GOTHENBURG, Sweden - Patients with a history of chronic lymphocytic leukemia have an elevated risk of developing malignant melanoma of a particularly aggressive nature.
A new analysis of data from the National Cancer Institute's Surveillance, Epidemiology, and End Results registry demonstrates that individuals with a history of chronic lymphocytic leukemia (CLL) are at 2.5-fold increased risk of subsequently developing melanoma. And once they do, these patients have an adjusted 2.7-fold greater 10-year all-cause mortality and a 2.8-fold increased mortality caused by melanoma, compared with melanoma patients without prior CLL, Dr. Jerry D. Brewer reported at the annual congress of the European Academy of Dermatology and Venereology .
Dr. Jerry D. Brewer
"Melanoma and CLL is a dangerously common association with bad outcomes," said Dr. Brewer, a dermatologic surgeon at the Mayo Clinic, Rochester, Minn.
The pattern of worse outcomes in melanoma patients with a history of CLL was significant across all categories of Breslow tumor depth and Clark's level, but it was most striking in patients with thicker lesions. For example, melanoma patients with a Breslow depth greater than 4.0 mm had a 2-year overall survival rate of just 36% if they had a history of prior CLL, compared with 71% if they did not. Their 2-year melanoma-specific survival was 50% with prior CLL and 82% without such a history.
These findings have important implications for clinical practice, according to the dermatologist. For example, patients with CLL have to get serious about daily sun protection, and they need to learn how to do regular skin self-examinations.
"We also need to educate our professional colleagues, specifically our hematologists/oncologists, that if their patients with CLL have a lot of moles or a lot of risk factors for melanoma, they should consider referring those patients to a dermatologist sooner, to catch melanomas earlier," he continued.
The population-based study included 212,245 melanoma patients in the SEER database in the years 1990-2006. Among them were 1,246 patients with a prior diagnosis of lymphoma, of which 31% were CLL. Those diagnosed with melanoma after CLL were on average 12 years older than patients diagnosed with melanoma without prior CLL, a difference adjusted for in determining standardized mortality ratios.
The 10-year overall survival in patients diagnosed with melanoma preceded by CLL was 19%, compared with an expected 55% if they had no history of prior CLL. The 10-year melanoma-specific survival rates were 62% with a prior diagnosis of CLL and 84% without.
Other investigators have previously reported higher rates of metastasis and worse survival in patients with squamous cell carcinoma or Merkel cell carcinoma preceded by CLL. "Now we know that’s true for melanoma, too," Dr. Brewer said.
The impetus for the SEER study was an earlier small study he and his coinvestigators conducted involving 69 Mayo Clinic patients with CLL and melanoma. They found worse outcomes in patients who had CLL prior to melanoma than in those diagnosed with melanoma prior to CLL (Dermatol. Surg. 2010;36:368-76).
One case in that series that particularly impressed Dr. Brewer involved a documented metastasis in a patient with a history of CLL prior to diagnosis of melanoma in situ. This was a melanoma in situ without an inflammatory infiltrate, so there was no confusion about the lesion's true depth. It was unmistakably a melanoma in situ, yet after standard therapy it recurred and metastasized.
Like patients with a history of CLL, organ transplant recipients are also at increased risk of aggressive skin cancers. Theories abound as to why immunosuppression, whether caused by lymphoma or organ transplantation, should have this effect. Among the proposed explanations are decreased immune surveillance, direct carcinogenesis caused by chemotherapeutic agents or antitransplant-rejection drugs, and an increased rate of infections with human papillomavirus.
However, Dr. Brewer thinks the most likely explanation involves a shared underlying genetic predisposition. Patients with CLL are rife with genetic aberrations. For example, 7%-10% of patients with CLL have a deletion mutation at 17 p.
"That's where the p53 gene is, which is the strongest predictor of poor survival in patients with CLL, with a median survival of only 32 months. Maybe these patients also have a higher risk of developing aggressive skin cancer; that’s something we just don't know yet," he noted.
Another genetic aberration worthy of further study involves the proto-oncogene B-cell lymphoma 2 (Bcl-2), which suppresses apoptosis. Bcl-2 expression is elevated in 95% of patients with CLL and in 90% of melanoma patients. Intriguingly, the antisense oligonucleotide oblimersen, which is targeted at Bcl-2, has shown encouraging results in combination with dacarbazine in patients with advanced melanoma (Eur. J. Cancer 2009;45:1807-14).