Clinicopathological analysis of HPV-related and non-HPV-related oral/oropharyngeal squamous cell carcinoma

doi:10.3969/j.issn.1005-4979.2023.03.004

Abstract

Abstract:

Objective: To make a clinicopathological analysis of human papilloma virus (HPV)-related and non-HPV-related oral/oropharyngeal squamous cell carcinoma (OSCC/OPSCC) diagnosed in our hospital, and to further understand the differences between the two diseases in clinical and pathological aspects. Methods: The cases of OSCC/OPSCC diagnosed from December 1, 2018 to November 30, 2021 in the Hospital of Stomatology, Jilin University were collected. The diagnoses of HPV-related and non-HPV-related squamous cell carcinoma were made based on the detection of p16 by immunohistochemical staining, HPV DNA by polymerase chain reaction (PCR), and high-risk HPV subtypes by PCR-reverse dot hybridization. Statistical analyses were made according to the basic information, clinical characteristics, and pathological manifestations of patients. Results: There was a significant difference in the depth of invasion (DOI) between HPV-related and non-HPV-related OSCC; there was a statistical difference between HPV-related and non-HPV-related OPSCC in terms of the Ki-67 positive rate, whether over 70% or not. Conclusion: To distinguish HPV-related and non-HPV-related OSCC/OPSCC in diagnosis so as to provide a basis for the selection of treatment options and a reference index for the prognosis of patients, and enrich the clinicopathological data in the field of HPV-related head and neck squamous carcinoma (HNSCC), thus improve the knowledge of HPV-related OSCC/OPSCC.

Key words: high-risk human papilloma virus, oral squamous cell carcinoma, oropharyngeal squamous cell carcinoma, p16

摘要：

目的：对我院诊断的人乳头瘤病毒（human papilloma virus, HPV）相关性和非HPV相关性口腔鳞状细胞癌（oral squamous cell carcinoma, OSCC）和口咽鳞状细胞癌（oropharyngeal squamous cell carcinoma, OPSCC）进行临床病理分析，以深入认识二者在临床和病理学上的差异性。方法：收集从2018年12月1日至2021年11月30日就诊于吉林大学口腔医院并经病理诊断为OSCC/OPSCC的病例，通过免疫组织化学染色法检测p16的表达、聚合酶链反应（polymerase chain reaction, PCR）检测HPV DNA、PCR-反向点杂交技术检测高危HPV亚型，将其分为HPV相关性鳞状细胞癌和非HPV相关性鳞状细胞癌。分别从患者的基本信息、临床特征和病理学表现等方面对二者进行统计学分析。结果：HPV相关性OSCC和非HPV相关性OSCC在浸润深度（depth of invasion, DOI）方面的差异具有统计学意义（P<0.05）；HPV相关性OPSCC和非HPV相关性OPSCC在Ki-67阳性率是否大于70%方面，差异具有统计学意义（P<0.001）。结论：在诊断时，区分HPV相关性和非HPV相关性OSCC/OPSCC能为该病治疗方案的选择提供依据，并为患者的预后提供可参考指标，能丰富HPV相关性头颈部鳞状细胞癌（head and neck squamous cell carcinoma, HNSCC）领域的临床病理资料，提高对HPV相关性OSCC/OPSCC的认知。

关键词: 高危型人乳头瘤病毒, 口腔鳞状细胞癌, 口咽鳞状细胞癌, p16

CLC Number:

R782

WANG Xiaoling, QIANG Jinbiao, QU Ming, ZHANG Yuqing, QIAO Chunyan, ZHANG Zebing, SHI Ce. Clinicopathological analysis of HPV-related and non-HPV-related oral/oropharyngeal squamous cell carcinoma[J]. 《Journal of Oral and Maxillofacial Surgery》, 2023, 33(3): 155-163.

王晓玲, 强金彪, 曲明, 张雨晴, 乔春燕, 张泽兵, 史册. HPV相关性和非HPV相关性口腔/口咽鳞状细胞癌的临床病理分析[J]. 《口腔颌面外科杂志》, 2023, 33(3): 155-163.

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URL: https://journal06.magtech.org.cn/Jweb_joms/EN/10.3969/j.issn.1005-4979.2023.03.004

https://journal06.magtech.org.cn/Jweb_joms/EN/Y2023/V33/I3/155

Figures/Tables 9

References 39

[1]	Chow LQM. Head and neck cancer[J]. N Engl J Med, 2020, 382(1):60-72. doi: 10.1056/NEJMra1715715 URL
[2]	Johnson DE, Burtness B, Leemans CR, et al. Head and neck squamous cell carcinoma[J]. Nat Rev Dis Primers, 2020, 6(1):92. doi: 10.1038/s41572-020-00224-3 pmid: 33243986
[3]	Zhang LW, Li J, Cong X, et al. Incidence and mortality trends in oral and oropharyngeal cancers in China, 2005-2013[J]. Cancer Epidemiol, 2018, 57:120-126. doi: S1877-7821(18)30260-1 pmid: 30396144
[4]	Jemal A, Bray F, Center MM, et al. Global cancer statistics[J]. CA A Cancer J Clin, 2011, 61(2):69-90. doi: 10.3322/caac.v61:2 URL
[5]	Chi AC, Day TA, Neville BW. Oral cavity and orophary-ngeal squamous cell carcinoma—an update[J]. CA Cancer J Clin, 2015, 65(5):401-421. doi: 10.3322/caac.v65.5 URL
[6]	Sun YM, Wang Z, Qiu SF, et al. Therapeutic strategies of different HPV status in head and neck squamous cell carcinoma[J]. Int J Biol Sci, 2021, 17(4):1104-1118. doi: 10.7150/ijbs.58077 pmid: 33867833
[7]	Bhat GR, Hyole RG, Li J. Head and neck cancer：Current challenges and future perspectives[J]. Adv Cancer Res, 2021, 152:67-102.
[8]	Sichero L, Tagliabue M, Mota G, et al. Biomarkers of human papillomavirus (HPV)—driven head and neck cancer in Latin America and Europe study：Study design and HPV DNA/p16^INK4a status[J]. Head Neck, 2022, 44(1):122-133. doi: 10.1002/hed.v44.1 URL
[9]	Scott-Wittenborn N, D'Souza G, Tewari S, et al. Prevalence of human papillomavirus in head and neck cancers at tertiary care centers in the United States over time[J]. Cancer, 2022, 128(9):1767-1774. doi: 10.1002/cncr.34124 pmid: 35132635
[10]	Ndiaye C, Mena M, Alemany L, et al. HPV DNA, E6/E7 mRNA, and p16INK4a detection in head and neck cancers：A systematic review and meta-analysis[J]. Lancet Oncol, 2014, 15(12):1319-1331. doi: 10.1016/S1470-2045(14)70471-1 pmid: 25439690
[11]	Chaturvedi AK, Anderson WF, Lortet-Tieulent J, et al. Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers[J]. J Clin Oncol, 2013, 31(36):4550-4559. doi: 10.1200/JCO.2013.50.3870 pmid: 24248688
[12]	Meng HX, Miao SS, Chen KX, et al. Association of p16 as prognostic factors for oropharyngeal cancer：Evaluation of p16 in 1 470 patients for a 16 year study in northeast China[J]. Biomed Res Int, 2018, 2018:9594568.
[13]	Lam EW, Chan JY, Chan AB, et al. Prevalence, clinico-pathological characteristics, and outcome of human pap-illomavirus—associated oropharyngeal cancer in southern Chinese patients[J]. Cancer Epidemiol Biomarkers Prev, 2016, 25(1):165-173. doi: 10.1158/1055-9965.EPI-15-0869 URL
[14]	WHO Classification of Tumours Editorial Board. Head and neck tumours[M/OL]// WHO classification of tumours series. 5th ed. vol. 9. Lyon: IARC, 2022 [published online ahead of print]. https://tumourclassification.iarc.who.int/login.
[15]	Sathish N, Wang X, Yuan Y. Human papillomavirus (HPV)-associated oral cancers and treatment strategies[J]. J Dent Res, 2014, 93(7_Suppl):29S-36S. doi: 10.1177/0022034514527969 URL
[16]	Maxwell JH, Grandis JR, Ferris RL. HPV-associated head and neck cancer：Unique features of epidemiology and clinical management[J]. Annu Rev Med, 2016, 67:91-101. doi: 10.1146/med.2015.67.issue-1 URL
[17]	Amin MB, Greene FL, Edge SB, et al. The Eighth Edition AJCC Cancer Staging Manual：Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging[J]. CA Cancer J Clin, 2017, 67(2):93-99. doi: 10.3322/caac.v67.2 URL
[18]	Kozak MM, Shah J, Chen M, et al. Depth of invasion alone as a prognostic factor in low-risk early-stage oral cavity carcinoma[J]. Laryngoscope, 2019, 129(9):2082-2086. doi: 10.1002/lary.v129.9 URL
[19]	McIlwain WR, Sood AJ, Nguyen SA, et al. Initial symptoms in patients with HPV-positive and HPV-negative oroph-aryngeal cancer[J]. JAMA Otolaryngol Head Neck Surg, 2014, 140(5):441-447. doi: 10.1001/jamaoto.2014.141 URL
[20]	Panarese I, Aquino G, Ronchi A, et al. Oral and Orophary-ngeal squamous cell carcinoma：Prognostic and predictive parameters in the etiopathogenetic route[J]. Expert Rev Anticancer Ther, 2019, 19(2):105-119. doi: 10.1080/14737140.2019.1561288 URL
[21]	Oliveira AC, Cavalcanti de Lima IC, Frez Marques VM, et al. Human papillomavirus prevalence in oral and oropharyngeal squamous cell carcinoma in South America：A systematic review and meta-analysis[J]. Oncol Rev, 2022, 16(1):552. doi: 10.4081/oncol.2022.552 pmid: 35432780
[22]	Herrero R, Castellsagué X, Pawlita M, et al. Human papillomavirus and oral cancer: The International Agency for Research on Cancer multicenter study[J]. J Natl Cancer Inst, 2003, 95(23): 1772-1783. doi: 10.1093/jnci/djg107 pmid: 14652239
[23]	Balaram P, Nalinakumari KR, Abraham E, et al. Human papillomaviruses in 91 oral cancers from Indian betel quid chewers—high prevalence and multiplicity of infections[J]. Int J Cancer, 1995, 61(4): 450-454. doi: 10.1002/ijc.2910610403 pmid: 7759149
[24]	Anaya-Saavedra G, Ramírez-Amador V, Irigoyen-Camacho ME, et al. High association of human papillomavirus infection with oral cancer：A case-control study[J]. Arch Med Res, 2008, 39(2):189-197. doi: 10.1016/j.arcmed.2007.08.003 pmid: 18164962
[25]	de Sanjosé S, Brotons M, Pavón MA. The natural history of human papillomavirus infection[J]. Best Pract Res Clin Obstet Gynaecol, 2018, 47:2-13. doi: S1521-6934(17)30133-5 pmid: 28964706
[26]	Zito Marino F, Ronchi A, Stilo M, et al. Multiplex HPV RNA in situ hybridization/p16 immunohistochemistry：A novel approach to detect papillomavirus in HPV-related cancers. A novel multiplex ISH/IHC assay to detect HPV[J]. Infect Agent Cancer, 2020, 15:46. doi: 10.1186/s13027-020-00310-x
[27]	Kühn JP, Schmid W, Körner S, et al. HPV status as prognostic biomarker in head and neck cancer-which method fits the best for outcome prediction？[J]. Cancers (Basel), 2021, 13(18):4730. doi: 10.3390/cancers13184730 URL
[28]	Prigge ES, Arbyn M, von Knebel Doeberitz M, et al. Diagnostic accuracy of p16^INK4a immunohistochemistry in oropharyngeal squamous cell carcinomas：A systematic review and meta-analysis[J]. Int J Cancer, 2017, 140(5):1186-1198. doi: 10.1002/ijc.v140.5 URL
[29]	Larsson GL, Helenius G. Digital droplet PCR (ddPCR) for the detection and quantification of HPV 16, 18, 33 and 45 -a short report[J]. Cell Oncol, 2017, 40(5):521-527. doi: 10.1007/s13402-017-0331-y URL
[30]	Kim KY, Lewis Jr JS, Chen Z. Current status of clinical testing for human papillomavirus in oropharyngeal squamous cell carcinoma[J]. J Pathol Clin Res, 2018, 4(4):213-226. doi: 10.1002/cjp2.2018.4.issue-4 URL
[31]	Thammaiah S, Venkobarao MC, Sathyavanthan H, et al. Quantitative polymerase chain reaction-based detection of HPV 16 E6 and E7 DNA in oral squamous cell carci-noma[J]. J Oral Pathol Med, 2018, 47(9):873-879. doi: 10.1111/jop.12770 pmid: 30059164
[32]	Guo M, Gong Y, Deavers M, et al. Evaluation of a comm-ercialized in situ hybridization assay for detecting human papillomavirus DNA in tissue specimens from patients with cervical intraepithelial neoplasia and cervical carcinoma[J]. J Clin Microbiol, 2008, 46(1):274-280. doi: 10.1128/JCM.01299-07 URL
[33]	Paver EC, Currie AM, Gupta R, et al. Human papilloma virus related squamous cell carcinomas of the head and neck：Diagnosis, clinical implications and detection of HPV[J]. Pathology, 2020, 52(2):179-191. doi: 10.1016/j.pathol.2019.10.008 URL
[34]	Liu CX, Mann D, Sinha UK, et al. The molecular mechanisms of increased radiosensitivity of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC)：An extensive review[J]. Le J D'oto Rhino Laryngol De Chir Cervico Faciale, 2018, 47(1):59.
[35]	Wong KS, Krane JF, Jo VY. Heterogeneity of p16 immun-ohistochemistry and increased sensitivity of RNA in situ hybridization in cytology specimens of HPV-related head and neck squamous cell carcinoma[J]. Cancer Cytopathol, 2019, 127(10):632-642. doi: 10.1002/cncy.v127.10 URL
[36]	Singh V, Husain N, Akhtar N, et al. p16 and p53 in HPV-positive versus HPV-negative oral squamous cell carcinoma：Do pathways differ？[J]. J Oral Pathol Med, 2017, 46(9):744-751. doi: 10.1111/jop.2017.46.issue-9 URL
[37]	Chung CH, Zhang Q, Kong CS, et al. p16 protein exp-ression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma[J]. J Clin Oncol, 2014, 32(35):3930-3938. doi: 10.1200/JCO.2013.54.5228 URL
[38]	Sun PM, Song YY, Ruan GY, et al. Clinical validation of the PCR-reverse dot blot human papillomavirus genotyping test in cervical lesions from Chinese women in the Fujian Province：A hospital-based population study[J]. J Gynecol Oncol, 2017, 28(5):e50. doi: 10.3802/jgo.2017.28.e50 URL
[39]	Dong BH, Chen LH, Lin WY, et al. Cost-effectiveness and accuracy of cervical cancer screening with a high-risk HPV genotyping assay vs a nongenotyping assay in China：An observational cohort study[J]. Cancer Cell Int, 2020, 20:421. doi: 10.1186/s12935-020-01512-4

引物名称	引物序列（5'-3'）	扩增长度/bp
广谱引物1: CPI/Ⅱ		188
正向: CPI	TTA TCW TAT GCC CAY TGT ACC AT
反向: CPII	ATG TTA ATW SAG CCW CCA AAA TT
广谱引物2: GP5⁺/6⁺		150
正向: GP5⁺	TTT GTT ACT GTG GTA GAT ACT AC
反向: GP6⁺	GAA AAA TAA ACT GTA AAT CAT ATT C
广谱引物3: MY09/11		450
正向: MY11	GCM CAG GGW CAT AAY AAT GG
反向: MY09	CGT CCM ARR GGA WAC TGA TC

引物名称	引物序列（5'-3'）	扩增长度/bp
广谱引物1: CPI/Ⅱ		188
正向: CPI	TTA TCW TAT GCC CAY TGT ACC AT
反向: CPII	ATG TTA ATW SAG CCW CCA AAA TT
广谱引物2: GP5⁺/6⁺		150
正向: GP5⁺	TTT GTT ACT GTG GTA GAT ACT AC
反向: GP6⁺	GAA AAA TAA ACT GTA AAT CAT ATT C
广谱引物3: MY09/11		450
正向: MY11	GCM CAG GGW CAT AAY AAT GG
反向: MY09	CGT CCM ARR GGA WAC TGA TC

基本信息	HPV相关性[n(%)]	非HPV相关性[n(%)]	合计/例	比例	P值	基本信息	HPV相关性[n(%)]	非HPV相关性[n(%)]	合计/例	比例	P值
性别					0.47	蒙古族	0	8(100)	8	0∶8.0
男	8(5.52)	137(94.48)	145	1∶17.1		满族	0	3(100)	3	0∶3.0
女	6(8.00)	69(92.00)	75	1∶11.5		外国血统	0	1(100)	1	0∶1.0
发病年龄/岁						居住地					0.35
平均值±标准差	61.00±9.36	59.02±10.30			0.49	城市	10(7.63)	121(92.37)	131	1∶12.1
中位数	62.5(46~72)	59.0(26~83)				农村	4(4.49)	85(95.51)	89	1∶21.3
(最小值~最大值)						婚姻状况					0.37
20~29	0	3(100)	3	0∶3.0	0.07	已婚	13(6.37)	191(93.63)	204	1∶14.7
30~39	0	6(100)	6	0∶6.0		离婚	0	9(100)	9	0∶9.0
40~49	4(18.18)	18(81.82)	22	1∶4.5		丧偶	1(25.00)	3(75.00)	4	1∶3.0
50~59	1(1.20)	82(98.80)	83	1∶82.0		未婚	0	3(100)	3	0∶3.0
60~69	5(6.94)	67(93.06)	72	1∶13.4		血型					0.52
70~79	4(12.50)	28(87.50)	32	1∶7.0		A	2(3.23)	60(96.77)	62	1∶30.0
80~89	0	2(100)	2	0∶2.0		B	5(7.04)	66(92.96)	71	1∶13.2
民族					0.80	AB	3(11.54)	23(88.46)	26	1∶7.7
汉族	14(7.07)	184(92.93)	198	1∶13.1		O	4(6.56)	57(93.44)	61	1∶14.3
朝鲜族	0	10(100)	10	0∶10.0		总计	14(6.36)	206(93.64)	220	1∶14.7

基本信息	HPV相关性[n(%)]	非HPV相关性[n(%)]	合计/例	比例	P值	基本信息	HPV相关性[n(%)]	非HPV相关性[n(%)]	合计/例	比例	P值
性别					0.47	蒙古族	0	8(100)	8	0∶8.0
男	8(5.52)	137(94.48)	145	1∶17.1		满族	0	3(100)	3	0∶3.0
女	6(8.00)	69(92.00)	75	1∶11.5		外国血统	0	1(100)	1	0∶1.0
发病年龄/岁						居住地					0.35
平均值±标准差	61.00±9.36	59.02±10.30			0.49	城市	10(7.63)	121(92.37)	131	1∶12.1
中位数	62.5(46~72)	59.0(26~83)				农村	4(4.49)	85(95.51)	89	1∶21.3
(最小值~最大值)						婚姻状况					0.37
20~29	0	3(100)	3	0∶3.0	0.07	已婚	13(6.37)	191(93.63)	204	1∶14.7
30~39	0	6(100)	6	0∶6.0		离婚	0	9(100)	9	0∶9.0
40~49	4(18.18)	18(81.82)	22	1∶4.5		丧偶	1(25.00)	3(75.00)	4	1∶3.0
50~59	1(1.20)	82(98.80)	83	1∶82.0		未婚	0	3(100)	3	0∶3.0
60~69	5(6.94)	67(93.06)	72	1∶13.4		血型					0.52
70~79	4(12.50)	28(87.50)	32	1∶7.0		A	2(3.23)	60(96.77)	62	1∶30.0
80~89	0	2(100)	2	0∶2.0		B	5(7.04)	66(92.96)	71	1∶13.2
民族					0.80	AB	3(11.54)	23(88.46)	26	1∶7.7
汉族	14(7.07)	184(92.93)	198	1∶13.1		O	4(6.56)	57(93.44)	61	1∶14.3
朝鲜族	0	10(100)	10	0∶10.0		总计	14(6.36)	206(93.64)	220	1∶14.7

临床情况	HPV相关性[n(%)]	非HPV相关性[n(%)]	合计/例	比例	P值
病史时长(t)/月					0.58
0<t≤6	10(5.62)	168(94.38)	178	1∶16.8
6<t≤12	3(12.50)	21(87.50)	24	1∶7.0
12<t≤24	1(12.50)	7(87.50)	8	1∶7.0
24<t≤36	0	6(100)	6	0∶6.0
t>36	0	4(100)	4	0∶4.0
首发/复发					0.70
首发	13(6.22)	196(93.78)	209	1∶15.1
复发	1(9.09)	10(90.91)	11	1∶10.0
发病部位					0.84
舌前2/3	7(8.43)	76(91.57)	83	1∶10.9
唇黏膜	0	15(100)	15	0∶15.0
颊黏膜	2(9.52)	19(90.48)	21	1∶9.5
口底	3(6.67)	42(93.33)	45	1∶14.0
牙龈	2(3.77)	51(96.23)	53	1∶25.5
硬腭	0	2(100)	2	0∶2.0
磨牙后区	0	1(100)	1	0∶1.0
自觉症状					0.97
无明显症状	2(7.14)	26(92.86)	28	1∶13.0
疼痛	11(6.32)	163(93.68)	174	1∶14.8
舌体运动受限	0	15(100)	15	0∶15.0
破溃出血	1(7.14)	13(92.86)	14	1∶13.0
麻木	0	5(100)	5	0∶5.0
不适	0	3(100)	3	0∶3.0
张口受限	0	1(100)	1	0∶1.0
发音不清	0	1(100)	1	0∶1.0
不良嗜好
吸烟	7(5.60)	118(94.40)	125	1∶16.9	0.59
不吸烟	7(7.37)	88(92.63)	95	1∶12.6
饮酒	5(5.56)	85(94.44)	90	1∶17.0	0.68
不饮酒	9(6.92)	121(93.08)	130	1∶13.4
只吸烟	2(4.76)	40(95.24)	42	1∶20.0	0.79
只饮酒	0	7(100)	7	0∶7.0
吸烟、饮酒	5(6.02)	78(93.98)	83	1∶15.6
不吸烟、不喝酒	7(7.95)	81(92.05)	88	1∶11.6
系统病史					0.69
健康	10(7.58)	122(92.42)	132	1∶12.2
心脑血管疾病	2(2.90)	67(97.10)	69	1∶33.5
糖尿病	3(15.79)	16(84.21)	19	1∶5.3
消化系统疾病	0	5(100)	5	0∶5.0
癌症后	0	3(100)	3	0∶3.0
肺部疾病	0	4(100)	4	0∶4.0
肾脏疾病	0	2(100)	2	0∶2.0
血液疾病	0	1(100)	1	0∶1.0
其他	0	1(100)	1	0∶1.0
肿物形态					0.70
浸润型	7(8.05)	80(91.95)	87	1∶11.4
外生型	3(4.92)	58(95.08)	61	1∶19.3
溃疡型	4(5.56)	68(94.44)	72	1∶17.0
T分期					0.22
T1	5(13.89)	31(86.11)	36	1∶6.2
T2	4(4.30)	89(95.70)	93	1∶22.3
T3	3(6.67)	42(93.33)	45	1∶14.0
T4	2(4.35)	44(95.65)	46	1∶22.0
总计	14(6.36)	206(93.64)	220	1∶14.7

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