Next Article in Journal
Cellular and Molecular Effects of Eribulin in Preclinical Models of Hematologic Neoplasms
Previous Article in Journal
Exercise and Bone Health in Cancer: Enemy or Ally?
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 14
Issue 24
10.3390/cancers14246079
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Current Insights and Progress in the Clinical Management of Head and Neck Cancer

by
Mariana Neves Amaral
1,2,
Pedro Faísca
3,
Hugo Alexandre Ferreira
2,
Maria Manuela Gaspar
1,* and
Catarina Pinto Reis
1,2,*
1
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal
2
Instituto de Biofísica e Engenharia Biomédica (IBEB), Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisbon, Portugal
3
Laboratório Veterinário, Faculdade de Medicina Veterinária—Universidade Lusófona de Humanidades e Tecnologias/DNAtech, 1749-024 Lisbon, Portugal
*
Authors to whom correspondence should be addressed.
Cancers 2022, 14(24), 6079; https://doi.org/10.3390/cancers14246079
Submission received: 13 November 2022 / Revised: 5 December 2022 / Accepted: 6 December 2022 / Published: 10 December 2022
Browse Figures
Versions Notes

Abstract

:

Simple Summary

Head and neck cancer (HNC) incidence has been steadily increasing since the 1990s. While the multimodal treatment approach for localized HNC is well established and renders a good treatment response, this is not the case for advanced or recurrent/metastatic HNC. Most patients present HNC at an advanced stage at the time of diagnosis, and the lack of effective treatment results in the death of half of patients diagnosed with advanced or recurrent/metastatic HNC. This review aims to present a current summary of the epidemiology, diagnosis, histopathology, current treatment and novel treatment approaches for HNC.

Abstract

Head and neck cancer (HNC), also known as the cancer that can affect the structures between the dura mater and the pleura, is the 6th most common type of cancer. This heterogeneous group of malignancies is usually treated with a combination of surgery and radio- and chemotherapy, depending on if the disease is localized or at an advanced stage. However, most HNC patients are diagnosed at an advanced stage, resulting in the death of half of these patients. Thus, the prognosis of advanced or recurrent/metastatic HNC, especially HNC squamous cell carcinoma (HNSCC), is notably poorer than the prognosis of patients diagnosed with localized HNC. This review explores the epidemiology and etiologic factors of HNC, the histopathology of this heterogeneous cancer, and the diagnosis methods and treatment approaches currently available. Moreover, special interest is given to the novel therapies used to treat HNC subtypes with worse prognosis, exploring immunotherapies and targeted/multi-targeted drugs undergoing clinical trials, as well as light-based therapies (i.e., photodynamic and photothermal therapies).

Graphical Abstract

1. Introduction

Head and neck cancer (HNC), the 6th most common type of cancer, also commonly known generating the malignant tumours between the dura mater and the pleura, affects structures such as the naso-, oro- and hypopharynx, larynx, nasal cavity, oral cavity, the floor of the mouth, the palate, tongue, tonsils, oesophagus, middle ear, paranasal sinuses, salivary glands, thyroid gland skin (melanoma), etc. [1,2,3,4,5,6]. Furthermore, the histopathology of HNC varies according to the structures affected, and thus HNC is also characterized as presenting molecular heterogeneity. Due to the low awareness of HNC, most cases are identified at advanced stages, resulting in death for half of all the patients diagnosed with this malignancy [7].

2. Epidemiology and Etiology

As mentioned, HNC is a diverse family of cancers affecting this very broad anatomical region. However, as a whole, HNC is one of the mostly occurring frequent malignancies in the world [8,9]. Yearly, HNC accounts for more than 830,000 cases, which translates into 8% of all cancer diagnosis, and at least 430,000 deaths worldwide [3,4,5,10]. These numbers are expected to rise, as the HNC incidence has been steadily increasing since the 1990s in many countries, and this seems to be the trend worldwide [11,12,13,14]. The incidence and mortality of each malignancy comprised in the HNC group varies according to the exposure to risk factors, demographics and geography, and the epidemiologic data regarding the most prevalent subtypes of HNC in 2020 is presented in Figure 1 [8]. Although less prevalent, lymphomas are the second most common group of malignancies affecting the head and neck, next to malignancies of epithelial origin, accounting for 15% of all HNC diagnosis [15,16,17,18]. Most head and neck lymphomas affect the anatomical structures of the Waldeyer’s ring (base of the tongue, soft palate, pharynx and the tonsils) [17,18,19]. Sarcomas are a rare type of cancer arising from bone and soft tissues. They represent 1% of all cancer diagnoses, and only 10% of sarcomas occur in the head and neck, thus constituting a rare subtype of HNC [20,21,22]. Less prevalent subtypes of HNC also include major salivary gland cancer, accounting for 1–5% of cases, and sinonasal malignancies of various origins (i.e., carcinomas, lymphomas and sarcomas), representing less than 5% of all HNC diagnosis [23,24,25,26]. Moreover, the incidence of HNC is higher in men than in women and seems to increase with age [27]. The gender disparities in HNC incidence has been connected to the higher exposure to risk factors, such as alcohol and/or tobacco consumption, by men when compared to women [28,29].
The etiological factors related to HNC are summarized in Table 1 and can be classified as non-infectious or infectious [1,5]. There are different non-infectious risk factors for the development of HNC, the most important being tobacco and alcohol use. Although they contribute to the risk of HNC when consumed separately, their combination results in a synergistic increase in the risk of developing HNC [3,5,30,31]. Approximately 90% of all HNC patients have a history of tobacco consumption (i.e., smoked, snuffed or chewed) [27]. Different forms of tobacco consumption increase the risk of development of HNC differently, i.e., five- to ten-fold for smoked tobacco and four-fold for smokeless tobacco (if consumed for ≥10 years) [27,32]. Alcohol is another non-infectious etiological factor for the development of HNC [31]. When combined, alcohol and tobacco consumption can increase the risk of HNC by more than 40-fold [33]. This increase in risk, related to the combined use of alcohol and tobacco, is due to the fact that alcohol acts as a solvent to the tobacco substances, enhancing mucosal exposure to carcinogens [33]. There are some subtypes of HNC more prevalent amongst alcohol and/or tobacco users, such as laryngeal and oropharyngeal cancers, and some subtypes of head and neck squamous cell carcinoma (HNSCC) [34]. Moreover, some risk factors have been directly linked to certain subtypes of HNC, as is the case of salivary HNC and occupational exposure to radiation [35,36]. It is also important to note that the radiation exposure related to diagnostic testing is thought to be a contributing factor to the development of salivary cancer [35]. Poor oral and dental hygiene also represent another type of non-infectious risk factor for the development of HNC as it will lead to oral infections and to the presence of polymicrobial supragingival plaque, promoting cancer development [33,37]. Solar exposure, especially exposure to UV radiation, is also a known risk factor for the development of HNC, namely HNC affecting the skin [38]. There are also etiologic factors that are region-specific, as is the case of betel nut chewing, an etiologic factor highly specific to Asian countries [39,40].
The main infectious risk factor associated with the development of HNC are infections by oncogenic forms of HPV, particularly HPV16 (>90% of HPV-positive HNSCC cases) and HPV18 [41,42,43]. HPV infection seems to especially increase the risk of developing HNSCC [42]. In the past, the majority of HNSCC diagnoses were related to non-infectious etiological factors. However, recently, there has been a change in the paradigm, with a rise in HPV-related HNSCC. Indeed, HPV seems to be the main etiological factor driving carcinogenesis for most HNSCC cases, especially in young adults [44,45]. The anatomical structures presenting a higher incidence of HPV-related HNSCC include the oro- and hypopharynx [33,46,47]. Although HPV-related HNC patients tend to be younger, and smoke and drink less than non-HPV-related HNC patients, there are still HNC diagnoses simultaneously related to non-infectious and infectious etiological factors. In fact, drinkers and/ or smokers that are HPV-positive account for 10–30% of all HNSCC cases, and the combination of non-infectious and infectious risk factors seem to have an additive effect [41,48].
EBV, also an infectious risk factor for the development of HNC, has been strongly associated with nasopharyngeal cancer [49,50]. The first association between nasopharyngeal cancer and EBV was described in 1996, and EBV infection is strongly related to the undifferentiated subtype of this malignancy, with latent EBV being present in 95% of cases [51]. Many EBV infections occur during childhood, with the individual becoming a lifelong carrier of this virus as the virus becomes latent and survives in the pool of infected memory B cells [52]. Over time, EBV is able to revert from its latent state to a lytic state, acting as a tumour promoting-agent, and causing cells to transform and originate malignant tumours, such as nasopharyngeal carcinomas [49,50,52].

3. Clinical Presentation and Diagnosis

3.1. Diagnosis

HNC patients usually display symptoms related to trouble and/or pain in swallowing (dysphagia and odynophagia, respectively), hoarseness, otalgia, irregular mucosae, mucosae ulcers, oral and/or pharyngeal pain, weight loss, occurrence of unexplained neck mass, etc., usually presented to their primary care physician or dentists [3,53,54]. When justified, imaging techniques are generally employed prior to biopsies [3]. Due to the vast group of anatomical structures involved in this pathology, the diagnosis of HNC uses many techniques, traditionally nasopharyngolaryngoscopy, sinuses contrast-enhanced computed tomography (CT), head magnetic resonance imaging (MRI) and/or CT, panoramic dental X-ray, PET/CT, and chest imaging using different techniques [55,56]. If a biopsy is required, fine-needle aspiration is preferable for histological analysis. Nevertheless, complete nodal resection may be required [3].
Less invasive techniques for HNC diagnosis are being studied, such as serological and salivary biomarkers, as well as exhaled breath analysis and liquid biopsies [57,58,59]. The latter can be performed by the NA-NOSE, a nanoscale artificial nose developed by Haick and co-workers, that has already been shown to be able to distinguish between breathing of healthy cohorts and breast, lung, prostate and colon cancer [60], and more recently between healthy cohorts and HNC patients [56,61]. Some biomarkers have been shown to have diagnostic and prognosis-predictive value, including epidermal growth factor receptor (EGFR), HPV, EBV, phosphatase and tensin homolog (PTEN), p16, interleukin-8 (IL-8), B-cell lymphoma extra-large (Bcl-xL)/Bcl-2, and the upregulation of genes (i.e., EMS1, CCDN and FGFR1) [55,62]. Although the relevancy of some of these biomarkers for HNC prognosis has been confirmed (i.e., IL-8, HPV and p16), their detection in biological samples remains a challenge due to their low concentrations [55]. Another technique being studied extensively for treatment of HNC and its subtypes is liquid biopsies. These enable diagnostic and prognosis/predictive applications, making use of circulating tumour cells, circulating tumour DNA, micro-RNAs, extracellular vesicles, etc. [59]. Liquid biopsies have been suggested as a useful and less-invasive tool to track the malignancy and to obtain samples from less-accessible tumours. Moreover, they allow researchers to track tumour changes during the disease course, allowing them to monitor the treatment response, disease progression and the likelihood of disease relapse [63,64]. A major challenge in the screening and early detection of HNC is the lack of specific tumour markers that may be overcome using liquid biopsies. For instance, patients’ urine may be used to detect the presence of EBV-DNA, a biomarker for the diagnosis of nasopharyngeal cancer presenting a sensitivity of 96%, and thus constituting a promising non-invasive screening strategy for this subtype of HNC [64]. Besides their role in the treatment of nasopharyngeal cancer, liquid biopsies have also been explored to detect HNSCC, especially using blood (plasma or serum) and saliva, thus providing a vast list of biomarker candidates through the quantification of cell-free DNA (i.e., cfHPV DNA), cell-free RNA, circulating tumour cells and extracellular vesicles [65,66]. There has been cargo of extracellular vesicles associated with the onset and development of certain subtypes of HNC, as is the case of HNSCC and associated proteins (CD9, EpCAM, HSP90, FGFR2, CAV1 and gp96), micro RNAs (miR-486–5p, miR-486–3p, miR-10b-5p, miR-142–3p, miR-186–5p, miR-195–5p, miR-374b-5p, miR-574–3p and miR-21), long non-coding RNA (MALAT1, Linc-ROR and lncRNA00152) and circular RNA (circRNA_100290); nasopharyngeal cancer and associated proteins (LMP1) and micro RNAs (miR-BART7-3p, hsa-miR-24–3p, hsa-miR-891ª, hsa-miR-106a-5p, hsa-miR-20a-5p and hsa-miR-1908); and, thyroid carcinoma and associated proteins (HSP27, HSP60, HSP90, SRC, TLN1, ITGB2 and CAPNS1) and circular RNA (hsacirc_007293, hsacirc_031752 and hsacirc_020135) [67].

3.2. An Overview of the Pathophysiology and Histology of HNC

Overall, HNC staging follows the TNM system, taking into consideration the tumour characteristics (T), the presence of lymph nodes metastasis (N) and distant metastasis (M), and also HPV and EBV status for the staging of naso- and oropharynx HNC [68,69]. Over the years, the American Joint Committee on Cancer (AJCC)’s TNM system has been evolving to increase the system’s predictive value, and currently staging of HNC follows the 8th Edition of the AJCC, as described in Table 2.
Histopathologic analysis is very important for an adequate diagnosis and treatment of HNC, as well as the identification of key predictive or prognostic markers, as specific tumours present typical histological patterns [71,72]. For instance, HPV (i.e., HPV+ oropharynx HNSCC has a more favorable prognosis compared to HPV), EBV (i.e., EBV+ has a worse prognosis than EBV-), protein p16 (i.e., p16+ HNSCC present poorer differentiation but better prognosis), and EGFR (i.e., overexpression is correlated with increased recurrence and decreased survival) are some of the most relevant predictive and/or prognostic markers in HNSCC [73,74]. Moreover, it is important to score the tumour according to one of four grades (grade 1, 2, 3 or 4). This grading system varies per the HNC subtype (i.e., SCC, carcinoma, adenocarcinoma, sarcomas, and lymphomas). For instance, according to Anneroth’s (1987) and Bryne’s (1992) grading systems, to grade HNSCC the pathologist must take into account the degree of keratinization, the presence of nuclear polymorphisms, the number of mitoses in a high-power field, the pattern of growth and/or invasion of the surrounding tissues and the presence of lymphoplasmacytic infiltration [75,76]. In contrast, larynx and other HNC neuroendocrine carcinomas are graded according to their tumour subtype (i.e., grade 1—well-differentiated neuroendocrine carcinoma; grade 2—moderately differentiated neuroendocrine carcinoma; grade 3—poorly differentiated small- or large-cell neuroendocrine carcinomas) [77]. Similar to neuroendocrine HNCs, sarcomas of the head and neck are also graded according to their differentiation degree [78]. There is a large variety of histopathological subtypes of HNC, summarized in Table 3, as well as variety in their histopathological presentation. Due to the large variety of malignancies affecting the head and neck anatomical structures, one of the most important features to consider for histopathological diagnosis and subtyping is to the anatomical structure where the mass is localized.

3.3. Current Treatment Approaches

Like other malignancies, the treatment of HNC differs according to subtype, primary site and disease stage (i.e., localized or locally advanced disease), and is described in the NCCN Clinical Practice Guidelines in Oncology [4,81,82,83]. A generalized representation of the different treatment approaches for HNC is presented in Figure 2. Regarding localized HNC (TNM stage I-II), treatment is very similar regardless of the anatomical structure affected (i.e., lip, oral cavity, oropharynx, larynx, hypopharynx and paranasal sinuses) or malignancy subtype (i.e., epithelial, HNSCC, lymphoma or sarcoma), focusing on treating the primary tumour site by complete surgical resection or with radiotherapy (if the patient is unfit for surgery) [3,84]. Patients that present with localized HNC of epithelial nature usually have improved long-term survival prospects (70–90% of patients with early-stage disease) after surgery or radiotherapy. In all cases, the risk of occult neck metastasis is evaluated, with selective neck dissection, elective neck dissection with more extensive removal of lymph nodes or prophylactic neck radiotherapy be potentially offered [3]. Regarding the specific case of soft tissue sarcomas of the head and neck, neck metastasis is rare (3% of cases), and thus neck dissection is only indicated when palpable lymph nodes are identified [78]. In the case of high-grade soft tissue sarcomas, chemotherapy is also offered in combination with surgery and radiotherapy [78,85]. Regarding lymphomas of the head and neck, treatment differs from the regimens of other solid HNCs and mainly depends on the malignancy being low- or high-grade. While localized low-grade lymphomas are treated solely with radiotherapy, localized high-grade lymphomas are treated with chemotherapy followed by radiotherapy [86]. The majority of extra-nodal lymphomas of the head and neck are treated with rituximab and CHOP, a multiagent chemotherapy regimen combining cyclophosphamide, doxorubicin or epirubicin, bleomycin and vincristine, or its variants (i.e., R-CHOP) [86,87]. In the case of very aggressive head and neck lymphomas, such as Burkitt’s lymphoma and lymphoblastic lymphoma, chemotherapy must be combined with central nervous system (CNS) prophylaxis due to high rates of CNS involvement, and in some cases, patients may be eligible for stem cell transplants. Hodgkin’s lymphoma is standardly treated with a combination of radiotherapy and multiagent chemotherapy, combining adriamycin, bleomycin, vinblastine and dacarbazine [87].
Patients with locally advanced disease (TNM stage III, IVa and IVb) are treated with a multimodal approach, including not only localized treatments (i.e., surgical resection and radiotherapy), but also systemic treatments (i.e., chemotherapy) [84,88]. A multidisciplinary approach for HNC treatment focuses on maximizing survival while preserving function and structures, with a team of surgeons, oncologists and radiotherapists being responsible for tumour control [53,89,90]. The main task of this team is to promote specialized decision making regarding diagnostic techniques, treatment options and treatment recommendations for each patient, establishing an adequate quality of life [90].
Regarding advanced HNSCC, the most commonly used chemotherapy agents are platinum-based, and can be used in combination with 5-fluorouracil (5-FU) to treat HNC. However, no platinum-based chemotherapy agent was shown to be significantly superior [88,91,92]. Moreover, in the case of advanced HNSCC, treatment with chemoradiation (i.e., chemotherapy as radiosensitizers before subsequent or concurrent radiotherapy) is very frequent [88,91]. EGFR is commonly overexpressed in HNSCC and has been associated with a poorer prognosis. Thus, cetuximab is routinely used in advanced HNSCC treatment and has been proven useful in platinum-resistant HNSCC treatment [92]. In fact, the addition of cetuximab to platinum-5-FU chemotherapy has been the only improvement in the clinical management of metastatic HNSCC, leading to increased survival rates [91]. To improve quality of life and provide symptomatic relief for these groups of patients, palliative radiotherapy may be provided to treat distant metastasis [92]. Still, regarding advanced HNSCC, HPV status does not change the treatment regimen, with HPV+ positive patients being treated similarly to their HPV- counterparts [92]. Some HPV+ positive HNC subtypes may have higher response rates to therapies, improved overall survival, disease-free survival and locoregional disease control when compared to their HPV- counterparts [93]. One example of this is oropharyngeal cancer, in which patients diagnosed with HPV+ oropharyngeal cancer have higher response rates to chemoradiation and increased survival [41]. This increased sensitivity to chemo- and radiotherapy has been attributed to the presence of unmutated p53 and higher sensitivity to cytotoxic agents and DNA damage, both of which induce apoptosis [41,93].
To maintain the patient’s quality of life, a multidisciplinary care team must be put in place, encompassing not only physicians specializing in surgery, oncology and radiotherapy, but also dentists, nutritionists, speech therapists, and occupational- and physiotherapy, audiometry and psychosocial services [3].

4. Therapeutic Advances in HNC

HNC continues to face major treatment challenges due to a variety of reasons, one of them being the high diversity of cancers englobed by this group of malignancies. They vary not only in the anatomical regions affected but also in histologic subtype, and also in HNC presenting early development of drug-resistance pathways, leading to treatment failure. Thus, although there are effective treatments available for localized HNC, with favorable response rates, the prognosis of advanced HNC, especially HNSCC, that relies in the response to systemic therapies (i.e., chemotherapy) is uncertain, mainly due to poor treatment response rates [94,95]. Besides low efficacy, the current treatment modalities (i.e., chemo- and radiotherapy) also present high toxicity, leading to adverse reactions to treatment and even premature treatment cessation. These challenges result in up to 65% of patients diagnosed with advanced HNSCC presenting a high risk of disease reoccurrence, and low survival rates; less than 50% of patients reach the 5-year survival mark [3].
The rationale behind immunotherapy is to induce or improve the anti-tumour response, as well as avoid immune evasion. The fact that HNSCC and other advanced HNC present an extremely immunosuppressive tumour microenvironment, high tumour mutation burden and high expression of immune checkpoint inhibitors (programmed cell death protein 1, PD-1; and cytotoxic T-lymphocyte-associated protein 4, CTLA4) makes them very attractive candidates for cancer immunotherapy [96,97]. Cetuximab was approved as a targeted therapy for recurrent/metastatic HNSCC after the EXTREME study, targeting EGFR, but it has shown limited efficacy in the clinical setting [81,94,98]. Soon after, in 2017, after the CheckMate 141 study, and in 2019, after the KEYNOTE-048 study, respectively, nivolumab was approved as a second-line treatment for platinum-resistant recurrent/metastatic HNSCC and pembrolizumab was approved as mono- and combination therapy for localized and recurrent/metastatic HNSCC, and both were checkpoint inhibitors targeting PD-1 [94,97,98,99,100]. Immunotherapy approaches using PD-L1 and PD-1 inhibitors (i.e., pembrolizumab and nivolumab) revolutionized the treatment of many solid malignancies, with durable treatment responses [101]. Immune checkpoint inhibitors seem to be promising therapeutic approaches for recurrent/metastatic HNSCC, as 85% of these tumours are positive for PD-L1 [97]. However, similar to cetuximab, these immune checkpoint inhibitors showed low efficacy in the clinical setting. Patients undergoing treatments with these drugs present median overall survivals of 7.7 months, for nivolumab, and 14.7–14.9 months, for pembrolizumab [94,98]. Nevertheless, patient outcomes were improved by using immune checkpoint inhibitors when compared with the standard therapies. The CheckMate 141 trial reported a doubling of the 1-year overall survival of patients that received nivolumab (36%) compared with conventional chemotherapy (17%), and a nearly tripling of the 2-year overall survival rate (17% versus 6%) [97,101,102].
Patients receiving nivolumab also reported fewer adverse effects of grade 3 and 4 (13.1%), indicating less toxicity than what is seen with conventional chemotherapy regimens (35.1%) [102,103]. The KEYNOTE-048 trial, that resulted in pembrolizumab’s approval for the treatment of recurrent/metastatic HNSCC, also reported, very importantly, that patients treated with this immune checkpoint inhibitor presented not only improved overall response to treatment and overall survival, but longer-lasting responses. A total of 85% of tumour responses to treatment lasted at least 6 months, and 71% of responses lasted a year or more [102]. Information drawn from clinical trials using immune checkpoint inhibitors to treat other metastatic malignancies (i.e., melanoma) indicate that some patients continue to benefit from these drugs long after treatment discontinuation, with tumours presenting long-term responses to treatment [104]. Currently, the FDA recommends immune checkpoint inhibitors for the treatment of recurrent/metastatic HNSCCs that are inoperable and are not candidates for radiotherapy, as follows: pembrolizumab plus cisplatin or 5-FU, if previous platinum chemotherapy resulted in a disease-free interval longer than 6 months and tumour is PD-L1 negative; pembrolizumab or pembrolizumab plus cisplatin or 5-FU, if previous platinum chemotherapy resulted in a disease-free interval longer than 6 months and tumour is PD-L1 positive; and nivolumab or pembrolizumab, if previous platinum chemotherapy resulted in a disease-free interval of 6 months or lower [97]. Now, there is the urgent need to identify which patients benefit from immunotherapeutic strategies such as immune checkpoint inhibitors, and also the optimal time points for these therapies (i.e., neoadjuvant, locally advanced disease, metastatic disease) [105]. This is still an ongoing challenge for researchers, but based on what is known regarding tumour response to immune checkpoint inhibitors by other cancers, tumour mutation burden (i.e., lung cancer) and microsatellite instability (i.e., colon cancer) seem to be the most useful markers besides PD-1/PD-L1 score [106,107].
Another immunotherapeutic approach under study to treat HNC are the therapeutic vaccines for HPV-related HNC, such as HPV+ oropharyngeal cancer. HPV16 is the only associated viral cancer-causing agent in this subtype of HNC, and thus some therapeutic vaccines have been developed for this malignancy. Different therapeutic vaccine types are undergoing clinical trials for their’ application in HPV+ oropharyngeal HNC, e.g., peptide-based vaccine (registered in ClinicalTrials.gov under the identifier NCT00257738), DNA vaccine (registered in ClinicalTrials.gov under the identifier NCT01493154) and live-attenuated virus vaccine (registered in ClinicalTrials.gov under the identifier NCT01598792) [4,8,97,99,100,108,109]. Moreover, other therapeutic vaccines are undergoing clinical trials for the treatment of HNC, targeting HPV, EBV, MUC1, p53 and others [108]. In the case of EBV+ nasopharyngeal carcinoma, adoptive and active immunotherapeutic approaches have also been studied. The first is based on activating EBV-specific T cells ex vivo, which are passively transferred to patients after expansion. Active immunotherapeutic approaches are based upon loading autologous immune cells, with EBV antigens and transferring these cells to patients [8,99,100,109,110].
Besides immunotherapy, many biological-targeted therapies are under study for HNC, focusing on targeting growth factors and growth factor receptors, signal transduction, cell cycle targets, prostaglandin production, protein degradation, hypoxia and angiogenesis, etc. [91]. Examples of drugs and targets of interest of biological-targeted agents for HNC currently undergoing clinical trials are presented in Table 4, either as a single or combined therapy. Moreover other drugs have undergone clinical trials for HNC in the past, including PI3K inhibitors (i.e., metformin, parsaclisib, copanlisib, sonolisib, piliralisib); mTOR inhibitors (i.e., sirolimus/rapamycin, everolimus, CC-115, temsirolimus, ridaforolimus); AKT inhibitors (i.e., MK-2206, perifosine, temsirolimus); JAK/STAT (i.e., ruxolitinib, danvatirsen, TTI-101, itacitinib); dual PI3K/mTOR inhibitors (i.e., dactolisib, bimiralisib, PF-04691502, gedatolisib, voxtalisib, SF1126); VEGFR inhibitors (i.e., vandetanib, sunitinib, pazopanib, axitinib, nintedanib, cediranib, semaxinib); MET inhibitors (i.e., capmatinib, ficlatuzumab, AMG337, golvatinib, foretinib, tivantinib, trametinib, mirdametinib); EGFR inhibitors (i.e., panitumumab, afatanib, gefinitib, zalutumumab, tarloxotinib, nimotuzumab, DBPR112, iressa); Smoothened inhibitor (i.e., saridegib, vismodegib); Bcl-Arb inhibitor (i.e., imatinib, ponatinib, dasatinib, nilotinib); CDK4/6 inhibitors (i.e., abemaciclib, flavopiridol, riviciclib, palbociclib, ribociclib); NADPH inhibitor (i.e., setanaxib); and SUMOylation inhibitors (i.e., subasumstat), etc. [81,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134].
Alternative treatment approaches are also being explored for the treatment of HNC. This is the case with light-based therapies, such as photodynamic- and photothermal therapy. Photodynamic therapy (PDT) is used to treat malignant and non-malignant diseases by producing reactive oxygen species through the light-mediated excitation of photosensitizer drugs [135]. PDT mainly presents clinical applications as second-line treatment options for second primary or recurrent superficial HNC, especially of the oral cavity, pharynx and larynx [136,137]. In both the oral cavity and the larynx, PDT is of special interest in the case of diffuse but superficial field cancerization [137,138]. For well-defined disease in the oral cavity, PDT’s efficacy is competitive with surgery, while in the larynx PDT can be used as a primary treatment when surgical excision proves difficult [137]. Photosensitizer drugs have been approved for PDT for curative treatment of esophageal cancer (Photofrin®) and early-stage HNSCC (Foscan®), and palliative treatment of advanced HNSCC (Foscan®) [137,138,139]. In early-stage HNSCC (T1 and T2 tumours), PDT response rates and cure rates are similar to those observed with conventional therapy, 79–91% and 71–89%, respectively. When conventional therapy is compared to PDT in advanced and incurable HNSCC, studies have reported a longer survival time with improved quality of life when PDT is preferred. [138,140] However, despite its benefits, PDT presents several drawbacks for HNC management. One of these is a high rate of recurrence in patients after PDT treatment [138]. This is most likely due to the limitation of light penetration in tissues (less than 5 mm), as inefficiently reaches the as a consequence tumour [137,138]. Another drawback associated with PDT is the severe acute pain at the treatment site reported by patients and pronounced swelling, attributed to high inflammatory response post-PDT of the tumour and tissues surrounding it [138].
Photothermal therapy (PTT) is another type of light-based therapy that entails the use of a light source to irradiate and increase the temperature of a superficial tissue (i.e., tumour), leading to thermal ablation through the excitation of endogenous chromophores [141,142,143,144,145,146,147,148]. Contrary to PDT, with photosensitizers approved by regulatory agencies like EMA and FDA to be used clinically, PTT is yet to be approved for clinical applications [147]. To increase PTT’s specificity and efficacy, photothermal nanoparticles (i.e., gold nanoparticles, AuNPs) able to convert light into heat can be used [142,143,144,145,146,149]. Different applications of AuNPs-based PTT for HNC have been studied in vitro [144,150,151] and in vivo [144,152,153], with some systems undergoing clinical trials [151,154]. Our group has previously developed AuNPs with high specificity for a rare subtype of thyroid cancer (part of HNC), anaplastic thyroid carcinoma, for AuNPs-based PTT of this aggressive malignancy with promising results, both in vitro and in vivo [144]. Moreover, other forms of AuNPs-based PTT are under clinical evaluation. One example is Aurolase® (Nanospectra), a PEGylated gold nanosphere that underwent a pilot study clinical trial, concluded in 2014, for PTT of refractory and/or recurrent HNC (registered in ClinicalTrials.gov under the identifier NCT00848042) [151,154]. Besides monotherapy with PTT, applications of AuNPs-based PTT for HNC also include combining PTT with other therapies (i.e., radio-, chemo- and immunotherapy) and theranostic approaches, combining imaging and therapy [155,156].

5. Conclusions

The incidence of HNC has been steadily increasing since the 1990s, and thus this vast group of malignancies has become an important issue. Although the treatment for localized/early-stage HNC is well established, most patients present advanced and/or recurrent/metastatic disease when diagnosed, resulting in survival rates below 50%. Although efforts have been made to improve treatment for advanced HNC, little progress has been achieved as the efficacy of the newly approved therapies did not translate to the clinical setting. Currently, the focus on clinical trials for advanced and/or recurrent/metastatic HNC has shifted to targeted/multi-targeted therapies, immunotherapy and light-based therapeutic approaches (i.e., PDT and PTT). These strategies aim to improve the quality of life of these patients as well as the management of this challenging group of malignancies.

Author Contributions

Writing—original draft preparation, M.N.A.; writing—review and editing, M.N.A., P.F., H.A.F., M.M.G. and C.P.R.; supervision, P.F., H.A.F., M.M.G. and C.P.R.; funding acquisition, M.M.G. and C.P.R. All authors have read and agreed to the published version of the manuscript.

Funding

The authors acknowledge Fundação para a Ciência e Tecnologia (FCT) for financial support through projects UIDB/00645/2020, UIDB/04138/2020, and UIDP/04138/2020, but also the PhD fellowship SFRH/BD/05377/2021.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Leonel, A.; Bonan, R.; Pinto, M.; Kowalski, L.; Perez, D. The Pesticides Use and the Risk for Head and Neck Cancer: A Review of Case-Control Studies. Med. Oral. Patol. Oral Cir. Bucal 2021, 26, e56–e63. [Google Scholar] [CrossRef] [PubMed]
  2. Heroiu Cataloiu, A.-D.; Danciu, C.E.; Popescu, C.R. Multiple Cancers of the Head and Neck. Maedica 2013, 8, 80–85. [Google Scholar] [PubMed]
  3. Chow, L.Q.M. Head and Neck Cancer. N. Engl. J. Med. 2020, 382, 60–72. [Google Scholar] [CrossRef] [PubMed]
  4. Cramer, J.D.; Burtness, B.; Le, Q.T.; Ferris, R.L. The Changing Therapeutic Landscape of Head and Neck Cancer. Nat. Rev. Clin. Oncol. 2019, 16, 669–683. [Google Scholar] [CrossRef] [PubMed]
  5. Halicek, M.; Little, J.V.; Wang, X.; Chen, A.Y.; Fei, B. Optical Biopsy of Head and Neck Cancer Using Hyperspectral Imaging and Convolutional Neural Networks. J. Biomed. Opt. 2019, 24, 1. [Google Scholar] [CrossRef] [Green Version]
  6. Lopes, J.; Rodrigues, C.M.P.; Gaspar, M.M.; Reis, C.P. Melanoma Management: From Epidemiology to Treatment and Latest Advances. Cancers 2022, 14, 4652. [Google Scholar] [CrossRef]
  7. Poddar, A.; Aranha, R.R.; Muthukaliannan, G.K.; Nachimuthu, R.; Jayaraj, R. Head and Neck Cancer Risk Factors in India: Protocol for Systematic Review and Meta-Analysis. BMJ Open 2018, 8, e020014. [Google Scholar] [CrossRef] [Green Version]
  8. Pezzuto, F.; Buonaguro, L.; Caponigro, F.; Ionna, F.; Starita, N.; Annunziata, C.; Buonaguro, F.M.; Tornesello, M.L. Update on Head and Neck Cancer: Current Knowledge on Epidemiology, Risk Factors, Molecular Features and Novel Therapies. Oncology 2015, 89, 125–136. [Google Scholar] [CrossRef] [PubMed]
  9. Jou, A.; Hess, J. Epidemiology and Molecular Biology of Head and Neck Cancer. Oncol. Res. Treat. 2017, 40, 328–332. [Google Scholar] [CrossRef]
  10. Kase, S.; Baburin, A.; Kuddu, M.; Innos, K. Incidence and Survival for Head and Neck Cancers in Estonia, 1996–2016: A Population-Based Study. Clin. Epidemiol. 2021, 13, 149–159. [Google Scholar] [CrossRef]
  11. Kawakita, D.; Oze, I.; Iwasaki, S.; Matsuda, T.; Matsuo, K.; Ito, H. Trends in the Incidence of Head and Neck Cancer by Subsite between 1993 and 2015 in Japan. Cancer Med. 2022, 11, 1553–1560. [Google Scholar] [CrossRef] [PubMed]
  12. Thompson-Harvey, A.; Yetukuri, M.; Hansen, A.R.; Simpson, M.C.; Adjei Boakye, E.; Varvares, M.A.; Osazuwa-Peters, N. Rising Incidence of Late-stage Head and Neck Cancer in the United States. Cancer 2020, 126, 1090–1101. [Google Scholar] [CrossRef] [PubMed]
  13. Ludwig, D.C.; Morrison, S.D.; Dillon, J.K. The Burden of Head and Neck Cancer in the United States, 1990–2017. J. Oral Maxillofac. Surg. 2021, 79, 2162–2170. [Google Scholar] [CrossRef] [PubMed]
  14. Jakobsen, K.K.; Grønhøj, C.; Jensen, D.H.; Karnov, K.K.S.; Agander, T.K.; Specht, L.; von Buchwald, C. Increasing Incidence and Survival of Head and Neck Cancers in Denmark: A Nation-Wide Study from 1980 to 2014. Acta Oncol. 2018, 57, 1143–1151. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Cabeçadas, J.; Martinez, D.; Andreasen, S.; Mikkelsen, L.H.; Molina-Urra, R.; Hall, D.; Strojan, P.; Hellquist, H.; Bandello, F.; Rinaldo, A.; et al. Lymphomas of the Head and Neck Region: An Update. Virchows Arch. 2019, 474, 649–665. [Google Scholar] [CrossRef] [PubMed]
  16. Khan, U.; Alamgir, W.; Ashraf, A.; Haider, A.; Rashid, S.; Abrar, F. Clinicopathological and Immunohistochemical Profile of Lymphoma of Head and Neck Region. Pak. J. Pathol. 2021, 32, 142–146. [Google Scholar]
  17. Singh, R.; Shaik, S.; Negi, B.; Rajguru, J.; Patil, P.; Parihar, A.; Sharma, U. Non-Hodgkin’s Lymphoma: A Review. J. Fam. Med. Prim. Care 2020, 9, 1834. [Google Scholar]
  18. Kuo, C.-Y.; Shih, C.-P.; Cheng, L.-H.; Liu, S.-C.; Chiu, F.-H.; Lin, Y.-Y.; Hu, J.-M.; Chu, Y.-H. Head and Neck Lymphomas: Review of 151 Cases. J. Med. Sci. 2020, 40, 215. [Google Scholar]
  19. Kamiński, B. Lymphomas of the Head-and-Neck Region. J. Cancer Res. Ther. 2021, 17, 1347. [Google Scholar] [CrossRef]
  20. Scelsi, C.L.; Wang, A.; Garvin, C.M.; Bajaj, M.; Forseen, S.E.; Gilbert, B.C. Head and Neck Sarcomas: A Review of Clinical and Imaging Findings Based on the 2013 World Health Organization Classification. Am. J. Roentgenol. 2019, 212, 644–654. [Google Scholar] [CrossRef]
  21. Fabiano, S.; Contiero, P.; Barigelletti, G.; D’Agostino, A.; Tittarelli, A.; Mangone, L.; Bisceglia, I.; Bongiorno, S.; De Lorenzis, L.E.; Mazzoleni, G.; et al. Epidemiology of Soft Tissue Sarcoma and Bone Sarcoma InItaly: Analysis of Data from 15 Population-Based Cancer Registries. Sarcoma 2020, 2020, 6142613. [Google Scholar] [CrossRef]
  22. Kalavrezos, N.; Sinha, D. Head and Neck Sarcomas in Adulthood: Current Trends and Evolving Management Concepts. Br. J. Oral Maxillofac. Surg. 2020, 58, 890–897. [Google Scholar] [CrossRef] [PubMed]
  23. Becker, C.; Dahlem, K.K.K.; Pfeiffer, J. Prognostic Value of Comorbidities in Patients with Carcinoma of the Major Salivary Glands. Eur. Arch. Oto-Rhino-Laryngol. 2017, 274, 1651–1657. [Google Scholar] [CrossRef] [PubMed]
  24. Becker, C.; Pfeiffer, J.; Lange, K.; Dahlem, K.K.K. Health-Related Quality of Life in Patients with Major Salivary Gland Carcinoma. Eur. Arch. Oto-Rhino-Laryngol. 2018, 275, 997–1003. [Google Scholar] [CrossRef] [PubMed]
  25. Thawani, R.; Kim, M.S.; Arastu, A.; Feng, Z.; West, M.T.; Taflin, N.F.; Thein, K.Z.; Li, R.; Geltzeiler, M.; Lee, N.; et al. The Contemporary Management of Cancers of the Sinonasal Tract in Adults. CA Cancer J. Clin. 2022. [Google Scholar] [CrossRef] [PubMed]
  26. Sjöstedt, S.; Jensen, D.H.; Jakobsen, K.K.; Grønhøj, C.; Geneser, C.; Karnov, K.; Specht, L.; Agander, T.K.; von Buchwald, C. Incidence and Survival in Sinonasal Carcinoma: A Danish Population-Based, Nationwide Study from 1980 to 2014. Acta Oncol. 2018, 57, 1152–1158. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Rettig, E.M.; D’Souza, G. Epidemiology of Head and Neck Cancer. Surg. Oncol. Clin. N. Am. 2015, 24, 379–396. [Google Scholar] [CrossRef]
  28. Park, J.-O.; Nam, I.-C.; Kim, C.-S.; Park, S.-J.; Lee, D.-H.; Kim, H.-B.; Han, K.-D.; Joo, Y.-H. Sex Differences in the Prevalence of Head and Neck Cancers: A 10-Year Follow-Up Study of 10 Million Healthy People. Cancers 2022, 14, 2521. [Google Scholar] [CrossRef]
  29. Mazul, A.L.; Naik, A.N.; Zhan, K.Y.; Stepan, K.O.; Old, M.O.; Kang, S.Y.; Nakken, E.R.; Puram, S.V. Gender and Race Interact to Influence Survival Disparities in Head and Neck Cancer. Oral Oncol. 2021, 112, 105093. [Google Scholar] [CrossRef]
  30. Tataru, D.; Mak, V.; Simo, R.; Davies, E.A.; Gallagher, J.E. Trends in the Epidemiology of Head and Neck Cancer in London. Clin. Otolaryngol. 2017, 42, 104–114. [Google Scholar] [CrossRef] [Green Version]
  31. Mehanna, H.; Paleri, V.; West, C.M.L.; Nutting, C. Head and Neck Cancer--Part 1: Epidemiology, Presentation, and Prevention. BMJ 2010, 341, c4684. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Wyss, A.; Hashibe, M.; Chuang, S.-C.; Lee, Y.-C.A.; Zhang, Z.-F.; Yu, G.-P.; Winn, D.M.; Wei, Q.; Talamini, R.; Szeszenia-Dabrowska, N.; et al. Cigarette, Cigar, and Pipe Smoking and the Risk of Head and Neck Cancers: Pooled Analysis in the International Head and Neck Cancer Epidemiology Consortium. Am. J. Epidemiol. 2013, 178, 679–690. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Galbiatti, A.L.S.; Padovani-Junior, J.A.; Maníglia, J.V.; Rodrigues, C.D.S.; Pavarino, É.C.; Goloni-Bertollo, E.M. Head and Neck Cancer: Causes, Prevention and Treatment. Braz. J. Otorhinolaryngol. 2013, 79, 239–247. [Google Scholar] [CrossRef] [PubMed]
  34. Cohen, N.; Fedewa, S.; Chen, A.Y. Epidemiology and Demographics of the Head and Neck Cancer Population. Oral Maxillofac. Surg. Clin. North Am. 2018, 30, 381–395. [Google Scholar] [CrossRef] [PubMed]
  35. Del Signore, A.G.; Megwalu, U.C. The Rising Incidence of Major Salivary Gland Cancer in the United States. Ear, Nose Throat J. 2017, 96, E13–E16. [Google Scholar] [CrossRef]
  36. Pan, S.Y.; de Groh, M.; Morrison, H. A Case-Control Study of Risk Factors for Salivary Gland Cancer in Canada. J. Cancer Epidemiol. 2017, 2017, 4909214. [Google Scholar] [CrossRef]
  37. Hashim, D.; Sartori, S.; Brennan, P.; Curado, M.P.; Wünsch-Filho, V.; Divaris, K.; Olshan, A.F.; Zevallos, J.P.; Winn, D.M.; Franceschi, S.; et al. The Role of Oral Hygiene in Head and Neck Cancer: Results from International Head and Neck Cancer Epidemiology (INHANCE) Consortium. Ann. Oncol. 2016, 27, 1619–1625. [Google Scholar] [CrossRef]
  38. Porceddu, S.V.; Veness, M.J.; Guminski, A. Nonmelanoma Cutaneous Head and Neck Cancer and Merkel Cell Carcinoma: Current Concepts, Advances, and Controversies. J. Clin. Oncol. 2015, 33, 3338–3345. [Google Scholar] [CrossRef] [Green Version]
  39. Su, Y.-Y.; Chien, C.-Y.; Luo, S.-D.; Huang, T.-L.; Lin, W.-C.; Fang, F.-M.; Chiu, T.-J.; Chen, Y.-H.; Lai, C.-C.; Hsu, C.-M.; et al. Betel Nut Chewing History Is an Independent Prognosticator for Smoking Patients with Locally Advanced Stage IV Head and Neck Squamous Cell Carcinoma Receiving Induction Chemotherapy with Docetaxel, Cisplatin, and Fluorouracil. World J. Surg. Oncol. 2016, 14, 86. [Google Scholar] [CrossRef] [Green Version]
  40. Rahman, Q.B.; Iocca, O.; Kufta, K.; Shanti, R.M. Global Burden of Head and Neck Cancer. Oral Maxillofac. Surg. Clin. N. Am. 2020, 32, 367–375. [Google Scholar] [CrossRef]
  41. Marur, S.; D’Souza, G.; Westra, W.H.; Forastiere, A.A. HPV-Associated Head and Neck Cancer: A Virus-Related Cancer Epidemic. Lancet Oncol. 2010, 11, 781–789. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Gillison, M.L.; Castellsagué, X.; Chaturvedi, A.; Goodman, M.T.; Snijders, P.; Tommasino, M.; Arbyn, M.; Franceschi, S. Eurogin Roadmap: Comparative Epidemiology of HPV Infection and Associated Cancers of the Head and Neck and Cervix. Int. J. Cancer 2014, 134, 497–507. [Google Scholar] [CrossRef] [PubMed]
  43. Abogunrin, S.; Di Tanna, G.L.; Keeping, S.; Carroll, S.; Iheanacho, I. Prevalence of Human Papillomavirus in Head and Neck Cancers in European Populations: A Meta-Analysis. BMC Cancer 2014, 14, 968. [Google Scholar] [CrossRef] [PubMed]
  44. Gooi, Z.; Chan, J.Y.K.; Fakhry, C. The Epidemiology of the Human Papillomavirus Related to Oropharyngeal Head and Neck Cancer. Laryngoscope 2016, 126, 894–900. [Google Scholar] [CrossRef] [PubMed]
  45. Betiol, J.; Villa, L.L.; Sichero, L. Impact of HPV Infection on the Development of Head and Neck Cancer. Braz. J. Med. Biol. Res. 2013, 46, 217–226. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Wittekindt, C.; Wagner, S.; Mayer, C.S.; Klussmann, J.P. Basics of Tumor Development and Importance of Human Papilloma Virus (HPV) for Head and Neck Cancer. GMS Curr. Top. Otorhinolaryngol. Head Neck Surg. 2012, 11, Doc09. [Google Scholar]
  47. Syrjänen, S. The Role of Human Papillomavirus Infection in Head and Neck Cancers. Ann. Oncol. 2010, 21, vii243–vii245. [Google Scholar] [CrossRef]
  48. Sinha, P.; Logan, H.L.; Mendenhall, W.M. Human Papillomavirus, Smoking, and Head and Neck Cancer. Am. J. Otolaryngol. 2012, 33, 130–136. [Google Scholar] [CrossRef] [Green Version]
  49. Tsang, C.M.; Lui, V.W.Y.; Bruce, J.P.; Pugh, T.J.; Lo, K.W. Translational Genomics of Nasopharyngeal Cancer. Semin. Cancer Biol. 2020, 61, 84–100. [Google Scholar] [CrossRef]
  50. Shah, K.M.; Young, L.S. Epstein–Barr Virus and Carcinogenesis: Beyond Burkitt’s Lymphoma. Clin. Microbiol. Infect. 2009, 15, 982–988. [Google Scholar] [CrossRef] [Green Version]
  51. Raghupathy, R.; Hui, E.P.; Chan, A.T.C. Epstein-Barr Virus as a Paradigm in Nasopharyngeal Cancer: From Lab to Clinic. Am. Soc. Clin. Oncol. Educ. B. 2014, 34, 149–153. [Google Scholar] [CrossRef] [PubMed]
  52. Fernandes, Q.; Merhi, M.; Raza, A.; Inchakalody, V.P.; Abdelouahab, N.; Zar Gul, A.R.; Uddin, S.; Dermime, S. Role of Epstein–Barr Virus in the Pathogenesis of Head and Neck Cancers and Its Potential as an Immunotherapeutic Target. Front. Oncol. 2018, 8, 257. [Google Scholar] [CrossRef] [PubMed]
  53. Mody, M.D.; Rocco, J.W.; Yom, S.S.; Haddad, R.I.; Saba, N.F. Head and Neck Cancer. Lancet 2021, 398, 2289–2299. [Google Scholar] [CrossRef] [PubMed]
  54. Polverini, P.J.; Lingen, M.W. A History of Innovations in the Diagnosis and Treatment of Oral and Head and Neck Cancer. J. Dent. Res. 2019, 98, 489–497. [Google Scholar] [CrossRef] [PubMed]
  55. Ruiz-Pulido, G.; Medina, D.I.; Barani, M.; Rahdar, A.; Sargazi, G.; Baino, F.; Pandey, S. Nanomaterials for the Diagnosis and Treatment of Head and Neck Cancers: A Review. Materials 2021, 14, 3706. [Google Scholar] [CrossRef] [PubMed]
  56. Hakim, M.; Billan, S.; Tisch, U.; Peng, G.; Dvrokind, I.; Marom, O.; Abdah-Bortnyak, R.; Kuten, A.; Haick, H. Diagnosis of Head-and-Neck Cancer from Exhaled Breath. Br. J. Cancer 2011, 104, 1649–1655. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Mäkitie, A.A.; Almangush, A.; Youssef, O.; Metsälä, M.; Silén, S.; Nixon, I.J.; Haigentz, M.; Rodrigo, J.P.; Saba, N.F.; Vander Poorten, V.; et al. Exhaled Breath Analysis in the Diagnosis of Head and Neck Cancer. Head Neck 2020, 42, 787–793. [Google Scholar] [CrossRef]
  58. Arantes, L.M.R.B.; De Carvalho, A.C.; Melendez, M.E.; Lopes Carvalho, A. Serum, Plasma and Saliva Biomarkers for Head and Neck Cancer. Expert Rev. Mol. Diagn. 2018, 18, 85–112. [Google Scholar] [CrossRef]
  59. Cabezas-Camarero, S.; Pérez-Segura, P. Liquid Biopsy in Head and Neck Cancer: Current Evidence and Future Perspective on Squamous Cell, Salivary Gland, Paranasal Sinus and Nasopharyngeal Cancers. Cancers 2022, 14, 2858. [Google Scholar] [CrossRef]
  60. Peng, G.; Hakim, M.; Broza, Y.Y.; Billan, S.; Abdah-Bortnyak, R.; Kuten, A.; Tisch, U.; Haick, H. Detection of Lung, Breast, Colorectal, and Prostate Cancers from Exhaled Breath Using a Single Array of Nanosensors. Br. J. Cancer 2010, 103, 542–551. [Google Scholar] [CrossRef]
  61. Dharmawardana, N.; Woods, C.; Watson, D.I.; Yazbeck, R.; Ooi, E.H. A Review of Breath Analysis Techniques in Head and Neck Cancer. Oral Oncol. 2020, 104, 104654. [Google Scholar] [CrossRef] [PubMed]
  62. Konings, H.; Stappers, S.; Geens, M.; De Winter, B.Y.; Lamote, K.; van Meerbeeck, J.P.; Specenier, P.; Vanderveken, O.M.; Ledeganck, K.J. A Literature Review of the Potential Diagnostic Biomarkers of Head and Neck Neoplasms. Front. Oncol. 2020, 10, 1020. [Google Scholar] [CrossRef] [PubMed]
  63. Schmidt, H.; Kulasinghe, A.; Perry, C.; Nelson, C.; Punyadeera, C. A Liquid Biopsy for Head and Neck Cancers. Expert Rev. Mol. Diagn. 2016, 16, 165–172. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Meng, Y.; Bian, L.; Zhang, M.; Bo, F.; Lu, X.; Li, D. Liquid Biopsy and Their Application Progress in Head and Neck Cancer: Focus on Biomarkers CTCs, CfDNA, CtDNA and EVs. Biomark. Med. 2020, 14, 1393–1404. [Google Scholar] [CrossRef] [PubMed]
  65. Chantre-Justino, M.; Alves, G.; Delmonico, L. Clinical Applications of Liquid Biopsy in HPV-negative and HPV-positive Head and Neck Squamous Cell Carcinoma: Advances and Challenges. Explor. Target. Anti-Tumor Ther. 2022, 3, 533–552. [Google Scholar] [CrossRef] [PubMed]
  66. Pantel, K. Circulating Tumor Cells in Head and Neck Carcinomas. Clin. Chem. 2019, 65, 1193–1195. [Google Scholar] [CrossRef] [PubMed]
  67. Cao, J.; Zhang, M.; Xie, F.; Lou, J.; Zhou, X.; Zhang, L.; Fang, M.; Zhou, F. Exosomes in Head and Neck Cancer: Roles, Mechanisms and Applications. Cancer Lett. 2020, 494, 7–16. [Google Scholar] [CrossRef]
  68. Cramer, J.D.; Reddy, A.; Ferris, R.L.; Duvvuri, U.; Samant, S. Comparison of the Seventh and Eighth Edition American Joint Committee on Cancer Oral Cavity Staging Systems. Laryngoscope 2018, 128, 2351–2360. [Google Scholar] [CrossRef]
  69. Shah, J.P.; Montero, P.H. New AJCC/UICC Staging System for Head and Neck, and Thyroid Cancer. Rev. Médica Clínica Las Condes 2018, 29, 397–404. [Google Scholar] [CrossRef]
  70. Edge, S.B.; Amin, M.B. AJCC Cancer Staging Manual, 8th ed.; Springer: Cham, Switzerland, 2017. [Google Scholar]
  71. Mishra, M.; Upadhyaya, N.; Dive, A.; Bodhade, A. Histological Patterns of Head and Neck Tumors: An Insight to Tumor Histology. J. Oral Maxillofac. Pathol. 2014, 18, 58. [Google Scholar] [CrossRef] [Green Version]
  72. Helliwell, T.R.; Giles, T.E. Pathological Aspects of the Assessment of Head and Neck Cancers: United Kingdom National Multidisciplinary Guidelines. J. Laryngol. Otol. 2016, 130, S59–S65. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Mendelsohn, A.H.; Lai, C.K.; Shintaku, I.P.; Elashoff, D.A.; Dubinett, S.M.; Abemayor, E.; St. John, M.A. Histopathologic Findings of HPV and P16 Positive HNSCC. Laryngoscope 2010, 120, 1788–1794. [Google Scholar] [CrossRef] [PubMed]
  74. Kang, H.; Kiess, A.; Chung, C.H. Emerging Biomarkers in Head and Neck Cancer in the Era of Genomics. Nat. Rev. Clin. Oncol. 2015, 12, 11–26. [Google Scholar] [CrossRef] [PubMed]
  75. Wunschel, M.; Neumeier, M.; Utpatel, K.; Reichert, T.E.; Ettl, T.; Spanier, G. Staging More Important than Grading? Evaluation of Malignancy Grading, Depth of Invasion, and Resection Margins in Oral Squamous Cell Carcinoma. Clin. Oral Investig. 2021, 25, 1169–1182. [Google Scholar] [CrossRef] [PubMed]
  76. Dissanayake, U. Malignancy Grading of Invasive Fronts of Oral Squamous Cell Carcinomas. Transl. Res. Oral Oncol. 2017, 2, 2057178X1770887. [Google Scholar] [CrossRef]
  77. Perez-Ordoñez, B. Neuroendocrine Carcinomas of the Larynx and Head and Neck: Challenges in Classification and Grading. Head Neck Pathol. 2018, 12, 1–8. [Google Scholar] [CrossRef] [PubMed]
  78. Aljabab, A.S.; Nason, R.W.; Kazi, R.; Pathak, K.A. Head and Neck Soft Tissue Sarcoma. Indian J. Surg. Oncol. 2011, 2, 286–290. [Google Scholar] [CrossRef] [Green Version]
  79. Haines, G.K. Pathology of Head and Neck Cancer I: Epithelial and Related Tumors. In Head & Neck Cancer: Current Perspectives, Advances, and Challenges; Springer: Dordrecht, The Netherlands, 2013; pp. 257–287. [Google Scholar]
  80. Haines, G.K. Pathology of Head and Neck Cancer II: Mesenchymal and Lymphoid Tumors. In Head & Neck Cancer: Current Perspectives, Advances, and Challenges; Springer: Dordrecht, The Netherlands, 2013; pp. 289–311. [Google Scholar]
  81. Alsahafi, E.; Begg, K.; Amelio, I.; Raulf, N.; Lucarelli, P.; Sauter, T.; Tavassoli, M. Clinical Update on Head and Neck Cancer: Molecular Biology and Ongoing Challenges. Cell Death Dis. 2019, 10, 540. [Google Scholar] [CrossRef] [Green Version]
  82. Pfister, D.G.; Spencer, S.; Adelstein, D.; Adkins, D.; Anzai, Y.; Brizel, D.M.; Bruce, J.Y.; Busse, P.M.; Caudell, J.J.; Cmelak, A.J.; et al. Head and Neck Cancers, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Cancer Netw. 2020, 18, 873–898. [Google Scholar] [CrossRef]
  83. Caudell, J.J.; Gillison, M.L.; Maghami, E.; Spencer, S.; Pfister, D.G.; Adkins, D.; Birkeland, A.C.; Brizel, D.M.; Busse, P.M.; Cmelak, A.J.; et al. NCCN Guidelines® Insights: Head and Neck Cancers, Version 1.2022. J. Natl. Compr. Cancer Netw. 2022, 20, 224–234. [Google Scholar] [CrossRef]
  84. Cohen, E.E.W.; LaMonte, S.J.; Erb, N.L.; Beckman, K.L.; Sadeghi, N.; Hutcheson, K.A.; Stubblefield, M.D.; Abbott, D.M.; Fisher, P.S.; Stein, K.D.; et al. American Cancer Society Head and Neck Cancer Survivorship Care Guideline. CA Cancer J. Clin. 2016, 66, 203–239. [Google Scholar] [CrossRef] [PubMed]
  85. de Bree, R.; van der Waal, I.; de Bree, E.; René Leemans, C. Management of Adult Soft Tissue Sarcomas of the Head and Neck. Oral Oncol. 2010, 46, 786–790. [Google Scholar] [CrossRef] [PubMed]
  86. Beasley, M.J. Lymphoma of the Thyroid and Head and Neck. Clin. Oncol. 2012, 24, 345–351. [Google Scholar] [CrossRef] [PubMed]
  87. Zapater, E.; Bagán, J.; Carbonell, F.; Basterra, J. Malignant Lymphoma of the Head and Neck. Oral Dis. 2010, 16, 119–128. [Google Scholar] [CrossRef] [PubMed]
  88. Kundu, S.K.; Nestor, M. Targeted Therapy in Head and Neck Cancer. Tumor Biol. 2012, 33, 707–721. [Google Scholar] [CrossRef]
  89. Casey Fazer-Posorske, P.A.-C. A Multidisciplinary Approach to Head and Neck Cancer. J. Adv. Pract. Oncol. 2021, 12. [Google Scholar] [CrossRef]
  90. Barrera-Franco, J.L.; Gallegos-Hernández, J.F.; Granados-García, M.; Gurrola-Machuca, H. Multidisciplinary Approach in Head and Neck Cancer. Gac. Mex. Oncol. 2019, 16. [Google Scholar] [CrossRef] [Green Version]
  91. Vermorken, J.B.; Specenier, P. Optimal Treatment for Recurrent/Metastatic Head and Neck Cancer. Ann. Oncol. 2010, 21, vii252–vii261. [Google Scholar] [CrossRef]
  92. Price, K.A.R.; Cohen, E.E. Current Treatment Options for Metastatic Head and Neck Cancer. Curr. Treat. Options Oncol. 2012, 13, 35–46. [Google Scholar] [CrossRef]
  93. Dok, R.; Nuyts, S. HPV Positive Head and Neck Cancers: Molecular Pathogenesis and Evolving Treatment Strategies. Cancers 2016, 8, 41. [Google Scholar] [CrossRef] [Green Version]
  94. Kitamura, N.; Sento, S.; Yoshizawa, Y.; Sasabe, E.; Kudo, Y.; Yamamoto, T. Current Trends and Future Prospects of Molecular Targeted Therapy in Head and Neck Squamous Cell Carcinoma. Int. J. Mol. Sci. 2020, 22, 240. [Google Scholar] [CrossRef] [PubMed]
  95. Kaidar-Person, O.; Gil, Z.; Billan, S. Precision Medicine in Head and Neck Cancer. Drug Resist. Updat. 2018, 40, 13–16. [Google Scholar] [CrossRef] [PubMed]
  96. Cheng, G.; Dong, H.; Yang, C.; Liu, Y.; Wu, Y.; Zhu, L.; Tong, X.; Wang, S. A Review on the Advances and Challenges of Immunotherapy for Head and Neck Cancer. Cancer Cell Int. 2021, 21, 406. [Google Scholar] [CrossRef] [PubMed]
  97. Cramer, J.D.; Burtness, B.; Ferris, R.L. Immunotherapy for Head and Neck Cancer: Recent Advances and Future Directions. Oral Oncol. 2019, 99, 104460. [Google Scholar] [CrossRef] [PubMed]
  98. Neal, M.E.H.; Haring, C.T.; Mann, J.E.; Brenner, J.C.; Spector, M.E.; Swiecicki, P.L. Novel Immunotherapeutic Approaches in Head and Neck Cancer. J. Cancer Metastasis Treat. 2019, 5, 76. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  99. Bauml, J.M.; Cohen, R.B.; Aggarwal, C. Immunotherapy for Head and Neck Cancer: Latest Developments and Clinical Potential. Ther. Adv. Med. Oncol. 2016, 8, 168–175. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  100. Szturz, P.; Vermorken, J.B. Immunotherapy in Head and Neck Cancer: Aiming at EXTREME Precision. BMC Med. 2017, 15, 110. [Google Scholar] [CrossRef] [Green Version]
  101. Bauml, J.M.; Aggarwal, C.; Cohen, R.B. Immunotherapy for Head and Neck Cancer: Where Are We Now and Where Are We Going? Ann. Transl. Med. 2019, 7, S75. [Google Scholar] [CrossRef]
  102. Fasano, M.; Della Corte, C.M.; Di Liello, R.; Viscardi, G.; Sparano, F.; Iacovino, M.L.; Paragliola, F.; Piccolo, A.; Napolitano, S.; Martini, G.; et al. Immunotherapy for Head and Neck Cancer: Present and Future. Crit. Rev. Oncol. Hematol. 2022, 174, 103679. [Google Scholar] [CrossRef]
  103. Rischin, D.; Harrington, K.J.; Greil, R.; Soulières, D.; Tahara, M.; de Castro, G., Jr.; Psyrri, A.; Braña, I.; Neupane, P.; Bratland, Å.; et al. Pembrolizumab Alone or with Chemotherapy for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Health-Related Quality-of-Life Results from KEYNOTE-048. Oral Oncol. 2022, 128, 105815. [Google Scholar] [CrossRef]
  104. Marron, T.U.; Ryan, A.E.; Reddy, S.M.; Kaczanowska, S.; Younis, R.H.; Thakkar, D.; Zhang, J.; Bartkowiak, T.; Howard, R.; Anderson, K.G.; et al. Considerations for Treatment Duration in Responders to Immune Checkpoint Inhibitors. J. Immunother. Cancer 2021, 9, e001901. [Google Scholar] [CrossRef] [PubMed]
  105. Sepulveda, I.; Ascui, R.; Capizzano, A.A. Checkpoint Inhibitors in Head and Neck Cancer. Memo Mag. Eur. Med. Oncol. 2019, 12, 249–252. [Google Scholar] [CrossRef]
  106. Addeo, R.; Ghiani, M.; Merlino, F.; Ricciardiello, F.; Caraglia, M. CheckMate 141 Trial: All That Glitters Is Not Gold. Expert Opin. Biol. Ther. 2019, 19, 169–171. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Wise-Draper, T.M.; Bahig, H.; Tonneau, M.; Karivedu, V.; Burtness, B. Current Therapy for Metastatic Head and Neck Cancer: Evidence, Opportunities, and Challenges. Am. Soc. Clin. Oncol. Educ. book. Am. Soc. Clin. Oncol. Annu. Meet. 2022, 42, 527–540. [Google Scholar] [CrossRef] [PubMed]
  108. Wang, C.; Dickie, J.; Sutavani, R.V.; Pointer, C.; Thomas, G.J.; Savelyeva, N. Targeting Head and Neck Cancer by Vaccination. Front. Immunol. 2018, 9, 830. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  109. Schoenfeld, J.D. Immunity in Head and Neck Cancer. Cancer Immunol. Res. 2015, 3, 12–17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. Qureshi, H.A.; Lee, S.M. Immunotherapy Approaches Beyond PD-1 Inhibition: The Future of Cellular Therapy for Head and Neck Squamous Cell Carcinoma. Curr. Treat. Options Oncol. 2019, 20, 31. [Google Scholar] [CrossRef]
  111. Simpson, D.R.; Mell, L.K.; Cohen, E.E.W. Targeting the PI3K/AKT/MTOR Pathway in Squamous Cell Carcinoma of the Head and Neck. Oral Oncol. 2015, 51, 291–298. [Google Scholar] [CrossRef] [Green Version]
  112. Bowles, D.W.; Keysar, S.B.; Eagles, J.R.; Wang, G.; Glogowska, M.J.; McDermott, J.D.; Le, P.N.; Gao, D.; Ray, C.E.; Rochon, P.J.; et al. A Pilot Study of Cetuximab and the Hedgehog Inhibitor IPI-926 in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma. Oral Oncol. 2016, 53, 74–79. [Google Scholar] [CrossRef] [Green Version]
  113. Musumeci, F.; Greco, C.; Grossi, G.; Molinari, A.; Schenone, S. Recent Studies on Ponatinib in Cancers Other Than Chronic Myeloid Leukemia. Cancers 2018, 10, 430. [Google Scholar] [CrossRef] [Green Version]
  114. Forster, M.D.; Mendes, R.; Harrington, K.J.; Guerrero Urbano, T.; Baines, H.; Spanswick, V.J.; Ensell, L.; Hartley, J.A.; Adeleke, S.; Gougis, P.; et al. ORCA-2: A Phase I Study of Olaparib in Addition to Cisplatin-Based Concurrent Chemoradiotherapy for Patients with High Risk Locally Advanced Squamous Cell Carcinoma of the Head and Neck. J. Clin. Oncol. 2016, 34, TPS6108. [Google Scholar] [CrossRef]
  115. Cohen, E.E.W.; Rosen, F.; Stadler, W.M.; Recant, W.; Stenson, K.; Huo, D.; Vokes, E.E. Phase II Trial of ZD1839 in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck. J. Clin. Oncol. 2003, 21, 1980–1987. [Google Scholar] [CrossRef] [PubMed]
  116. Schettini, F.; De Santo, I.; Rea, C.G.; De Placido, P.; Formisano, L.; Giuliano, M.; Arpino, G.; De Laurentiis, M.; Puglisi, F.; De Placido, S.; et al. CDK 4/6 Inhibitors as Single Agent in Advanced Solid Tumors. Front. Oncol. 2018, 8, 608. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. Marur, S.; Wang, H.; Quon, H.; Chung, C.H.; Gillison, M.L.; Agrawal, N.; Richmon, J.; Subramaniam, R.M.; Koch, W.; Gourin, C.G.; et al. A Phase I (Ph1) Study of Dasatinib (D) with Cetuximab (Cet) /Radiation (IMRT) +/− Cisplatin (P) in Stage II, III/IV Head and Neck Squamous Cell Carcinoma (HNSCC). J. Clin. Oncol. 2015, 33, e17036. [Google Scholar] [CrossRef]
  118. Kim, Y.; Lee, S.J.; Park, K.; Lee, S.; Sun, J.M.; Keam, B.; An, H.J.; Cho, J.Y.; Kim, J.-S.; Lee, H.; et al. Phase II Trial of Nintedanib in Patients with Recurrent or Metastatic Salivary Gland Cancer: A Multicenter Phase II Study. J. Clin. Oncol. 2016, 34, 6090. [Google Scholar] [CrossRef]
  119. Karivedu, V.; Riaz, M.K.; Mathews, M.; Kurtzweil, N.; Monroe, I.; Romano, A.; Wise-Draper, T.M. A Phase II Study Evaluating the Efficacy of Niraparib and Dostarlimab (TSR-042) in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma. J. Clin. Oncol. 2022, 40, TPS6105. [Google Scholar] [CrossRef]
  120. Sola, A.M.; Johnson, D.E.; Grandis, J.R. Investigational Multitargeted Kinase Inhibitors in Development for Head and Neck Neoplasms. Expert Opin. Investig. Drugs 2019, 28, 351–363. [Google Scholar] [CrossRef]
  121. Adkins, D.R.; Lin, J.-C.; Sacco, A.; Ley, J.; Oppelt, P.; Vanchenko, V.; Komashko, N.; Yen, C.-J.; Wise-Draper, T.; Lopez-Picazo Gonzalez, J.; et al. Palbociclib and Cetuximab Compared with Placebo and Cetuximab in Platinum-Resistant, Cetuximab-Naïve, Human Papillomavirus-Unrelated Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Double-Blind, Randomized, Phase 2 Trial. Oral Oncol. 2021, 115, 105192. [Google Scholar] [CrossRef]
  122. Seebacher, N.A.; Stacy, A.E.; Porter, G.M.; Merlot, A.M. Clinical Development of Targeted and Immune Based Anti-Cancer Therapies. J. Exp. Clin. Cancer Res. 2019, 38, 156. [Google Scholar] [CrossRef] [Green Version]
  123. Guo, C.-X.; Huang, X.; Xu, J.; Zhang, X.-Z.; Shen, Y.-N.; Liang, T.-B.; Bai, X.-L. Combined Targeted Therapy and Immunotherapy for Cancer Treatment. World J. Clin. Cases 2021, 9, 7643–7652. [Google Scholar] [CrossRef]
  124. Harrington, K.; Cohen, E.; Siu, L.; Rischin, D.; Licitra, L.; Vermorken, J.; Le, Q.-T.; Tahara, M.; Machiels, J.-P.; Hawk, N.; et al. 351 Pembrolizumab plus Lenvatinib vs Chemotherapy and Lenvatinib Monotherapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma That Progressed on Platinum Therapy and Immunotherapy: LEAP-009. J. Immunother. Cancer 2020, 8, A214. [Google Scholar]
  125. Kordbacheh, F.; Farah, C.S. Current and Emerging Molecular Therapies for Head and Neck Squamous Cell Carcinoma. Cancers 2021, 13, 5471. [Google Scholar] [CrossRef] [PubMed]
  126. McLean, L.S.; Morris, T.A.; Gramza, A.; Liu, S.; Khan, S.A.; Colevas, A.D.; Pearce, T.; Rischin, D. A Phase II Study of Tarloxotinib (a Hypoxia Activated Prodrug of a Pan-Erb Tyrosine Kinase Inhibitor) in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck or Skin. Investig. New Drugs 2022, 40, 782–788. [Google Scholar] [CrossRef] [PubMed]
  127. Donnini, S.; Filippelli, A.; Ciccone, V.; Spini, A.; Ristori, E.; Ziche, M.; Morbidelli, L. Antiangiogenic Drugs: Chemosensitizers for Combination Cancer Therapy. In Antiangiogenic Drugs as Chemosensitizers in Cancer Therapy; Elsevier: Amsterdam, The Netherlands, 2022; pp. 29–66. [Google Scholar]
  128. Suh, Y.; Amelio, I.; Guerrero Urbano, T.; Tavassoli, M. Clinical Update on Cancer: Molecular Oncology of Head and Neck Cancer. Cell Death Dis. 2014, 5, e1018. [Google Scholar] [CrossRef] [Green Version]
  129. Vander Broek, R.; Mohan, S.; Eytan, D.; Chen, Z.; Van Waes, C. The PI3K/Akt/MTOR Axis in Head and Neck Cancer: Functions, Aberrations, Cross-Talk, and Therapies. Oral Dis. 2015, 21, 815–825. [Google Scholar] [CrossRef] [PubMed]
  130. Santuray, R.T.; Johnson, D.E.; Grandis, J.R. New Therapies in Head and Neck Cancer. Trends Cancer 2018, 4, 385–396. [Google Scholar] [CrossRef] [PubMed]
  131. Harsha, C.; Banik, K.; Ang, H.L.; Girisa, S.; Vikkurthi, R.; Parama, D.; Rana, V.; Shabnam, B.; Khatoon, E.; Kumar, A.P.; et al. Targeting AKT/MTOR in Oral Cancer: Mechanisms and Advances in Clinical Trials. Int. J. Mol. Sci. 2020, 21, 3285. [Google Scholar] [CrossRef] [PubMed]
  132. Marquard, F.E.; Jücker, M. PI3K/AKT/MTOR Signaling as a Molecular Target in Head and Neck Cancer. Biochem. Pharmacol. 2020, 172, 113729. [Google Scholar] [CrossRef]
  133. Anna Szymonowicz, K.; Chen, J. Biological and Clinical Aspects of HPV-Related Cancers. Cancer Biol. Med. 2020, 17, 864–878. [Google Scholar] [CrossRef]
  134. Kroonen, J.S.; Vertegaal, A.C.O. Targeting SUMO Signaling to Wrestle Cancer. Trends Cancer 2021, 7, 496–510. [Google Scholar] [CrossRef]
  135. Gunaydin, G.; Gedik, M.E.; Ayan, S. Photodynamic Therapy—Current Limitations and Novel Approaches. Front. Chem. 2021, 9, 691697. [Google Scholar] [CrossRef] [PubMed]
  136. Meulemans, J.; Delaere, P.; Vander Poorten, V. Photodynamic Therapy in Head and Neck Cancer: Indications, Outcomes, and Future Prospects. Curr. Opin. Otolaryngol. Head Neck Surg. 2019, 27, 136–141. [Google Scholar] [CrossRef] [PubMed]
  137. Civantos, F.J.; Karakullukcu, B.; Biel, M.; Silver, C.E.; Rinaldo, A.; Saba, N.F.; Takes, R.P.; Vander Poorten, V.; Ferlito, A. A Review of Photodynamic Therapy for Neoplasms of the Head and Neck. Adv. Ther. 2018, 35, 324–340. [Google Scholar] [CrossRef] [PubMed]
  138. Marchal, S.; Dolivet, G.; Lassalle, H.-P.; Guillemin, F.; Bezdetnaya, L. Targeted Photodynamic Therapy in Head and Neck Squamous Cell Carcinoma: Heading into the Future. Lasers Med. Sci. 2015, 30, 2381–2387. [Google Scholar] [CrossRef] [PubMed]
  139. Ramsay, D.; Stevenson, H.; Jerjes, W. From Basic Mechanisms to Clinical Research: Photodynamic Therapy Applications in Head and Neck Malignancies and Vascular Anomalies. J. Clin. Med. 2021, 10, 4404. [Google Scholar] [CrossRef]
  140. Saini, R.; Lee, N.; Liu, K.; Poh, C. Prospects in the Application of Photodynamic Therapy in Oral Cancer and Premalignant Lesions. Cancers 2016, 8, 83. [Google Scholar] [CrossRef] [Green Version]
  141. Silva, C.O.; Rijo, P.; Molpeceres, J.; Ascensão, L.; Roberto, A.; Fernandes, A.S.; Gomes, R.; Pinto Coelho, J.M.; Gabriel, A.; Vieira, P.; et al. Bioproduction of Gold Nanoparticles for Photothermal Therapy. Ther. Deliv. 2016, 7, 287–304. [Google Scholar] [CrossRef]
  142. Costa, E.; Ferreira-Gonçalves, T.; Cardoso, M.; Coelho, J.M.P.; Gaspar, M.M.; Faísca, P.; Ascensão, L.; Cabrita, A.S.; Reis, C.P.; Figueiredo, I.V. A Step Forward in Breast Cancer Research: From a Natural-Like Experimental Model to a Preliminary Photothermal Approach. Int. J. Mol. Sci. 2020, 21, 9681. [Google Scholar] [CrossRef]
  143. Ferreira-Gonçalves, T.; Gaspar, M.M.; Coelho, J.M.P.; Marques, V.; Viana, A.S.; Ascensão, L.; Carvalho, L.; Rodrigues, C.M.P.; Ferreira, H.A.; Ferreira, D.; et al. The Role of Rosmarinic Acid on the Bioproduction of Gold Nanoparticles as Part of a Photothermal Approach for Breast Cancer Treatment. Biomolecules 2022, 12, 71. [Google Scholar] [CrossRef]
  144. Amaral, M.; Charmier, A.J.; Afonso, R.A.; Catarino, J.; Faísca, P.; Carvalho, L.; Ascensão, L.; Coelho, J.M.P.; Gaspar, M.M.; Reis, C.P. Gold-Based Nanoplataform for the Treatment of Anaplastic Thyroid Carcinoma: A Step Forward. Cancers 2021, 13, 1242. [Google Scholar] [CrossRef]
  145. Lopes, J.; Ferreira-Gonçalves, T.; Figueiredo, I.V.; Rodrigues, C.M.P.; Ferreira, H.; Ferreira, D.; Viana, A.S.; Faísca, P.; Gaspar, M.M.; Coelho, J.M.P.; et al. Proof-of-Concept Study of Multifunctional Hybrid Nanoparticle System Combined with NIR Laser Irradiation for the Treatment of Melanoma. Biomolecules 2021, 11, 511. [Google Scholar] [CrossRef] [PubMed]
  146. Lopes, J.; Coelho, J.M.P.; Vieira, P.M.C.; Viana, A.S.; Gaspar, M.M.; Reis, C. Preliminary Assays towards Melanoma Cells Using Phototherapy with Gold-Based Nanomaterials. Nanomaterials 2020, 10, 1536. [Google Scholar] [CrossRef] [PubMed]
  147. Li, X.; Lovell, J.F.; Yoon, J.; Chen, X. Clinical Development and Potential of Photothermal and Photodynamic Therapies for Cancer. Nat. Rev. Clin. Oncol. 2020, 17, 657–674. [Google Scholar] [CrossRef] [PubMed]
  148. Lopes, J.; Rodrigues, C.M.P.; Gaspar, M.M.; Reis, C.P. How to Treat Melanoma? The Current Status of Innovative Nanotechnological Strategies and the Role of Minimally Invasive Approaches like PTT and PDT. Pharmaceutics 2022, 14, 1817. [Google Scholar] [CrossRef] [PubMed]
  149. Chen, F.; Cai, W. Nanomedicine for Targeted Photothermal Cancer Therapy: Where Are We Now? Nanomedicine 2015, 10, 1–3. [Google Scholar] [CrossRef] [PubMed]
  150. Chen, J.; Li, Q.; Wang, F.; Yang, M.; Xie, L.; Zeng, X. Biosafety, Nontoxic Nanoparticles for VL–NIR Photothermal Therapy Against Oral Squamous Cell Carcinoma. ACS Omega 2021, 6, 11240–11247. [Google Scholar] [CrossRef] [PubMed]
  151. Fernandes, N.; Rodrigues, C.F.; Moreira, A.F.; Correia, I.J. Overview of the Application of Inorganic Nanomaterials in Cancer Photothermal Therapy. Biomater. Sci. 2020, 8, 2990–3020. [Google Scholar] [CrossRef]
  152. Ali, M.R.K.; Rahman, M.A.; Wu, Y.; Han, T.; Peng, X.; Mackey, M.A.; Wang, D.; Shin, H.J.; Chen, Z.G.; Xiao, H.; et al. Efficacy, Long-Term Toxicity, and Mechanistic Studies of Gold Nanorods Photothermal Therapy of Cancer in Xenograft Mice. Proc. Natl. Acad. Sci. USA 2017, 114, E3110–E3118. [Google Scholar] [CrossRef] [Green Version]
  153. Dickerson, E.B.; Dreaden, E.C.; Huang, X.; El-Sayed, I.H.; Chu, H.; Pushpanketh, S.; McDonald, J.F.; El-Sayed, M.A. Gold Nanorod Assisted Near-Infrared Plasmonic Photothermal Therapy (PPTT) of Squamous Cell Carcinoma in Mice. Cancer Lett. 2008, 269, 57–66. [Google Scholar] [CrossRef] [Green Version]
  154. Ali, M.R.K.; Wu, Y.; El-Sayed, M.A. Gold-Nanoparticle-Assisted Plasmonic Photothermal Therapy Advances Toward Clinical Application. J. Phys. Chem. C 2019, 123, 15375–15393. [Google Scholar] [CrossRef]
  155. Betzer, O.; Ankri, R.; Motiei, M.; Popovtzer, R. Theranostic Approach for Cancer Treatment: Multifunctional Gold Nanorods for Optical Imaging and Photothermal Therapy. J. Nanomater. 2015, 16, 381. [Google Scholar] [CrossRef]
  156. Riley, R.S.; Day, E.S. Gold Nanoparticle-mediated Photothermal Therapy: Applications and Opportunities for Multimodal Cancer Treatment. WIREs Nanomed. Nanobiotechnol. 2017, 9, e1449. [Google Scholar] [CrossRef] [PubMed]
Cancers 14 06079 g001 550
Figure 1. Incidence, mortality, and respective crude rates of the most prevalent subtypes of Head and Neck Cancer (HNC) worldwide in 2020, according to the Global Cancer Observatory (GCO), as determined by the International Agency for Research on Cancer (IARC).
Figure 1. Incidence, mortality, and respective crude rates of the most prevalent subtypes of Head and Neck Cancer (HNC) worldwide in 2020, according to the Global Cancer Observatory (GCO), as determined by the International Agency for Research on Cancer (IARC).
Cancers 14 06079 g001
Cancers 14 06079 g002 550
Figure 2. Generalized guidelines for the treatment of HNC (CRT—Chemoradiotherapy, RT—Radiotherapy and ChT—Chemotherapy).
Figure 2. Generalized guidelines for the treatment of HNC (CRT—Chemoradiotherapy, RT—Radiotherapy and ChT—Chemotherapy).
Cancers 14 06079 g002
Table
Table 1. Etiologic factors of HNC.
Table 1. Etiologic factors of HNC.
Non-infectious Risk FactorsSubstance UseTobacco
Betel chewing
Alcohol
BehaviouralPoor oral and dental hygiene
Solar exposure
Dietary DeficienciesInadequate nutrition
Vitamin A
Iron (in Plummer–Vinson Syndrome)
Occupational HazardsAsbestos
Radium
Mustard Gas
Nickel
Radiation
Leather tanning by-products
Woodworking by-products
Chromium
Infectious Risk FactorsHPV
EBV
HPV—Human Papillomavirus; EBV—Epstein–Barr virus.
Table
Table 2. TNM staging system of Head and Neck cancer (HNC) according to the 8th Edition of the American Joint Committee of Cancer (AJCC) Staging Manual (2017) [70].
Table 2. TNM staging system of Head and Neck cancer (HNC) according to the 8th Edition of the American Joint Committee of Cancer (AJCC) Staging Manual (2017) [70].
Anatomical LocationTNMStage
UnknownT0 (location unknown)N1 (≤3 cm ipsilateral nodal metastasis and ENE-)M0III
N2 (3–6 cm ipsilateral nodal metastasis and ENE-)M0IVA
N3 (≥6 cm ipsilateral nodal metastasis and ENE-, or any ENE+ nodal metastasis)M0IVB
Any NM1IVC
Lip and Oral CavityT1 (tumour ≤ 2 cm, DOI ≤ 5 mm) N0 (no regional nodal metastasis)M0I
T2 (tumour ≤ 2 cm, DOI 5–10 mm)II
T3 (tumour > 4 cm or DOI >10 mm)III
T1,2,3N1 (≤3 cm ipsilateral nodal metastasis and ENE-)
T4a (moderate local disease)N0,1IVA
T1,2,3,4aN2 (3–6 cm ipsilateral nodal metastasis and ENE-, or multiple ≤6 cm ipsilateral nodal metastasis and ENE-, or ≤6 cm bilateral or contralateral nodal metastasis)
Any TN3 (≥6 cm ipsilateral nodal metastasis and ENE-, or any ENE+ nodal metastasis)IVB
T4b (very advanced local disease)Any N
Any TM1IVC
Major Salivary GlandsTis (carcinoma in situ)N0 (no regional nodal metastasis)M00
T1 (tumour ≤ 2 cm, w/o extraparenchymal extension)I
T2 (tumour 2–4 cm, w/o extraparenchymal extension)II
T3 (tumour ≥ 4 cm, and/or with extraparenchymal extension)III
T0,1,2,3N1 (≤3 cm ipsilateral nodal metastasis and ENE-)
T4a (moderate local disease)N0,1IVA
T0, 1, 2, 3, 4aN2 (3–6 cm ipsilateral nodal metastasis and ENE-, or multiple ≤ 6 cm ipsilateral nodal metastasis and ENE-, or ≤ 6 cm bilateral or contralateral nodal metastasis)
Any TN3 (≥6 cm ipsilateral nodal metastasis and ENE-, or any ENE+ nodal metastasis)IVB
T4b (very advanced local disease)Any N
Any TM1IVC
NasopharynxTisN0 (no regional nodal metastasis)M00
T1 (tumour limited to the naso-, or with locoregional invasion of the oropharynx and nasal cavity)I
T1,0 (tumour not identified, EBV+ cervical nodes)N1 (≤6 cm unilateral cervical lymph nodes metastasis, or uni-/bilateral retropharyngeal lymph nodes metastasis, above the cricoidal cartilage caudal border)II
T2 (tumour invading parapharyngeal space and/or adjacent soft tissue) N0
N1
T1, 0 N2 (≤6 cm bilateral retropharyngeal lymph nodes metastasis above the cricoidal cartilage caudal border)III
T2
T3 (tumour invading surrounding bone structures)N0
N1
N2
T4 (tumour with extensive soft tissue invasion and/or with intracranial extension)N0IVA
N1
N2
Any TN3 (>6 cm uni-/bilateral retropharyngeal lymph nodes metastasis and/or below the cricoidal cartilage caudal border)
Any NM1IVB
HPV+ OropharynxT0,1,2 (tumour not identified; tumour ≤ 2 cm or 2–4 cm)N0,1 (no regional nodal metastasis; one or more ≤6 cm ipsilateral nodal metastasis)M0I
N2 (≤6 cm contralateral or bilateral nodal metastasis)II
T3 (tumour < 4 cm or with invasion of epiglottis lingual surface)N0,1,2
T0,1,2,3,4N3 (>6 cm nodal metastasis)III
T4 (moderate locoregional invasion)N0,1,2,3
Any TAny NM1IV
HPV- Oropharynx and HypopharynxTis (carcinoma in situ)N0 (no regional nodal metastasis)M00
T1 (tumour ≤ 2 cm)I
T2 (tumour 2–4 cm)II
T3 (tumour < 4 cm or with invasion of epiglottis lingual surface)III
T1,2,3N1 (≤3 cm ipsilateral nodal metastasis and ENE-)
T4a (tumour with moderate locoregional invasion)N0,1IVA
T1,2,3,4aN2 (3–6 cm ipsilateral nodal metastasis and ENE-, or multiple ≤ 6 cm ipsilateral nodal metastasis and ENE-)
Any TN3 (≥6 cm ipsilateral nodal metastasis and ENE-, or any ENE+ nodal metastasis)IVB
T4b (very advanced locoregional invasion)Any N
Any TM1IVC
Nasal Cavity and Paranasal SinusesTis (carcinoma in situ)N0 (no regional nodal metastasis)M00
T1 (limited to one subsite, with or without bone invasion)I
T2 (two subsites or invading adjacent subsites, with or without bone invasion)II
T3 (locoregional invasion of orbital medial wall or floor, maxillary sinus, palate, and cribriform plate)III
T1,2,3N1 (≤3 cm ipsilateral nodal metastasis and ENE-)
T4a (moderate locoregional invasion)N0,1IVA
T1,2,3,4aN2 (3–6 cm ipsilateral nodal metastasis and ENE-, or multiple ≤ 6 cm ipsilateral nodal metastasis and ENE-, or ≤ 6 cm bilateral or contralateral nodal metastasis)
Any TN3 (≥6 cm ipsilateral nodal metastasis and ENE-, or any ENE+ nodal metastasis)IVB
T4b (very advanced locoregional invasion)Any N
Any TM1IVC
Larynx
(T classification depends on tumour location: supraglottis, glottis, subglottis)		Tis (carcinoma in situ)N0 (no regional nodal metastasis)M00
T1 I
T2 II
T3 III
T1,2,3N1 (≤3 cm ipsilateral nodal metastasis and ENE-)
T4a N0,1IVA
T1,2,3,4aN2 (3–6 cm ipsilateral nodal metastasis and ENE-, or multiple ≤ 6 cm ipsilateral nodal metastasis and ENE-, or ≤ 6 cm bilateral or contralateral nodal metastasis)
Any TN3 (≥6 cm ipsilateral nodal metastasis and ENE-, or any ENE+ nodal metastasis)IVB
T4b Any N
Any TM1IVC
Cutaneous HNSCCTis (carcinoma in situ)N0 (no regional nodal metastasis)M00
T1 (tumour ≤ 2 cm)I
T2 (tumour 2–4 cm)II
T3 (tumour ≥ 4 cm, or minor bone invasion, or perineural invasion, or deep soft tissue invasion)III
T1N1 (≤3 cm ipsilateral nodal metastasis and ENE-)
T2
T3
T1N2 (3–6 cm ipsilateral nodal metastasis and ENE-, or multiple ≤ 6 cm ipsilateral nodal metastasis and ENE-, or ≤6 cm bilateral or contralateral nodal metastasis)IV
T2
T3
Any TN3 (≥6 cm ipsilateral nodal metastasis and ENE-, or any ENE+ nodal metastasis)
T4 (major cortical bone/marrow invasion, skull base invasion or skull base foramen invasion) Any N
Any TM1
Thyroid CancerDifferentiated<55 years oldAny TAny NM0I
M1II
≥55 years oldT1 (tumour ≤ 2 cm, confined to the thyroid)N0/NX (no regional nodal metastasis; regional lymph nodes cannot be assessed)M0I
N1 (regional nodal metastasis) II
T2 (tumour 2–4 cm, confined to the thyroid)N0/NXI
N1 II
T3 (tumour ≥ 4 cm, confined to the thyroid or locoregional invasion of surrounding muscles)Any N
T4a (gross extrathyroidal invasion of subcutaneous soft tissues, larynx, trachea, oesophagus)III
T4b (gross extrathyroidal invasion of prevertebral fascia, or encasing of the carotid artery or mediastinal vessels of any size)IVA
Any TM1IVB
Anaplastic
(T and N w/ same definition as for differentiated thyroid carcinoma)		T1,2,3aN0/XM0IVA
N1IVB
T3bAny N
T4
Any TM1IVC
Medullary
(T and N with same definition as for differentiated thyroid carcinoma)		T1N0M0I
T2II
T3
T1,2,3N1aIII
T4aAny NIVA
T1,2,3N1b
T4bAny NIVB
Any TM1IVC
T—tumour; N—node; M—metastasis; ENE—Extranodal Extension; DOI—Depth of Tumour Invasion; EBV—Epstein–Barr virus; HPV—Human Papillomavirus; HNSCC—Head and Neck Squamous Cell Carcinoma; M0—no distant metastasis; M1—the presence of distant metastasis.
Table
Table 3. Histopathology of HNC and their main characteristics [79,80].
Table 3. Histopathology of HNC and their main characteristics [79,80].
Histopathological SubtypeMain Characteristics
EpithelialConventionalSquamous Cell CarcinomaCharacteristics of squamous epithelium that penetrated the basement membrane. Different degrees of differentiation.
VerrucousResembles common wart with a pushing border and blunt bulbous projections in a chronically inflamed stroma.
PapillaryNarrow papillae with fibrovascular cores (rare variant). HPV-positive or -negative.
BasaloidCribriform nests of small cells with high nuclear to cytoplasm ratio (aggressive variant). Oropharyngeal forms are likely to be HPV+.
Spindle cellPolypoid mass with areas of conventional SCC (rare variant). Bone and cartilage may also be present.
LymphoepithelialEBV+ undifferentiated carcinoma presents as a nest or single-cell population in the presence of lymphocytes.
Intestinal-typeSinonasal AdenocarcinomaResembles the aggressive form of colon adenocarcinoma.
Non-intestinal-typeResemble normal sero-mucinous glands, with solid growth pattern, necrosis and marked nuclear atypia.
Sinonasal UndifferentiatedCarcinomaUnknown etiology, presenting as sheets of mitotically active large cells with large nucleoli (aggressive variant). Sometimes presents p16 expression when negative for HPV.
NasopharyngealKeratinizing, non-keratinizing or non-keratinizing undifferentiated. The latter two are EBV+.
Large Cell NeuroendocrineLarge cells with abundant cytoplasm and typical neuroendocrine immunophenotype.
Small Cell NeuroendocrineResembles its lung namesake.
MucoepidermoidLow-grade tumours usually present larger populations of mucous cells, while high-grade forms present epithelioid and intermediate cells. Translocation t(11;19) is a marker of favourable prognostic.
Adenoid CysticTumour of the major or minor salivary glands, presenting as tubules, cribriform or solid nests, with patterns of luminal or abluminal differentiation.
Acinic CellResembles the normal parotid gland, with absent ducts.
Epithelial–MyoepithelialTumours with the highest degree of luminal and abluminal differentiation, with focal areas containing bi-layered ducts, with columnar epithelial and myoepithelial cells.
Salivary DuctInfiltrating cord, papillae, and large nests with necrosis. Usually expresses androgen receptor (AR), overexpresses HER2, and is negative for oestrogen (ER) and progesterone (PR) receptors.
Polymorphous Low GradeAdenocarcinomaTumour of the minor salivary glands similar to adenoid cystic carcinoma, but with polymorphous architecture, and no luminal or abluminal differentiation.
Basal CellProminent basement membrane and hyaline globules scattered within a nest architecture.
Ceruminous GlandSimilar features to salivary gland carcinomas, presenting as an infiltrative cribriform nest, with luminal and/or abluminal cells.
Olfactory NeuroblastomaUniform blue cells arranged in rosettes in neurofibrillary background. Poorly differentiated forms loose lobular architecture and present necrosis.
Ewing’s SarcomaSmall blue cells with t(11;22) translocation involving EWS and FLI-1 genes, seen in adolescents and young adults.
Primitive Neuroectodermal TumourSimilar to Ewing’s sarcoma but seen in any age group and presents neuroendocrine differentiation. Mutation in p53 signifies a poorer prognosis.
MelanomaSame presentation of melanoma at other sites.
Carcinoma ex Pleomorphic AdenomaA benign tumour mixed with adenocarcinoma, composed of epithelial and/or mesenchymal entities.
AmeloblastomaOdontogenic epithelium, resembling the enamel organ of developing tooth.
MesenchymalOsteosarcomaResembles osteosarcoma of other sites.
LaryngealChondrosarcomaLobulated nodules of cartilage, with increased cellularity with nuclear pleomorphism. Spindle cells may be present.
MesenchymalRare form with distinctive biphasic appearance, presenting as nodules of hyaline cartilage surrounded by sheets of small or spindle cells.
ConventionalChondromasPseudoencapsulated tumours with fibrous bands, with the cells growing in cords, sheets, or pseudo-glandular entities, in a mucinous matrix.
DedifferentiatedLike conventional chondromas, but lack mucinous matrix.
ChondroidConventional chondrosarcoma with the addition of cartilage foci.
EmbryonalRhabdo-myosarcomaA wide range of presentations, from undifferentiated cells to those resembling foetal muscle. Stains for skeletal muscle-specific markers.
BotryoidPolypoid masses, formed by hypocellular zones separated from the epithelium by a hypocellular layer of connective tissue.
AlveolarSmall round cells separated by dense fibrous septae into nests, with dicohesive cells in the centre.
Mesenchymal Extrarenal Rhabdoid Tumour Rhabdoid cells and loss of nuclear INI1 expression.
Alveolar Soft PartsSarcomaHighly vascular tumours presenting as nests, formed by dicohesive cells, with haemorrhagic and necrotic areas.
Synovialt(X;18) (p11;q11) translocation.
Follicular Dendritic CellSpindle cells present in fascicular, storiform or diffuse pattern, in the presence of lymphocytes.
LymphoidConventionalLymphomaCan present as Hodgkin’s or non-Hodgkin’s lymphoma (NHL).
Diffuse Large B-cellMost common lymphoma of the head and neck, presenting as sheets/clusters of intermediate-to-large cells, with large necrotic areas.
PlasmablasticRare variant of diffuse large B-cell lymphoma, presenting as large plasmocytic cells, proliferating diffusely, with abundant apoptotic bodies. They may also present necrotic regions.
MALTSmall-to-medium lymphocytes in size with pale cytoplasm, or plasmacytic features. Translocation t(11;18) (q21;q21) is frequent.
Extranodal NK-/-T-Cell of Nasal TypeMixture of cells with different dimensions, irregular nuclei and amounts of pale cytoplasm, and chronic inflammatory infiltrates. The overlying mucosa usually presents as ulcerated but can range to hyperplastic. Commonly EBV+.
Burkitt’sUniform mitotic lymphoid cells, with interspersed macrophages and phagocytized apoptotic tumour cells. Can be EBV+.
PlasmacytomaSheets and nests of plasma cells, sometimes with plasmablastic features, and scattered multinucleated giant tumour cells.
SCC—Squamous Cell Carcinoma; HPV—Human Papilloma Virus; EBV—Epstein–Barr Virus; HNC—Head and Neck Cancer; AR—Androgen Receptor; ER—Oestrogen Receptor; PR—Progesterone Receptor; NHL—Non-Hodgkin’s Lymphoma; MALT—Mucosa-Associated Lymphoid Tissue; NK—Natural Killer T Cell.
Table
Table 4. Examples of different targeted therapies in clinical trials for HNC and respective targets.
Table 4. Examples of different targeted therapies in clinical trials for HNC and respective targets.
TargetDrugTherapeutic Indication(s)PhaseClinicalTrials.Gov ID
PI3KBuparlisibR/M HNSCCIIINCT04338399
AlpelisibIINCT04997902
CopanlisibINCT03735628
EganelisibINCT02637531
DuvelisibR/M and non-R/M HNSCCIINCT05057247
PI3K and mTORGedatolisibR/M or Advanced HNCINCT03065062
AKTIpatasertibINCT05172245
NCT05172258
II
p53COTI-2HNCINCT02433626
AdvexinR/M HNSCCIINCT03544723
EGFRErlotinibIINCT00076310
NCT01927744
NCT00954226
HNSCCII
HNCI
AfatinibR/M HNSCCIINCT02979977
Resectable HNSCCIINCT05517330
NCT05516589
II
R/M HNSCCIIINCT01856478
DacomitinibIINCT04946968
LapatinibLocalized HNSCCIINCT01612351
HNCIINCT01711658
PARPOlaparibINCT02308072
INCT02229656
NiraparibR/M HNSCCIINCT04313504
HNCIINCT05169437
IINCT04779151
SmoothenedSonidegibR/M HNSCCINCT04007744
VEGFRBevacizumabLocalized HNSCCIINCT01588431
HNCIIINCT05063552
NCT00588770
R/M HNSCCIII
Localized HNSCCI and IINCT03134846
HNCIINCT03818061
LenvatinibR/M HNSCCIINCT04977453
CabozantinibHNCIINCT05136196
INCT03170960
HNSCCINCT03667482
R/M HNSCCIINCT03468218
R/M HNCINCT04514484
SorafenibR/M HNSCCIINCT00494182
SurufatinibR/M HNCIINCT04910854
AbemaciclibR/M HNSCCIINCT03356223
HNSCCIINCT04169074
RibociclibINCT04000529
HNC—Head and Neck Cancer; HNSCC—Head and Neck Squamous Cell Carcinoma; R/M—Recurrent/metastatic.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Amaral, M.N.; Faísca, P.; Ferreira, H.A.; Gaspar, M.M.; Reis, C.P. Current Insights and Progress in the Clinical Management of Head and Neck Cancer. Cancers 2022, 14, 6079. https://doi.org/10.3390/cancers14246079

AMA Style

Amaral MN, Faísca P, Ferreira HA, Gaspar MM, Reis CP. Current Insights and Progress in the Clinical Management of Head and Neck Cancer. Cancers. 2022; 14(24):6079. https://doi.org/10.3390/cancers14246079

Chicago/Turabian Style

Amaral, Mariana Neves, Pedro Faísca, Hugo Alexandre Ferreira, Maria Manuela Gaspar, and Catarina Pinto Reis. 2022. "Current Insights and Progress in the Clinical Management of Head and Neck Cancer" Cancers 14, no. 24: 6079. https://doi.org/10.3390/cancers14246079

APA Style

Amaral, M. N., Faísca, P., Ferreira, H. A., Gaspar, M. M., & Reis, C. P. (2022). Current Insights and Progress in the Clinical Management of Head and Neck Cancer. Cancers, 14(24), 6079. https://doi.org/10.3390/cancers14246079

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop