Presence and Influence of Human Papillomaviruses (HPV) in Tonsillar Cancer

Hanna Mellin Dahlstrand; Tina Dalianis    Department of Oncology-Pathology, Karolinska Institute, Karolinska University Hospital, 171 76, Stockholm, Sweden

I INTRODUCTION

When zur Hausen (zur Hausen, 1976) proposed that cervical cancer might be caused by human papillomavirus (HPV), the scientific community accepted that HPV could potentially be involved in the development of some but definitely not all cervical cancers. Today, it is fully accepted that different types of HPVs are present and instrumental in the induction of almost all cervical cancers as well as some other types of human cancer (zur Hausen, 1996, 1999). In addition, several mechanisms by which HPVs exhibit their oncogenic potential have also been revealed (zur Hausen, 1996, 1999). The possibility that preventive vaccines against HPV may soon reach clinical practice (Koutsky et al., 2002; Lehtinen and Dillner, 2002) has drawn even more attention to the association of HPV with other types of cancer. However, HPV is only present in a proportion of other types of cancer, e.g., head and neck cancer, anogenital cancer, and nonmelanoma skin cancer, and much less is known about the role of HPV in these tumors (Alani and Munger, 1998; de Villiers, 1991, 1997; Gillison et al., 1999; Licitra et al., 2002; Mork et al., 2001; Snijders et al., 1992).

Nonetheless, tonsillar carcinoma is of particular interest, since it is the head and neck cancer where HPV is most commonly found (Gillison et al., 2000; Mork et al., 2001; Paz et al., 1997; Snijders et al., 1996). Approximately half of all tonsillar cancers are HPV positive (Andl et al., 1998; Klussmann et al., 2001; Mellin et al., 2000; Paz et al., 1997). In addition, recent reports suggest that patients with HPV-positive tonsillar tumors have a lower risk of relapse and longer survival compared to patients with HPV-negative tonsillar tumors (Gillison et al., 2000; Mellin et al., 2000). These data motivate further comparisons between HPV-positive and HPV-negative tonsillar tumors with regard to clinical outcome, sensitivity to radiotherapy, biology of the tumor, and genetic stability in order to better understand possible options for treatment and vaccination studies. The purpose of this article is to review current knowledge on the status and significance of HPV in tonsillar cancer.

II TONSILLAR CANCER

Cancer of the palatine tonsil, in the lymphoid region called the Waldeyer’s ring, is usually referred to as tonsillar cancer. Tonsillar cancer is the most common of the oropharyngeal malignancies, and 75% of all tonsillar carcinomas are squamous cell carcinomas (Genden et al., 2003).

As with all head and neck squamous cell carcinomas (HNSCC), smoking and alcohol abuse are regarded as the main etiological factors for tonsillar cancer and are known to account for 80 to 90% of all HNSCC (Decker and Golstein, 1982; Licitra et al., 2002). However, HNSCC and tonsillar cancer also occur in some 15 to 20% of patients without these risk factors (Gillison et al., 2001; Licitra et al., 2002). In many of these instances, viruses are most likely to be involved in the development of HNSCC, and data now indicate that high-risk types of HPV, similar to those observed in cervical cancer, are associated with a subset of HNSCC (Alani and Munger, 1998; de Villiers, 1991; Gillison et al., 2000, 2001; Gissmann et al., 1982; Mork et al., 2001; Naghashfar et al., 1985; Snijders et al., 1992; Syrjanen et al., 1983).

Patients with tonsillar cancer do not normally seek health care until the tumor is fairly large and presents symptoms like swallowing-related pain or difficulties in swallowing (Mashberg and Samit, 1995). This is because small tumors generally do not cause any discomfort. Other common first symptoms are pain in the ear or a lump in the neck due to the tumor spreading to the lymph nodes (Mashberg and Samit, 1995). In advanced cases, vital functions such as breathing, eating, and speaking may be significantly affected. Further suffering may be caused by cancer growth in the face and the neck. Later on, the curative treatments of surgery and radio-therapy (Genden et al., 2003; Mellin et al., 2000) can be disabling and disfiguring.

Tonsillar cancer is generally treated with (pre-operative or post-operative) full-dose radiotherapy (64 Gy) against the primary tumor and the neck. The extent of the surgical intervention depends on the size of the primary tumor, the presence of metastases in the neck lymph nodes, and the response to the radiotherapy given. Overall survival for patients with oropharyngeal cancer is 67% with stage I, 46% with stage II, 31% with stage III, and 32% with stage IV (Pugliano et al., 1997). However, the overall survival for patients with oropharyngeal cancer is only about 38% (Pugliano et al., 1997). Despite similar histology and stage, as well as standardized treatment, it is not easy to predict the outcome of each individual case. Hence, both predictive and prognostic markers would be of significant clinical value in order to tailor treatment for individual tonsillar cancer patients. This would allow for optimization of therapy to give the most efficient treatment with minimal impact on function and form. Moreover, given the high proportion of HPV-16 associated with tonsillar cancer (see following text), patients could obtain substantial benefit from the use of the same prophylactic and adjuvant therapeutic strategies that are being developed to prevent and/or treat HPV-associated anogenital cancers (for reviews, see Devaraj et al., 2003; Ling et al., 2000). However, before using such treatment, it is important to investigate in which cases this could be an option.

III HUMAN PAPILLOMAVIRUS (HPV)

There are more than 100 HPV types, and for general reviews on HPV and cancer, as well as, more specifically, head, neck, and oral cancer, see, for example, Zur Hausen (1996), de Villiers (1997), Syrjanen (2003), and Scully (2002). Some HPV types are associated with common warts, while others are associated with chondylomas and papillomas. Finally, there are HPV types such as HPV 16, 18, 31, 33, and others that are associated with malignant tumors. Nevertheless, the genomes of all HPVs are similar and consist of double-stranded circular DNA with a size of 7 to 8 Kb. The genome is enclosed in a 52- to 55-nm viral capsid, and is arbitrarily divided into a noncoding region and two coding regions, the early and late regions. The early region encodes for the early proteins E1-E2 and E4-E7, which are important for pathogenesis and transformation, while the late region encodes for L1 and L2, the two capsid proteins.

Of particular interest in this context is that among the HPV types associated with malignant tumors, E6 and E7 are classified as oncogenes. E6 binds to the cellular protein p53 and degrades it, while E7 binds to pRB and abrogates its function (Dyson et al., 1989, 1992; Scheffner et al., 1990). Under these conditions, the intracellular levels of normal p53 and pRB are reduced and this combination results in the inhibition of cell cycle control and facilitation of tumor development (for reviews, see Hanahan and Weinberg, 2000; zur Hausen, 1996).

Also of interest is that the L1, the major capsid protein, can self assemble and form viruslike particles (Kirnbauer et al., 1993), which are useful for vaccination against HPV infections.

IV HUMAN PAPILLOMAVIRUS (HPV) IN TONSILLAR CANCER

A Frequency and Type of HPV in Tonsillar Cancer

HPV DNA has been shown to be present in 45 to 100% of all tonsillar tumors (Andl...