineural invasion[J]. Cell Death Dis, 2024,15(8):636. doi:10.1038/s41419-024-07030-9
8 CHEN X, DUAN H, ZHAO H, et al. Perineural invasion in cervical cancer: A multicenter retrospective study[J]. Eur J Surg Oncol, 2024,50(6):108313. doi:10.1016/j.ejso.2024.108313
9 CAI G, ZHANG S, GAO S, et al. What is the impact of perineural invasion on the prognosis of cervical cancer: A systematic review and meta-analysis[J]. BMC Cancer, 2025,25(1):491. doi:10.1186/s12885-025-13838-1
10 ELSAHWI K S, BARBER E, ILLUZZI J, et al. The significance of perineural invasion in early-stage cervical cancer[J]. Gynecol Oncol, 2011,123(3):561-564. doi:10.1016/j.ygyno.2011.08.028
11 WAN T, TU H, LIU L, et al. Perineural Invasion Should Be Regarded as an Intermediate-Risk Factor for Recurrence in Surgically Treated Cervical Cancer: A Propensity Score Matching Study[J]. Dis Markers, 2021,2021:1375123. doi:10.1155/2021/1375123
12 SKRET-MAGIERLO J E, SOJA P J, SKRET A, et al. Perineural space invasion in cervical cancer (FIGO IB1-IIB) accompanied by high-risk factors for recurrence[J]. J Cancer Res Ther, 2014,10(4):957-961. doi:10.4103/0973-1482.138126
13 WEI Y S, YAO D S, LONG Y. Evaluation of the association between perineural invasion and clinical and histopathological features of cervical cancer[J]. Mol Clin Oncol, 2016,5(3):307-311. doi:10.3892/mco.2016.941
14 HORN L C, MEINEL A, FISCHER U, et al. Perineural invasion in carcinoma of the cervix uteri--Prognostic impact[J]. J Cancer Res Clin Oncol, 2010,136(10):1557-1562. doi:10.1007/s00432-010-0813-z
15 MEINEL A, FISCHER U, BILEK K, et al. Morphological parameters associated with perineural invasion (PNI) in carcinoma of the cervix uteri[J]. Int J Surg Pathol, 2011,19(2):159-163. doi:10.1177/1066896910381898
16 CHO H C, KIM H, CHO H Y, et al. Prognostic significance of perineural invasion in cervical cancer[J]. Int J Gynecol Pathol, 2013,32(2):228-233. doi:10.1097/pgp.0b013e318257df5f
17 祖新慧, 刘贵鹏. 神经侵犯与宫颈癌临床病理特征的关系及预后分析[J]. 现代肿瘤医学,2018,26(5):754-758. doi:10.3969/j.issn.1672-4992.2018.05.026
18 TANG M, LIU Q, YANG X, et al. Perineural invasion as a prognostic risk factor in patients with early cervical cancer[J]. Oncol Lett, 2019,17(1):1101-1107.
19 OZAN H, OZUYSAL S, EDIZ B. Perineural invasion in early-stage cervical carcinoma[J]. Eur J Gynaecol Oncol, 2009,30(4):379-383.
20 ZHOU J, CHEN Y, ZHANG P, et al. Ovarian preservation in adenocarcinoma of the uterine cervix[J]. J Ovarian Res, 2017,10(1):48. doi:10.1186/s13048-017-0339-y
21 ALKATOUT I, SCHUBERT M, GARBRECHT N, et al. Vulvar cancer: Epidemiology, clinical presentation, and management options[J]. Int J Womens Health, 2015,7:305-313. doi:10.2147/ijwh.s68979
22 LONG Y, YAO D S, WEI Y S, et al. Prognostic significance of perineural invasion in vulvar squamous cell carcinoma[J]. Cancer Manag Res, 2019,11:4461-4469. doi:10.2147/cmar.s198047
23 FERRARI F, FORTE S, ARDIGHIERI L, et al. Multivariate analysis of prognostic factors in primary squamous cell vulvar cancer: The role of perineural invasion in recurrence and survival[J]. Eur J Surg Oncol, 2019,45(11):2115-2119. doi:10.1016/j.ejso.2019.07.029
24 GADDUCCI A, PISTOLESI S, COSIO S, et al. Perineural Invasion Correlates With Common Pathological Variables and Clinical Outcomes of Patients With Squamous Cell Carcinoma of the Vulva Treated With Primary Radical Surgery and Inguinal-femoral Lymphadenectomy[J]. In Vivo, 2021,35(2):1051-1056. doi:10.21873/invivo.12349
25 MICHELETTI L, BORELLA F, PRETI M, et al. Perineural Invasion in Vulvar Squamous-Cell Carcinoma Is an Independent Risk Factor for Cancer-Specific Survival, but Not for Locoregional Recurrence: Results from a Single Tertiary Referral Center[J]. Cancers (Basel), 2021,14(1):124. doi:10.3390/cancers14010124
26 HOLTHOFF E R, JEFFUS S K, GEHLOT A, et al. Perineural Invasion Is an Independent Pathologic Indicator of Recurrence in Vulvar Squamous Cell Carcinoma[J]. Am J Surg Pathol, 2015,39(8):1070-1074. doi:10.1097/pas.0000000000000422
27 SALCEDO M P, SOOD A K, DOS REIS R, et al. Perineural invasion (PNI) in vulvar carcinoma: A review of 421 cases[J]. Gynecol Oncol, 2019,152(1):101-105. doi:10.1016/j.ygyno.2018.10.035
28 ZHENG Z, LI X, CHEN G, et al. Transcriptome analyses reveal new insights on key determinants of perineural invasion in high-grade serous ovarian cancer[J]. Front Cell Dev Biol, 2023,11:1109710. doi:10.3389/fcell.2023.1109710
29 ZHANG H, QU M, SUN C, et al. Association of Mu-Opioid Receptor Expression With Long-Term Survival and Perineural Nerve Invasion in Patients Undergoing Surgery for Ovarian Cancer[J]. Front Oncol, 2022,12:927262. doi:10.3389/fonc.2022.927262
30 NI T, HUANG T, GU S L, et al. DRG Neurons Promote Perineural Invasion of Endometrial Cancer via GluR2[J]. J Cancer, 2020,11(9):2518-2528. doi:10.7150/jca.40055
31 KWON J, EOM K Y, KIM I A, et al. Prognostic Value of Log Odds of Positive Lymph Nodes after Radical Surgery Followed by Adjuvant Treatment in High-Risk Cervical Cancer[J]. Cancer Res Treat, 2016,48(2):632-640. doi:10.4143/crt.2015.085
32 BAIOCCHI G, MANTOAN H, DE BROT L, et al. How important is the pathological margin distance in vulvar cancer?[J]. Eur J Surg Oncol, 2015,41(12):1653-1658. doi:10.1016/j.ejso.2015.09.024
33 DIAS-SANTAGATA D, SELIM M A, SU Y, et al. KIT mutations and CD117 overexpression are markers of better progression-free survival in vulvar melanomas[J]. Br J Dermatol, 2017,177(5):1376-1384. doi:10.1111/bjd.15836
34 SANTORO A, ANGELICO G, TRAVAGLINO A, et al. Prognostic role of perineural invasion in vulvar squamous cell carcinoma: A systematic review and meta-analysis[J]. Eur J Surg Oncol, 2022,48(12):2354-2359. doi:10.1016/j.ejso.2022.06.031
35 PERGIALIOTIS V, FEROUSIS L, ROUVALI A, et al. Perineural Invasion as a Predictive Biomarker of Groin Metastases and Survival Outcomes in Vulvar Cancer: A Meta-Analysis[J]. Cancer Invest, 2022,40(8):733-741. doi:10.1080/07357907.2022.2070918
36 KIETPEERAKOOL C, AUE-AUNGKUL A, GALAAL K, et al. Nerve-sparing radical hysterectomy compared to standard radical hysterectomy for women with early stage cervical cancer (stage Ia2 to IIa)[J]. Cochrane Database Syst Rev, 2019,2(2):CD012828. doi:10.1002/14651858.cd012828.pub2
37 MUALLEM M Z, ARMBRUST R, NEYMEYER J, et al. Nerve Sparing Radical Hysterectomy: Short-Term Oncologic, Surgical, and Functional Outcomes[J]. Cancers (Basel), 2020,12(2):483. doi:10.3390/cancers12020483
38 中国医师协会妇产科医师分会妇科肿瘤学组. 保留盆腔自主神经的子宫颈癌根治性手术中国专家共识[J]. 中华肿瘤杂志,2021,43(7):736-742. doi:10.3760/cma.j.cn112152-20210525-00411
39 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer (Version 1.2025)[EB/OL]. (2024-12-19)[2025-01-10].
40 CHEN G, SUN H, CHEN Y, et al. Perineural Invasion in Cervical Cancer: A Hidden Trail for Metastasis[J]. Diagnostics (Basel), 2024,14(14):1517. doi:10.3390/diagnostics14141517
41 SKRET A, SKRET-MAGIERLO J E, KSI??EK M, et al. The Diagnosis of Perineural Invasion: A Crucial Factor in Novel Algorithm of Coexistence of Conventional and Nerve-Sparing Radical Hysterectomy[J]. Diagnostics (Basel), 2021,11(8):1308. doi:10.3390/diagnostics11081308
42 石宇, 张国楠. 宫颈癌保留神经手术的现状与争议[J]. 中国实用妇科与产科杂志,2019,35(10):1108-1112.
43 张国楠. 从PNI看宫颈癌NSRH术式的适应证[J]. 肿瘤预防与治疗,2015,28(6):307-309. doi:10.3969/j.issn.1674-0904.2015.06.001
44 ZHU Y, ZHANG G N, SHI Y, et al. Perineural invasion in cervical cancer: Pay attention to the indications of nerve-sparing radical hysterectomy[J]. Ann Transl Med, 2019,7(9):203. doi:10.21037/atm.2019.04.35
45 HUANG T, FAN Q, WANG Y, et al. Schwann Cell-Derived CCL2 Promotes the Perineural Invasion of Cervical Cancer[J]. Front Oncol, 2020,10:19. doi:10.3389/fonc.2020.00019
46 CHEN G, ZHENG Z, SUN H, et al. Dedifferentiated Schwann cells promote perineural invasion mediated by the PACAP paracrine signalling in cervical cancer[J]. J Cell Mol Med, 2023,27(23):3692-3705. doi:10.1111/jcmm.17897
47 龙颖, 姚德生, 韦有生,等. 神经生长因子及受体与早期宫颈癌嗜神经侵袭的相关性[J]. 肿瘤防治研究,2018,45(10):781-785.
48 LONG Y, YAO D S, WEI Y S, et al. Effects of Nerve Growth Factor Expression on Perineural Invasion and Worse Prognosis in Early-Stage Cervical Cancer[J]. Chin Med J (Engl), 2018,131(19):2360-2363. doi:10.4103/0366-6999.241808
49 龙颖, 黄芳依, 韦有生. NGF/TrkA轴对宫颈癌SiHa细胞增殖、凋亡和侵袭的影响[J]. 天津医药,2023,51(8):809-814. doi:10.11958/20230318
50 BAIOCCHI G, DE FREITAS R R, BOVOLIM G, et al. Immunohistochemical expression of ErbB/HER family proteins in patients with vulvar cancer[J]. Int J Gynaecol Obstet, 2022,157(1):102-109. doi:10.1002/ijgo.13829
51 LAVORATO-ROCHA A M, DE MELO MAIA B, RODRIGUES I S, et al. Prognostication of vulvar cancer based on p14ARF status: molecular assessment of transcript and protein[J]. Ann Surg Oncol, 2013,20(1):31-39. doi:10.1245/s10434-012-2560-7
Outlines

/