Malignant melanoma (MM) is an immunologic tumor Citation[1–6], with hypotheses of MM behaving worse in the setting of immunosuppression. However, outcomes data are limited. This area of research is challenging due to the complexities involved in the genetics of MM, in addition to the multiple facets of immunosuppression. However, there are numerous studies looking at MM in two common forms of immunosuppression; namely in solid-organ transplant recipients and in patients with lymphoproliferative disorders, specifically chronic lymphocytic leukemia (CLL).
Malignant melanoma-induced immunosuppression
Malignant melanoma can induce immunosuppression in a variety of ways. FOXP3 regulatory T cells have been found to be able to suppress immune responses Citation[7]. Documented failure of clinical response of MM to immune therapies has been linked to elevated levels of T regulatory cells Citation[8]. Peripheral blood mononuclear cells that have been exposed to MM-conditioned media have higher proportions of FOXP3 regulatory T cells than those exposed to control media (3.4 vs 1.3%) Citation[7]. There have also been other investigations that have found an increased concentration of T regulatory cells in the lymph nodes in patients with metastatic melanoma Citation[9]. This suggests that MM may influence the presence or behavior of certain T cells that function in suppressing immune responses that could be part of the tumor surveillance system. In addition, other proposed mechanisms for MM-induced immunosuppression include MM cell secretion of TGF-β, IL-10 and indoleamine 2,3-dioxygenase (IDO) Citation[10]. TGF-β can be produced by tumor cells, acts in an autocrine and paracrine fashion and promotes an immunosuppressive phenotype in T lymphocytes as well as dendritic cells Citation[10]. IL-10 is produced by T lymphocytes and tumor cells, and also has a suppressive effect on T lymphocytes and dendritic cells Citation[10,11]. Finally, IDO is an enzyme that is mainly produced by antigen-presenting cells of myeloid origin. IDO functions in suppressing T-lymphocyte-related antigenic-specific immune responses, and has been associated with progression of colorectal cancer, hemangiomas and MM Citation[12–14].
Other forms of MM-associated immunosuppression include certain ligands present on tumor cells that have the ability of blocking natural killer responses. In addition, these ligands may behave as cytotoxic T-lymphocyte-activating receptors, which may induce apoptosis of surrounding T cells. These ligands include a bioactive soluble Fas ligand, APO2-ligand/TNF-related apoptosis-associated ligand and NKG2D-ligand/MIC-A/B Citation[10].
Because of these multiple forms of melanoma-induced immunosuppression, it is no wonder MM can be very challenging to control and treat. MM thus has many ways of causing a local tumor-induced immunosuppression, and one could speculate that in the setting of an immunosuppressed host, MM may behave even more aggressively Citation[15].
Melanoma in organ transplant recipients
Organ transplant recipients (OTRs) have a higher incidence of MM than the general population. Three main clinical scenarios exist with MM in OTRs: OTRs with a history of MM prior to transplantation, MM as a result of transmission from the organ donor Citation[16] and, finally, OTRs who develop MM de novo post-transplantation. Because MM may behave more aggressively in the setting of immunosuppression, specific queries as to the incidence and clinical course of MM after transplantation have arisen.
There have been multiple studies looking at the incidence of MM post-transplantation. These studies have found the incidence of MM to be two- to five-times higher than average, with one study demonstrating an eight-fold higher chance of developing MM Citation[17–21]. Another study found the risk of MM development post-transplantation to be 17.2-times higher in African–Americans Citation[22].
Another interesting phenomenon seen in OTRs is eruptive nevi Citation[23,24]. This has been documented most frequently in the post renal transplantation population Citation[25,26]. Having a large number of nevi is a risk factor for MM Citation[27], making this phenomenon intriguing. There has been some speculation as to whether the amount of nevi in the setting of renal transplantation and other organ transplantation may correlate with the duration or amount of immunosuppression; however, conflicting data exist Citation[27–29].
The clinical course of melanoma has also been investigated in OTRs. There are scattered small reports in the literature, with surprising responses of OTRs with metastatic melanoma responding extremely well to the cessation of immunosuppression Citation[30–33]. These reports beg the question of how much of a role the immune system really plays in the overall behavior and course of MM. One recent multicentered retrospective analysis looked at 100 MMs in 95 patients post-transplantation and found the 2-, 5- and 10-year survival to be no different when compared with the general population Citation[34]. However, this study did find that MMs deeper than 2 mm had significantly worse outcomes, with a 0 versus 70% 5-year overall survival (hazard ratio of 11.49; p < 0.0001) compared with the general population Citation[34]. This does suggest that deeper melanomas in the setting of organ transplantation could potentially behave more aggressively. However, other studies have not been able to duplicate this finding. Specifically, a recent study looking at 31 patients with melanoma post transplantation demonstrated no difference in 5-year overall and melanoma-specific survival compared with the general population, regardless of melanoma depth Citation[35].
Melanoma in the setting of chronic lymphocytic leukemia
Chronic lymphocytic leukemia is another condition associated with immunosuppression and a 2.2-times higher incidence of a secondary malignancy, skin cancer being the most common Citation[36]. Specifically, an association between CLL and MM has been well documented, with the increased risk of developing MM in the setting of CLL being 2.3- to 3.1-times higher than average Citation[37–40]. One of our recent studies looking at MM in the setting of CLL demonstrated an overall survival of 60.9% in patients who develop MM after the diagnosis of CLL, versus a 96.2% overall survival in patients with MM prior to the development of CLL Citation[41]. Although this study did not have statistically significant hazard ratios, the mortality trend was striking and does cause speculation as to whether MM behaves more aggressively with certain genetic alterations or impaired immune functions present in the setting of CLL.
Bcl-2 is a proto-oncogene that is a suppressor of apoptosis. Bcl-2 promotes resistance to anticancer immune responses and has been found to be elevated in 95% of patients with CLL, and may be one of the reasons why patients with CLL develop an accumulation of long-lived lymphocytes Citation[42]. Intriguingly, patients with MM also have an elevation of bcl-2 90% of the time Citation[43,44]. This may be one of the reasons why patients with MM seem to have a resistance to radiation, chemotherapy and withdrawal of growth factors. It is interesting to speculate that patients with CLL and MM may have a significantly elevated bcl-2 level, perhaps affecting the prognosis and outcome of both forms of cancer.
In addition, patients with CLL have a deletion in the 17P chromosome 7–10% of the time Citation[45]. This correlates with the p53 gene and is the strongest predictor of poor survival in the setting of CLL. In fact, patients with this mutation have an average survival of 32 months and poor responses to therapy Citation[45]. Patients with CLL and p53 mutations could potentially be more prone to not only developing MM, but also to developing a more aggressive form of MM with higher chances of metastasis and MM-specific death. Finally, there are subsets of patients with CLL who lack the retinoblastoma gene. This occurs in both early and late stages of CLL Citation[46], and is another genetic focus in the setting of CLL that could influence the development and behavior of MM in these patients.
Conclusion
According to the bulk of research, there appears to be no greater risk of recurrence of MM in patients who develop MM prior to receiving a solid organ transplant Citation[47]. There is, however, a well-documented increased incidence of MM after transplantation. Conflicting evidence exists as to whether the survival and recurrence of MM is different in patients with organ transplantation compared with the general population. At this point, however, it appears that overall survival is no worse in OTRs who develop MM, specifically in patients with thinner MMs.
Similarly, multiple studies have documented an increased incidence of MM in the setting of lymphomas, specifically CLL. However, outcomes are very limited. There are, however, small studies suggesting a very interesting trend towards worse outcomes. Because of the complexities involved in the behavior and genetics of MM, as well as the immune system, there are potentially many factors that could influence the behavior, development and progression of MM in this clinical setting. In addition, there are potentially subsets of patients with CLL that may be genetically predisposed to the development and progression of an aggressive MM. Larger population-based studies are needed to elucidate the behavior of MM in the setting of CLL.
Until these answers can be found, it would be prudent to monitor immunosuppressed patients, specifically OTRs and patients with CLL, more frequently, with a lower threshold for biopsying worrisome or changing pigmented lesions. In addition, an immunosuppressed patient who goes on to develop MM may require closer follow-up and a more aggressive treatment approach. Finally, although many questions remain unanswered, education of patients with MM and immunosuppression with regards to more vigilant sun-protective practices, regular self-skin examinations and frequent dermatologic follow-up is warranted.
Financial & competing interests disclosure
Jerry Dewayne Brewer is a Dermatology Foundation Career Development Award recipient for the study of lymphoma-associated skin cancer. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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