Human Papillomavirus as a Marker of the Natural History and Response to Therapy of Head and Neck Squamous Cell Carcinoma

doi:10.1016/j.semradonc.2011.12.004

Seminars in Radiation Oncology

Volume 22, Issue 2, April 2012, Pages 128-142

https://doi.org/10.1016/j.semradonc.2011.12.004 Get rights and content

There has been a gradual change in the demographics of head and neck carcinoma. Although relatively uncommon, the incidence of oropharyngeal carcinoma has been increasing despite declining tobacco consumption and contrary to a diminishing incidence of cancers at other head and neck sites. It is now clear that the incidence of human papillomavirus (HPV)-associated oropharyngeal cancers is rising, likely as a consequence of changing life styles and sexual behaviors. Many studies have contributed to understanding the characteristics of HPV-related oropharyngeal carcinoma, which usually presents as nonkeratinizing squamous cell carcinoma of low to intermediate T-category and affects middle-aged white men, having higher socioeconomic status and no or brief history of tobacco consumption. The diagnosis of this distinct neoplastic entity can be firmly established by a combination of p16 immunohistochemical and in situ hybridization assays. Compared with the traditional smoking-associated head and neck squamous cell carcinoma, HPV-related oropharyngeal carcinoma has a favorable natural history and responds better to treatment. Consequently, patients with this cancer have better long-term survival than those with HPV-unrelated head and neck squamous cell carcinoma (eg, 5-year overall survival rate of >80% versus ∼40% for patients with stage III-IV tumors), and hence they are more likely to experience chronic therapy-induced morbidity. Therefore, changes in evaluation, staging, and treatment are needed for this patient group. However, attempts to change the treatment for HPV-associated oropharyngeal carcinoma should take place in a closely monitored clinical trial setting. In this article, we summarize the epidemiology, diagnosis, and clinical behavior of HPV-associated oropharyngeal carcinoma, with emphasis on prognostic and biomarker discovery aspects, and discuss briefly the current thoughts on changing the treatment paradigms aimed at reducing morbidity while preserving the high tumor control probability through well-coordinated prospective trials.

Section snippets

Changing Epidemiology of Head and Neck Cancer

HNSCC is one of several cancers that are strongly associated with tobacco use.⁴ As presented by Giovino⁵ in an overview article and illustrated in Figure 1A, smoking of manufactured cigarettes accounted for 1% of all tobacco consumed in the United States in the 1880s, but this form of use increased progressively to about 80% by 1950 when overall annual tobacco consumption peaked at about 13 pounds per person per year. After mounting evidence of the association between tobacco use and lung

Emergence of HPV-Associated Oropharyngeal Carcinoma

The role of some of HPV types, most notably HPV16 and HPV18, in the pathogenesis of cancer of the uterine cervix has been recognized for over 2 decades (reviewed by zur Hausen9, 10). It is now accepted that carcinogenic effects are mainly mediated through 2 high-risk HPV oncoproteins, E6 and E7, which inactivate the tumor protein 53 (TP53) (also referred to as protein 53 [p53]) and retinoblastoma tumor suppressor gene products, respectively,11, 12 thereby disrupting cell cycle regulatory

Histology

There has not been a uniform terminology for reporting of HPV-associated oropharyngeal carcinoma until recently. Histologically, HPV-associated oropharyngeal carcinomas have been misinterpreted as poorly differentiated carcinomas based on the immature appearance of tumor cells or often described as “basaloid” carcinoma based on the lobular growth of cells with hyperchromatic nuclei and a high nuclear to cytoplasmic ratio. A recent study showed that the “basaloid” subtype consists of a mixed

Case Control Series

Several single institutional, retrospective series published about a decade ago suggested that patients with HPV-positive oropharyngeal carcinomas have much better prognosis than those with HPV-negative tumors (Table 1). Most of these early series used PCR-based methods to detect the presence of HPV.

Mellin et al,⁴⁶ for example, assayed pretreatment biopsies from 60 patients with primary tonsillar carcinomas, treated with radiotherapy alone (45%) or combined with surgery (55%), for presence of

Interaction Between HPV Status and Tobacco Consumption

The rather large sample size of the RTOG series and the systematic data collection enabled assessment of the interaction between tumor HPV status and smoking.⁴² Of the 206 patients with HPV-positive oropharyngeal carcinoma, 59 (29%) and 110 (53%) were never smokers or were former smokers, respectively. The corresponding numbers for the 117 patients with HPV-negative oropharyngeal tumor were 14 (12%) and 54 (46%), respectively. The median pack-years of tobacco smoking were 12.2 (range: 0-152)

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Spatially-aware clustering improves AJCC-8 risk stratification performance in oropharyngeal carcinomas
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Evaluate the effectiveness of machine learning tools that incorporate spatial information such as disease location and lymph node metastatic patterns-of-spread, for prediction of survival and toxicity in HPV+ oropharyngeal cancer (OPC).
675 HPV+ OPC patients that were treated at MD Anderson Cancer Center between 2005 and 2013 with curative intent IMRT were retrospectively collected under IRB approval. Risk stratifications incorporating patient radiometric data and lymph node metastasis patterns via an anatomically-adjacent representation with hierarchical clustering were identified. These clusterings were combined into a 3-level patient stratification and included along with other known clinical features in a Cox model for predicting survival outcomes, and logistic regression for toxicity, using independent subsets for training and validation.
Four groups were identified and combined into a 3-level stratification. The inclusion of patient stratifications in predictive models for 5-yr Overall survival (OS), 5-year recurrence free survival, (RFS) and Radiation-associated dysphagia (RAD) consistently improved model performance measured using the area under the curve (AUC). Test set AUC improvements over models with clinical covariates, was 9 % for predicting OS, and 18 % for predicting RFS, and 7 % for predicting RAD. For models with both clinical and AJCC covariates, AUC improvement was 7 %, 9 %, and 2 % for OS, RFS, and RAD, respectively.
Including data-driven patient stratifications considerably improve prognosis for survival and toxicity outcomes over the performance achieved by clinical staging and clinical covariates alone. These stratifications generalize well to across cohorts, and sufficient information for reproducing these clusters is included.
SMYD3 represses tumor-intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck
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Cancers often display immune escape, but the mechanisms are incompletely understood. Herein, we identify SMYD3 as a mediator of immune escape in human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), an aggressive disease with poor response to immunotherapy with pembrolizumab. SMYD3 depletion induces upregulation of multiple type I interferon (IFN) response and antigen presentation machinery genes in HNSCC cells. Mechanistically, SMYD3 binds to and regulates the transcription of UHRF1, encoding for a reader of H3K9me3, which binds to H3K9me3-enriched promoters of key immune-related genes, recruits DNMT1, and silences their expression. SMYD3 further maintains the repression of immune-related genes through intragenic deposition of H4K20me3. In vivo, Smyd3 depletion induces influx of CD8⁺ T cells and increases sensitivity to anti-programmed death 1 (PD-1) therapy. SMYD3 overexpression is associated with decreased CD8 T cell infiltration and poor response to neoadjuvant pembrolizumab. These data support combining SMYD3 depletion strategies with checkpoint blockade to overcome anti-PD-1 resistance in HPV-negative HNSCC.
Prognostic and predictive values of baseline and mid-treatment FDG-PET in oropharyngeal carcinoma treated with primary definitive (chemo)radiation and impact of HPV status: Review of current literature and emerging roles
2023, Radiotherapy and Oncology
This study provides a review of the literature assessing whether semiquantitative PET parameters acquired at baseline and/or during definitive (chemo)radiotherapy (“prePET” and “iPET”) can predict survival outcomes in patients with oropharyngeal squamous cell carcinoma (OPC), and the impact of human papilloma virus (HPV) status.
A literature search was carried out using PubMed and Embase between 2001 to 2021 in accordance with PRISMA.
The analysis included 22 FDG-PET/CT studies [1-22], 19 pre-PET and 3 both pre-PET and iPET, The analysis involved 2646 patients, of which 1483 are HPV-positive (17 studies: 10 mixed and 7 HPV-positive only), 589 are HPV-negative, and 574 have unknown HPV status.
Eighteen studies found significant correlations of survival outcomes with pre-PET parameters, most commonly primary or “Total” (combined primary and nodal) metabolic tumour volume and/or total lesional glycolysis. Two studies could not establish significant correlations and both employed SUVmax only. Two studies also could not establish significant correlations when taking into account of the HPV-positive population only. Because of the heterogeneity and lack of standardized methodology, no conclusions on optimal cut-off values can be drawn.
Ten studies specifically evaluated HPV-positive patients: five showed positive correlation of pre-PET parameters and survival outcomes, but four of these studies did not include advanced T or N staging in multivariate analysis, and two studies only showed positive correlations after excluding high risk patients with smoking history or adverse CT features. Two studies found that prePET parameters predicted treatment outcomes only in HPV-negative but not HPV-positive patients.
Two studies found that iPET parameters could predict outcomes in HPV-positive patients but not prePET parameters.
The current literature supports high pre-treatment metabolic burden prior to definitive (chemo)radiotherapy can predict poor treatment outcomes for HPV-negative OPC patients. Evidence is conflicting and currently does not support correlation in HPV-positive patients.
Mid-treatment Fluorodeoxyglucose Positron Emission Tomography in Human Papillomavirus-related Oropharyngeal Squamous Cell Carcinoma Treated with Primary Radiotherapy: Nodal Metabolic Response Rate can Predict Treatment Outcomes
2021, Clinical Oncology
To evaluate whether biomarkers derived from fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) performed prior to (prePET) and during the third week (interim PET; iPET) of radiotherapy can predict treatment outcomes in human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPC).
This retrospective analysis included 46 patients with newly diagnosed OPC treated with definitive (chemo)radiation and all patients had confirmed positive HPV status (HPV+OPC) based on p16 immunohistochemistry. The maximum standardised uptake value (SUV_max), metabolic tumour volume (MTV) and total lesional glycolysis (TLG) of primary, index node (node with the highest TLG) and total lymph nodes and their median percentage (≥50%) reductions in iPET were analysed, and correlated with 5-year Kaplan–Meier and multivariable analyses (smoking, T4, N2b-3 and AJCC stage IV), including local failure-free survival, regional failure-free survival, locoregional failure-free survival (LRFFS), distant metastatic failure-free survival (DMFFS), disease-free survival (DFS) and overall survival.
There was no association of outcomes with prePET parameters observed on multivariate analysis. A complete metabolic response of primary tumour was seen in 13 patients; the negative predictive value for local failure was 100%. More than a 50% reduction in total nodal MTV provided the best predictor of outcomes, including LRFFS (88% versus 47.1%, P = 0.006, hazard ratio = 0.153) and DFS (78.2% versus 41.2%, P = 0.01, hazard ratio = 0.234). More than a 50% reduction in index node TLG was inversely related to DMFFS: a better nodal response was associated with a higher incidence of distant metastatic failure (66.7% versus 100%, P = 0.009, hazard ratio = 3.0).
The reduction (≥50%) of volumetric nodal metabolic burden can potentially identify a subgroup of HPV+OPC patients at low risk of locoregional failure but inversely at higher risk of distant metastatic failure and may have a role in individualised adaptive radiotherapy and systemic therapy.
Low-dose fractionated radiation with induction docetaxel and cisplatin followed by concurrent cisplatin and radiation therapy in locally advanced nasopharyngeal cancer: A randomized phase II–III trial
2021, Hematology/ Oncology and Stem Cell Therapy
To evaluate the efficacy and outcome of adding low-dose fractionated radiotherapy (LDFRT) to induction chemotherapy plus concurrent chemoradiation in locally advanced nasopharyngeal carcinoma (LANPC).
A single-institute, phase II–III, prospectively controlled randomized clinical trial was performed at King Faisal Specialist Hospital and Research Centre. Patients aged 18–70 years with WHO type II and III, stage III–IVB nasopharyngeal carcinoma, Eastern Cooperative Oncology Group performance score of 0–2, with adequate hematological, renal, and hepatic function were eligible. In total, 108 patients were enrolled in this trial. All patients received two cycles of induction docetaxel and cisplatin (75 mg/m² each) chemotherapy on Days 1 and 22, followed by concurrent chemoradiation therapy. Radiation therapy consisted of 70 Gy in 33 fractions, with concurrent cisplatin 25 mg/m² for 4 days on Days 43 and 64. Patients were randomly assigned to either adding LDFRT (0.5 Gy twice daily 6 hours apart for 2 days) to induction chemotherapy in the experimental arm (54 patients) or induction chemotherapy alone in the control arm (54 patients).
There was no significant difference in the post-induction response rates (RRs) or in toxicity between the two treatment arms. The 3-year overall survival (OS), locoregional control (LRC), and distant metastases-free survival (DMFS) rates for experimental arm and control arm were 94% versus 93% (p = .8), 84.8% versus 87.5% (p = .58), and 84.1% versus 91.6% (p = .25), respectively.
The results showed no benefit from adding LDFRT to induction chemotherapy in terms of RR, OS, LRC, and DMFS.

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Human Papillomavirus as a Marker of the Natural History and Response to Therapy of Head and Neck Squamous Cell Carcinoma

Section snippets

Changing Epidemiology of Head and Neck Cancer

Emergence of HPV-Associated Oropharyngeal Carcinoma

Histology

Case Control Series

Interaction Between HPV Status and Tobacco Consumption

Am J Prev Med

Cell

Semin Cancer Biol

Vaccine

Oral Surg Oral Med Oral Pathol Oral Radiol Endodontol

Oral Oncol

Lancet Oncol

Radiother Oncol

Ann Oncol

Otolaryngol Head Neck Surg

Eur J Cancer

Lancet

Radiother Oncol

Lancet Oncol

Global cancer statistics

CA Cancer J Clin

Estimates of worldwide burden of cancer in 2008: Globocan 2008

Int J Cancer

Cancer statistics

CA Cancer J Clin

Smoking and drinking in relation to cancers of the oral cavity, pharynx, larynx, and esophagus in northern Italy

Cancer Res

Trends in head and neck cancer incidence in relation to smoking prevalence: An emerging epidemic of human papillomavirus-associated cancers?

Cancer

Trends in incidence and prognosis for head and neck cancer in the United States: A site-specific analysis of the seer database

Int J Cancer

Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States

J Clin Oncol

Molecular pathogenesis of cancer of the cervix and its causation by specific human papillomavirus types

Curr Top Microbiol Immunol

Papillomaviruses and cancer: From basic studies to clinical application

Nat Rev Cancer

Human papillomavirus and cancers of the upper aerodigestive tract: A review of epidemiological and experimental evidence

Cancer Epidemiol Biomarkers Prev

Human papillomavirus and risk of oral cancer

Laryngoscope

Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck

N Engl J Med

Human papillomavirus types in head and neck squamous cell carcinomas worldwide: A systematic review

Cancer Epidemiol Biomarkers Prev

Human papillomavirus and head and neck cancer: A systematic review and meta-analysis

Clin Otolaryngol

Human papillomavirus type 16 infection and squamous cell carcinoma of the head and neck in never-smokers

Clin Cancer Res

P53 codon 72 polymorphism associated with risk of human papillomavirus-associated squamous cell carcinoma of the oropharynx in never-smokers

Carcinogenesis

Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: An epidemic of viral-induced carcinoma?

Int J Cancer

Human papillomavirus and survival in patients with base of tongue cancer

Int J Cancer

Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer

Int J Cancer

Evidence for a causal association between human papillomavirus and a subset of head and neck cancers

J Natl Cancer Inst