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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 4  |  Issue : 2  |  Page : 85-91

The global scenario of melanoma


Department of Dermatology, STD & Leprosy, Government Medical College, University of Kashmir, Srinagar, Jammu and Kashmir, India

Date of Web Publication1-Dec-2017

Correspondence Address:
Yasmeen J Bhat
Department of Dermatology, STD & Leprosy, Government Medical College, University of Kashmir, Srinagar, Jammu and Kashmir
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2349-5847.219670

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  Abstract 


Melanoma is a malignant neoplasm of the melanocytes, in which there is invasion either horizontally and upwards into the epidermis or vertically downwards. This review describes the global scenario of melanoma with respect to its epidemiology, clinical features, diagnosis and newer treatment modalities.

Keywords: Global, melanocytic invasion, melanoma


How to cite this article:
Bhat YJ, Zeerak S, Hassan I. The global scenario of melanoma. Pigment Int 2017;4:85-91

How to cite this URL:
Bhat YJ, Zeerak S, Hassan I. The global scenario of melanoma. Pigment Int [serial online] 2017 [cited 2017 Dec 14];4:85-91. Available from: http://www.pigmentinternational.com/text.asp?2017/4/2/85/219670




  Introduction Top


Nowadays, cutaneous malignancies are on the rise, and the situation for cutaneous melanoma is no different. This uncommon malignancy of olden times is now increasingly being encountered in modern clinical practice. This could be due to an increased diagnosis of early melanomas, probably as a result of secondary prevention efforts.[1] The clinical picture varies with various clinical subtypes being identified by their distinct morphological features, anatomical sites involved and racial distribution. Because of its high morbidity and mortality, a proper clinical evaluation is essential to avoid missing out on its detection. Moreover, newer modalities for diagnosis have emerged, which can help in timely diagnosis and, thus, lead to adequate and complete treatment.


  Global perspective Top


Even though melanoma accounts for <5% of all skin cancers diagnosed, the burden of melanoma is significant, accounting for a considerable number of deaths (estimated 50,000 deaths annually) worldwide.[2] The epidemiology varies, with certain races and countries showing an increased incidence of this malignancy. The relative frequency of the various clinical types also varies in the two sexes, in various body areas and in different age groups.

Worldwide, the highest incidence is seen in New Zealand and Australia. Among the various racial groups, Caucasians show the highest incidence.[3] Within the Asian subcontinent, acral lentiginous melanoma (ALM) is the most common variant seen.[4] The median age of diagnosis is 59–63 years for Caucasian patients and 52–56 years for Hispanics, American Indians and Asians. Even though age-specific incidence rates vary, melanomas are more frequently found in males, and the survival rates are also lower in them.[5]


  Cause and risk factors Top


The exact cause is not known, but a multitude of risk factors contribute to melanoma’s increased susceptibility in certain individuals. These factors are broadly divided as follows: environmental factors, genetic factors and the phenotypic manifestations of genetic and environmental interactions.[6],[7]

The main environmental factor is sun exposure, and the type and duration of exposure often govern the clinical variant of melanoma. Intermittent sun exposure is more important when determining risk than total lifetime exposure.[8] The main carcinogen in sunlight is the ultraviolet component, especially the ultraviolet A (UVA) and ultraviolet B (UVB) components.[9] The causality of ultraviolet (UV) radiation in melanoma has been proposed to be due to its deoxyribonucleic acid (DNA) damaging, inflammatory and immunosuppressive properties. All of these factors contribute to the initiation, progression and metastasis of primary melanoma.[10] Recent research suggests that indirect DNA damage due to reactive oxygen species (generated due to UV radiation) and direct DNA damage mainly contribute in initiating and promoting this neoplastic process.[11]

However, sunlight is not the sole risk factor for malignant melanoma. A few studies have incriminated chronic trauma as an important risk factor, especially for ALM.[12] Some other environmental causes include photosensitising drugs, cosmetic ingredients such as para-aminophenol (PAP) and para-phenylenediamine (PPD).[13] Artificial tanning (sunbeds), phototherapy, psoralen in combination with UVA radiation (PUVA) therapy and ionising radiation are also carcinogenic and increase melanoma risk.[14]

Genetic and host susceptibility factors include dysplastic nevi, an increased number of nevi, freckling, a personal history of solid tumours (the brain, breast, prostate and others), a family history of melanoma, fair complexion, light eyes and blonde or red hair.[15] Among all these factors, fair skin is one of the main predisposing factors for melanoma. Some potential oncogenes implicated in melanoma pathogenesis are formed due to activating point mutations in genes such as BRAF, NRAS, GNAQ and GNA11; activating fusions of BRAF; and the receptor tyrosine kinases such as ALK, ROS1, RET, MET and NTRK1.[16] In addition, mutations in the C-KIT gene have been found to be more common in patients with the acral lentiginous variant of melanoma.

Xeroderma pigmentosum, immunosuppression, chemical exposures, scars and Marjolin’s ulcer are other miscellaneous predisposing factors.[17] A few studies have also incriminated Parkinson’s disease as a possible risk factor.[18]

Some studies point towards the role of chronic stress in initiating and promoting melanoma development through a variety of hormones, growth factors and other mediators.[19]

Finally, the interaction of environmental factors and genetic/host factors influences the susceptibility of melanomas, with greater UV exposure increasing the risk significantly more in fair-skinned than in dark-skinned populations.


  Clinical presentation Top


Malignant melanoma was first classified by Wallace Clark into superficial spreading melanoma (SSM), lentigo malignant melanoma (LMM) and nodular melanoma (NM).[20] A fourth type called ALM was later introduced by Dr. Richard Reed.[21] The clinical features of each type vary, with each type showing distinct site distribution.


  Diagnosis Top


Clinical diagnosis

Clinical diagnosis requires a proper and a detailed history (including the duration of the lesion, change in its morphology, family history, the presence of other nevoid lesions, and occupational and recreational history). This needs to be supplemented by a proper clinical examination and other investigations.

A good clinical assessment is one of the first steps to diagnose a melanoma. Some useful clinical aids include the ‘ABCDE’ rule (asymmetry, border irregularity, colour variegation, diameter >6 mm and an evolving lesion), the ‘EFG’ acronym (elevated, firm and growing progressively for more than a month) and ‘the 3 Rs’ (red, raised lesion, with recent change).[22],[23],[24] These are quite helpful, but are not highly accurate and reliable.

Some new improved scoring systems include the ‘Glasgow 7-point check list’ (7PCL) and the ‘Revised/Weighted 7PCL’.[25] However, these rules and scoring systems are not applicable for all variants. In patients with ALM, an evolving pigmented lesion with an acral location (at the site of trauma with occasional bleeding) should be considered as a useful sign for identifying suspected lesions.

Dermoscopy

Dermoscopy facilitates the early diagnosis of many melanomas and reduces the need for unnecessary biopsies. When performed by experts, this enhances diagnostic sensitivity without diminishing specificity. Usually, pigmented networks, globules, dots or streaks are seen in melanocytic lesions, and variation/heterogeneity in these can help to identify a malignant melanoma. In addition, objectivity can be increased by using dermoscopic scoring systems such as asymmetry, border irregularity, colour variegation, diameter >6  (ABCD) rule, Pattern analysis, Menzies method, 7-point checklist, modified asymmetry, border irregularity, colour variegation (ABC)-point list and CASH (colour, architecture, symmetry and homogeneity).[26] Therefore, these scoring systems help us to identify whether the melanocytic lesion is benign, suspicious or frankly malignant. Serial dermoscopy and photography also enable the detection of malignant changes in suspicious nevi over time, because the images are saved for future comparison. However, dermoscopy is not the ultimate tool for diagnosis, because a large number of evolving melanomas are often not identified by it and no defined guidelines/criteria have been proposed till date in such cases.

Confocal scanning laser microscopy

Confocal scanning laser microscopy is a new modality that enables detailed real-time in-vivo imaging of skin lesions at variable depths in horizontal planes. By a technique known as optical sectioning, several sections of the lesion are examined and evaluated using specialised reconstruction software. Even though highly sensitive for the diagnosis of melanomas, high cost limits its clinical application, especially in the developing countries.[27],[28]

Multispectral digital dermoscopy and computer-based analysis

Multispectral digital dermoscopy enables the in-depth visualisation of cutaneous structures through a sequence of images taken at different wavelengths coupled with computer-based analysis. Two devices based on this technique have been devised, namely, SIAscopy (spectrophotometric intracutaneous analysis) and MelaFind. The former is a chromophore-based system that analyses 1–2 cm areas of the skin using wavelengths in the range of 400–1000 nm. The spectrally filtered images so obtained are then used to assess the amount of collagen, haemoglobin, melanin and melanin distribution in the epidermis and dermis, which enables to distinguish benign from malignant melanocytic lesions (using maps called SIAscans). The latter obtains 10 images for each examined lesion, encompassing the visible and near-infrared spectrum. Thereafter, using constrained linear classifiers, six images are obtained for each lesion. This also enables the differentiation of melanoma from other pigmented lesions.[26]

Optical coherence tomography

Optical coherence tomography technique, usually employed for ocular lesions, is being investigated for diagnosing melanomas; however, it is not widely used.

Reflex transmission imaging

Reflex transmission imaging is a form of high-resolution ultrasound that is employed in combination with white light digital photography for the classification of pigmented lesions especially melanomas.[29]

Histopathological diagnosis

SSM shows poor circumscription of the malignant melanocytes and single melanocytes predominating over the nests of melanocytes (i.e. abundant single atypical melanocytes are distributed haphazardly in the epidermis with a predominant lateral spread of malignant cells within it and along the dermoepidermal junction). Additionally, melanocytes above the basal layer are seen (pagetoid spread) due to biochemical alterations by malignant melanocytes resulting in the passive elimination of tumour cells above this layer. The atypical cells are often vesicular with eosinophilic cytoplasm. The dermis shows a lack of maturation, mitotic activity, asymmetrical inflammatory response, fibrosis and neovascularisation in addition to atypical melanocytes.[30]

NM resembles SSM histologically, except for poor lateral extension and being well circumscribed with a sharp demarcation in the epidermis paralleling the dermal growth of the lesion producing a symmetrical architectural pattern. This is often soon followed by more dermal extension of atypical melanocytes. SSM and NM are, thus, often called as radial growth phase and vertical growth phase melanomas, respectively.[31]

Coming to the histological–genetic correlation, some studies indicate that BRAF mutation is less common in NM than SSM and is more frequently mutated in AML melanomas.[32],[33] Additionally, CDKN2A gene mutation is also found more in SSM than NM and other histological subtypes.[34]

LMM shows an atrophic epidermis with the localisation of atypical melanocytes along the dermoepidermal junction with occasional multinucleate melanocytes (starburst forms). Dermal invasion is an early feature. Significant solar elastosis is another change seen in the dermis.

ALM shows melanocytes as nests and single cells along the dermal epidermal junction with pagetoid upward migration. Dermal invasion is seen here also.[30]

Immunohistochemistry

Immunohistochemistry is based on the identification of immunohistochemical markers such as human melanoma black-45, melan-A, MART-1, tyrosinase, microphthalmia transcription factor, MIB1 (anti-Ki-67), glycoprotein 100 (gp 100) and S100. These melanocyte markers are expressed by normal melanocytes, as well as benign and malignant melanocytic lesions.[35] However, their pattern and distribution vary from the top to the bottom of the lesion (as well as being different in benign and malignant lesions). This often helps in distinguishing a malignant melanoma from a benign nevus, for example, gp 100 is strongly and diffusely expressed in the benign, pre-existent blue nevus, while its expression becomes patchy in the malignant areas.[36] However, these stains are not highly specific for melanomas, and the diagnosis needs to be substantiated by other methods.

Staging

Staging helps to assess the depth and extent of the tumour and, thus, governs prognosis and treatment.

Clark staging (1969) includes five levels and is based on the depth of microinvasion into the dermis and subcutaneous tissue. Greater the depth of invasion, worse is the prognosis.[37] Breslow staging (1970) is a better method for assessing prognosis, because it measures the vertical depth of invasion in millimetres.[38]

The main staging system used is the American Joint Committee on Cancer staging system. This is a four-stage system based on the extent of the primary tumour, the involvement of nodes and metastatic spread.[39]

Additionally, imaging systems such as radiography, ultrasound scanning, magnetic resonance imaging and computed tomography help to assess the presence and extent of metastasis. Gallium-67 scintigraphy or immunoscintigraphy (using monoclonal antibodies directed against melanoma-associated antigens) is also used.[40] In addition, whole-body 18F-FDG PET (18F-fluorodeoxyglucose positron-emission tomography) has been introduced as a novel diagnostic procedure for melanoma staging.[41]

Fluorescent in-situ hybridisation and array comparative genomic hybridisation (aCGH) have recently been employed as novel diagnostic tools. They detect specific gene mutations by identifying specific copy number aberrations in various oncogenes and, thus, predict genomic instability and tumorogenesis.[16]

Treatment options

The treatment modalities are multiple, the choice being governed by lesional parameters, patient characteristics and treatment modalities available.

Surgical excision

Excisional biopsy represents the gold standard among the various modalities available for melanoma (being both diagnostic as well as therapeutic). The main aim of excision is to ensure histologically negative margins. After a proper baseline evaluation, the primary lesion is microstaged and then subjected to wide and deeper excision to ensure complete removal. For lesions that are 1.01- to 2.0-mm thick, excision with 1- to 2-cm margins is usually recommended, whereas for melanomas greater than 2.0-mm thickness, excision with 2-cm margins is preferred.[42] Another recommendation suggests excising at least 1 cm and no more than 2 cm clinically measured around the primary tumour.[43] However, the recommendations are not universal and vary from centre to centre. Mohs micrographic surgery has been tried in the treatment of malignant melanoma [especially the lentiginous melanoma (LM) variant], but its widespread applicability is still a matter of debate.[44]

Sentinel lymph node (SLN) biopsy: SLN is a minimally invasive procedure that identifies occult metastases by selective sampling and focused pathologic analysis of the first nodes on the afferent lymphatic pathway from a primary cutaneous melanoma.[45] Therefore, it identifies patients with nodal metastases and who could, thus, be candidates for complete lymph node dissection.

Criteria for SLN biopsy − Clinical Practice Guidelines include an overview of the ASCO (Annals of Surgical Oncology and Society of Surgical Oncology) Joint Clinical Practice Guidelines. These include the following:
  • Intermediate-thickness melanomas: SLN biopsy is recommended for patients with cutaneous melanomas of 1- to 4-mm Breslow thickness at any anatomic site.
  • Thick melanomas: SLN biopsy may be recommended for staging purposes and to facilitate regional disease control for patients with melanomas that are T4 or >4-mm Breslow thickness.
  • Thin melanomas: There is insufficient evidence to support routine SLN biopsy for patients with melanomas that are T1 or <1-mm Breslow thickness, although it may be considered in selected high-risk patients.
  • Completion lymph node dissection is recommended for all patients with a positive SLN biopsy.[46]


However, its impact on the patients’ overall survival is not significant, and no definite systemic adjuvant therapy is available that can benefit patients who are sentinel node positive. Additionally, it causes significant post-operative morbidity, especially if the positive patient is subjected to complete lymphadenectomy.[47] A few studies even suggest that the procedure is counterproductive and enhances the risk of dissemination of the malignancy.

Adjuvant treatment options

  1. Chemotherapy: A few chemotherapeutic agents have been tried in the palliation of metastatic malignant melanoma. These include dacarbazine and temzolomide, often given singly or in combination regimens.[48] Dacarbazine has been approved by the food and drug administration (FDA) for the treatment of malignant melanoma. Its common side effects include nausea, emesis and myelosuppression. Temzolomide (an imidazotetrazine oral drug) is as efficacious as dacarbazine and has convenient dosing and lesser side effects. Some combination regimens include CVD regimen (dacarbazine, cisplatin and vinblastine), Dartmouth regimen (dacarba­zine, carmustine, cisplatin and tamoxifen), BOLD regimen (bleomycin, vincristine, lomustine and dacarbazine) and CBDT regimen (cisplatin, carmustine, dacarbazine and tamoxifen).[49],[50]
  2. Interferon alpha 2b (IFNα2b): IFNα2b is tried as an adjuvant treatment modality in numerous patients and is currently FDA approved for the treatment of stage IIB and stage III melanoma. A few trials show significantly increased disease-free survival but no increase in overall survival.[44]
  3. Interferon gamma (IFNγ): IFNγ is another treatment option used due to its immunomodulatory effects on natural killer cell-mediated cytotoxicity and human leucocyte antigen (HLA) class II antigen expression.[51]
  4. Interleukin-2 (IL-2): IL-2 is also FDA approved for treating metastatic melanoma. Used singly or in combination, significant response is seen in 15–20% of patients, with complete responses observed in 4–6%.[44]
  5. Immunotherapy: Immunotherapy is another novel modality of treatment that has been shown to produce histological partial regression in up to 20% of cases. The rationale behind it is providing the host with tumour antigens in the correct context to allow the generation of an immune response.[52] GM2/bacillus calmette guerin (BCG) vaccine and BCG vaccine are two vaccines tried for this malignancy.[53] A vaccine comprising HLA-A*0201-restricted peptides derived from the melanosomal protein, glycoprotein 100 (gp100), has been found to yield good results when given with interleukin 2. Treated autologous cells (lymphokine-activated killer cells and dendritic cells) have also been tried for immunotherapy.[54]
  6. Targeted therapy: Targeted therapy is based on the concept of ‘oncogene addiction’, which states that cancer cells rely more heavily on hyperactivated pathways (and their activated oncogenes that drive those pathways) than do normal cells. Therefore, the inhibition of the enzyme end products of these genes can result in more specific cancer treatment.[55] Some of these include multi-kinase inhibitors (sorafenib), BRAF inhibitors (dabrafenib and vemurafenib), MEK inhibitors (trametinib), c-kit inhibitors (imatinib and nilotinib) and CTLA-4 inhibitors (ipilimumab).[55],[56],[57] Ipilimumab and tremelimumab are monoclonal antibodies that target CTLA-4. Both of these drugs have demonstrated good clinical responses in recent clinical trials and may be tried more commonly in patients with malignant melanoma in the future.[58],[59] Anti-PD-1/PD-L1 (programmed cell death protein 1/programmed death-ligand 1) therapy has been tried with agents such as nivolumab and pembrolizumab, monoclonal antibodies directed against PD-1, with both having been found to have good clinical efficacy in advanced melanoma.[60],[61]
  7. Biochemotherapy: Biochemotherapy employs the use of chemotherapeutic drugs in conjunction with other agents such as interferon alpha.
  8. Gene therapy: In gene therapy, autologous tumour cells are transfected by retrovirus-mediated herpes simplex type 1 thymidine kinase suicide genes or IL-2 genes in vitro. This is followed by injecting those cells back in the host to generate an immune response.[62],[63]
  9. A few studies have found that there is a beta-adrenergic stimulation of melanoma via the β1-, β2- and β3 adrenergic receptors (ARs). This can be reduced by a direct blockade of these β-ARs using their selective blocking agents.[64] In this context, it has been observed that the non-cardioselective β-blocker propranolol can actively reduce melanoma progression.[65]



  Conclusion Top


The incidence and prevalence of malignant melanoma is increasing globally, leading to considerable disease-specific morbidity and mortality. Therefore, a reasonable level of clinical suspicion can help enable a dermatologist to identify a lesion at the earliest and, thus, improve patient survival. Moreover, proper awareness about this malignancy among the general population can also help in this regard.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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