The following module was designed to supplement medical students’ learning in the clinic. Please take the time to read through each section by clicking the headings below. Information on anatomy, epidemiology, prevention, pathophysiology, classification, diagnosis, staging, prognosis, treatment, and follow-up of melanoma is provided.
By the end of the tutorial, the following objectives should be addressed:
The skin is divided into the epidermis and dermis. The epidermis has 3 types of cells – flat squamous cells at the surface, round basal cells under the squamous cells, and melanocytes in between the basal cells. Melanoma is a malignant tumour that starts in melanocytes (melanin-producing cells).
Melanoma most often starts as a slow-growing superficial tumour in the epidermis. It may be localized in the epidermis for many years. This stage is known as the horizontal or “radial” growth phase. If a melanoma is found in this stage, it can almost always be cured by surgical excision alone. If the tumour invades deep into the dermis, they enter the “vertical” growth phase and have metastatic potential.
Below is the stepwise progression from dysplasia to melanoma in situ to invasive malignant melanoma. As with all cancers, invasive melanomas can spread locally, lymphatically and hematogenously.
Superficial horizontal/radial growth phase
Deep vertical growth phase
Can spread to almost any organ (e.g. brain, bone, liver, lung, adrenals etc.)
Melanoma is the 8th most common cancer in men and 9th most common cancer in women. As of 2010, the incidence is about 1 in 57 for Canadian men and 1 in 74 for Canadian women. (1) There has been a significant increase in the rates of melanoma in the past. This is most likely due to increased sunlight from recreational exposure, as well as increased UVB radiation, although increases in screening practices account for some of this increase in incidence. (2) Currently, the incidence of melanoma continue to rise in men over 45 and women over 65, but have rates have stabilized in the younger population. (3)
UV radiation is the most important risk factor for developing all types of skin cancer. Although UVB radiation causes sunburn and more acute DNA damage than UVA, 10 to 100 times more UVA radiation reaches the earth’s surface so UVA radiation is also a major contributor to the development of melanoma (4). The following are UV radiation related risk factors.
For more on UV light exposure, see non-melanoma skin cancer risk factors.
Nevi are strong phenotypic markers of increased melanoma risk, especially if a patient has numerous nevi or has a family history of melanoma.
Lentigo maligna is a melanoma in situ that consists of malignant cells but is not invasive. Having lentigo maligna increases the risk of developing lentigo maligna melanoma. Lentigo maligna may appear as a flat, spreading brown patch, often varied in colour. It is commonly found in sun-exposed areas. (12)
Approximately 10% of melanomas are familial. 4 to 10% of melanoma patients have a family history of melanoma in a 1st degree relative. The major gene involved is the CDKN2A gene on Chromosome 9p (also known as the p16INK4A or MTS1 gene).
Immunosuppressed individuals, such as organ transplant recipients, lymphoma patients or HIV patients, are at a higher risk of melanoma
The Melanoma Risk Assessment Tool (MRAT) calculates absolute risk of melanoma over the next 5 years up to age 70. It is not intended for individuals with a family history of melanoma. The MRAT involves:
The survey assesses a patient’s awareness of typical and atypical nevi. It is to be completed before a clinical encounter.
Screening refers to a short physical examination to identify suspicious lesions that require further evaluation. Screening of high risk patients is very important. High risk patients include those with family or personal history of melanoma, more than 10 atypical nevi, greater than 50 normal nevi, blistering sunburns in the first two decades of life, and older aged males with light hair colour. These high risk patients should be counselled on prevention and should undergo periodic dermatologic evaluation.
Patient education is important for both early detection (detection during the radial growth phase) of melanoma and prevention of melanoma. Below is a list of patient education topics.
Patients should be educated on wearing proper clothing and hats, avoiding direct sunlight, avoiding indoor tanning and wearing sunscreen.
Skin Self Examinations are useful for tracking skin changes and can help identify melanoma in its early stages. A useful tool for skin self examinations is a body map, where patients can mark down all existing skin lesions on a drawing of a human body, and track the appearance of new lesions over time. High risk individuals should perform monthly skin self examinations. For more information on how to conduct a proper skin self examination, you can visit The American Academy of Dermatology’s website or The Skin Cancer Foundation’s website.
To help patients identify a lesion of concern, the ABCDE diagnostic aid can be taught to patients. ABCDE stands for asymmetry, border irregularities, color variegation (different colours in the same region), diameter greater than 6 mm, and evolving. Evolving lesions may include lesions that become pruritic or begin to bleed, or may include lesions that change in colour, size or shape. Any lesions that develop above age 40 should also be considered seriously.Relevant inherited syndromesPatients with Familial Atypical Multiple Mole Melanoma (FAMMM syndrome) or other inherited syndromes should have a complete baseline examination and be monitored closely. They should be educated about seeing their dermatologist every 3 to 6 months for a total-body examination. They should also know to report any skin changes, so that pigmented lesions of concern can be excised or treated appropriately.
The pathophysiology of melanoma follows the standard carcinogenesis model of tumor induction and tumor promotion. For example, UV light can be an inducer, but many promotion events, such as additional sunburns, are usually necessary before cancer develops. Promotion events are significant if they damage a cell rather than killing it, as killing the developing cancer cell would actually be more beneficial than causing replication of damaged DNA.
UV light is below 400 nm in wavelength. It is the most important carcinogen in skin cancer development.
UVC light encompasses wavelengths less than 290 nm, and is highly carcinogenic, but does not reach the Earth’s surface because it is blocked by the ozone layer.
UVB light, which encompasses wavelengths 290 to 320 nm, is the next most carcinogenic. UVB light follows the melanin-independent pathway, which is associated with direct UVB-induced DNA damage that leads strand breaks and rapid formation of cyclobutane pyrimidine dimers which turn cytosine to thymine. UVB light is an important source of Vitamin D synthesis in the summer, but Vitamin D can also come from milk or oily fish. Year round Vitamin D supplements are advised in Canada.
UVA light includes wavelengths 320 to 400 nm. The UVA light that contributes most to the development of melanoma is the light between 320 and 340 nm, which cause direct DNA damage. Wavelengths between 340 to 400 nm follows the pigment-dependent pathway, which through other activated photosenstiziers like reactive oxygen species, causes indirect damage to melanocytes and a slow (3+ hour) formation of cyclobutane pyrimidine dimers. UVA light is also responsible for tanning and wrinkling of the skin.
Melanomas can arise from damaged melanocytes. Damaged melanocytes may manifest as freckles, nevi, atypical nevi, or melanoma.
Freckles are activated melanocytes, which produce increased numbers of melanin granules.
Nevi are the result of melanocyte division. They can be junctional nevi, which appear at the epidermal-dermal junction, compound nevi, which occur in both the epidermis and dermis, or dermal nevi, which appear within the dermis. Nevi tend to begin as junctional in childhood and progress to become dermal. Once they get to the dermis, many undergo apoptosis.Typical nevi do not typically become melanoma, although a large number of nevi is associated with a higher risk of developing melanoma.
Atypical nevi are nevi that have border and color irregularities. Border irregularities imply variations in growth rate of the cells in the nevus. Color irregularities imply variations in melanin production. An inherited trait called dysplastic nevus syndrome can cause a predisposition for more atypical nevi. Unlike typical nevi, they tend to remain flat and extend sideways instead of into the dermis. Atypical nevi may become a melanoma.
There are 4 major subtypes of invasive cutaneous melanoma based on their histological differences.
Note: Lentigo maligna melanoma is not to be confused with lentigo maligna.
Lentigo maligna melanoma is a type of true melanoma that arises from a lentigo maligna (a melanoma in situ that consists of malignant cells but is not invasive).
Mucosal lentiginous melanoma: Rare type of melanoma that occurs in melanocytes that line respiratory, gastrointestinal and genitourinary tracts.
Intraocular melanoma: Rare type of melanoma that occurs in the eye.
The first step in establishing a diagnosis of melanoma is to gather a history. This allows physicians to assess a patient’s risk factors and address any concerns the patient may have. Important information obtained from a history include:
The most important part of the clinical assessment for skin cancer is the physical examination. A total body skin examination (TBSE) should be done. While the patient is sitting up, the face, rest of head, neck, scalp, arms and hands are examined. The patient is then asked to lie down on his or her back and the chest, abdomen, anterior thighs, anterior legs, dorsal feet, soles and toe webs are examined. Finally, the patient is asked to turn over and the calves, posterior thighs, buttocks and back are examined. The lymph nodes near lesions should also be palpated.
Below are some diagnostic aids used during the physical examination:
ABCDE stands for:
A – asymmetry,
B – border irregularities,
C – color variegation (different colours in the same region)
D – diameter greater than 6 mm
E – evolving.
These features correlate with the most frequent clinical signs associated with melanoma. The ABCDE diagnostic aid can be used by clinicians as well as patients to inspect suspicious lesions.
Scores equal or greater to 3 points suggest referral. (1)
The British Association of Dermatologists suggest the following indications for referral:
Note: For high risk individuals, monthly self-examinations should also be done. See section on Prevention.
The following table reviews some potential types of skin lesions
Dermoscopy, or Epiluminescence Microscopy (ELM), uses a dermatoscope (a handheld 10x lens microscope) or computerized digital imaging to visualize a lesion. Dermoscopy is a multistep process that determines whether a lesion is melanocytic, benign or suspicious. Melanocytic lesions are likely to have a pigment network (such as polygonal lines), globules/dots or streaks. It is rarely used in primary care and usage requires special training.
Pathology is required to confirm diagnosis and help determine prognosis. Biopsies are done for suspicious or atypical lesions. Melanomas tend to be polyclonal and variable so placement of biopsy is very important. If there is variation in pigmentation, then more than 1 area should be sampled. If there is any portion of the tumour that is elevated or nodular, it should be sampled.
Excisional biopsy, which includes removing normal tissue around the periphery of the lesion, is preferred over incisional biopsy, where only part of the lesion is removed. This is because excisional biopsy allows better histological examination and measurement of the lesion’s thickness. If excisional biopsy is not possible, then single or multiple incisional or punch biopsies may be used instead. Superficial shave biopsy is discouraged. Fine needle aspiration is not useful for primary lesion diagnosis but can be useful for metastatic assessment, such as in evaluation for metastasis in satellite skin nodules or regional lymph nodes.
Sentinel Lymph Node Biopsy, or SLNB, is a technique used for staging patients with moderate risk melanoma (>1mm) and clinically negative lymph nodes. The sentinel (initial draining) node is identified using a dye and radioisotope, and removed for analysis. This is usually done at the same time as the surgery for the removal of the primary melanoma. SLNB is used to stage, help determine prognosis, as well as guide treatment of cancer.
If patients are asymptomatic with localized melanoma, routine blood tests and imaging are usually not recommended. In general, imaging studies such as Chest X rays, CT, and PET have relatively high false-positive rates. Therefore, imaging should only be done for investigations of suspicious signs or symptoms that may influence clinical management.
Lactate dehydrogenase indicates a worse prognosis if the cancer has metastasized. However, it is insensitive as a marker for metastatic disease and not usually clinically useful.
Imaging can be done to assess the extent of the disease for higher risk lesions.
Ultrasound can be used to monitor or check the lymph nodes for metastasis.
Although it has poor sensitivity for the detection of early lung metastasis, a Chest X ray can be done to obtain a baseline image for future comparison.
Computed Tomography (CT) is recommended for symptom evaluation and in staging higher-risk melanoma. CT can be used to image the neck, chest, lungs, liver, abdomen, and pelvis; and if MRI is not available, the brain as well.
MRI can be used to assess potential metastasis to the brain or spinal cord. Patients often obtain a CT scan before an MRI is performed.
PET can be used to evaluate metastases to lymph nodes or other organs for high risk melanomas. It is not done routinely.
The Breslow’s method stages tumors according to its thickness. The thickness of the tumour is measured in millimeters with an ocular micrometer, measured from the top of the tumour to the deepest cells. This thickness is used in TNM staging for melanoma. The Breslow method is the preferred method of microstaging, as it is the most accurate type of microstaging.
The Clark’s Method Levels I to V are defined according to the depth of penetration into dermal layers and subcutaneous fat. It is less accurate than the Breslow’s method.
Prognosis is dependent on many factors. Depth of invasion is the most important determinant of prognosis and depth of invasion and presence of ulceration is the best predictor of recurrence.
0.85 to 1.69
1.70 to 3.64
5 Year Survival
The treatment of localized melanoma is primarily surgical. A local excision, with a wide margin depending on the depth of invasion, is recommended. Melanoma of the finger or toe sometimes requires amputation of the proximal digit. In addition, a sentinel lymph node biopsy should be considered for all but pT1a disease without high risk features including mitotic rate or lymphovascular invasion. The final decision to perform a sentinel lymph node biopsy should also account for patients' age and individual factors such as comorbodities.
The recommended clinical margins for clinically localized disease are summarized below .
There are multiple lines of retrospective evidence suggesting decreased local failure among patients with desmoplastic melanoma treated with post-operative radiotherapy, particularly in the setting of pure demsmoplastic melanoma, perineural invasion, inadequate margins [2-5]. Postoperative radiotherapy can therefore be considered for patients with desmoplastic melanoma case by case.
Stage III most commonly presents as metastasis to a draining local lymph node basin, but may also present with a local recurrence at the edge of a scar or graft, as satellite metastases (separated from scar but still within 2-5 cm of scar), or as in-transit metastasis (>5 cm from the scar). Stage IV presents more distantly but may still be resectable in some oligometastatic cases.
These patients generally require further staging investigations to rule out metastatic disease and workup as follows:
Management of resectable stage III-IV melanoma generally entails two parts: resection and adjuvant therapy.
If nodal metastases is detected on sentinel lymph node biopsy, the area should be assessed further by either completion lymph node dissection or ultrasound surveillance. Completion lymph node dissection appears to improve disease free survival, but two Phase 3 trials have failed to find a benefit in overall or melanoma-specific survival [6, 7]. The decision on undertaking completion lymph node dissection should be individualized, with consideration of the extent of sentinel lymph node biopsy, size of largest sentinel lymph node, number of sentinel lymph nodes, distribution of nodes, and primary tumor stage; these have all been found to predict non-sentinel lymph node positivity . If undergoing surveillance, then nodal basin ultrasound and clinical examination should be performed every 4 months during the first 2 years and every 6 months in the next 3 years in accordance with the original trials [6, 7].
Pathologic confirmation should be obtained if there are clinically positive lymph nodes, satellites, or metastases. Ideally, this is achieved by fine needle aspiration or core needle biopsy, but incisional or excisional biopsy are alternatives if required. Once confirmed to be malignant, complete therapeutic lymph node dissection is recommended for clinically positive nodes. Satellites or in-transit metastases should be excised to clear margins where feasible. Resection of stage IV melanoma should also be considered if it is feasible in view of evidence of improved survival . If margins are positive, local therapies may improve both local control as well as induce a distant response. These include T-VEC , IL-2 injections [10, 11], BCG injections , rose bengal injections , and radiotherapy. However, it is worth noting that most of the trials supporting local injections predate the use of PD-1 inhibitor and BRAF V600-targeted therapy.
The melanoma treatment paradigm has changed significantly with the emergence of immunotherapy and targeted therapy. Adjuvant systemic therapy should be considered for all patients with stage III melanoma, particularly those with clinically positive nodes or nodal recurrences. Both adjuvant nivolumab  and adjuvant pembrolizumab  have been shown to improve recurrence-free survival significantly with little toxicity in patients with resected Stage III melanoma. Dabrafenib plus trametinib has also been found to reduce recurrence among patients with BRAF V600E/K-mutated melanoma in resected stage III melanoma , although its optimal sequencing with anti-PD-1 therapy has yet to be established. Presently, beginning with either anti-PD-1 therapy or targeted therapy is considered appropriate.
Adjuvant nodal radiotherapy may have a role in select patients with high-risk nodal metastases (at least 1 parotid, 2 cervical or axillary or 3 groin positive nodes; a maximum nodal diameter of at least 3 cm in neck, or 4 cm in the axilla or groin; or nodal extracapsular extension) [17, 18]. However, the studies supporting this practice were conducted prior to modern immunotherapy and targeted therapy, which may be more suitable as first-line adjuvant treatment.
Finally, there may be an indication for local adjuvant radiotherapy in stage III desmoplastic melanoma, as in the case of localized disease.
Systemic therapy is the mainstay of treatment for unresectable melanoma. An important exception is brain metastases, which are treated with surgical resection, stereotactic radiotherapy, and/or whole brain radiotherapy depending on size, accessibility, and number of metastases as well as patient characteristics. The treatment of brain and other CNS metastases will not be discussed in this module. The interested reader is referred to the published guidelines (e.g. NCCN Central Nervous System Cancers) and original literature for details.
Nivolumab and pembrolizumab have largely supplanted ipilimumab as first-line immunotherapy for advanced melanoma with evidence of superior overall survival [19, 20]. The combination of nivolumab and ipilimumab shows superior overall survival to ipilimumab alone as well as a higher response rate compared to nivolumab alone, albeit at increased toxicity . On this basis, the combination of nivolumab and ipilimumab is appropriate for those desiring more aggressive first-line treatment and may be especially suitable for patients with lower PD-L1 expression, although this remains an area of active research .
Targeted therapy is also available as first-line treatment in patients with BRAF V600E/K-activating mutations. Combination BRAF/MEK inhibitors are preferred to BRAF inhibitors alone for a more sustained response. These agents are particularly helpful when a rapid response is desirable, seeing the 9-12-week time to response more typical of anti-PD-1 therapy . Combinations with established efficacy include vemurafenib/cobimetinib , dabrafenib/trametinib , and encorafenib/binimetinib . As with adjuvant therapy, no prospective comparisons exist between targeted therapy and anti-PD-1 agents.
A possible follow-up schedule for treated patients without evidence of residual disease, depending on original extent of disease, is below. Characteristics unique to each patient should be considered when developing the surveillance plan.
History and physical examination, with particular attention to skin and nodes, every 6–12 months for 5 years. Then annually as clinically indicated.
Use your mouse to click through the slides and answer each question in the text box provided.
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