Human Papilloma Virus and Malignant Melanoma
Human Papilloma Virus and Malignant Melanoma
ABSTRACT & COMMENTARY
Synopsis: Human papilloma virus (HPV) may play a role in the progression of malignant melanoma. In this study, the presence of HPV in biopsy specimens correlated with the death rate and survival time of patients with malignant melanoma.
Source: Dreau D, et al. Ann Surg 2000;231:664-671.
In this report, dreau and colleagues from the Carolinas Medical Center in Charlotte, N.C., studied 12 patients with malignant melanoma to evaluate the relationship between human papilloma virus (HPV) and malignant melanoma. The presence of HPV in biopsy specimens was determined by using a polyclonal antibody raised against bovine papilloma virus 1, which reacts with all HPV isolates. Results were expressed as the number of HPV-positive cells per field. The diagnosis of melanoma was confirmed with immunohistochemical stains for gp-100 and S-100. Melanoma cell cultures were attempted for all specimens and their ability to grow was correlated with the HPV status of the tumor.
HPV was detected infrequently in normal tissue adjacent to the malignant area. This was true whether the tumor stained positively or negatively for HPV. By definition, the tumor was HPV-negative if there was less than one HPV cell per field. This occurred in five of the 12 patients with 0.33 ± 0.2 HPV-positive cells per field. Seven patients had HPV-positive tumors with 3.9 HPV-positive cells per field. The number of HPV-positive cells per field in this group was well below the 80.0 HPV-positive cells seen in the positive controls of condyloma biopsies.
Twelve patients with recurrent malignant melanoma were enrolled in this study. Nine patients recurred in the regional nodes (stage III) and three with distant metastatic disease (stage IV). Each patient underwent complete excision of all sites of disease and their clinical progression was then correlated with both the tumor’s HPV status and its capability of sustained growth in cell culture. Nine patients did receive various immunotherapy programs although details were not provided.
The results indicated that the presence of HPV in the tumor was associated with rapid melanoma progression. For example, all seven patients with HPV-positive tumors died after an average of 15.2 months (range, 1.3 - 34.6). In comparison, only one of the five patients with HPV-negative tumors died and the average survival time of this group was 40.4 months. The two groups seemed balanced with respect to stage, treatment, and age. The relationships between HPV and melanoma recurrence, death rate, and survival time were all statistically significant by the chi-square test.
COMMENT by Kenneth W. Kotz, MD
The results of this study suggest that patients with recurrent melanoma (stages III and IV) whose tumors are positive for HPV by immunohistochemical staining have a much higher death rate and poorer survival time. This aggressiveness was also seen in cell culture results: none of the HPV-negative tumor cells grew in vitro, whereas five of seven (71%) cell cultures from HPV-positive tumors were capable of sustained growth. The immunostain used in this study was a polyclonal antibody that recognizes all HPV isolates. Dreau et al are currently studying which subtypes of HPV were present in their biopsy specimens.
If confirmed by other studies, the presence of HPV by immunostaining could prove to be a useful prognostic tool for recurrent melanoma. How this will relate to well-studied risk factors, such as LDH, patient age and gender, performance status, and location of metastases, is unknown. Other techniques, such as detection of circulating melanoma cells by quantitative RT-PCR, may also eventually be useful as prognostic tools.
Dreau et al discuss possible mechanisms for a relationship between the human papilloma virus and the development and progression of malignant melanoma. For example, the HPV E6 protein interferes with the action of p53, a tumor suppressor protein involved in the repair of UV-type DNA damage,1 a known risk factor for the development of malignant melanoma. The HPV E7 protein may shorten the G1/S phase of the cell cycle via its interaction with the cell cycle protein regulator pRb protein.2 Interestingly, the introduction of HPV E6 and E7 proteins into cultures of normal human melanocytes results in the immortalization of the cells.3 Naturally, the complex relationship between HPV and melanoma will need further study at both the biologic and clinical levels, and the report by Dreau et al is an interesting start.
References
1. Smith ML, et al. Oncogene 1995;10:1053-1059.
2. Amellem O, et al. Br J Cancer 1998;77:862-872.
3. Le Poole IC, et al. In Vitro Cell Dev Biol Anim 1997;33: 42-49.
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