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Keywords:

  • melanocyte;
  • melanoma;
  • immunosurveillance;
  • halo nevus;
  • Meyerson’s nevus;
  • melanoma-associated depigmentation;
  • regression

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Halo nevus (Sutton’s nevus)
  5. Meyerson’s nevus
  6. Regression in melanoma
  7. Melanoma-associated depigmentation
  8. Discussion
  9. Conclusion
  10. References

Spontaneous regression of benign and malignant melanocytic lesions can be a visible sign of immunosurveillance. In this review, we discuss different immune reactions against melanocytic lesions: halo nevus, Meyerson’s nevus, regression in melanoma and melanoma-associated depigmentation. These entities present with particular clinical aspects, histology and evolution. In all entities, a melanocyte-specific T-cell reaction has been assumed but a different degree of melanocyte destruction is present. A focus on the immune responses in melanocytic lesions reveals several aspects of an adequate skin immunity and may help to identify the key points in the immune destruction of melanocytes. These insights can add to the knowledge of how to optimize immunotherapeutic strategies in melanoma.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Halo nevus (Sutton’s nevus)
  5. Meyerson’s nevus
  6. Regression in melanoma
  7. Melanoma-associated depigmentation
  8. Discussion
  9. Conclusion
  10. References

The skin immune system

The skin, being the body’s most exposed barrier, has particular innate and adaptive immune mechanisms. The skin immune system is a complex interplay, as approximately half of the cell types in the skin are involved in the immune response. The major site of immunological activity resides in the papillary dermis, where T cells, monocytes and dendritic cells (DCs) are preferentially distributed (Bos and Luiten, 2009). Keratinocytes, mast cells, macrophages, Langerhans cells (LCs) and dermal DCs are the first barrier of the skin immune system. Keratinocytes have the capacity to produce a broad range of immune-stimulating and downregulating cytokines [interleukin (IL)-1, IL-6, IL-10, IL-12, regulated upon activation, normal T cell expressed and secreted, interferon (IFN)-α/β, macrophage colony-stimulating factor (M-CSF), tumor necrosis factor (TNF)-α, granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor, transforming growth factor (TGF)-β, β-defensin]. Various stimuli trigger keratinocytes to produce some of these molecules capable of controlling cell proliferation, migration of cells and activation of lymphocytes, DCs, mast cells and macrophages (Kupper and Fuhlbrigge, 2004; Woods et al., 2005). Besides protection against parasites, mast cells play a complex role in the innate and adaptive immune system. The initiating activity of mast cells on the innate immune response is suggested by the expression of multiple pathogen recognition receptors, such as Toll-like receptors (TLR) (Herschko and Rivera, 2010).

The TLR family is considered an important defense mechanism against various infectious pathogens and is a major player in the pathophysiology of inflammatory and neoplastic disorders of the skin. Toll-like receptor expression has been reported on keratinocytes, immune cells (T lymphocytes, DCs, LCs, mast cells, monocytes, eosinophils, neutrophils), vascular endothelial cells, fibroblasts and adipocytes in the skin. Binding of the TLRs by factors such as pathogen-associated molecular patterns (PAMPs), which are shared by a large group of pathogens, results in the activation of the nuclear factor (NF)-κB signaling pathways. In addition, TLRs can sense endogenous molecular signatures of tissue damage, also known as ‘danger-associated molecular patterns’ (DAMPs), which includes high-mobility group box-1 (HMGB1), extracellular ATP, heat shock proteins and extracellular matrix breakdown products. NF-κB is a major inducer of the inflammatory response and links the innate to the adaptive immune system. Activation of NF-κB leads to the production of inflammatory cytokines, chemokines, antimicrobial peptides, matrix metalloproteinases, nitric oxide synthase and the upregulation of adhesion molecules [E-selectin, P-selectin, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM1)]. Besides a direct cytotoxicity to pathogens or aberrant cells, both innate and adaptive immune cells are recruited to the site of inflammation (Kupper and Fuhlbrigge, 2004; Miller and Modlin, 2007).

The primary adaptive skin immune surveillance consists of antigen-presenting cells (epidermal LCs, dermal DCs, macrophages) which phagocytose foreign antigens and present them to lymphocytes in the skin-draining lymph nodes. Dendritic cells are key regulators of the skin immune system and form a bridge between the innate and adaptive immune system (Bos and Luiten, 2009). Langerhans cells, a subtype of DCs residing in the epidermis, are considered potent inducers of T-cell responses. Their maturity state is divided into three stages that represent the phases needed to capture and present antigens, also called the ‘LC paradigm’. Immature LCs form an organized network in the suprabasal layer of the epidermis to detect pathogens invading the epidermis. Immature LCs are characterized by a low major histocompatibility complex (MHC)-II surface expression and no co-stimulatory molecules (e.g. CD80, CD86) and have endocytotic, migratory and antigen-presenting capacities. In a second stage, LCs become activated due to microbial products and inflammatory cytokines (such as TNF-α) largely derived from surrounding keratinocytes. Subsequently, LCs lose E-cadherin expression, express chemokine receptors (e.g. CCR7) and secrete metalloproteinases, allowing migration to the lymph node (Igyarto and Kaplan, 2010). During the migration process, LCs become functionally mature by acquiring co-stimulatory molecules and producing inflammatory cytokines. Mature LCs are potent primers of naïve T cells, which acquire subsequently a skin-homing capacity, proliferate clonally and mature into effectory and memory T cells (Kupper and Fuhlbrigge, 2004). Immature LCs presenting (self-)antigens in the lymph node without co-stimuli (such as CD80, CD86, MHC–peptide complexes, chemokine receptors) induce peripheral tolerance (Hawiger et al., 2001). In the dermis, DCs and macrophages have a remarkable heterogeneity and functionality, ranging from DCs expressing BDCA-1 (CD1c) and DC-SIGN (CD209) to macrophages expressing CD163 (Nestle and Nickoloff, 2007). The exact function of the recently identified subset of langerin expressing dermal DCs which accounts for up to 30–60% of the Langerin+ DCs in the skin-draining lymph nodes of mice, remains to be elucidated (Romani et al., 2010). Dermal DCs and LCs not only have an antigen-presenting function but also skew the effector immune reaction by sensing ‘danger signals’ and are therefore considered cutaneous sentinels (Girardi, 2007). Plasmacytoid dendritic cells (pDCs) are a subtype of DCs, present in the blood, lymphoid tissues and inflammatory skin. ‘Resting’ pDCs are poor antigen-presenting cells and are even considered to be tolerogenic (Conrad et al., 2009; Swiecki and Colonna, 2010). However, pDCs are specialized in sensing nucleic acids from viral pathogens through endosomal TLRs such as TLR3, 7, 8 and 9 and induces the production of massive amounts of type-I interferons. Interestingly, although endogenous DNA cannot by itself cause pDC activation, damage to keratinocytes results in the release of the antimicrobial peptide LL37 (Cathelicidin antimicrobial peptide). When complexed and aggregated with LL37, self-DNA released by damaged cells can trigger TLR9 and produce a robust pDC-derived IFN-α response. This mechanism is thought to underly the pathological pDC-dependent auto-immune activation of T cells within psoriatic lesions (Lande et al., 2007). This is an illustration of how a DC subset can translate innate danger signals into an (inappropriate) adaptive immune response.

In the secondary immune surveillance phase, T lymphocytes in the draining lymph node become activated, express the appropriate homing receptors [such as cutaneous lymphocyte-associated antigen (CLA), lymphocyte function-associated antigen-1, very late activation antigen-4 (VLA-4) and chemokine receptors CXCR3, CCR4 and CCR10] and bind the skin-specific receptors on post-capillary venules [E-selectin, CC-chemokine ligand 17 (CCL17) and ICAM-1]. Once at the target site, the T lymphocytes become functionally active due to the inflammatory environment and influence the nature and activation state of the infiltrate by modifying the chemokine balance and producing inflammatory cytokines (e.g. IFN-γ, TNF-α). In contrast, a subpopulation of T cells, the so-called regulatory T cells (Tregs), dampen the inflammation and induce tolerance. In the tertiary phase, the antigen-specific memory cells migrate to other lymph nodes, providing a rapid immune response in case of second exposure to the same antigen (Kupper and Fuhlbrigge, 2004).

The melanocyte interplay with the immune system

Melanocytes, originally derived from the neural crest, are situated just above the basal membrane. The best known function of melanocytes is the production of melanin pigment. The dendritic structure of melanocytes, creating extensive contacts, especially with keratinocytes, suggests a complex signaling network (=the melanocyte-epidermal unit) (Lu et al., 2002).

Common acquired melanocytic nevi are neoplasms arising mostly during the first 3 decades of life, whereas congenital nevi are present from birth (Gelfer and Rivers, 2007). Despite their usually benign nature, expression of melanoma-associated antigens occurs (Cui and Willingham, 2004). Melanoma, the malignant counterpart, expresses a broad range of tumor-associated antigens roughly divided into four classes: cancer/testis-antigens [e.g. melanocyte-associated antigen (MAGE), B melanoma antigen (BAGE), G-antigen (GAGE), New York esophageal squamous cell carcinoma 1 (NY-ESO-1)], melanocyte differentiation antigens [e.g. tyrosinase, Melan A/melanoma antigen recognized by T cells (MART-1), tyrosinase-related protein 1 and 2 (TYRP-1 and TYRP-2), glycoprotein 100], tumor-specific mutated proteins (e.g. cycline-dependent kinase 4, β-catenin, fibronectin) and a group of aberrantly translated intronic sequences [e.g. melanoma-associated antigen (mutated)-1 (MUM-1), p15, N-acetylglucosaminyltransferase V] (Dranoff, 2009; Ram and Shoenfeld, 2007).

Spontaneous immune-mediated regression of nevi is particularly common in childhood and adolescence and could be a reflection of an active immune system that eliminates normal and neoplastic melanocytes and prevents tumor development (Cui and Willingham, 2004). Immunodeficiency is associated with a higher incidence of melanocytic nevi (Baron and Krol, 2005). During immunosuppression, numerous eruptive nevi may develop, accompanied by an increased lymphocytic infiltration (Piaserico et al., 2006). Involution of such nevi in transplant patients after suspension of immunosuppressive therapy has been reported. This illustrates the skin immunosurveillance against melanocytic proliferation (Zattra et al., 2009). Moreover, a decrease in the number of nevi has been reported in patients with chronic-graft-versus-host disease, suggesting that an increased inflammation in the skin may stimulate the immune reaction against nevi (Andreani et al., 2002). A 4- to 7-fold increase in melanoma risk has been reported in the immunosuppressed population compared to age- and gender-matched controls (Jensen et al., 1999).

The hurdles of immunotherapy for melanoma

Melanoma is considered a highly immunogenic tumor, accounting for 11% of spontaneously regressing tumors while representing only 1.8% of the total cancer burden (Everson and Cole, 1966). Spontaneous regression has been reported in all progression stages. A higher frequency of tumor-infiltrating lymphocytes (TILs) is associated with a better prognosis in melanoma (Oble et al., 2009). However, although melanoma-specific T-cell responses (e.g. Melan-A/MART-1 and gp100) have been detected in melanoma lesions, complete spontaneous or therapy-induced regression in advanced disease is a rare phenomenon.

Increasing evidence indicates that the tumoral cells skew the immune system to a more immunosuppressed state and acquire some mechanisms to escape an efficient immune response. Tumors are able to recruit and stimulate Tregs under the influence of certain, yet unknown factors (Serafini et al., 2006). These cells are important in controlling autoimmunity in physiological conditions, but they also appear to suppress a cytotoxic T-cell-mediated response against autoantigens on the tumor (Viguier et al., 2004). Several immunomodulating proteins can be expressed at the tumoral level. Tumoral overexpression of Programmed Death Ligand-1 (PD-L1) and, to a smaller degree, Programmed Death Ligand-2 (PD-L2) can diminish the antigen-receptor signalling by binding to the receptors on T and B lymphocytes (Freeman et al., 2000). Tumoral PD-L1 expression has recently been linked to a worse prognosis in melanoma (Hino et al., 2010). Loss of MHC-I in melanoma is associated with disease progression (Chang et al., 2005). Melanoma cells are also able to express MHC-II, but the costimulating molecules CD80 and CD86 are often absent, which induces tolerance (Denfeld et al., 1995). Ectopic expression of HLA-G, a nonclassic MHC-I molecule, can protect melanoma cells against natural killer (NK)-cells (Paul et al., 1998). Expression and secretion of Fas ligand by melanoma cells leads to apoptosis of immune cells (Andreola et al., 2002). In more advanced melanoma stages, the absence of P-selectin expression could play a role in inhibiting an efficient antitumoral response (Nooijen et al., 1998).

In spite of the existence of different immunotherapeutic interventions in melanoma, significant clinical responses are only observed in a subset of patients. Currently, these responders cannot be identified in advance. The pathogenesis of regression in melanocytic lesions is a complex phenomenon. Insights into the immune responses to different melanocytic lesions may help to identify the mechanisms and triggers of an efficient immunological elimination of melanocytes.

Halo nevus (Sutton’s nevus)

  1. Top of page
  2. Summary
  3. Introduction
  4. Halo nevus (Sutton’s nevus)
  5. Meyerson’s nevus
  6. Regression in melanoma
  7. Melanoma-associated depigmentation
  8. Discussion
  9. Conclusion
  10. References

Clinical signs

A halo nevus is a nevus surrounded by a symmetrical circle of depigmentation, resulting in spontaneous regression of the nevus. The central lesion is most commonly a compound, junctional or intradermal nevus and the halo usually varies in size from 0.5 to 5 cm. The clinical involution of a Sutton’s nevus can be divided into four stages (Figure 1). Stage I is characterized by the appearance of a depigmented halo. In stage II, the central nevus becomes paler and has a more erythematous appearance. The regression of the central nevus is completed in stage III. Stage IV shows a residual depigmentation, which may be present for years, until spontaneous repigmentation occurs (Barnhill et al., 1995).

image

Figure 1.  Clinical picture of halo nevus, Meyerson’s nevus, regressing melanoma and vitiligo-like depigmentation.

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Halo nevi develop in up to 1% of the general population, especially in children and adolescents (average age of onset is 15 yr). No marked gender predisposition is observed (Rhodes, 1993). A family history of halo nevi or vitiligo may be present. Vitiligo patients have an increased frequency of halo nevi, which varies greatly in the literature between 1 and 48% (Frank and Cohen, 1964; Gauthier et al., 1975; Wayte and Helwig, 1968). Predilection areas are the trunk and, in the case of multiple halo nevi, the back. In all, 25–50% of the patients have two or more halo nevi (Sotiriadis et al., 2006).

In contrast with acquired nevi, spontaneous involution of congenital nevi is uncommon. Induration and ulceration may precede the regression of giant congenital melanocytic nevi (Cusack et al., 2009). A halo phenomenon is reported sporadically in Spitz and blue nevi (Kolm et al., 2006). Nevi may also show regression without the presence of a surrounding rim of depigmentation. The standard histology of these ‘halo nevi without halo’ is similar to halo nevi (Rados et al., 2009).

Histology and pathophysiology

The pre-regression stage shows a dense band-like inflammatory infiltrate characterized predominantly by T lymphocytes around centrally located nests of nevus cells (Moretti et al., 2007; Sotiriadis et al., 2006). B lymphocytes are sparse and are not detected within the nevus nests. In the early phase, the number of T cells and LCs increases. The late phase of regression is characterized by a dense infiltration of mainly CD8+ and also CD4+ cells between and within the nests of nevus cells (Figure 2). The majority of the T cells are positive for granzyme B, perforin and Fas ligand, illustrating their cytotoxic activity (Musette et al., 1999). A few scattered CD68+ macrophages are also found in the lesion. Finally, the complete regression displays an absence of melanocytes and a modest remaining infiltrate (Bayer-Garner et al., 2004).

image

Figure 2.  Histologic pictures. (A) Halo nevus: a dense band-like infiltrate of predominantly T lymphocytes around nests of nevus cells. (B) Meyerson’s nevus: a perivascular infiltrate with T lymphocytes, mast cells and some eosinophils. (C) Regressing melanoma: a marked area of regression with fibrosis replacing the tumoral cells. (D) Vitiligo-like depigmentation: early stage with focal lymphocytic infiltrate and almost complete absence of melanocytes.

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The pathophysiology of halo depigmentation remains obscure, although the involvement of cytotoxic T-cell activity in the destruction of melanocytes seems evident (Figure 3). The upregulation of MHC-I on melanocytes, which is correlated with the density of the inflammatory infiltrate, makes them vulnerable to immune destruction (Bayer-Garner et al., 2004). The majority of infiltrating T cells express a skin homing protein (CLA). In a study by Musette et al. (1999) the T-cell receptor (TCR)-β chain repertoire of the T-cell infiltrate in halo nevi mainly consisted of non-activated or polyclonally activated T cells expressing CLA. A limited subset represented a clonal expression of specific T-cell clones. The same clones recur in different halo nevi of the same patient and could not be detected in the blood. These clones were not directed against classic melanoma-associated antigens (MAGE, BAGE, GAGE) (Musette et al., 1999). A number of questions are currently unsolved: the exact antigen that triggers the immune reaction in halo nevi and the mechanism of the varying size of the halo are currently unknown.

image

Figure 3.  Pathophysiology of halo nevus, Meyerson’s nevus, regressing melanoma and vitiligo-like depigmentation.

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Prognosis and management

Spontaneous fading with a remaining depigmentation is expected within 2 yr. Differential diagnosis should be made with regressing melanoma especially in case of a suspected history, an asymmetrical halo and older age of the patient. Halo nevi do not require treatment (Mandalia et al., 2002).

Meyerson’s nevus

  1. Top of page
  2. Summary
  3. Introduction
  4. Halo nevus (Sutton’s nevus)
  5. Meyerson’s nevus
  6. Regression in melanoma
  7. Melanoma-associated depigmentation
  8. Discussion
  9. Conclusion
  10. References

Clinical picture

Meyerson’s nevi (or halo dermatitis) are characterized by pruritic, erythematous, scaly lesions encircling pre-existing pigmented nevi (Figure 1) (Nicholls and Mason, 1988). This phenomenon can be confined to one or multiple nevi of a patient. The major predilection area is the trunk, followed by the proximal and the distal extremities. A Meyerson’s phenomenon is mostly observed in young, male, atopic individuals during summer. The benign, eczematous halo usually disappears spontaneously after several weeks or months without regression of the nevus, although occasional progression to halo nevus has been described (Brandt et al., 2005; Cook-Norris et al., 2008; Ramón et al., 2000).

Histology and pathophysiology

Histopathology shows a junctional or compound nevus without atypia or regression (Cook-Norris et al., 2008). The early stage is characterized by a subacute eczema with variable focal spongiosis, occasional parakeratosis, and acanthosis of the overlying epidermis. A dense, perivascular infiltrate is present which is mainly composed of activated CD4+ lymphocytes with occasional eosinophils and mast cells (Figures 2 and 3) (Fernández Herrera et al., 1988). The modest presence of CD8+ cells and markers of cytotoxic activity would explain the absence of histologic regression of the pigmentary lesion. The infiltrating T cells of Meyerson’s nevi demonstrate a reduced expression of IL-2 receptors, which is in contrast to the marked IL-2 receptor expression in contact dermatitis (Brandt et al., 2005; Cook-Norris et al., 2008). Increased ICAM-1 expression on keratinocytes and endothelial cells has been detected in Meyerson’s nevi (Feal-Cortizas et al., 1997). The responsible antigen that triggers the immune reaction remains to be elucidated (Cook-Norris et al., 2008).

Prognosis and management

No treatment is necessary and spontaneous resolution is common. Excision of the central nevus results in a complete resolution of the inflammation, illustrating the melanocyte-specific reaction (Brandt et al., 2005). The application of topical steroids may result in a faster resolution of the inflammation, although recurrence has been commonly reported (Cook-Norris et al., 2008). Lesions may persist for several months and a slowly resolving rim of post-inflammatory hypopigmentation can be present (Meyerson, 1971).

Regression in melanoma

  1. Top of page
  2. Summary
  3. Introduction
  4. Halo nevus (Sutton’s nevus)
  5. Meyerson’s nevus
  6. Regression in melanoma
  7. Melanoma-associated depigmentation
  8. Discussion
  9. Conclusion
  10. References

Clinical picture

Local areas of regression in primary melanomas are a well-known phenomenon, but complete regression is rare (Moretti et al., 2007). However, there have been some reports of complete regression of the primary melanoma in patients with metastases (Ng and Chave, 2006). In general, the regression area is clinically irregular and patchy without an obvious predilection for the border. It presents as a white, red or grayish zone within the melanoma lesion (Figure 1). A regressing melanoma presents a dermatoscopic picture of a scar-like depigmentation with a whitish-pink background color, remnants of pigmentation and linear-irregular vessels or a globular vascular pattern of the vessels (Bories et al., 2008).

A depigmented halo (=leukoderma acquisitum centrifuguum) around a melanoma is extremely rare and has a more asymmetrical shape than in halo nevi. Usually, a melanoma with a surrounding halo regresses completely, but local and distant metastases may occur (Rubegni et al., 2009). Remarkably, regression is more common in adult patients (Requena et al., 2009).

Histology and pathophysiology

Histological regression is observed in up to 20–30% of (especially thin) melanomas. In the early stage of regression, lymphocytes, macrophages and LCs infiltrate the tumor (Blessing and McClaren, 1992). Regressing melanomas have an increased CD4+/CD8+ ratio and elevated expression of the IL-2 receptor on T cells (Tefany et al., 1991). B cells and NK cells are usually absent or sparse. The inflammatory infiltrate is usually asymmetric and patchy and surrounds only local parts of the tumor (Figure 3). In the intermediate phase, the tumoral cells in the papillary dermis and the overlying epidermis are reduced or even completely replaced by lymphocytes, melanophages and fibrosis (Figure 2). Necrotic melanocytes or keratinocytes can be identified as small eosinophilic bodies (Civatte bodies). The late phase is characterized by a marked area of regression in the tumor or sometimes a complete involution of the melanoma. Fibrous stroma gradually replaces the dermis, mostly at the center of the tumor, and an increased vascularity is present. The epidermis becomes atrophic with the disappearance of the rete ridges. A few remnant melanoma cells may be observed at the junction. Instead of atrophy, an epidermal hyperplasia is sometimes present (Requena et al., 2009). In some cases, complete regression is only characterized by a remaining melanosis (Ng and Chave, 2006). If further progression occurs, a decrease in the frequency of TILs and the amount of CD8+ granzyme B+ cells is observed between radial growth phase, vertical growth phase and metastases (Mourmouras et al., 2007).

Prognosis and management

The prognostic implications of regression in melanoma are unclear. Various studies have come to different conclusions and several authors have suggested an adverse effect on prognosis (Brochez et al., 2006). However, in theory, an immune response eliminating the tumoral cells should be expected to have a beneficial influence. On the other hand, the immune cells may not be able to destroy all malignant cells, which results in no or only a partial regression. The most malignant clones may survive and escape recognition by the immune system (immunoselection). Regression in melanoma may give an underestimation of the initial Breslow index. Extensive regression in thin melanomas seems to have a worse prognosis, although the tumor is usually partially destructed (Slingluff et al., 1988). Melanoma patients presenting with signs of regression are reported to have an almost 10-fold higher probability of sentinel node involvement, which could mean that the phenomenon of regression is a reflection of higher tumor load. Therefore, a sentinel node procedure might be considered in regressing melanomas with a Breslow depth <1 mm (Olàh et al., 2003). In the study by Shaw et al. (1989) all patients with thin (<0.76 mm) melanomas and concurrent regional lymph node metastasis demonstrated histological signs of regression in the primary tumor. It is hypothesized that melanoma spread to regional lymph nodes could increase the immune reaction against the primary melanoma. In patients with multiple primary melanomas, histological regression is more frequently found in the latest diagnosed lesion, which is correlated with an increased presence of circulating melanoma-specific cytotoxic T lymphocytes. This phenomenon may be similar to the enhanced immune recognition of tumor-associated antigens observed after repeated immunizations in experimental murine models and may be the result of an immunization effect (Saleh et al., 2001).

Melanoma-associated depigmentation

  1. Top of page
  2. Summary
  3. Introduction
  4. Halo nevus (Sutton’s nevus)
  5. Meyerson’s nevus
  6. Regression in melanoma
  7. Melanoma-associated depigmentation
  8. Discussion
  9. Conclusion
  10. References

Clinical picture

Spontaneous or immunotherapy-induced MAD is observed in 2–7% of melanoma patients. A recent study with 2954 melanoma patients showed the presence of leukoderma in 20% before and in 80% after diagnosis (median time 3.4 yr, range 2–20 months). MAD was found in all melanoma stages (46% stage I–II, 42% stage II–III, 12% stage IV, 24% after therapy) (Quaglino et al., 2010). MAD is clinically similar to classic vitiligo, although some differences are reported. It often has an asymmetrical distribution and is commonly located on the face (including the perioral/periorbital area), neck, upper trunk and extremities. Halo phenomena around cutaneous metastases and scars are commonly reported (25.7%) in melanoma patients with vitiligo-like depigmentation (Brochez et al., 2006; Quaglino et al., 2010). There is no correlation between MAD and the location of the primary tumor (Hartmann et al., 2008). The incidence of vitiligo-like depigmentation in melanoma patients is 7–10-fold higher than in the normal population. The age of onset of MAD is higher (53 yr) than in vitiligo vulgaris (18–31 yr) (Liu et al., 2005; Paravar and Lee, 2010; Quaglino et al., 2010).

Histology and pathophysiology

The combination of melanoma and vitiligo-like depigmentation is supposed to be due to an immune-mediated reaction against antigens shared between normal melanocytes and melanoma cells. The pathogenic process probably relies on a cytotoxic T-cell-mediated immune response targeted against melanocyte/melanoma differentiation antigens (e.g. MART-1, tyrosinase, gp100, TYRP-1 and TYRP-2) and results in the destruction of melanocytes and the development of depigmented areas (Cunha et al., 2009). Melanoma and vitiligo patients develop similar antibodies against melanocyte- and melanoma-specific antigens (Ram and Shoenfeld, 2007). The titers of anti-melanocyte antibodies are not increased in patients with melanoma-associated vitiligo, suggesting a limited role of tumor-associated antigen (TAA)-specific antibodies in the development of MAD (Lu et al., 2002).

The histological image of MAD is similar to that of classic vitiligo. The amounts of epidermal melanocytes, DCs and the type of inflammation are indistinguishable (Figures 2 and 3). Melanin and MART-1+ melanocytes are decreased or absent. At the margin with the non-lesional skin, a lymphohistiocytic infiltrate mainly composed of CD4 T-lymphocytes is often found. The CD8 T-lymphocytes have a clonal or oligoclonal TCR profile, illustrating the specific antigen-stimulating effect (Hartmann et al., 2008; Le Gal et al., 2001). CD8-specific T cells for gp100 and tyrosinase epitopes have been detected in MAD lesions of melanoma patients vaccinated with melanocyte differentiation antigens (Jacobs et al., 2009). Similarly to vitiligo, MAD affects only some parts of the body and the reason why some regions are attacked and others are not, remains to be elucidated.

Prognosis and management

MAD is an independent favorable prognostic factor in stage III and IV metastatic melanoma patients. The occurrence of vitiligo-like depigmentation is also associated with a higher prevalence of other autoimmune diseases compared with patients without depigmentation (8.4 versus 2.8%) (Quaglino et al., 2010). The development of autoantibodies or clinical manifestations of autoimmunity has also been reported to be associated with a better prognosis in patients who also received high-dose interferon (Gogas et al., 2006). These data suggest that MAD reflects an immune-based antitumoral response.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Halo nevus (Sutton’s nevus)
  5. Meyerson’s nevus
  6. Regression in melanoma
  7. Melanoma-associated depigmentation
  8. Discussion
  9. Conclusion
  10. References

Although immunosurveillance is a widely discussed topic, clinical signs of a host-immunity-mediated resistance against neoplasia are scarce (Dunn et al., 2002). Regression phenomena in both benign and malignant melanocytic lesions are not uncommon in clinical practice and may be a reflection of the skin immune surveillance system. Recently, CTLA-4 inhibition has confirmed the feasibility of skewing the immune system in melanoma patients to a more efficient antitumoral immune response and enhancing survival in metastatic melanoma (Hodi et al., 2010). As immune escape is a multi-step process, the identification and targeting of different key molecules seem mandatory to establish an efficient immune response (Igney and Krammer, 2002). Several aspects of the complex interplay between the host immune system and the tumoral environment are discernible by comparison of different immune reactions to melanocytic lesions.

Halo nevi, halo dermatitis, regression in melanoma and MAD are four examples of immune-mediated reactions against melanocyte-specific antigens and are characterized by particular clinical, histological and prognostic features and different endstages. The comparison of Meyerson’s nevi with halo nevi illustrates the plasticity of the anti-melanocytic immune response, which offers opportunities for immunotherapeutic interventions. The absence of melanocyte elimination in Meyerson’s nevi despite the presence of activated immune cells seems attributable to a different inflammatory infiltrate compared to halo nevi and suggests that both phenomena are based on distinct pathophysiologic mechanisms. However, Ramón et al. (2000) described a case with progression of Meyerson’s nevi to halo nevi, indicating that both processes may form a continuum. Several cases with both Meyerson’s nevi and halo nevi have been described. Inflammatory nevi have been observed in patients receiving immunotherapeutics (e.g. IFN-α-2b) which resulted in some cases in a lasting vitiligo-like depigmentation, suggesting similar pathways (such as increased ICAM-1 expression) may be used in spontaneous and immunotherapy-induced reactions (Cook-Norris et al., 2008).

Crucial factors in immunosurveillance remain to be elucidated. Halo nevi represent an efficient melanocyte-specific immune reaction leading to complete regression of the lesion. However, why some nevi are attacked and other, similar nevi are unaffected remains unclear. Research focusing on the antigen expression in halo nevi and mechanisms involved in the downregulation of immune tolerance may be of particular relevance to understanding the mechanisms of the immunosurveillance of melanocytic lesions. Vascular adhesion receptors (E-selectin, P-selectin, ICAM-I), which are often not expressed in melanoma metastases, could play an essential role in the recruitment of TAA-specific cytotoxic T lymphocytes (Weishaupt et al., 2007).

The complex mechanism of immune escape is illustrated by the differences between regression in melanoma and halo nevi. Both phenomena result in the disappearance of tumoral melanocytic cells. most likely due to an immune-mediated cell destruction. However, regression in melanoma is often incomplete, in contrast with the involution of halo nevi. Regressing melanomas have a patchier infiltrate, sparing parts of the malignant lesion as well as a lower number of CD8+ lymphocytes, a higher prevalence of CD68+ cells and a higher CD4+/CD8+ ratio compared to halo nevi (Moretti et al., 2007). The incomplete involution of a regressing melanoma may be due to the heterogeneity of the tumoral cells within the tumor, which may use various immune escape mechanisms. Different expression levels of membrane-bound factors (loss of MHC-I expression, elevated PD-L1 and HLA-G expression) and an enhanced production of immunosuppressive cytokines (IL-10, TGF-β) are involved in melanoma progression. One explanation for the poorer prognosis of extensive regressing lesions would be that the remaining tumor parts represent areas of tumor escape that may be highly resistant to further immune attacks. Partial regression in melanoma may be an example of the multi-step process of immune escape and suggests the need to target several key molecules to establish an efficient antitumoral immunity.

The importance of overcoming tumor-induced peripheral tolerance becomes evident when incomplete regression in melanoma and MAD are compared. Regression in both melanoma and MAD originates from an antitumoral immune response. MAD is associated with better clinical responses, whereas the prognosis of regression remains unclear. The generation and recruitment of TAA-specific immune cells are insufficient for an adequate immune response. Jacobs et al. (2009) reported a case of melanoma progression despite the presence of circulating functional melanoma-specific T cells, induced by vaccination. Increasing data confirm the frequent presence of TAA-specific T cells infiltrating or surrounding melanoma lesions. However, TILs, including MART-1 CD8 cells, often express PD-1. Upregulation of PD-1 on tumor-specific T cells leads to impaired antitumoral immune responses (Ahmadzadeh et al., 2009). The capacity of the melanoma cells to influence the immune response is illustrated by the finding that the T-cell infiltrate varies in different areas of the (regressing) melanoma lesion and two metastatic lesions in the same patient can have a different CD8+ T-cell repertoire. It appears that the local tumor micro-environment locally determines the functionality of effector T cells (Bernsen et al., 2004). Recently developed treatments provide evidence that an inadequate antitumoral immune response can be reverted to a more efficient one. The CTLA-4 antibodies (ipilimumab, tremelimumab) break the immune tolerance and induce auto-immunity by blocking the CTLA-4 receptor on T cells. CTLA-4 inhibition seems to be a major breakthrough in the therapy of stage IV melanoma (Hodi et al., 2010). However, some serious immune-related adverse events have been described (most commonly colitis-associated diarrhea). Remarkably, patients developing autoimmune phenomena (such as therapeutic-induced MAD) have the best clinical outcome, which points to the downregulation of immune tolerance as the major pathophysiologic pathway for both the efficacy and the toxicity of CTLA-4 inhibition (Hodi, 2010). In response to the encouraging results of the ipilimumab trials, new studies with anti-CD25 and anti-PD-1 antibodies are being carried out to reverse the anergic state of TAA-specific immune cells. Currently, trials combining CTLA-4 antibodies with other immunotherapeutics such as vaccination are being conducted.

The different melanocyte-specific reactions described in this paper illustrate the complex relation between the host immune system and the neoplastic environment, determining the type and functional state of infiltrating immune cells. Insights in different models of immune reactions in both benign and malignant melanocytic lesions expand knowledge about the prerequisites for an efficient antitumoral response.

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Halo nevus (Sutton’s nevus)
  5. Meyerson’s nevus
  6. Regression in melanoma
  7. Melanoma-associated depigmentation
  8. Discussion
  9. Conclusion
  10. References

The accessibility of the skin offers the ideal possibility to observe signs of immunosurveillance. Halo nevus, Meyerson’s nevus, regression in melanoma and MAD all result from specific immune responses against melanocyte- and melanoma-specific antigens, but show different clinical and histological aspects. Moreover, these phenomena have a different efficacity to eliminate melanocytes. A better understanding of the clinically observed immune responses in pigmentary lesions may help to identify the key checkpoints of an adequate skin immunity and to select possible targets for optimization of current immunotherapeutic options and the development of new options.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Halo nevus (Sutton’s nevus)
  5. Meyerson’s nevus
  6. Regression in melanoma
  7. Melanoma-associated depigmentation
  8. Discussion
  9. Conclusion
  10. References