Why melanoma and a small handful of other tumor types undergo spontaneous regression is unknown and difficult to study. Some scientists believe that the immune system is involved, but many questions remain unanswered.
Laboratory studies have shown that melanomas induce immune responses and that some patients have immunity to their melanomas that keep the tumor under some sort of control. In most cases, the tumor outgrows the capability of the immune system to destroy it. In some cases, however, the immune system manages to win, either partially or completely destroying the tumor and resulting in spontaneous regression.
There are no hard statistics on how many melanomas regress completely without leaving metastases, but Ross Barnetson, M.D., of the Royal Prince Alfred Hospital at the University of Sydney in Australia, estimates that the rate is between 10% and 20%, based on histological studies that show that 25% of melanomas have evidence of partial regression.
There is some evidence that other tumor types undergo spontaneous regression, but the phenomenon may appear more frequently in melanoma because it is easier to observe than in internal cancers such as breast or lung cancers, said Alan Houghton, M.D., chief of immunology at Memorial Sloan-Kettering Cancer Center, New York.
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Difficult to Study
Spontaneous regression is not easy to study because the majority of melanoma patients receive treatment, so it is difficult to tell whether the regression was spontaneous or whether it was enhanced by specific treatments, experts say.
Halliday is part of a research team at the University of Sydney that has been a major contributor to the small body of literature on spontaneous regression of melanoma and other skin cancers. Australia has the highest incidence of skin cancer, including melanoma, in the world, making clinical material relatively easy to obtain. The Sydney Melanoma Unit is the largest of its kind in the Southern Hemisphere.
In melanoma and in basal cell carcinoma, the Australian groups studies have shown that activated CD4+ T lymphocytes are important in the induction of regression and that Th1 cytokines are involved. They observed an increased number of CD4+ T lymphocytes in regressing tumors only within the regressing lesions themselves, not in surrounding tissues.
The lymphocytes appeared to be breaking up nests of tumor cells, suggesting that the CD4+ T cells were destroying tumor cells. Apoptotic cell death also appears to play a role in regression. Nevertheless, the exact mechanism by which these cells mediate regression remains unknown.
Barnetson and his colleagues also have studied regression in basal cell carcinomas of the skin, where there is evidence of regression in as many as 50% of tumors. In studies on the effect of interferon alfa on basal cell carcinoma carried out over the past 15 years, tumors disappeared in 20% of patients on the placebo arm of the trial, indicating that about 20% of basal cell carcinomas undergo complete spontaneous regression.
Sloan-Ketterings Houghton is somewhat skeptical of the conclusions of the Australian groups studies.
"The question is whether their findings really implicate immunity or not," he said. "Any sort of tissue damage, such as cutting yourself, might give similar findings if you looked at the right time points. If there were other mechanisms for regression, the T cells they observed could have been a consequence of regression, not a cause of it."
Unanswered Questions
Still, Houghton agrees that regression of the primary melanoma site is not that unusual and that there are a lot of questions that remain unanswered. The very nature of a cancer that regresses makes it nearly impossible to assemble a group of patients for a clinical study, which forces researchers to focus on isolated cases. These "n = 1 studies," as Houghton describes them, are almost essential to study a phenomenon that cannot be predicted.
Houghton cited an example of a patient he and his colleagues first saw around 1975. A teenager at the time, the patient had a very aggressive melanoma that would not respond to various treatments.
"He was in a group [of patients] that never should have survived," Houghton said. "After a year, however, his melanoma went away, and he is alive today and doing well."
Investigators at Sloan-Kettering and in Europe have studied this patients blood and lymphocytes, in which they found at least three different antigens. The genes encoding these antigens have been cloned and used in vaccines that are undergoing clinical trials in the United States and Europe, Houghton said. The patients T cells also recognized a mutation in a gene called CDKN4 that may have helped cause his melanoma.
"What we can learn from individual patients is often overlooked in oncology," he said, adding that many of these remarkable cases have led to the development of new treatment strategies for melanoma such as vaccinations against specific antigens and bone marrow transplantation. "From clinical observation, we can learn a lot from these remarkable cases," he said.
Meanwhile, the Australian group said it will not pursue further studies because it has been unable to obtain additional funding to study spontaneous regression.
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