Section 2 Epidemiology

## **Chapter 2** Epidemiology of Melanoma

*Kasimu Umar Adoke*

#### **Abstract**

Melanoma is a malignant tumour that arises from melanocytic cells. The incidence is increasing worldwide in white population where fair skin people receive excessive sun exposure. Although relatively uncommon in Africa-Americans, recent trends show increase incidence in Africa- Americans. Prognosis is affected by histological and clinical factors in addition to site of the lesion. It is a well-established facts that the MAPK signaling pathway is hyper activated in up to 90% of melanomas. The dependence of melanoma on this activated pathway has been exploited successfully in the clinics by selectively inhibiting this pathway mainly the BRAF mutated melanoma, which is mutated in approximately 50% of melanomas, although resistance develop in some cases. The improved understanding of the regulatory pathways of the immune system provides great hope for significant clinical impact in some patients. Antibodies inhibiting CTLA-4 and PD-1/PD-L1 signaling have been developed and approved, as monotherapies or in combination, after showing great improvement in patient survival but show limited efficacy in some patients that develop resistance and adverse effects. Better biomarkers are needed in the future to help select better immunothrapeutic agents with potent efficacy, less side effects and less likelihood to develop resistance.

**Keywords:** melanoma, targeted therapy, immunotherapy, resistance

#### **1. Introduction**

Melanocytes are specialised cells in the body that are responsible for the production of the pigment melanin [1, 2]. The melanin is transported in organelles called melanosomes via the elongated dendrites of the melanocytes and functions as a protective barrier against the harmful ultraviolet (UV) radiation, ultimately avoiding DNA damage [3, 4]. Melanoma is the most lethal form of skin cancer and represent less than 5% of all cutaneous malignancies and if diagnosed early it is associated with favourable outcome. Most instances melanoma is associated with distance metastasis with a dismal survival rate **Figures 1** and **2**. Risk factors for melanoma include family history of melanoma, exposure to ultraviolet radiation, the presence of dysplastic nevus, skin colour, hair colour, eye colour, altitude, latitude, xeroderma pigmentosum, immunosuppression, scars, chemical exposures and Marjolin ulcers [5, 6].

**Figure 1.** *Subungual melanoma in a 62-year-old male with ulceration.*

**Figure 2.** *Metastasis of subungual melanoma to the axillary lymph node in the same patient in* **Figure 1***.*

#### **2. Incidence**

In the last few years, there has been an increased incidence of melanoma in all populations [5]. The incidence rate of cutaneous melanoma is greater in white population groups compared to Hispanic, African-American, Indo-American, and Asian population groups [6]. Increase in incidence rate vary across geographical, ethnicity and gender [7, 8]. The marked differences in the incidence rates are attributed to different pigmentation characteristics that predominate in the populations of different regions, but also to the discrepancy in frequency of recreational sun exposure among countries [9–11]. The annual age-adjusted incidence of malignant melanoma in African American women is approximately 0.7 per 100,000 Although the incidence in Caucasian women and men differs, many reports have found narrow incidence rates between African American women and men (0.7 and 1.0 per 100,000, respectively [12, 13] **Figure 3**. While the incidence of malignant melanoma is not well documented in African populations, the sole of the foot is the commonest site, which has prompted speculations that trauma rather than UV-radiation as etiological factor in African cutaneous melanoma [14]. As in African Americans, acral lentiginous melanoma is the most common type of melanoma found in Asians, with a poor prognosis and 5–10-year survival rates of 80.3% and 67.5%, respectively. Acral lentigenous melanoma is said to occur more in the elderly, commoner on the feet and lacks BRAF mutation. Interestingly, approximately 7.5% of all melanoma in Asians are found in the oral cavity, 60% of which develop from pigmented oral lesions [15]. The superficial spreading melanoma is the most common sub-type representing 70% of melanoma cases (**Table 1**). It can arise denovo in sun exposed areas of the body or in association with a nevus. Nodular melanoma account for 5% of cutaneous melanoma and occurs in the trunk or limbs in the elderly patients with male preponderance. Lentigo maligna melanoma constitutes 4–15% of cutaneous melanoma and correlates with long time sun exposure and increasing age. This lesion affects mostly the head and neck area of the body. Superficial spreading melanoma nearly always arises in white skin individuals and less common in black or brown skin individuals. In a study it constitutes two third of cases of melanoma in Australia and new zealand [16].

#### **Figure 3.**

*Melanoma distribution by age and sex (Globocan 2020).*


#### **Table 1.**

*Melanoma subtypes.*

Mucosal melanomas primarily involve the mucosa of the mouth, anogenital regions, nasal and paranasal sinuses although other mucosal sites can be involved, it has an aggressive course and poor prognosis. It is a rare subtype of melanoma in the Caucasians but it is the second most common subtype in Asians [17]. Mucosal melanoma has a lower mutational burden, a higher rate of NRAS and KIT mutation with low rate of BRAF V600E alterations. Uveal melanoma constitutes less than 5% of all melanomas in the United States and unlike its cutaneous counterpart, it arises from the interstitial melanocytes found abundant in the iris, choroid and ciliary body.

Non-Hispanic white Caucasians have the highest incidence of uveal (5–6) per million and conjunctival melanoma (5–8) per million. The incidence of uveal melanoma in Africans is estimated at (0.3) per million although, the study was mostly derived from African-Americans [18, 19].

#### **3. Risk factors**

Studies have shown that people living in geographical areas with increased UV exposure which is inversely correlated with latitude have a higher risk of developing melanoma [20]. Both UVA and UVB are considered carcinogenic to humans but, it is UVB that causes direct damage through formation of pyrimidine dimers while UVA causes DNA damage through production of reactive oxygen species. Melanomas in chronically sun exposed skin tends to have BRAF mutation, inactivation mutation in of NF1, activation mutation in KIT and increase mutational frequency in TP53. In Africa and Asians, cutaneous melanoma is seen in the foot highlighting the fact that trauma could be a causative agent in this region other the UV radiation. Early neonatal exposure to blue-light in cases of hyperbilirubinemia increases the chances of nevi and melanoma [21]. Melanomas can develop in any tissue involved by a nevus and the risk increases with the size and cellularity of the nevus. Familial melanomas have an autosomal dominant pattern of inheritance with high penetrance genes namely CDKN2A and CDK4 [22]. Uveal nevi are well known to transform into uveal melanoma and a minority of families with uveal melanoma carry a germline mutation in the BAP1 (BRCA 1 associated protein-1) gene [23].

#### **4. Melanoma pathways**

The mitogen-activated protein kinase (MAPK) pathway are serine-threonine kinases that control cellular pathways such as proliferation, growth, cell transformation and apoptosis hence, plays a critical role in the development of cancers [24]. Mutations in the KRAS, NRAS and KIT have been correlated with the development of melanoma with BRAF V600E seen in almost 50% of melanoma patients, with populations in the US, Brasil, Sweden and Australia correlating to mutations in BRAF melanoma [25]. The activation of this signaling pathway leads to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway that leads to among other thing decrease apoptosis, increase invasiveness and increase metastatic behavior by the tumour cells. KIT gene mutations are present in 39% of mucosal melanomas and 36% of acral lentigenous melanomas with populations in China, Japan, Turkey and Russia [25, 26]. NRAS mutations are found commonly in sun- damaged areas and is present in 20% of melanomas. It's presence correlate with nodular melanoma and with populations in US, Italy, Spain, Sweden [25, 27]. Uveal melanoma carries activation mutation of GNAQ or GNA11 in almost 80% of patients. The genes encode a heterotrimetric GTP-binding protein α- subunit that encodes a G- protein- couple receptor signaling to the MAPK pathway. Mutations in GNAQ has been found in approximately 50% of uveal melanomas while, GNA11 mutations are seen in 32% of uveal melanoma and constitute the commonest mutations seen in metastatic cases. Conjunctival melanomas have BRAF mutations with no GNAQ [28]. Recently, BAP1 has been found in 84% of patients with uveal melanoma and strongly correlates with metastatic behavior in ocular melanoma.

#### **5. Treatment and recent advances**

Surgical resection might cure patients with localised primary melanomas, despite surgical resection being the primary treatment option in most malignant melanoma tumours, it is not always enough to reduce the risk of resistance and improve survival. Chemotherapy was the earliest treatment option for advanced-stage melanoma yet, it has proven to be insufficient to improve the overall survival of patients, even when administered in combination with other drugs [29]. Standard chemotherapy for metastatic melanoma is associated with toxicity and in some cases myelosupression. The dependency of melanoma on the MAPK signaling pathways has been exploited successfully by selectively inhibiting this pathway although resistance do develop in some case [30–32]. The genomic landscape of melanoma is also defined by epigenetic changes in complexes of proteins that interact with DNA to regulate gene expression. Development of targeted therapies has been driven by the advanced understanding of the molecular pathways and mechanism of melanoma vis a vis therapy for patients with BRAF V600E mutations has been encouraging with key challenges in some clinical settings. Combination treatment of BRAF with MEK inhibitors have resulted in a better outcome in patients with melanoma, with some having progression free survival of three to six months compared with single therapy with BRAF inhibitors. Recently, the combination of BRAF/MEK inhibitors is used to treat two stages of melanoma namely stage III and IV BRAF mutated melanomas [33, 34]. However, most treated patients will eventually exhibit disease progression due to a constellation of resistance mechanisms emerging from tumor heterogeneity within an individual patient. One of the common strategies of the tumours to develop resistance is to

activate the parallel signaling pathway PI3K-AKT-mTOR by activating mutations in PI3KCA or loss of PTEN [34].

During the last decade, the increasing knowledge about the role of the immune system in tumour progression allowed the development of many different immunotherapies. The treatment of advanced melanoma was revolutionised with the development and establishment of immune checkpoint inhibitors (ICIs). Immune checkpoint blockade with anti- cytotoxic T- lymphocyte- associated protein 4 (anti-CTLA-4), anti- programme cell death 1 (anti-PD-1) and its ligand currently form the most effective therapy for metastatic and late stage cutaneous melanoma [35]. Ipilimumab, an anti-CTLA-4 has proven to be effective in T- cell inhibition by tumour cells and activation and proliferation of effector T-cells [36]. Also, Pembrolizumab and nivolumab have shown higher efficacy and less toxicity than ipilimumab [37, 38].

Although cancer immunotherapies have a major impact on patient outcomes, about 60% of patients develop primary resistance, while others experience initial clinical benefit and later on develop secondary resistance. Overall, this highlights the importance of both developing alternative therapeutic strategies to immune check point inhibitors and also identifying better prognostic targets to effectively select patients to undergo a specific type of therapy. Therapies such as intratumoral injection of oncolytic viruses, autologus tumour infiltrating lymphocytes (TIL) and anti-PD-1/anti- LAG have shown promising results in some cases of advanced melanoma.

#### **6. Summary**

Melanoma is a highly complex disease comprised of different layers of molecular information, the discovery of additional mutations in human melanomas, as well as strategies for inhibiting their activity, will require continued collaboration between basic and clinical scientists for improved survival and minimised side effects of various therapy.

#### **Acknowledgements**

I wish to acknowledge the entire staff of the Department of Pathology, Federal Medical Centre Birnin Kebbi, Nigeria for their assistance toward writing this chapter.

#### **Conflict of interest**

I declare no conflict of interest.

*Epidemiology of Melanoma DOI: http://dx.doi.org/10.5772/intechopen.107095*

### **Author details**

Kasimu Umar Adoke Federal Medical Centre Birnin Kebbi, Nigeria

\*Address all correspondence to: kasimuadoke@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 3
