Commentary (Zweizig)-Human Papillomaviruses: Their Clinical Significance in the Management of Cervical Carcinoma

Hines and colleagues provide a comprehensive review of the human papillomavirus (HPV) and its association with cervical carcinoma. It is now widely appreciated that HPV infection is important in the etiology of cervical dysplasia and carcinoma. Although the incidence of cervical carcinoma has decreased in the United States over the past 50 years, as the authors point out, it still is responsible for 500,000 deaths per year worldwide. Furthermore, the rate of detection of HPV infection has increased dramatically over the past 2 decades, causing substantial patient morbidity and financial burden relative to the evaluation and treatment of preinvasive disease. In an age in which cost containment has assumed greater importance, strategies for disease prevention need to be developed. In their detailed description of pathogenesis, Hines et al offer a convincing rationale for this need for HPV-associated disease prevention.

The association between HPV and cervical carcinoma has been extensively studied. More than 70 HPV types have been identified, and 90% of cervical cancer specimens are found to contain DNA for this virus. Patients undergoing surgical procedures for the staging and treatment of cervical carcinoma have been studied for the presence of HPV DNA in histologically normal lymph nodes. In the study of Ikenberg et al, 41% of histologically negative lymph nodes were found to contain HPV DNA identical to that found in the primary tumor [1]. Of the stage IB/IIA patients who survived, only 23% had viral DNA in their lymph nodes. In contrast, among patients who died of the disease, 64% of histologically negative nodes were found to harbor HPV DNA. Thus, it seems that the presence of HPV DNA in lymph tissue may be a prognostic indicator in cervical carcinoma and, as such, deserves further study.

The oncogenic risk varies among HPV types, with types 16 and 18 being found more commonly in high-grade dysplasia and carcinoma. Other HPV types, such as types 6 and 11, are associated with a more indolent course and are commonly seen in benign venereal warts. Although many HPV infections are latent and most mild dysplasias spontaneously regress, the authors point out that some will progress to malignancy.

In addition to viral type, immune status plays an important role in determining the outcome of HPV infection. Women with immunodeficiency states (eg, organ transplant recipients and HIV-infected individuals) have a higher prevalence of cervical carcinoma; this underscores the importance of cellular immunity in the control of HPV infection. In addition, cervical carcinoma in HIV-infected women is a more aggressive disease, presenting at a more advanced stage with poorer response to treatment. The severity of malignant disease has been shown to correlate with CD4 count; thus, patients with CD4 counts over 500 have a better prognosis.

Advances in Prevention and Treatment

The development of a vaccine that prevents subsequent oncogenic viral infections could have a substantial impact on the incidence of cervical carcinoma. The authors describe the production of recombinant HPV capsids that maintain native conformational epitopes and react with neutralizing antibodies specific for a particular HPV type. Such type-specific antigens have not been previously available and represent an advance in the development of a vaccine. In addition to being type-specific, these recombinant virus-like particles do not contain DNA that could be carcinogenic to the recipient, which is important for vaccine safety.

One potential problem in vaccine design was described by Kadish in a recent editorial on research carried out by Hines et al [2]. She emphasized the fact that many HPV types infect the female genital tract, and that in one population, 37.6% of the viral types could not be completely identified with available probes. Consequently, she suggested that a polyvalent vaccine, with antigenic representation from several different HPV types, might improve the success of immunization efforts.

Another type of therapeutic strategy being explored in cervical carcinoma is gene therapy. The HPV 16 and 18 protein products E6 and E7 bind to and inactivate the tumor-suppressor gene products of p53 and the retinoblastoma-suppressor gene, thus promoting malignant transformation. Hamada et al [3] used a recombinant adenoviral vector, Ad5CMV-p53, to transfer a wild-type p53 tumor-suppressor gene to a human cervical cancer cell line. This strategy resulted in inhibition of cell growth. Similar gene therapies are being investigated in ovarian carcinoma.

The research described by Hines et al represents significant advances in the potential prevention of HPV-associated disease, as well as the identification of populations at risk and the improvement and expansion of treatment strategies.

References:

1. Ikenberg H, Wiegering I, Schmitt B, et al: HPV DNA detected by PCR in histologically tumor-free lymph nodes of cervical carcinoma patients-A possible prognostic marker. Abstracts 26th Annual Meeting Soc Gyn Oncol p 108, 1995.

2. Kadish A: Recombinant virus-like particles retain conformational epitopes of native human papilloma viruses and may be useful for vaccine development (editorial). Gyn Oncol 55:10-12, 1995.

3. Hamada K, Zhang W, Alemany R, et al: Growth inhibition of human cervical cancer cells by the recombinant adeno virus-mediated transfer of a wild-type p53 gene. Abstracts 26th Annual Meeting Soc Gyn Oncol Soc Gyn Oncol p 30, 1995.