Management of HPV-Related Squamous Cell Carcinoma of the Head and Neck: Pitfalls and Caveat

Abstract

Head and neck squamous cell carcinomas (HNSCCs) are a very heterogeneous group of malignancies arising from the upper aerodigestive tract. They show different clinical behaviors depending on their origin site and genetics. Several data support the existence of at least two genetically different types of HNSCC, one virus-related and the other alcohol and/or tobacco and oral trauma-related, which show both clinical and biological opposite features. In fact, human papillomavirus (HPV)-related HNSCCs, which are mainly located in the oropharynx, are characterized by better prognosis and response to therapies when compared to HPV-negative HNSCCs. Interestingly, virus-related HNSCC has shown a better response to conservative (nonsurgical) treatments and immunotherapy, opening questions about the possibility to perform a pretherapy assessment which could totally guide the treatment strategy. In this review, we summarize molecular differences and similarities between HPV-positive and HPV-negative HNSCC, highlighting their impact on clinical behavior and on therapeutic strategies.Cancers 2020, 12, 975 2 of 14 papilloma virus (HPV)-related tumors [1][2][3]. Several lines of evidence support the existence of at least two genetically different types of HNSCC, one virus-related and the other alcohol and/or tobacco and oral trauma-related, characterized by both clinical and biological opposite features [3,4]. Unlike HPV-negative HNSCC, HPV-positive HNSCC often occurs in younger patients with minimal or no tobacco exposure [5,6]. HPV-positive HNSCC, similarly to its HPV-negative counterpart, has a male predominance, with men suffering a three-to-five times higher incidence than women worldwide [7].HPV-positive HNSCC carries a favorable prognosis if compared to HPV-negative tumors. In fact, five-year survival rates for patients with advanced-stage HPV-positive HNSCC are 75-80%, versus values less than 50% in patients with similarly staged HPV-negative tumors [8,9]. The cause of the aforementioned different behavior is the different chemo-and radiosensitivity shown by the HPV-positive and HPV-negative HNSCCs. In fact, several clinical trials have shown that HPV-positive HNSCC patients have a better response to chemotherapy and radiation therapy than HPV-negative cases [10][11][12]. The reasons for this different behavior should be searched in the opposite genetic features which characterize the two types of tumors.In this review, we will analyze the genetics of both HPV-positive and HPV-negative HNSCC, highlighting their impact on the clinical behavior and finally on the therapeutic strategies. Genetics of HPV-Positive HNSCCCarcinogenesis, which is the complex process through which the normal cell is pushed to transform itself into a cancer cell, is very different between HPV-related and non-HPV-related HNSCC. Viral carcinogenesis in HNSCC is partly due to HPV infection, with the oropharynx being the most commonly involved site. HPV-mediated carcinogenesis is driven by a few viral oncoproteins expressed by high-risk HPV genotypes....

Lack of CD44 overexpression and application of concurrent chemoradiotherapy with cisplatin independently indicate excellent prognosis in patients with HPV-positive oropharyngeal cancer

“…It is also worth to notice, that in all meta-analyses regarding relation between HPV infection and prognosis, this relation was tested irrespectively of treatment type [4][5][6][7]. Therefore, other factors, including stimulation of immune response through viral infection and/or beneficial epidemiological and clinical features (younger age, white race, better performance status, no addiction to nicotine and alcohol) of HPV positive patients may be responsible for better prognosis [3]. Summarizing this part of discussion, it seems that OPSCC patients with HPV positivity respond better to CisPt-CRT, however, the results of research aimed at explaining mechanisms related to this observation are inconclusive.…”

“…Some studies suggest that there may be a subpopulation of cancer stem cells (CSCs), which simultaneously exhibit unlimited ability to self-renew and differentiate towards neoplastic cells [2]. However, with regard to prognosis of HNSCC patients, it should be taken into account that, as was shown in many studies (for review see [3]) and meta-analyses [4][5][6][7], better prognosis is related to Human Papillomavirus (HPV) infection. This infection (most often with HPV16) is currently considered an important etiological factor in the development of squamous cell carcinoma of the oropharynx (OPSCC) [3][4][5][6][7].…”

Topical 5% Imiquimod Sequential to Surgery for HPV-Related Squamous Cell Carcinoma of the Lip

“…This case suggests that the combination of surgery and subsequent application of topical 5% imiquimod may reduce the risk of relapses when surgery has not been radical, proposing an alternative treatment in elderly patients or in areas where surgical enlargement may be cosmetically unacceptable, has been refused, or is not possible. Testing SCC for HPV positivity may help select the better treatment available, as HPV-related SCC is usually less invasive [8]. This kind of treatment could also be proposed to selected patients with a superficial disease, no risk of metastasis, and when standard care has been refused or is not possible.…”

“…HPV 16 accounts for 90% of cases. HPV-associated cancers tend to have increased survival and better outcomes [8], although SCC affecting the perioral region tends to have a worse prognosis than other types of SCC [9].…”

Human Papillomavirus and Cancers

“…Numerous studies have shown that virus-related HNSCCs possess peculiar clinical and biological features. Perri et al described the molecular differences and similarities between HPV-negative and HPV-positive HNSCC including the better prognosis and response to therapies of the latter group of patients [ 15 ]. Remarkably, patients with HPV-driven HNSCCs are frequently more responsive to conservative treatments and immunotherapy, opening questions about the use of pre-therapy assessment in order to guide the treatment strategy.…”