To characterize programmed death–ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) positivity for locally aggressive or regionally metastatic cutaneous head and neck squamous cell carcinoma (cHNSCC).
Study Design
Retrospective chart review, followed by immunohistochemical staining of archived tumor specimens.
Setting
Tertiary academic medical center.
Subjects and Methods
After identification of 101 patients treated surgically for locally advanced or regionally metastatic cHNSCC, archived tissue was stained and graded for PD-L1 expression in addition to TIL presence. Cross-tabulation was performed to examine the association between either of these variables and clinicopathologic features and outcomes.
Results
A total of 101 patients met inclusion criteria, but archived tissue was available only for 83 (31 primaries, 52 metastases). The majority of primary tumors demonstrated grade 1 PD-L1 staining, while grade 2 staining was more likely for metastases. Neither high- nor low-grade PD-L1 expression correlated with any clinicopathologic variable for primary tumors. However, for metastases, high-grade staining was significantly associated with regional recurrence (15 of 19, P = .02). TILs were present for 65% of primary tumors and 90% of regional metastases but did not correlate with any clinicopathologic variables.
Conclusion
Diffuse expression of PD-L1 in this study highlights the possibility of using immunotherapy in the form of programmed death 1/PD-L1 blockade to improve treatment for this devastating disease. However, further studies are needed to clarify the significance of PD-L1 expression and TIL positivity for locally advanced or regionally metastatic cHNSCC.
KrausDHCarewJFHarrisonLB.Regional lymph node metastasis from cutaneous squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 1998;124:582-587.
2.
Jambusaria-PahlajaniAKanetskyPAKariaPSet al. Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system. JAMA Dermatol. 2013;149:402-410.
3.
GiviBAndersenPEDiggsBSWaxMKGrossND. Outcome of patients treated surgically for lymph node metastases from cutaneous squamous cell carcinoma of the head and neck. Head Neck. 2011;33:999-1004.
Jambusaria-PahlajaniAMillerCJQuonHSmithNKleinRQSchmultsCD. Surgical monotherapy versus surgery plus adjuvant radiotherapy in high-risk cutaneous squamous cell carcinoma. Dermatol Surg. 2009;35:574-584.
6.
VenessMJMorganGJPalmeCEGebskiV. Surgery and adjuvant radiotherapy in patients with cutaneous head and neck squamous cell carcinoma metastatic to lymph nodes: combined treatment should be considered best practice. Laryngoscope. 2005;115:870-875.
7.
SweenyLZimmermanTCarrollWRSchmalbachCEDayKERosenthalEL. Head and neck cutaneous squamous cell carcinoma requiring parotidectomy: prognostic indicators and treatment selection. Otolaryngol Head Neck Surg. 2014;150:610-617.
8.
O’BrienCJMcNeilEBMcMahonJDPathakILauerCSJacksonMA. Significance of clinical stage, extent of surgery, and pathologic findings in metastatic cutaneous squamous carcinoma of the parotid gland. Head Neck. 2002;24:417-422.
9.
OddoneNMorganGJPalmeCEet al. Metastatic cutaneous squamous cell carcinoma of the head and neck: the Immunosuppression, Treatment, Extranodal spread, and Margin status (ITEM) prognostic score to predict outcome and the need to improve survival. Cancer. 2009;115:1883-1891.
10.
MakkiFMendezATaylorMet al. Prognostic factors for metastatic cutaneous squamous cell carcinoma of the parotid. J Otolaryngol Head Neck Surg. 2013;42:14.
11.
AndruchowJLVenessMJMorganGJet al. Implications for clinical staging of metastatic cutaneous squamous carcinoma of the head and neck based on a multicenter study of treatment outcomes. Cancer. 2006;106:1078-1083.
12.
AmoilsMLeeCSSunwooJet al. Node-positive cutaneous squamous cell carcinoma of the head and neck: survival, high-risk features, and adjuvant chemoradiotherapy outcomes. Head Neck. 2017;39:881-885.
13.
MizrachiAHadarTRabinovicsNet al. Prognostic significance of nodal ratio in cutaneous squamous cell carcinoma of the head and neck. Eur Arch Otorhinolaryngol. 2013;270:647-653.
14.
TanvetyanonTPadhyaTMcCaffreyJet al. Postoperative concurrent chemotherapy and radiotherapy for high-risk cutaneous squamous cell carcinoma of the head and neck. Head Neck. 2015;37:840-845.
SchmidtCMartinJMKhooEPlankAGriggR. Outcomes of nodal metastatic cutaneous squamous cell carcinoma of the head and neck treated in a regional center. Head Neck. 2015;37:1808-1815.
17.
ChoYAYoonHJLeeJIHongSPHongSD. Relationship between the expressions of PD-L1 and tumor-infiltrating lymphocytes in oral squamous cell carcinoma. Oral Oncol. 2011;47:1148-1153.
18.
PedoeemAAzoulay-AlfaguterIStrazzaMSilvermanGJMorA. Programmed death-1 pathway in cancer and autoimmunity. Clin Immunol. 2014;153:145-152.
19.
ChenJFengYLuLet al. Interferon-gamma-induced PD-L1 surface expression on human oral squamous carcinoma via PKD2 signal pathway. Immunobiology. 2012;217:385-393.
20.
KangMJKimKMBaeJSet al. Tumor-infiltrating PD1-positive lymphocytes and FoxP3-positive regulatory T cells predict distant metastatic relapse and survival of clear cell renal cell carcinoma. Transl Oncol. 2013;6:282-289.
21.
MuenstSSoysalSDGaoFObermannECOertliDGillandersWE. The presence of programmed death 1 (PD-1)–positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat. 2013;139:667-676.
22.
TakiarVBurksJKSulmanEPet al. PD-1 levels correlate with lymph node positivity in patients with squamous cell carcinoma of the cervix. Int J Radiat Oncol Biol Phys. 2014;90:S479-S480.
23.
ZandbergDPStromeSE. The role of the PD-L1:PD-1 pathway in squamous cell carcinoma of the head and neck. Oral Oncol. 2014;50:627-632.
24.
MalmIJBrunoTCFuJet al. Expression profile and in vitro blockade of programmed death-1 in human papillomavirus-negative head and neck squamous cell carcinoma. Head Neck. 2015;37:1088-1095.
25.
UkpoOCThorstadWLLewisJSJr.B7-H1 expression model for immune evasion in human papillomavirus-related oropharyngeal squamous cell carcinoma. Head Neck Pathol. 2013;7:113-121.
26.
TaubeJMAndersRAYoungGDet al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4:127ra137.
27.
GrossoJInzunzaDWuQet al. Programmed death-ligand 1 (PD-L1) expression in various tumor types. J Immunother Cancer. 2013;1(suppl 1):P53.
28.
FalchookGSLeidnerRStankevichEet al. Responses of metastatic basal cell and cutaneous squamous cell carcinomas to anti-PD1 monoclonal antibody REGN2810. J Immunother Cancer. 2016;4:70.
29.
PapadopoulosKPOwonikokoTKJohnsonMLet al. REGN2810: a fully human anti-PD-1 monoclonal antibody, for patients with unresectable locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC)—initial safety and efficacy from expansion cohorts (ECs) of phase I study [abstract 9503]. J Clin Oncol. 2017;35(suppl).
30.
ChangALKimJLucianoRSullivan-ChangLColevasAD. A case report of unresectable cutaneous squamous cell carcinoma responsive to pembrolizumab, a programmed cell death protein 1 inhibitor. JAMA Dermatol. 2016;152:105-106.
31.
ChangJZhuGACheungCLiSKimJChangAL. Association between programmed death ligand 1 expression in patients with basal cell carcinomas and the number of treatment modalities. JAMA Dermatol. 2017;153:285-290.
32.
SlaterNAGoogePB. PD-L1 expression in cutaneous squamous cell carcinoma correlates with risk of metastasis. J Cutan Pathol. 2016;43:663-670.
33.
WangAWangHYLiuYet al. The prognostic value of PD-L1 expression for non-small cell lung cancer patients: a meta-analysis. Eur J Surg Oncol. 2015;41:450-456.
34.
MuCYHuangJAChenYChenCZhangXG. High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol. 2011;28:682-688.
35.
SongMChenDSLuBet al. PTEN loss increases PD-L1 protein expression and affects the correlation between PD-L1 expression and clinical parameters in colorectal cancer. PloS one. 2013;8:e65821.
36.
KonishiJYamazakiKAzumaMKinoshitaIDosaka-AkitaHNishimuraM. B7-H1 expression on non–small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res. 2004;10:5094-5100.
37.
VassilakopoulouMAvgerisMVelchetiVet al. Evaluation of PD-L1 expression and associated tumor-infiltrating lymphocytes in laryngeal squamous cell carcinoma. Clin Cancer Res. 2016;22:704-713.
38.
GandiniSMassiDMandalaM. PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2016;100:88-98.
39.
ChenJJiangCCJinLZhangXD. Regulation of PD-L1: a novel role of pro-suvival signalling in cancer. Ann Oncol. 2016;27:409-416.
40.
TaubeJMKleinABrahmerJRet al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20:5064-5074.
41.
BerrySTaubeJM. Innate vs adaptive: PD-L1 mediated immune resistance by melanoma. Oncoimmunology. 2015;4:e1029704.
42.
De MeulenaereAVermassenTAspeslaghSVandecasteeleKRotteySFerdinandeL. TILs in head and neck cancer: ready for clinical implementation and why (not)?Head Neck Pathol. 2017;11:354-363.
43.
GalonJMlecnikBBindeaGet al. Towards the introduction of the “Immunoscore” in the classification of malignant tumours. J Pathol. 2014;232:199-209.
44.
GoodenMJde BockGHLeffersNDaemenTNijmanHW. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer. 2011;105:93-103.
45.
De MeulenaereAVermassenTAspeslaghSet al. Prognostic markers in oropharyngeal squamous cell carcinoma: focus on CD70 and tumour infiltrating lymphocytes. Pathology. 2017;49:397-404.
46.
DengLLiangHBurnetteBet al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124:687-695.
