Melanoma is a malignant tumor produced from malignant transformation of melanocytes. This can be sporadic or arise from a preexisting premalignant lesion. Due to that fact that melanocytes are of neural crest origin, melanomas can arise in other locations where neural crest cells are present including the brain and gastrointestinal tract. Approximately 10% to 25% of melanomas are found in the head and neck region. The most common sites are the occipital scalp and skin of the cheek. Common locations are face (40% to 60%), scalp (14% to 49%), neck (20% to 29%), and ear (8% to 11%). Location of the lesion is of particular importance when addressing melanoma in the head and neck as some locations had a worse prognosis. Additionally, the location requires different management compared to other parts of the body.[1][2][3][4]
Melanoma Risks
Melanoma has the highest incidence in areas with populations with fair skin and in locations with lots of sun exposure. Melanoma is the sixth most common cancer in the United States. Melanoma has been noted to be the fifth most common malignancy in men and seventh most common in women overall. Melanoma is the most common cancer in Caucasian women age 25 to 29 and the second most common cancer of women age 30 to 34. Melanoma is found more commonly in whites than Asians or blacks. In the United States during 2010, approximately 68,000 new cases of malignant melanoma were diagnosed with 8700 deaths from melanoma. Approximately 30% of melanomas are located within the head and neck. Recently, increases in incidence have been noted at 5% per year and mortality at 2% per year. This increase is faster than any other cancer except lung cancer in women. Melanoma accounts for the third highest number of deaths across all cancers.
Melanomas are malignant tumors of melanocytes, which are derived from neural crest cells. Melanoma can be sporadic or due to a transformation of a premalignant lesion. Upward of 80% of melanomas arise from preexisting lesions. A melanoma that develops in healthy skin is said to arise de novo (without evidence of a precursor lesion). These are often attributed to solar radiation. However, melanoma can occur in areas such as the palms, soles, and perineum.[5][6][7][8][9]
Precursor lesions of melanoma include the following nevi:
In sporadic melanoma, a number of pathways have been identified which are targets of therapy. Pathways of great interest are the RAS-RAF-MEK-ERK pathway, PI3K/PTEN, and c-Kit pathways.
In the RAS-RAF-MEK-ERK pathway, roughly up to 80% of melanomas have activating mutations affecting the structure of the Bioinformatics Resources and Applications Facility (BRAF) protein. Activating nuclear receptors are the most common RAS family mutations. This results in signaling through the RAF to MAP kinase pathway. BRAF inhibits are being studied in the treatment of melanoma. Inhibition of BRAF/MEK in patients with BRAF V600 (Most often a valine to glutamic acid)-mutated melanoma has resulted in improved survival. This is the most common mutation in melanoma. However, it should be noted that having the BRAF mutation alone is not sufficient to develop melanoma; it requires p53 inactivation as well.
The PI3K/PTEN is an important pathway. Activation is associated with cell proliferation and malignant transformation. Most commonly observed changes include activating mutations in PI3K, silencing of PTEN, and amplification of AKT. The PI3K-AKT pathway may be a crucial target for combination therapy as it plays a significant role in BRAF-/MEK-inhibitor resistance in patients with melanoma.
The c-KIT pathway is another targeted area. Mutations in this area are more commonly found in acral and mucosal melanoma, melanomas unrelated to sun exposure. KIT is a transmembrane tyrosine kinase receptor that is expressed on hematopoietic progenitor cells, mast cells, melanocytes, primordial germ cells, and interstitial cells of Cajal. Activating mutations and amplifications cause activation of growth and proliferation pathways. Drugs such as imatinib focus in on this pathway.
Major Types of Melanoma
There are 4 subtypes of melanoma: superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma.
Additional Subtypes
Clark’s Level
Breslow Thickness
Melanocytic Markers
S100
MART-1 (MELAN-A)
MITF-1
HMB-45
Special Considerations: Desmoplastic melanoma
Head and Neck Points
In melanoma of the head and neck, a thorough examination is warranted as several important considerations are different from management elsewhere. Head and neck melanoma have a worse prognosis than other sites; location of the lesion has a significant impact on prognosis. Scalp location has the worst prognosis, followed by ear, cheek, and neck, all in respected order. Additionally, management and resection take place at different levels.
Lymph Nodes
A thorough examination of lymph nodes at all levels of the neck should be emphasized. Additionally, the parotid gland should be examined, as there are parotid lymph nodes where the head drains. Parotid gland examination is particularly important for lesions on the anterior scalp, temple, and cheek. For lesions located on the posterior scalp and retroauricular, occipital lymph nodes should be examined thoroughly.
General Melanoma Physical Examination Information
When considering melanoma in physical examination, patients may have a new lesion or existing mole with changing characteristics. However, amelanotic melanoma will not have typical dark pigment from melanin. Amelanotic melanoma may be pink, red, purple, or normal skin color. The characteristics of melanoma are commonly known by the acronym ABCDE and include the following:
A: Asymmetry
B: Irregular border
C: Color variations, especially red, white, and blue tones in a brown or black lesion
D: Diameter greater than 6 mm
E: Evolution of the mole(s) has become the most important factor to consider when it comes to diagnosing a melanoma if a mole has recently changed in color and/or size or if there any signs of regression.
Additionally, physical examination for aggressive/advanced disease should be considered including ulceration, nodularity, and satellite lesions.
In head and neck melanoma, all suspicious lesions start with a biopsy with a method that will give a definitive diagnosis and depth of invasion. Shave biopsy should never be used for evaluation of melanoma. Depth is needed in the evaluation of melanoma; therefore, an excisional biopsy should be performed with 2 mm margins.
Biopsy Techniques
Sometimes lymphoscintigraphy, sentinel lymph node mapping, is utilized in the evaluation of malignant melanoma. This may lead to one using different biopsy techniques. However, excisional biopsy is the most commonly used method. If lymphoscintigraphy is planned, an excisional biopsy may disrupt lymphatic drainage, whereas an incisional/punch will not.
Excisional biopsy: This is an acceptable method with small lesions and used with 1mm to 2mm margins. If pathological examination results in malignant melanoma, then wide excision is necessary.
Incisional/punch biopsy: Through the thickest portion of the tumor. This allows for depth to be examined, does not disrupt lymphatic drainage, does not disrupt the borders. Often controversial depending on the source.
Baseline Laboratory
Radiological Imaging
Chest X-ray
CT with Intravenous (IV) Contrast
Metastatic Work-Up
Metastatic workup should be considered in patients that have melanomas greater than 4 mm, ulceration, satellite lesions, or any lesion that is recurrent.
Metastatic workup is required for patients with regional disease (any patient with laboratory and clinical exam)
Excisional Surgery
Excisional margins for melanoma depend on the thickness of the tumor (Breslow). There has been a debate on the margins to use.[10][11][12][13]
Most Widely Accepted Margins
1-cm margin
Greater than a 1-cm margin
2-cm margin
Unique Depth of Resection for Lesions in Specific Areas of the Head and Neck
Face
Lesions Overlying the Parotid Gland
Scalp
Ear
Sentinel Node Biopsy and Neck Dissection
Finite regions of skin have lymphatic drainage to an initial node within a nodal basin. This is known as the sentinel node (SLN). A tool to characterize the regional nodal basin in patients with cutaneous melanoma of the head and neck is the sentinel node biopsy. The frequency of SLN metastasis increases with increasing tumor thickness and other adverse clinicopathological prognostic factors.
Indications for SLN Biopsy
Parotidectomy
A superficial parotidectomy is required in patients with melanoma lesions on the anterior scalp, facial, temple, or ear with evidence of regional disease.
Melanoma on the chin or neck does not require a parotidectomy.
Medical Oncology
Agents that are used in the medical management of melanoma include the following:
Immunomodulators
Programmed Cell Death Protein-1 (PD-1) Inhibitors
Molecularly targeted therapy approved by FDA for the treatment of BRAF mutated melanoma
BRAF Inhibitors
MEK Inhibitors
BRAF and MEK Inhibitor Combinations
Radiation Therapy
Melanomas are radioresistant. Radiation therapy is used as adjuvant therapy for multiple positive nodes or macroscopic extranodal extension. It is used as primary therapy for elderly and nonsurgical patients. Radiation therapy is indicated for patients with brain metastasis (stereotactic radiosurgery). Radiation is generally reserved for palliation.[14]
Staging is carefully performed utilizing the most up to date American Joint Committee on Cancer (AJCC) Eighth Edition Guidelines for Melanoma. Important factors that go into determining the stage of cancer and communicating this information are TMN criteria (T, tumor mass; N, lymph nodes; M, metastases).
Prognostic Factors for Melanomas in General
Location in the head and neck has an impact on prognosis as melanoma in the head and neck has a worse prognosis than other sites of the body. The scalp has the worst prognosis.
Prognosis depends on the disease stage at diagnosis.
Stage I Disease
Stage II Disease
Stage III Disease
Metastatic Disease
Patients will need very close follow-up physical examinations after a diagnosis of melanoma from a surgical and dermatologic standpoint.
Patients should be advised to avoid sun exposure and take proper precaution after a melanoma diagnosis. Sun exposure increases the risk of developing melanoma.
Melanoma involves many practitioners and location of tumor impacts management. Dermatology, surgical oncology, otolaryngology (head and neck) surgery, hematology, and oncology. More advanced disease will likely need consults in gastroenterology, pulmonology, and neurology.
Approximately 25% of melanoma occurs on the head and neck. It is important to understand that melanoma of the head and neck is a complex disease where management differs to elsewhere body and that location can impact prognosis. Due to the aggressive nature of head and neck melanoma, it should be treated aggressively. A shave biopsy should never be performed on a pigmented lesion that is suspicious for melanoma as depth is necessary for the evaluation. There are many molecular pathways shown to play a role. The 2 most widely accepted prognostic factors of melanoma are Breslow depth greater than 1 mm and ulceration.[15]
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