In 2010, prevalence of oral HPV infection in the United States was estimated to be 6.9% and HPV16 oral infection was estimated to be 1% [10]. In another analysis, prevalence of high risk HPV oral infection was estimated to be significantly higher in males than females (7.3% vs. 1.4%) and males with same-sex partner(s) had even higher infection rate [11]. Among more than 150 HPV serotypes, HPV16 accounts for the majority of HPV associated SCCHN [12] and it primarily affects oropharynx by infecting lymphoid epithelium [13]. The proportion of HPV-positive disease among oropharyngeal cancer has recently increased over time regardless of sex and race, whereas the overall prevalence of SCCHN has remained stable or slightly decreased. In South Korea, prevalence of HPV varied widely depending on the disease site, ranging from 5.3% to 14.5% in oral cavity and from 23.5% to 73.1% in oropharynx [14].

Compared to HPV-negative SCCHN, HPV related SCCHN predominantly affects people with younger age, Caucasian race, and a relatively higher socioeconomic status [8,15]. Association with tobacco, alcohol use, and poor dentition is not very strong in HPV related SCCHN. Instead, there is a positive relationship with history of marijuana use [12]. As the viral infection is sexually transmitted, patients with HPV-positive SCCHN tend to have more lifetime sexual partners and more likelihood of having experience of oral-genital or oralanal contact [15,16]. In a recent cross-sectional study, prophylactic HPV vaccination has shown to be associated with significantly lower risk of having high risk HPV oral infection [17], which raises hope that population wide HPV vaccination program may end the epidemic of HPV related SCCHN in near future.

Once transmitted through close contact, HPV invades into micro-wounds of mucosa, and infects the cells in the basal layer of squamous epithelium. E6 and E7 oncoproteins from early phase of HPV life cycle inactivate two key cell cycle regulators, p53 and pRb [18]. E6 binds with E6-associated protein that has ubiquitin ligase activity, which degrades p53, a key tumor suppressor. On the other hand, E7 competitively binds to pRb, releasing transcription factor E2F, which migrates to nucleus and triggers transcription of several genes involved in cell cycle progression and inhibition of apoptosis (Fig. 1) [19]. Both E6 and E7 oncoproteins consequently conduce to abrogation of cell cycle checkpoints, proliferation of cells, and thus, amplification of viral genome. Cells that are persistently infected with HPV continue to propagate, uncoupled from differentiation. These uninhibited cell divisions are prone to accumulated DNA damages and chromosomal abnormalities, which increase oncogenic potential. Although most of the HPV infected cells are removed by immune response in 1 to 2 years, failure to clear the HPV infection results in development of cancer in decades [20,21].

Release of E2F mediated by E7 increases expression p16, which is used as a surrogate biomarker for HPV related oropharyngeal cancer (Fig. 2) [22]. Immunohistochemistry (IHC) for p16 in oropharyngeal SCCs have high sensitivity and specificity and can be reliably used to diagnose HPV related SCCHN [23]. For non-oropharyngeal SCCs, prevalence of HPV related SCCHN is much lower which makes p16 IHC unreliable. HPV DNA detection by polymerase chain reaction has been regarded as the gold standard, but recently direct visualization using RNA probe (RNA in situ hybridization) has been shown to be highly sensitive and specific in detecting transcriptionally active HPV in oropharyngeal cancers [24].

Comprehensive genomic analysis of SCCHN in The Cancer Genome Atlas (TCGA) demonstrated significant contrasts in the distribution of genomic alterations between HPV-positive and negative SCCHN [25]. HPV-positive SCCHN harbored frequent alterations of PIK3CA and TNF receptor-associated factor 3 (TRAF3), whereas mutations or copy number variations of TP53, cyclin-dependent kinase inhibitor 2A (CDKN2A), MYC, and cyclin D1 (CCND1) predominantly affected HPV-negative SCCHN. TRAF3, frequently affected in HPV-positive diseases, plays a critical role in innate immune defense, and cells lacking TRAF3 has impaired interferon response against viral infection [26]. Focal amplifications of receptor tyrosine kinase, such as EGFR, ERBB2, and fibroblast growth factor receptor 1 (FGFR1), favored HPV-negative disease. The most common genomic alteration in HPV-positive SCCHN was a helical domain mutation of PIK3CA which encodes a subunit of class 1 phosphoinositide 3-kinase (PI3K) [27]. PI3K receives a signal from cell surface receptors, such as EGFR, and attaches a phosphate group to the inositol head of phosphatidylinositol 4,5-bisphosphate (PIP2) in the cell membrane, converting it to phosphatidylinositol 3,4,5-triphosphate (PIP3) [28]. PIP3, in turn, sends down the signal of cellular growth through the cascade of Akt/protein kinase B and mammalian target of rapamycin (mTOR) [29]. In the TCGA data, mutations in the PI3KCA were concentrated in the frequent ‘hotspot’ mutations (E542, E545 in the helical domains) in HPV-positive SCCHN, whereas mutations were more spread out in HPV-negative diseases [25,27,30,31].

Patients with HPV-positive SCCHN tend to have less smaller primary tumors, larger cystic lymph node, better performance status, and better prognosis compared to patients with HPV negative SCCHN [8,32]. In vitro studies also have shown that HPV infected cancer cells are more prone to apoptosis in response to DNA damaging agents [33,34]. In a prospective cohort study of oropharyngeal and laryngeal SCC, patients with HPV-positive disease had longer progression free survival (PFS) and overall survival (OS), and the improved survival persisted after careful adjustment for age, tumor stage, and Eastern Cooperative Oncology Group (ECOG) performance status. Considering the sensitivity to treatment and better prognosis, patients with HPV-positive SCCHN may benefit from less toxic, de-intensified treatment strategy, which should be a focus of future studies. Differences of disease characteristics between HPV-positive and negative SCCHN are summarized in Table 1.

About 40% of the patients with SCCHN initially present with early stage, localized disease [35]. These patients can be effectively treated with a single modality therapy, either curative intent surgery or definitive radiation, depending on tumor location and the institution’s experience. While surgery has been the traditional treatment for these cancers, definitive radiation can safely replace surgery with comparable oncologic outcomes, and achieve better functional outcomes in larynx, hypopharynx, or oropharynx.

For patients with locally advanced SCCHN, multi-modality therapy involving at least two different modalities are required. If upfront surgery is offered, post-operative (adjuvant) radiation therapy should be considered with or without concurrent chemotherapy. Definitive radiotherapy with concurrent chemotherapy is also widely used, but it is not preferred upfront approach for oral cavity SCCHN for inferior oncologic outcomes and higher complication rates [36]. Recent developments in minimally invasive surgery, such as transoral robotic surgery (TORS), has enabled surgeons to gain easier access to certain areas of oropharynx such as base of tongue, which traditionally required an extensive procedure involving split of mandible. TORS has been widely adopted for treatment of HPV positive oropharyngeal SCC, as patients are expected liver longer and more motivated to avoid late consequences from radiotherapy and/or chemotherapy. A small randomized phase 2 trial comparing upfront TORS versus definitive (chemo)radiotherapy demonstrated that upfront radiotherapy was slightly better in terms of swallowing related quality of life (QOL) measure, but the difference was not clinically meaningful [37]. More clinical trials comparing definitive radiation and TORS are on-going in early stage oropharyngeal SCCs.

Chemotherapy alters DNA binding and creates reactive free radicals, enhancing the cytotoxic effect of radiation [38]. Besides, chemotherapy inhibits DNA repair and recovery from potentially lethal or sub-lethal damages in between radiation sessions [39]. Several clinical trials have confirmed that concomitant administration of chemoradiation significantly prolongs survival for locally advanced SCCHN, compared to radiation alone, or sequential administration of chemotherapy and radiation [40-45]. Concurrent chemoradiation was superior to radiation alone in postoperative settings as well for patients who have high risk pathologic features such as positive margins and/or extranodal extension [46,47]. Based on these findings, concurrent chemoradiation has been widely adopted for the treatment of locally advanced SCCHN.

Induction chemotherapy prior to definitive radiation or chemoradiation has been contemplated for long time to achieve immediate response and decrease risk of distant metastasis. However, a series of clinical trials of induction chemotherapy compared to upfront concurrent chemoradiation failed to demonstrate superior survival, even in the patients with high risk patients with bulky tumor or lymph node [48-50]. Furthermore, toxicities from induction chemotherapy may delay or interrupt definitive chemoradiation. Neoadjuvant chemotherapy prior to definitive surgery has been evaluated in a large phase 3 randomized trial in oral cavity cancers, but failed to demonstrate any overall or disease-free survival benefit [51]. Therefore, induction or neoadjuvant chemotherapy is not considered a standard treatment for locally advanced SCCHN. Nonetheless, for patients with bulky, symptomatic primary or nodal disease, induction chemotherapy can be started if the initiation of chemoradiation is delayed.

Cetuximab, an anti-EGFR antibody, has been used as a concurrent therapy with radiation. Cetuximab plus radiation demonstrated OS and PFS benefits compared to radiation alone for patients with locally advanced SCCHN [52], and cetuximab was viewed as a way to decrease treatment-related toxicity in definitive concurrent chemoradiation, especially for HPV related SCCHN patients who have excellent prognosis. Two large randomized clinical trials evaluated concurrent cetuximab in comparison to concurrent cisplatin with definitive radiotherapy in locoregionally advanced SCCHN with intent of demonstrating non-inferiority of outcomes. However, to the contrary of the expectations, concurrent cetuximab with radiation was shown to have worse OS and PFS in both studies [53,54]. For HPV negative SCCHN, it is not clear whether cisplatin would be still superior to cetuximab as a concurrent treatment, but cisplatin remains to be the standard concurrent systemic agent.

Although majority of patients with SCCHN present with locally advanced disease, approximately 30% to 40% of patients develop recurrence even with intensive multimodality treatment [45]. For selected patients with locoregional recurrence, surgical salvage or re-irradiation can be attempted, but it has not been very successful [55]. Recent retrospective case series suggests that surgical salvage for locoregional and distant failure in oropharyngeal SCC can be associated with improved OS in both HPV-positive and -negative patients, although the benefit in oligometastatic disease was largely limited to HPV positive disease [56]. Even after recurrent or metastatic disease, patients with HPV positive SCCHN have longer OS compared to the ones with HPV negative SCCHN [9,57]. However, median disease free survival after salvage surgery remains poor for both HPV-positive and HPV-negative patients [58]. Metastatic and/or recurrent disease not amenable for surgical salvage can be treated with systemic therapy which includes cytotoxic chemotherapy, targeted therapy and immune checkpoint inhibitors.

Combination of platinum, fluorouracil, and cetuximab (EXTREME regimen), which was shown to prolong OS to 10.1 months, used to be the standard of care for the 1st line treatment of recurrent and/or metastatic SCCHN [59]. Cetuximab has a modest single agent activity for SCCHN when used after failing prior platinum-based chemotherapy [60]. Generally, conventional systemic treatment options are limited as responses are generally short-lived and not durable with high toxicity toll. Immune checkpoint inhibitors bind to molecules that mediates immune tolerance such as programmed death 1 (PD1) receptors which are located on the membrane of T cells, B cells, and natural killer cells. When bound with ligands on tumor cell surface, these immune checkpoint molecules inhibit cancer cell apoptosis, and down-regulate cytotoxic T cell function [61,62]. Immune checkpoint inhibitors re-stimulate the immune function to target cancer cells.

Anti-PD1 antibodies have been evaluated in recurrent/metastatic (RM)-SCCHN patients in the 2nd line setting after progression on platinum containing chemotherapy. Pembrolizumab demonstrated overall response rate of 16% in a single arm study, which led to accelerated approval of pembrolizumab by the U.S. Food and Drug Administration. This trial included even patients with no programmed death-ligand 1 (PD-L1) expression, and 12% of these patients still demonstrated objective responses. Response rates were comparable between HPV-positive and negative groups [63]. Nivolumab was evaluated in a phase 3 randomized clinical trial, compared to a single agent therapy of investigators’ choice. This study demonstrated significant OS benefit with 1-year survival rate of 36% versus 16.6% [64]. Of note, patients who received nivolumab had better QOL outcome in terms of social function, fatigue, dyspnea, pain, and appetite. Median time to deterioration in several domains of QOL was significantly longer with nivolumab than with standard chemotherapy [65]. Nivolumab is currently approved by the U.S. Food and Drug Administration for the treatment of recurrent or metastatic SCCHN after progression on platinum-based chemotherapy.

More recently, pembrolizumab with or without chemotherapy was evaluated in the 1st line RM-SCCHN in comparison to the EXTREME regimen in a randomized, phase 3 clinical trial [66]. The study demonstrated that pembrolizumab alone has significant OS benefit in patients with PD-L1 expressing tumor (defined by combined positive score > 1) and combination of pembrolizumab and chemotherapy has significant OS benefit in all patients. Pembrolizumab with or without chemotherapy was approved based on this study for the 1st line use in RM-SCCHN. Of note, overall response rate of pembrolizumab alone was significantly lower than conventional chemotherapy, while that of pembrolizumab plus chemotherapy was comparable to the chemotherapy. This implies that pembrolizumab and chemotherapy combination might be more beneficial for or patients with bulky disease who would benefit from rapid reduction of tumor burden, regardless of PD-L1 expression status.

Approval of immune checkpoint inhibitors in the 1st line treatment of RM-SCCHN limits options for 2nd line treatment. A study suggests chemotherapy would be still active and viable option for patients who received immune checkpoint inhibitors in the first line setting. Objective response was seen in 37.5% of 16 patients who received cetuximab after anti-PD1 failure and 44.4% of 27 patients who received chemotherapy based regimen [67].