Human papillomavirus and oropharyngeal squamous cell carcinoma: what the clinician should know

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is rising in contrast to the decreasing incidence of carcinomas arising in other subsites of the head and neck. The human papillomavirus (HPV) infection has played an increasing role in these epidemiological changes and as the etiology for a significant fraction of head and neck squamous cell carcinomas, OPSCC in particular. Most importantly, many retrospective studies have shown that the prognosis differs significantly between patients with HPV-associated tumors and non-HPV associated tumors. Thus, questions arise on the choices of treatment for patients based on HPV status and the consequences of therapy. Given the recognized relevance of HPV status in OPSCC, many new questions concerning the biology, treatment, and prevention of HPV infection arise. This review is intended to highlight some of the major issues and frequently asked questions relevant for the clinician dealing with patients with OPSCC.     

外周血中性粒细胞与淋巴细胞比率及血小板与淋巴细胞比率对喉鳞状细胞癌预后价值的研究进展

喉鳞状细胞癌（LSCC）是头颈鳞状细胞癌最常见类型之一,由多种致癌因素共同影响所致且预后欠佳。LSCC预后因素包括个体状况、原发肿瘤大小、淋巴结受累情况、有无远处转移和人乳头状瘤病毒（HPV）感染等,均不能准确评估LSCC预后,因此,探寻新的指标显得尤为重要。在肿瘤的发生、发展、转移过程中,炎症因子起到了至关重要的作用,其中外周血中性粒细胞/淋巴细胞比率（NLR）、血小板/淋巴细胞比率（PLR）对LSCC预后价值较高且备受关注,因此本文将探讨NLR、PLR与LSCC预后价值的关系,为临床诊疗提供参考。     

Humane Papillomavirusinfektionen bei Plattenepithelkarzinomen des Kopf- und Halsbereichs

There is increasing evidence worldwide that human papillomavirus is a major risk factor for head and neck cancer. Only few studies on this association have been performed in Germany to date. For the purposes of the present study, tumor specimens from 223 patients with squamous cell cancer of the oral cavity, oropharynx, hypopharynx and larynx were analyzed for HPV DNA and p16INK4a expression. The prevalence of HPV genotype 16 (HPV16) DNA in the study population was 17.5?%. Further high-risk HPV types were not detected. All HPV16-positive tumors showed intense p16INK4a expression. HPV16 prevalence was highest in tonsillar carcinoma (37.5?%) and lowest in laryngeal cancer (2.8?%). We observed a significantly higher incidence of cervical lymph node metastases in patients with HPV16-positive tonsillar carcinoma in comparison to HPV-negative tumors (p?<?0.016). Tobacco and/or alcohol consumption was significantly lower in patients with HPV-positive tumors (p?<?0.0001).     

Frequent Mutations in TP53 and CDKN2A Found by Next-Generation Sequencing of Head and Neck Cancer Cell Lines

OBJECTIVE To conduct high-throughput mutational analysis in 6 commonly used head and neck cancer cell lines. Comprehensive mutation analysis of primary head and neck squamous cell carcinoma (HNSCC) tumors has recently been reported, and mutations in the NOTCH receptors, TP53 and CDKN2A, were key findings. Established cell lines are valuable tools to study cancer in vitro. Similar high-throughput mutational analysis of head and neck cancer cell lines is necessary to confirm their mutational profile. DESIGN DNA was extracted from American Type Culture Collection (ATCC) cell lines Cal27, Detroit562, FaDu, SCC4, SCC15, and SCC25. Cell line identity was confirmed by short tandem repeat (STR) analysis, and human papillomavirus (HPV) infection status was assessed by real-time polymerase chain reaction. A total of 535 cancer-associated genes were sequenced through a limited exome capture on the Illumina HiSeq system. SETTING London Regional Cancer Program. RESULTS The identity of the 6 cell lines was confirmed by STR analysis, and all lines tested negative for HPV infection. We achieved an average of 129-fold coverage with paired-end 100 base-pair reads. Sequencing revealed an average of 38 damaging mutations in each cell line (range, 30-45). The TP53 mutations, predicted to confer loss of function, were noted in all cell lines, and damaging CDKN2A mutations were found in all lines except SCC15. CONCLUSIONS High-throughput sequencing of head and neck cancer cell lines revealed similar mutations to those observed in primary tumors. Thus, these lines reflect the tumor biology of HNSCC and can serve as valuable models to study HNSCC in vitro.     

口咽部鳞状细胞癌与性行为和人乳头状瘤病毒感染

高危型人乳头状瘤病毒感染(high risk human papillomavirus, HR HPV)是头颈部鳞状细胞癌发生的一个重要相关因素,特别是原发口咽部、缺少烟酒等危险因素的患者。口咽肿瘤中确认发现HR HPV,以及流行病学病例对照研究明确HR HPV与口咽癌发病风险的关系,已阐明了二者的联系。重点论述口咽癌患者与非口咽癌患者在口腔、喉腔和下咽部位的比较及性行为方式的影响。明确头颈肿瘤的性行为危险因素对未来肿瘤预防是必不可少的,同时以利于理解现有的HPV疫苗对未来头颈肿瘤预防的潜在作用。同时还扩展到性行为作为口咽癌发生的一个危险因素以及其作为HPV暴露标记的作用,强调HR HPV是通过性行为传播到上呼吸消化道,增加HPV相关的口咽癌的发病风险。     

Rate of regional nodal metastases of cutaneous squamous cell carcinoma in the immunosuppressed patient

Purpose

Immunosuppressed solid organ transplant recipients (SOTRs) have an increased risk of developing cutaneous squamous cell carcinomas (cSCCs) with metastatic potential. This study sought to determine the rate of regional lymph node involvement in a large cohort of solid organ transplant patients with cutaneous head and neck squamous cell carcinoma.

The role of human papilloma virus infection in the etiology of oropharyngeal carcinoma

PURPOSE OF REVIEW: Evidence is growing that human papilloma virus is responsible for a subset of head and neck carcinomas. This review analyzes the history and current thinking regarding this relatively new etiologic agent of squamous cell carcinoma. RECENT FINDINGS: Research over the past year has confirmed that human papilloma virus is associated with subset of head and neck squamous cell carcinoma, especially tumors arising from the tonsil. Human papilloma virus 16 is the most common strain found in these tumors. Most studies also indicate that patients with human papilloma virus infection are more likely to have a better prognosis, engage in riskier sexual behavior, and have a history of less tobacco and alcohol consumption than patients who have human papilloma virus-negative tumors. Not all studies confirm these findings, however, and human papilloma virus, even the high-risk strains (16, 18, and 33) are found in a certain percentage of healthy individuals. SUMMARY: Human papilloma virus (especially strain 16) has been recognized as a probable etiologic agent for some head and neck squamous cell carcinomas. Most commonly, human papilloma virus is associated with tumors arising from the tonsillar epithelium. Because a definitive causal relationship is still to be identified, current research aims to delineate the specific mechanism whereby human papilloma virus produces squamous cell carcinoma. It is hoped that a vaccine may be produced in the near future that will serve as adjuvant therapy for patients with human papilloma virus-positive tumors.     

Squamous Cell Carcinoma in HIV-Positive Patients Under Age 45

Eight patients 45 years of age and under (range, 29 to 45) with squamous cell carcinoma of the head and neck and infection with the human immunodeficiency virus are reported. Primary tumor sites include nasopharynx, oral cavity, oropharynx, and larynx. Probes for the human papillomavirus were positive in two of the patients. Therapy consisted of surgery followed by radiation therapy in five patients, surgery alone in one patient, and radiation therapy in the remaining two patients. Follow-up ranged up to 2 years and revealed four deaths, three patients alive without disease, and one patient recently posttreatment with residual disease. The significance of the presence of the human papillomavirus in these individuals remains to be determined. The incidence of squamous cell carcinoma of the head and neck under age 45 is low, and whether there may be a higher incidence in HIV-positive patients cannot be determined from this small series.     

Human papillomaviruses in lymph node neck metastases of head and neck cancers

CONCLUSION: The results of this study corroborate earlier findings that human papillomavirus (HPV)16 is the most prevalent type of HPV in squamous cell carcinomas of the head and neck (SCCHNs) and reinforce a possible influence of HPV on SCCHN progression by showing that the majority of HPV-positive patients harbor HPV16 (or HPV33) both in their primary tumors and in lymph node neck metastases (LNNMs). OBJECTIVE: HPVs are causally associated with carcinomas of the uterine cervix and have also been linked to a subset of SCCHNs. In order to further investigate the predicted causative role of HPV in SCCHNs, we analyzed pairs of primary tumors and LNNMs or LNNMs alone for the presence of HPV DNA using polymerase chain reaction (PCR). MATERIAL AND METHODS: DNA was extracted from fresh frozen tissue samples of primary tumors and the corresponding LNNMs of 18 patients and from LNNMs alone in 17 patients. For the detection and typing of HPV, PCR was performed using both type-specific and consensus primer pairs, followed by Southern hybridization and, in selected cases, sequencing of the PCR products. RESULTS: Of the 35 patients investigated, 22 (63%) were found to have HPV DNA in their tumors: HPV16 DNA in 21 cases and HPV33 in 1. The highest HPV prevalence was detected in tumors of Waldeyer's tonsillar ring (8/9 patients; 89%). Of the 18 patients in whom primary tumors and LNNMs were analyzed, 7 (39%) were HPV-positive in both samples (HPV16, n = 6; HPV33, n = 1), in 3 (17%) the primary tumors were HPV-negative and the LNNMs HPV16-positive and in 1 (5.5%) the primary tumor contained HPV16 and the LNNM was negative. Interestingly, of the 7 patients in whom LNNMs had been detected only several months after diagnosis and treatment of the primary tumors, only 1 showed infection with HPV (HPV33).     

Immunohistochemical demonstration of multiple HPV types in laryngeal squamous cell carcinoma

The aim of this study was to determine the prevalence of human papillomaviruses (HPV) types 6, 11, 16, 18, 31, 33, 42, 51, 52, 56 and 58 in laryngeal squamous cell carcinoma specimens using immunohistochemical reactions and to correlate the presence of HPV with the clinical and pathological characteristics of these patients. Tissue samples were collected from 40 patients with primary laryngeal squamous cell carcinoma (LSCC) and from 33 subjects with non-neoplastic laryngeal lesions or laryngeal nodules, which served as a control group. Human papilloma virus was detected in 6 (15%) of the 40 patients. Five (83.4%) of six patients with HPV positive tumors had G2 (moderately differentiated), one patient (16.6%) had G3 (poorly differentiated), and no patient with HPV positive tumor had a G1 (well-differentiated) tumor. Four (66.6%) of the six HPV positive tumors were in the supraglottic region, one (16.6%) tumor was located in the glottis, and one (16.6%) HPV positive tumor was in the subglotic region. Five (83.4%) of six HPV positive tumors were T3-T4, and one was T2. Three of six HPV positive patients had no clinically evident cervical lymph nodes (N0), and three of the HPV positive patients were N1 or N2. Human papillomavirus was not detected in any of the samples from the control group. The presence of HPV infection in 15% of the cases may suggest a possible role in the etiology of laryngeal squamous cell carcinoma. However, no significant correlation between HPV incidence and histological grading and clinical staging could be demonstrated.     

Squamous cell carcinoma in the area of the parotid gland. Metastasis or primary tumor?

A total of 61 patients with a histological diagnosis of squamous cell carcinoma of the parotid gland were studied. The patients were classified into three categories. There were 34 patients with a metastasis to the parotid gland from a squamous cell carcinoma elsewhere within the head and neck who presented on average 2.1 years (range 3 months to 7 years) after diagnosis of the primary tumour; in one case a salivary gland tumor presented 32 years after irradiation of a squamous cell carcinoma of the temple. Six patients had histological evidence of a metastasis within the parotid gland, but no evidence of a primary tumour. Twenty-one patients presented with a primary epidermoid carcinoma of the parotid gland. Two patients showed a primary squamous cell carcinoma of the parotid arising in myoepithelial sialadenitis.     

Immunosuppression and the development of malignancies of the upper airway and related structures

In the general population, 90% of the malignancies developing in the upper respiratory tract are squamous cell carcinomas. Analysis of 1081 neoplasms in 1023 renal transplant patients reported to the Denver Transplant Tumor Registry indicates that squamous cell carcinoma reMayns the predominant malignancy which develops in the upper respiratory tract of immunosuppressed individuals. Comparing the incidence of cancers of the oral cavity (excluding lip cancers) in the immunosuppressed population with the general population it is rather similar (3.5% vs. 4%). When lip cancers are included, one sees a great excess of tumors developing in transplant patients (15% vs. 4.6%). Thus the excess of head and neck epithelial malignancies among these patients is confined to neoplasms of the lip. Examination of the 25 patients reported in this study reveals an unusually young age of the patients, the average age being 41.8 years compared with the general population where most head and neck tumors occur in the 55-65 age group. The average time posttransplantation when cancer developed was 5.3 years, supporting the concept that the more effective the immunosuppressive regimen for prevention of graft rejection, the greater the susceptibility for the development of cancer. Since 90% of transplant patients have serological or clinical evidence of active herpes virus infection, it is possible that this microorganism may play a role in the development of certain head and neck malignancies, especially those involving the lips.     

Impact of HPV-related head and neck cancer in clinical trials: opportunity to translate scientific insight into personalized care

Patients with human papillomavirus (HPV)-positive squamous cell carcinoma of the oropharynx (SCCOP) enjoy better treatment outcomes than patients suffering from HPV-negative head and neck cancer. To maintain the integrity and utility of future clinical trials, HPV-positive SCCOP must be studied as a distinct entity. The discovery of HPV-positive disease has (1) convoluted comparison of current phase II trial data to historical controls, (2) made formal stratification for HPV infection status an imperative for future phase III trial design, and (3) drawn focus toward opportunities for personalization of treatment intensity. This review discusses these research issues.     

Is human papillomavirus involved in laryngeal neuroendocrine carcinoma?

The purpose of this study was to detect human papillomavirus (HPV) infection in laryngeal neuroendocrine carcinoma (LNEC) and to explore the possible relationship between HPV-induced malignant transformation and prognosis in LNEC. Ten cases of LNEC from a tertiary referral hospital were retrospectively analyzed. Clinical data were subtracted from patients’ files. Pretreatment biopsy material was tested for the presence of HPV6, 11, 16, and 18 using a PCR-based detection method. Immunohistochemical staining was performed for Ki-67, p16^INK4A, and p53 expression. All cases were negative for the low-risk HPV types HPV6 and HPV11 that are associated with laryngeal papillomatosis. High-risk HPV was detected in two cases; an atypical carcinoid was positive for HPV16 and a large-cell neuroendocrine carcinoma for HPV18. Both HPV-positive tumors had a high Ki-67 labeling index. Two of the four cases with a good response to therapy were hrHPV-positive (both HPV DNA positive) compared with none of the five poor responders. Our findings show that HPV may play a role in the pathogenesis of LNEC. The relationship between HPV, improved prognosis and good response to therapy for squamous cell carcinoma of the head and neck may also be true for a subset of LNEC.     

Unusual presentation of HPV-positive squamous cell carcinoma of the nasolacrimal duct as carcinoma of unknown primary

Most human papillomavirus (HPV)-positive carcinomas of unknown primary (CUP) in the cervical lymph nodes are ultimately found to arise from the oropharynx, which has by far the highest prevalence of HPV-positivity among head and neck tumors. However, HPV is also detected in a subset of tumors from other sites. In this case report, we describe the first reported instance of a lacrimal sac carcinoma presenting as an HPV-positive CUP. A 64-year-old male presented with isolated right-sided neck swelling, found on core biopsy to be HPV-positive squamous cell carcinoma (SCC). Initial diagnostic workup did not reveal a primary site, and he was treated for T0N1M0 oropharyngeal SCC with chemoradiation. Shortly afterwards he developed epiphora and was found to have an FDG-avid lesion along his inferior right orbit. Biopsy revealed HPV-positive SCC, presumed to be the true primary site of his previously diagnosed CUP. He was treated with surgical resection, proton-beam radiation, and carboplatin-paclitaxel. He had an excellent outcome with no evidence of disease 18 months following treatment completion. This case underscores the importance of continued vigilance and thorough investigation for a primary tumor site even when cervical nodal metastases are HPV-positive. While the vast majority of HPV-positive head and neck tumors arise in the oropharynx, other anatomical sites may also harbor HPV-positive malignancies.     

The role of human papillomaviruses (HPV) in upper respiratory tract diseases

High-risk papillomaviruses (HPVs) are etiologic agents for anogenital tract cancers and have been detected in head and neck squamous cell carcinomas. Still a viral etiology of head and neck cancers had not been established unambiguously. For head and neck cancers two major risk factors (tobacco smoke and alcohol) have been recognised and HPV infection may play a synergistic role in the multifactorial etiology of the tumors. The occurrence rates for HPV DNA in the head and neck cancers varied from one study to another because of technical and demographic variables. The HPV infection in benign head and neck diseases were also presented.     

Hypernephroma as second neoplasm simultaneous in a patient whith larynx carcinoma

The presence of two or more different histologic types of neoplasms in patients treated for head and neck cancer is well known. It is provided the clinical case of a woman of 48 years old who developed two primary tumors, a squamous carcinoma of larynx and a clear cell carcinoma of kidney (hypernephroma). The diagnosis of second primary tumor was a casual find when an abdominal TC was being carried out. The more frequent association of a head and neck cancer is with a malignant tumors of lung, being unusual the malignant tumors of kidney association.     

Variability of genetic alterations in different sites of head and neck cancer

OBJECTIVE: Tumors arising from different sites of the head and neck area have different clinical behavior. However, most of the studies on genetic alterations in head and neck squamous cell carcinomas do not make a distinction between the sites within this area. The objective of this study is to compare the genetic alterations in three different sites of the head and neck (larynx, oropharynx, and hypopharynx). STUDY DESIGN: Prospective study. METHODS: Thirty-eight laryngeal, 29 oropharyngeal, and 37 hypopharyngeal carcinomas were studied. DNA from tumor and healthy tissue was evaluated for amplification of the oncogenes at 11q13 region (CCND1, FGF3, FGF4 and EMS1) and of the oncogenes MYC and ERBB1; for integration of the human papillomavirus (HPV) types 6b and 16; for loss of heterozygosity (LOH) at p53 and NAT2; and for the cellular DNA content. RESULTS: FGF3 and FGF4 showed a significantly higher frequency of amplification in hypopharyngeal tumors (P =.006 and P =.0002, respectively). CCND1 amplification had a nearly statistically significant (P =.072) higher frequency of amplification in hypopharyngeal tumors. Aneuploid tumors were found in a significantly lower proportion in the larynx (P =.03) compared with the other sites. For the other genetic alterations, no significant differences among the three sites were found. CONCLUSIONS: These results suggest that cancers originating from different sites in the head and neck may have different tumor biology. Therefore, they should be considered as different entities.     

Visual gravitational vertical perception in peripheral vestibular hypofunction

Conclusion The results of this study corroborate earlier findings that human papillomavirus (HPV)16 is the most prevalent type of HPV in squamous cell carcinomas of the head and neck (SCCHNs) and reinforce a possible influence of HPV on SCCHN progression by showing that the majority of HPV-positive patients harbor HPV16 (or HPV33) both in their primary tumors and in lymph node neck metastases (LNNMs).

Objective HPVs are causally associated with carcinomas of the uterine cervix and have also been linked to a subset of SCCHNs. In order to further investigate the predicted causative role of HPV in SCCHNs, we analyzed pairs of primary tumors and LNNMs or LNNMs alone for the presence of HPV DNA using polymerase chain reaction (PCR).

Material and methods DNA was extracted from fresh frozen tissue samples of primary tumors and the corresponding LNNMs of 18 patients and from LNNMs alone in 17 patients. For the detection and typing of HPV, PCR was performed using both type-specific and consensus primer pairs, followed by Southern hybridization and, in selected cases, sequencing of the PCR products.

Results Of the 35 patients investigated, 22 (63%) were found to have HPV DNA in their tumors: HPV16 DNA in 21 cases and HPV33 in 1. The highest HPV prevalence was detected in tumors of Waldeyer's tonsillar ring (8/9 patients; 89%). Of the 18 patients in whom primary tumors and LNNMs were analyzed, 7 (39%) were HPV-positive in both samples (HPV16, n=6; HPV33, n=1), in 3 (17%) the primary tumors were HPV-negative and the LNNMs HPV16-positive and in 1 (5.5%) the primary tumor contained HPV16 and the LNNM was negative. Interestingly, of the 7 patients in whom LNNMs had been detected only several months after diagnosis and treatment of the primary tumors, only 1 showed infection with HPV (HPV33).     

人乳头状瘤病毒阳性的头颈鳞状细胞癌特异性基因生物信息学研究

目的分析人乳头状瘤病毒(HPV)阳性的头颈鳞状细胞癌(鳞癌)特异表达基因及关键信号通路,为HPV相关头颈鳞癌筛选有价值的基因标记物,并为进一步的肿瘤机制研究提供参考。方法从GEO高通量基因芯片数据库中筛选出头颈鳞癌具有HPV感染信息的芯片,从中筛出差异基因进行基因本体分析及京都基因和基因组(KEGG)信号通路富集分析,并筛出头颈鳞癌的特征基因簇和通路,以及关键基因并进行蛋白质相互作用网络可视化分析。通过Cbioportal信息门户以及癌症基因组图谱(TCGA)数据库验证这些特异基因在HPV(+)与HPV(-)头颈鳞癌中的表达差异并分析特异基因与头颈鳞癌患者生存预后的相关性。结果从数据集GSE52088与GSE39366中筛选出42个共同差异基因,其中上调基因25个,下调基因17个,经Cytoscape两轮筛选确定白介素-6(IL-6)、细胞表面标记物CD44、基质金属蛋白酶1(MMP1)、CXC趋化因子配体基序1(CXCL1) 4个特异基因。信号通路富集分析显示共同差异基因参与细胞周期、NOD样受体信号通路、肿瘤坏死因子(TNF)信号通路途径等信号通路(P < 0.01)。经TCGA数据库以及Cbioportal检验证实特异基因在HPV(+)与HPV(-)头颈鳞癌中的表达差异,且IL-6、CD44表达水平与头颈鳞癌生存预后呈负相关(P < 0.01)。结论HPV(+)头颈鳞癌具有特异性基因表达,并可能参与关键信号通路调控肿瘤的发生发展。IL-6、CD44、MMP1、CXCL1 4个特异基因可能参与HPV(+)头颈鳞癌发展及侵袭过程,其中MMP1、CXCL1有望作为诊断及预后的标志物,IL-6、CD44与头颈鳞癌预后存在相关性,有望成为治疗HPV(+)头颈鳞癌的潜在靶点。