Предшественники, пути канцерогенеза и молекулярные маркеры плоскоклеточной карциномы вульвы. Литературный обзор

В обзоре проанализированы и обобщены результаты исследований, изучающих патогенез плоскоклеточного рака вульвы и особенности его  диагностики, рассмотрены предшествующие состояния и молекулярные подтипы карцином. Несмотря на  относительно низкую встречаемость опухоли, за  последние несколько десятилетий отмечается тенденция к росту заболеваемости, в том числе среди молодых женщин. Согласно последней классификации Всемирной организации здравоохранения опухолей нижнего отдела генитального тракта от 2020  г., плоскоклеточный рак вульвы подразделяется на ассоциированный с вирусом папилломы человека (ВПЧ) и ВПЧ-независимый. В то время как морфологически эти карциномы часто являются сходными, механизмы канцерогенеза, предшественники, а также клинические исходы у них различны. Только лишь обнаружение ДНК вируса в опухоли недостаточно для установки ВПЧ-статуса. В то же время иммуногистохимическое обнаружение экспрессии белков p16 и p53 позволяет не только разделить два патогенетических пути канцерогенеза, но и выявить его молекулярные подтипы. Получены данные о том, что экспрессию p16 и p53 возможно также использовать в качестве молекулярных маркеров прогноза заболевания. В  настоящее время тактика лечения и наблюдения пациенток не зависит от ВПЧ-статуса карциномы, однако результаты исследований последних лет говорят о том, что женщины с  ВПЧ-положительным раком вульвы имеют значительно более высокие показатели выживаемости и меньший риск возникновения рецидивов. Понимание механизмов канцерогенеза и усовершенствование его диагностики позволит улучшить оценку индивидуального риска прогресса предопухолевых состояний, а также исход и возникновение рецидива опухоли. 

1. Trietsch MD, Nooij LS, Gaarenstroom KN, van Poelgeest MI. Genetic and epigenetic changes in vulvar squamous cell carcinoma and its precursor lesions: A review of the current literature. Gynecol Oncol. 2015; 136: 143-157. https://doi.org/10.1016/j.ygyno.2014.11.002

2. Zhang J, Zhang Y, Zhang Z. Prevalence of human papillomavirus and its prognostic value in vulvar cancer: A systematic review and meta-analysis. PLoS One. 2018; 13(9): е0204162. https://doi.org/10.1371/journal.pone.0204162

3. Preti M, Rotondo JC, Holzinger D, Micheletti L, Gallio N, McKay-Chopin S, et al. Role of human papillomavirus infection in the etiology of vulvar cancer in Italian women. Infect Agent Cancer. 2020; 15: 20. https://doi.org/10.1186/s13027-020-00286-8

4. Eva LJ, Sadler L, Fong KL, Sahota S, Jones RW, Bigby SM. Trends in HPV-dependent and HPV-independent vulvar cancers: The changing face of vulvar squamous cell carcinoma. Gynecol Oncol. 2020; 157(2): 450-455. https://doi.org/10.1016/j.ygyno.2020.01.029

5. Kortekaas KE, Bastiaannet E, van Doorn HC, de Vos van Steenwijk PJ, Ewing-Graham PC, Creutzberg CL, et al. Vulvar cancer subclassification by HPV and p53 status results in three clinically distinct subtypes. Gynecol Oncol. 2020; 159(3): 649-656. https://doi.org/10.1016/j.ygyno.2020.09.024

6. Rasmussen CL, Sand FL, Frederiksen MF, Andersen KK, Kjaer SK. Does HPV status influence survival after vulvar cancer? Int J Cancer. 2018; 142(6): 1158-1165. https://doi.org/10.1002/ijc.31139

7. Sand FL, Nielsen DMB, Frederiksen MH, Rasmussen CL, Kjaer SK. The prognostic value of p16 and p53 expression for survival after vulvar cancer: A systematic review and metaanalysis. Gynecol Oncol. 2019; 152(1): 208-217. https://doi.org/10.1016/j.ygyno.2018.10.015

8. Carreras-Dieguez N, Guerrero J, Rodrigo-Calvo MT, RiberaCortada I, Trias I, Jares P, et al. Molecular landscape of vulvar squamous cell carcinoma. IntJ Mol Sci. 2021; 22(13): 7069. https://doi.org/10.3390/ijms22137069

9. Female genital tumours: WHO classification of tumours; 5th ed. Lyon, France: International Agency for Research in Cancer; 2020.

10. Zur Hausen H. Papillomaviruses and cancer: From basic studies to clinical application. Nat Rev Cancer. 2002; 2: 342-350. https://doi.org/10.1038/nrc798

11. Berman TA, Schiller JT. Human papillomavirus in cervical cancer and oropharyngeal cancer: One cause, two diseases. Cancer. 2017; 123(12): 2219-2229. https://doi.org/10.1002/cncr.30588

12. Mills AM, Dirks DC, Poulter MD, Mills SE, Stoler MH. HRHPV E6/E7 mRNA in situ hybridization: Validation against PCR, DNA in situ hybridization, and p16 immunohistochemistry in 102 samples of cervical, vulvar, anal, and head and neck neoplasia. Am J Surg Pathol. 2017; 41(5): 607-615. https://doi.org/10.1097/PAS.0000000000000800

13. Prieske K, Alawi M, Oliveira-Ferrer L, Jaeger A, Eylmann K, Burandt E, et al. Genomic characterization of vulvar squamous cell carcinoma. Gynecol Oncol. 2020; 158(3): 547-554. https://doi.org/10.1016/j.ygyno.2020.06.482

14. Singh N, Gilks CB. Vulval squamous cell carcinoma and its precursors. Histopathology. 2020; 76(1): 128-138. https://doi.org/10.1111/his.13989

15. Ward M, Amarnath S. Vulvar cancer. Essentials of clinical radiation oncology. NY: Springer Publishing Co; 2017: 430-437.

16. Dohopolski MJ, Horne ZD, Pradhan D, Bhargava R, Edwards RP, Kelley JL, et al. The prognostic significance of p16 status in patients with vulvar cancer treated with vulvectomy and adjuvant radiation. Int J Radiat Oncol Biol Phys. 2019; 103(1): 152-160. https://doi.org/10.1016/j.ijrobp.2018.08.014

17. Rodrigues IS, Lavorato-Rocha AM, Stiepcich MM, de Carvalho FM, Baiocchi G, et al. Epithelial-mesenchymal transition-like events in vulvar cancer and its relation with HPV. BrJ Cancer. 2013; 109(1): 184-194. https://doi.org/10.1038/bjc.2013.273

18. van de Nieuwenhof HP, van Kempen LC, de Hullu JA, Bekkers RLM, Bulten J, Melchers WJG, et al. The etiologic role of HPV in vulvar squamous cell carcinoma fine tuned. Cancer Epidemiol Biomarkers Prev. 2009; 18(7): 2061-2067. https://doi.org/10.1158/1055-9965.EPI-09-0209

19. Weberpals JI, Lo B, Duciaume MM, Spaans JN, Clancy AA, Dimitroulakos J, et al. Vulvar squamous cell carcinoma (VSCC) as two diseases: HPV status identifies distinct mutational profiles including oncogenic fibroblast growth factor receptor 3. Clin Cancer Res. 2017; 23(15): 4501-4510. https://doi.org/10.1158/1078-0432.CCR-16-3230

20. Cheng AS, Karnezis AN, Jordan S, Singh N, McAlpine JN, Gilks CB. p16 immunostaining allows for accurate subclassification of vulvar squamous cell carcinoma into HPV-associated and HPVindependent cases. Int J Gynecol Pathol. 2016; 35(4); 385-393. https://doi.org/10.1097/PGP.0000000000000263

21. Prigge ES, von Knebel Doeberitz M, Reuschenbach M. Clinical relevance and implications of HPV-induced neoplasia in different anatomical locations. Mutat Res Rev Mutat Res. 2017; 772: 51-66. https://doi.org/10.1016/j.mrrev.2016.06.005

22. Barlow EL, Lambie N, Donoghoe MW, Naing Z, Hacker NF. The clinical relevance of p16 and p53 status in patients with squamous cell carcinoma of the vulva. J Oncol. 2020; 2020: 3739075. https://doi.org/10.1155/2020/3739075

23. Garganese G, Inzani F, Fragomeni SM, Mantovani G, Corte L, Piermattei A, et al. The Vulvar Immunohistochemical Panel (VIP) project: Molecular profiles of vulvar squamous cell carcinoma. Cancers. 2021; 13(24): 6373. https://doi.org/10.3390/cancers13246373

24. Woelber L, Prieske K, Eulenburg C, Oliveira-Ferrer L, de Grigorio N, Klapdor R, et al. p53 and p16 expression profiles in vulvar cancer: A translational analysis by the Arbeitsgemeinschaft Gynakologische Onkologie Chemo and Radiotherapy in Epithelial Vulvar Cancer study group. Am J Obstet Gynecol. 2021; 224(6): 1-11. https://doi.org/10.1016/j.ajog.2020.12.1220

25. Nooij LS, Ter Haar NT, Ruano D, Rakislova N, van Wezel T, Smit THBM, et al. Genomic characterization of vulvar (pre)cancers identifies distinct molecular subtypes with prognostic significance. Clin Cancer Res. 2017; 23(22): 6781-6789. https://doi.org/10.1158/1078-0432.CCR-17-1302

26. Bonde JH, Sandri M-T, Gary DS, Andrews JC. Clinical utility of human papillomavirus genotyping in cervical cancer screening: A systematic review. J Low Genit Tract Dis. 2020; 24(1): 1-13. https://doi.org/10.1097/LGT.0000000000000494

27. Prati B, Marangoni B, Boccardo E. Human papillomavirus and genome instability: From productive infection to cancer. Clinics. 2018; 73(1): e539s. https://doi.org/10.6061/clinics/2018/e539s

28. Del Pino M, Rodriguez-Carunchio L, Ordi J. Pathways of vulvar intraepithelial neoplasia and squamous cell carcinoma. Histopathology 2013; 62(1): 161-175. https://doi.org/10.1111/his.12034

29. Zieba S, Chechlinska M, Kowalik A, Kowalewska M. Genes, pathways and vulvar carcinoma - New insights from nextgeneration sequencing studies. Gynecol Oncol. 2020; 158(20): 498-506. https://doi.org/10.1016/j.ygyno.2020.05.034

30. Li S, Hong X, Wei Z, Xie M, Li W, Liu G, et al., Ubiquitination of the HPV oncoprotein E6 is critical for E6/E6AP-mediated p53 degradation. Front Microbiol. 2019; 10: 2483. https://doi.org/10.3389/fmicb.2019.02483

31. Hoppe-Seyler K, Bossler F, Braun JA, Herrmann AL, Hoppe-Seyler F. The HPV E6/E7 oncogenes: Key factors for viral carcinogenesis and therapeutic targets. Trends Microbiol. 2018; 26(2): 158-168. https://doi.org/10.1016/j.tim.2017.07.007

32. Estevao D, Costa NR, Gil da Costa RM, Medeiros R. Hallmarks of HPV carcinogenesis: The role of E6, E7 and E5 oncoproteins in cellular malignancy. Biochim Biophys Acta Gene Regul Mech. 2019; 1862(2): 153-162. https://doi.org/10.1016/j.bbagrm.2019.01.001

33. Xing D, Liu Y, Park HJ, Baek I, Tran H, Cheang G, et al. Recurrent genetic alterations and biomarker expression in primary and metastatic squamous cell carcinomas of the vulva. Hum Pathol. 2019; 92: 67-80. https://doi.org/10.1016/j.humpath.2019.08.003

34. Liu Y, Ji J, Almadani N, Crawford R, Gilks C, Kinloch M, et al. Comparison of p53 immunohistochemical staining in differentiated vulvar intraepithelial neoplasia (dVIN) to inflammatory dermatoses and benign squamous lesions in the vulva. Histopathology. 2021; 78(3): 424-433. https://doi.org/10.1111/his.14238

35. Kashofer K, Regauer S. Analysis of full coding sequence of the TP53 gene in invasive vulvar cancers: Implications for therapy. Gynecol Oncol. 2017; 146(2): 314-318. https://doi.org/10.1016/j.ygyno.2017.05.018

36. Watkins JC, Howitt BE, Horowitz NS, Ritterhouse LL, Dong F, MacConaill LE, et al. Differentiated exophytic vulvar intraepithelial lesions are genetically distinct from keratinizing squamous cell carcinomas and contain mutations in PIK3CA. Mod Pathol. 2017; 30(3): 448-458. https://doi.org/10.1038/modpathol.2016.187

37. Rakislova N, Alemany L, Clavero O, Saco A, Torné A, del Pino M, et al. p53 immunohistochemical patterns in HPV-independent squamous cell carcinomas of the vulva and the associated skin lesions: A study of 779 cases. Int J Mol Sci. 2020; 21(21): 8091. https://doi.org/10.3390/ijms21218091

38. Tessier-Cloutier B, Pors J, Thompson E, Ho J, Prentice L, McConechy M, et al. Molecular characterization of invasive and in situ squamous neoplasia of the vulva and implications for morphologic diagnosis and outcome. Mod Pathol. 2021; 34(2): 508-518. https://doi.org/10.1038/s41379-020-00651-3

39. Williams EA, Werth AJ, Sharaf R, Montesion M, Sokol ES, Pavlick DC, et al. Vulvar squamous cell carcinoma: Comprehensive genomic profiling of HPV+ versus HPV- forms reveals distinct sets of potentially actionable molecular targets. JCO Precis Oncol. 2020; 4: 647-661. https://doi.org/10.1200/PO.19.00406

40. Han MR, Shin S, Park HC, Kim MS, Lee SH, Jung SH, et al. Mutational signatures and chromosome alteration profiles of squamous cell carcinomas of the vulva. Exp Mol Med. 2018; 50(2): e442. https://doi.org/10.1038/emm.2017.265

41. Proctor L, Hoang L, Moore J, Thompson E, Leung S, Natesan D, et al. Association of human papilloma virus status and response to radiotherapy in vulvar squamous cell carcinomа. Int J Gynecol Cancer. 2020; 30(1): 100-106. https://doi.org/10.1136/ijgc-2019-000793

42. Pils S, Gensthaler L, Alemany L, Horvat R, de Sanjose S, Joura EA. HPV prevalence in vulvar cancer in Austria. Wiener klinische Wochenschrift. 2017; 129: 805-809. https://doi.org/10.1007/s00508-017-1255-2

43. Wakeham K, Kavanagh K, Cuschieri K, Millan D, Pollock KG, Bell S, et al. HPV status and favourable outcome in vulvar squamous cancer. IntJ Cancer. 2017; 140(5): 1134-1146. https://doi.org/10.1002/ijc.30523

44. Hoang LN, Park KJ, Soslow RA, Murali R. Squamous precursor lesions of the vulva: Current classification and diagnostic challenges. Pathology. 2016; 48(4): 291-302. https://doi.org/10.1016/j.pathol.2016.02.015

45. Cohen PA, Anderson L, Eva L, Scurry J. Clinical and molecular classification of vulvar squamous pre-cancers. IntJ Gynecol Cancer. 2019; 29(4): 821-828. https://doi.org/10.1136/ijgc-2018-000135

46. Bigby SM, Eva LJ, Fong KL, Jones RW. The natural history of vulvar intraepithelial neoplasia, differentiated type: Evidence for progression and diagnostic challenges. Int J Gynecol Pathol. 2016; 35(6): 574-584. https://doi.org/10.1097/PGP.0000000000000280

47. van de Nieuwenhof HР, Massuger LF, van der Avoort IA, Bekkers RLM, Casparie M, Abma W, et al. Vulvar squamous cell carcinoma development after diagnosis of VIN increases with age. Eur J Cancer. 2009; 45(5): 851-856. https://doi.org/10.1016/j.ejca.2008.11.037

48. Jin C, Liang S. Differentiated vulvar intraepithelial neoplasia: A brief review of clinicopathologic features. Arch Pathol Lab Med. 2019; 143(6): 768-771. https://doi.org/10.5858/arpa.2018-0019-RS

49. Rakislova N, Alemany L, Clavero O, Del Pino M, Saco A, Marimon L, et al. HPV-independent precursors mimicking high-grade squamous intraepithelial lesions (HSIL) of the vulva. Am J Surg Pathol. 2020; 44(11): 1506-1514. https://doi.org/10.1097/PAS.0000000000001540

50. Heller DS, Day T, Allbritton JI, Scurry J, Radici G, Welch K, Preti M. Diagnostic criteria for differentiated vulvar intraepithelial neoplasia and vulvar aberrant maturation. J Low Genit Tract Dis. 2021; 25: 57-70. https://doi.org/10.1097/LGT.0000000000000572

51. Perez-Lopez FR, Vieira-Baptista P. Lichen sclerosus in women: A review. Climacteric. 2017; 20(4): 339-347. https://doi.org/10.1080/13697137.2017.1343295

52. Micheletti L, Preti M, Radici G, Boveri S, Di Pumpo O, Privitera SS, et al. Vulvar lichen sclerosus and neoplastic transformation: A retrospective study of 976 cases. J Low Genit Tract Dis. 2016; 20(2): 180-183. https://doi.org/10.1097/LGT.0000000000000186

53. McAlpine JN, Leung SCY, Cheng A, Miller D, Talhouk A, Gilks CBG, et al. Human papillomavirus (HPV)-independent vulvar squamous cell carcinoma has a worse prognosis than HPVassociated disease: A retrospective cohort study. Histopathology. 2017; 71(2): 238-246. https://doi.org/10.1111/his.13205

54. Leis M, Singh A, Li C, Ahluwalia R, Fleming P, Lynde CW. Risk of vulvar squamous cell carcinoma in lichen sclerosus and lichen planus: A systematic review. J Obstet Gynaecol Can. 2022; 44(2): 182-192. https://doi.org/10.1016/j.jogc.2021.09.023

55. Roy SF, Wong JW, Page CL, Tran-Thanh D, Barkati M, Pina A, et al. DEVIL, VAAD and vLSC constitute a spectrum of HPV-independent, p53-independent intra-epithelial neoplasia of the vulva. Histopathology. 2021; 79(6): 975-988. https://doi.org/10.1111/his.14451

56. Day T, Marzol A, Pagano R, Jaaback K, Scurry J. Clinicopathologic diagnosis of vulvar intraepithelial neoplasia and vulvar aberrant maturation. J Lower Genit Tract Dis. 2020; 24(4): 317-329. https://doi.org/10.1097/LGT.0000000000000569

57. Nascimento AF, Granter SR, Cviko A, Yuan L, Hecht JL, Crum CP. Vulvar acanthosis with altered differentiation: A precursor to verrucous carcinoma? Am J Surg Pathol. 2004; 28(5): 638-643. https://doi.org/10.1097/00000478-200405000-00012

58. Faber MT, Sand FL, Albieri V. Prevalence and type distribution of human papillomavirus in squamous cell carcinoma and intraepithelial neoplasia of the vulva. IntJ Cancer. 2017; 141(6): 1161-1169. https://doi.org/10.1002/ijc.30821

59. Rakislova N, Clavero O, Alemany L, Saco A, Quirós B, Lloveras B, et al. Histological characteristics of HPV-associated and -independent squamous cell carcinomas of the vulva: A study of 1594 cases. Int J Cancer 2017; 141(12): 2517-2527. https://doi.org/10.1002/ijc.31006

60. Dong F, Kojiro S, Borger DR, Growdon WB, Oliva E. Squamous cell carcinoma of the vulva: a subclassification of 97 cases by clinicopathologic, immunohistochemical, and molecular features (p16, p53, and EGFR). Am J Surg Pathol. 2015; 39: 1045-1053. https://doi.org/10.1097/PAS.0000000000000454

61. Koerber SA, Schoneweg C, Slynko A, Krug D, Haefner MF, Herfarth K, et al. Influence of human papillomavirus and p16(INK4a) on treatment outcome of patients with anal cancer. Radiother Oncol. 2014; 113(3): 331-336. https://doi.org/10.1016/j.radonc.2014.11.013

62. De Sanjosé S, Alemany L, Ordi J, Tous S, Alejo M, Bigby SM, et al. Worldwide human papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive lesions of the vulva. Eur J Cancer. 2013; 49(16): 3450-3461. https://doi.org/10.1016/j.ejca.2013.06.033

63. Sznurkowski JJ, Zawrocki A, Biernat W. The overexpression of p16 is not a surrogate marker for high-risk human papilloma virus genotypes and predicts clinical outcomes for vulvar cancer. BMC Cancer. 2016; 16: 465. https://doi.org/10.1186/s12885-016-2503-y

64. Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell. 2006; 127(2): 265-275. https://doi.org/10.1016/j.cell.2006.10.003

65. LaPak KM, Burd CE. The molecular balancing act of p16(INK4a) in cancer and aging. Mol Cancer Res. 2014; 12(2): 167-183. https://doi.org/10.1158/1541-7786.MCR-13-0350

66. Hacker NF, Eifel PJ, van der Velden J. Cancer of the vulva. IntJ Gynecol Obstet. 2015; 131: 76-83. https://doi.org/10.1016/j.ijgo.2015.06.002

67. Santos M, Landolfi S, Olivella A, Lloveras B, Klaustermeier J, Suárez H, et al. p16 overexpression identifies HPV-positive vulva squamous cell carcinomas. Am J Surg Pathol. 2006; 30(11): 1347- 1356. https://doi.org/10.1097/01.pas.0000213251.82940.bf

68. Cao H, Wang S, Zhang Z, Lou J. Prognostic value of overexpressed p16INK4a in vulvar cancer: A meta-analysis. PLoS One. 2016; 11(3): e0152459. https://doi.org/10.1371/journal.pone.0152459

69. Allo G, Yap ML, Cuartero J, Milosevic M, Ferguson S, Mackay H, et al. HPV-independent vulvar squamous cell carcinoma is associated with significantly worse prognosis compared with HPV-associated tumors. IntJ Gynecol Pathol. 2020; 39(4): 391- 399. https://doi.org/10.1097/PGP.0000000000000620

70. von Knebel Doeberitz M. The causal role of human papillomavirus infections in non-anogenital cancers. It’s time to ask for the functional evidence. Int J Cancer. 2016; 139: 9-11. https://doi.org/10.1002/ijc.30059

71. Tessier-Cloutier B, Kortekaas KE, Thompson E, Pors J, Chen J, Ho J, et al. Major p53 immunohistochemical patterns in in situ and invasive squamous cell carcinomas of the vulva and correlation with TP53 mutation status. Mod Pathol. 2020; 33(8): 1595-1605. https://doi.org/10.1038/s41379-020-0524-1

72. Kortekaas KE, Solleveld-Westerink N, Tessier-Cloutier B, Rutten TA, Van Poelgeest M, Gilks CB, et al. Performance of the pattern based interpretation of p53 immunohistochemistry as a surrogate for TP53 mutations in vulvar squamous cell carcinoma. Histopathology. 2020; 77(1): 92-99. https://doi.org/10.1111/his.14109 7

73. Köbel M, Ronnett BM, Singh N, Soslow RA, Gilks CB, McCluggage WG. Interpretation of P53 immunohistochemistry in endometrial carcinomas: Toward increased reproducibility. Int J Gynecol Pathol. 2019; 38: 123-131. https://doi.org/10.1097/PGP.0000000000000488 74. Na K, Sung JY, Kim HS. TP53 mutation status of tuboovarian and peritoneal high-grade serous carcinoma with a wildtype p53 immunostaining pattern. Anticancer Res. 2017; 37(12): 6697-6703. https://doi.org/10.21873/anticanres.12128

74. Hay CM, Lachance JA, Lucas FL, Smith KA, Jones MA. Biomarkers p16, human papillomavirus and p53 predict recurrence and survival in early stage squamous cell carcinoma of the vulva. J Low Genit Tract Dis. 2016; 20(3): 252-256. https://doi.org/10.1097/LGT.0000000000000182

75. Falcón MF, Paradeda MF, Kamermann FG, Maldonado V, Díaz L, Cardinal L. Immunohistochemistry of p16 and p53 in vulvar cancer. Medicina (B Aires). 2020; 80(2): 127-133.

76. Choschzick M, Hantaredja W, Tennstedt P, Gieseking F, Wölber L, Simon R. Role of TP53 mutations in vulvar carcinomas. Int J Gynecol Pathol. 2011; 30: 497-504. https://doi.org/10.1097/PGP.0b013e3182184c7a

77. Czogalla B, Pham D, Trillsch F, Rottmann M, Gallwas J, Burges A, et al. PD-L1 expression and survival in p16-negative and positive squamous cell carcinomas of the vulva. J Cancer Res Clin Oncol .2020; 146: 569-577. https://doi.org/10.1007/s00432-020-03126-9

78. Sznurkowski JJ, Zawrocki A, Sznurkowska K, Peksa R, Biernat W. PD-L1 expression on immune cells is a favorable prognostic factor for vulvar squamous cell carcinoma patients. Oncotarget. 2017; 8: 89903-89912. https://doi.org/10.18632/oncotarget.20911