**2. Main serum markers in CMM**

#### **2.1. Lactate Dehydrogenase (LDH)**

patients, at least for some of them. To date, no marker for early detection of melanoma

A melanoma patient around high risk (high risk of recurrence) can be defined as a patient with a 50% risk of relapse within up to 10 years, despite optimal initial surgical treatment. These high-risk patients should be carefully monitored and treated if possible with adjuvant therapeutic strategies. Interferon-α and, more recently, ipilimumab have been proposed as adjuvant therapies, but their effect on survival is still a matter of debate. To date, no predictive

The metastatic process involves the spread of cancer cells in locoregional or distant anatomic sites via the lymphatics and / or blood flow. In the case of melanoma, circulating cells can find a suitable microenvironment in the sentinel node (the first lymph drainage lymph node area),

In fact, the understanding of the biology and mechanism of metastatic cascade provides new molecular targets and can help us to discover new biomarkers. Biomarkers can be divided into diagnostic markers for disease detection and prognostic and predictive markers, which should predict response to treatment. Cancer biomarkers consist of many molecular structures such

other lymph nodes or distant organs (lymph nodes, liver, lungs, brain, bone).

metastases is unanimously recognized.

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**Figure 1.** Breslow index measures in mm the thickness of the lesion

marker of response has been described.

As mentioned above, this enzyme has been considered as the main serum prognostic param‐ eter in patients with metastatic melanoma (AJCC stages III and IV). Numerous studies have validated LDH as the factor most predictive of patient outcome, and this independently and statistically significant. This led to a stratification of the AJCC :patients with metastatic melanoma with high levels of LDH are designated as M1c whatever the site of metastasis [2].

Note, however, that Hamberg stated that in a series of 53 patients with stage IV AJCC melanoma only 38% had elevated LDH, suggesting that elevated LDH is not the ideal marker for this condition [4]. Moreover, in a multivariate analysis of 64 patients with AJCC stage IV melanoma Hauschild has failed to demonstrate the independent prognostic value of LDH [5]. It should be recalled that the LDH assay can be falsely positive due to hemolysis and other factors, including hepatitis.

However, Weide et al also insist in a study of 855 patients on the prognostic value of LDH [6].

#### **2.2. C-Reactive Protein (CRP)**

CRP is a nonspecific inflammatory parameter that may have a role in the detection of mela‐ noma progression. This protein is produced by hepatocytes as acute phase response of nonspecific inflammatory processes.

Elevated serum CRP was associated with a poor prognosis in various cancers. Deichmann et al. analyzed the prognostic significance of CRP compared to the LDH patients AJCC stage IV

**Figure 2.** LDH is a tetrameric enzymle and consists of several sub-units M and H, encoded by two different genes (Chromosome 11 and 12)

Moreover, it must be remembered that S100B is not specific to melanoma and its serum levels may be elevated in healthy subjects, patients with cancer of non-melanoma skin, neurological disorders, tumors of the nervous system central, and even in various gastrointestinal cancers,

**Figure 3.** Molecular structure of CRP, five sub-units each comprising 206 amino acids. The gene responsible for its syn‐

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The roles of this protein are multiple among them modulation of cell growth and cell adhesion. MIA rates are higher in the group of patients relapsing after initial surgery. Some authors consider that the sensitivity of the two molecules S100B and MIA is equal. For other authors, MIA is superior to LDH and CRP. In children and pregnant women (after week 38), MIA is

Gal-3 has been described to be overexpressed in malignant melanocytic lesions and its concentration in the serum of patients with melanoma is increased by the joint action of

increased and serum levels should be avoided in these two groups [12].

and patients infected with HIV.

thesis is located on chromosome 1.

**2.5. Galectin-3**

**2.4. Melanoma Inhibiting Activity (MIA)**

melanoma. With a definition of a threshold 3mg/dL, the identification of a stage IV can be done with a sensitivity of 76.9% and a specificity of 90.4%. In another prospective study of 67 patients, Deichmann found that CRP was the only prognostic factor even reliable [7-9]. These results are debated.

#### **2.3. S100-β proteins (S100B)**

Serum S100B is described as more related to the tumor burden and thus reflects both the clinical stage and tumor progression (the higher the rate of serum S100B, the greater the tumor burden). It may therefore be used to monitor the effectiveness of therapy whatever the type of treatment (surgical, chemotherapy, immunotherapy). Retsas et al. have suggested the use of S100B instead of LDH in the classification system of the AJCC while other authors consider that S100B has no added value when comparing the sensitivity and specificity of the CRP and LDH [10]. For some, S100B has probably become the most useful marker in clinical practice, but it interest seems to be limited to advanced stages III and IV [11]. In stages I and II S100B provides no independent prognostic information.

**Figure 3.** Molecular structure of CRP, five sub-units each comprising 206 amino acids. The gene responsible for its syn‐ thesis is located on chromosome 1.

Moreover, it must be remembered that S100B is not specific to melanoma and its serum levels may be elevated in healthy subjects, patients with cancer of non-melanoma skin, neurological disorders, tumors of the nervous system central, and even in various gastrointestinal cancers, and patients infected with HIV.

#### **2.4. Melanoma Inhibiting Activity (MIA)**

The roles of this protein are multiple among them modulation of cell growth and cell adhesion. MIA rates are higher in the group of patients relapsing after initial surgery. Some authors consider that the sensitivity of the two molecules S100B and MIA is equal. For other authors, MIA is superior to LDH and CRP. In children and pregnant women (after week 38), MIA is increased and serum levels should be avoided in these two groups [12].

#### **2.5. Galectin-3**

melanoma. With a definition of a threshold 3mg/dL, the identification of a stage IV can be done with a sensitivity of 76.9% and a specificity of 90.4%. In another prospective study of 67 patients, Deichmann found that CRP was the only prognostic factor even reliable [7-9]. These

**Figure 2.** LDH is a tetrameric enzymle and consists of several sub-units M and H, encoded by two different genes

Serum S100B is described as more related to the tumor burden and thus reflects both the clinical stage and tumor progression (the higher the rate of serum S100B, the greater the tumor burden). It may therefore be used to monitor the effectiveness of therapy whatever the type of treatment (surgical, chemotherapy, immunotherapy). Retsas et al. have suggested the use of S100B instead of LDH in the classification system of the AJCC while other authors consider that S100B has no added value when comparing the sensitivity and specificity of the CRP and LDH [10]. For some, S100B has probably become the most useful marker in clinical practice, but it interest seems to be limited to advanced stages III and IV [11]. In stages I and II S100B provides no

results are debated.

(Chromosome 11 and 12)

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**2.3. S100-β proteins (S100B)**

independent prognostic information.

Gal-3 has been described to be overexpressed in malignant melanocytic lesions and its concentration in the serum of patients with melanoma is increased by the joint action of

**Figure 4.** S100B is a 21-kD dimeric protein, consists of two β subunits. This protein is a member of a family of 19 pro‐ tein and was first isolated from bovine brain in the mid sixties. S100B is expressed by glial cells and melanocytes and is produced by brain tumors and melanomas. The roles of S100B are probably multiple and underestimated.

melanoma cells and inflammatory cells. Gal-3 plays an important role in cell proliferation, cell differentiation, cell adhesion, cell migration, angiogenesis and metastasis. Thus, Gal-3 deserves special attention. Clarification of the role of extracellular Gal-3 should help us to understand the significance of elevated serum levels of this molecule in patients with advanced melanoma [13].

these antigens have been used to induce or maintain a specific immune response. Mage-1 was the first identified MAA and now belongs to a large family of at least 12 antigens differentially expressed by benign and malignant melanocytic cells. Immune responses to these genes can

**Figure 5.** MIA is a 12kDa soluble protein, whose role has been characterized as an inhibitor of cell autocrine growth. It

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Tyrosinase RT-PCR detection in patients with melanoma is correlated with a higher risk of relapse (55% of these patients have a clinical relapse), but the specificity of this technique has yet to be optimized [15, 16]. When combined with a dosage of S-100, Domingo-Domenech showed that tyrosinase RT-PCR adds valuable prognostic information in patients with S-100 <0.15μg / l, although the team showed that S-100 had a higher predictive value. Curry et al. suggested that RT-PCR detection of tyrosinase can be useful to determine a subgroup of

Profiling of autoantibodies associated with certain MAA was different by Sabel et al as potentially useful to select patients with melanoma who should benefit from the research of a

be used as markers of progression and / or immunological response.

patients with an increased risk of metastases [17].

can be expressed by melanoma cells and chondrocytes.

These results have yet to be validated [18].

sentinel node.
