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Objectives

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:

  1. Understand the general anatomy of the skin including the types of cells.
  2. Describe the stepwise progression of melanoma from dysplasia to invasive melanoma.
  3. Describe the current rate of melanoma and its trend.
  4. Identify the risk factors associated with melanoma.
  5. Describe characteristics associated with high risk UV light exposure.
  6. Identify the different types of nevi and their metastatic potential.
  7. Discuss the relevant genetic risk factors associated with the development of melanoma.
  8. Describe the tools used by healthcare professionals for determining the risk of melanoma.
  9. Demonstrate an understanding of skin cancer screening and the importance of diagnosing melanoma at an early stage.
  10. Be able to inform patients how to conduct a self-skin examination.
  11. Understand the role of UV light exposure in the pathophysiology of melanoma development.
  12. Be able to distinguish between the different types of UV light and its effect on skin.
  13. Understand how nevi can change into melanoma.
  14. Describe the four major types of invasive cutaneous melanoma .
  15. Identify the common characteristics of each of the four major types of invasive cutaneous melanoma.
  16. List the physical characteristics of malignant melanoma
  17. Describe rare types of melanoma.
  18. Understand the algorithm used to approach a diagnosis of melanoma.
  19. Describe the differential diagnosis of nevi.
  20. Describe the diagnostic aids used during physical examination.
  21. Describe the different tools used to visualize a skin lesion.
  22. Understand the role of biopsy in the diagnosis of melanoma.
  23. Understand the types of imaging used to diagnose melanoma.
  24. Describe the different tumor, nodal and metastatic stages in melanoma .
  25. Understand the Roman Numeral staging for melanoma and how it relates to the TNM stages.
  26. Describe the Breslow and Clark’s method for staging.
  27. Describe the factors related to the prognosis of an individual with melanoma.
  28. Understand the relationship between tumor depth and survival rates.
  29. Identify the common methods of treatment for each stage of melanoma.
  30. Understand the relationship between the type of disease and the treatment.
  31. Describe the suggested general guidelines for followup

Anatomy

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.

Local Spread

Superficial horizontal/radial growth phase

  • Early stage of melanoma
  • Lesion expands horizontally at basal lamina
  • Tumor is thin and confined to epidermis
  • Can be melanoma in situ or micro-invasive melanoma

Deep vertical growth phase

  • Dermal invasion of lesion
  • Clear metastatic potential
  • Satellite lesions
  • Skin or subcutaneous lesions within 2 cm of primary tumor (intra-lymphatic extensions of primary mass)

Lymphatic

In-transit metastases

  • Spread via lymph vessel and grows more than 2 cm from primary lesion but before it reaches the nearest lymph node

Nodal spread

  • Spread reaches regional nodes

Hematogenous

Can spread to almost any organ (e.g. brain, bone, liver, lung, adrenals etc.)

Epidemiology

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)

Risk Factors

UV Radiation

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.

  • Intense intermittent sun exposure and sunburns 
    (In contrast, non-melanoma skin cancers are associated with cumulative sun exposure)
  • Sun exposed skin,
    especially if areas of exposed skin are susceptible to sunburn. Areas of high risk are those sporadically exposed to sun, like the back in men or the legs in women (In contrast, non-melanoma skin cancers are associated with areas of skin maximally exposed to sun like the face, dorsal hands and forearms)
  • Naturally light skin or skin which does not easily darken,
    due to more UV light penetration into skin (5)
  • Exposure early in life, such as severe sunburns in childhood and adolescence
  • Residence in equatorial geographic areas,
    due to more UVB radiation near the equator (UVB light is a more closely associated risk, but both UVA and UVB play a role in the development of melanoma.) Geographic relocation from northern to equatorial latitudes also contributes to risk, especially if relocation is during childhood (6,7)
  • Indoor tanning beds (3,8) especially if first exposure is before age 35. (3)
  • PUVA (ultraviolet A radiation) therapy 
    (use for the treatment of psoriasis and other conditions) is associated with late increase in risk of melanoma (16 or more years after exposure). (9)

For more on UV light exposure, see non-melanoma skin cancer risk factors.

Nevi

Nevi are strong phenotypic markers of increased melanoma risk, especially if a patient has numerous nevi or has a family history of melanoma.

  • Common Acquired Melanocytic Nevi
    Common acquired melanocytic nevi are benign growths equal or less than 5 mm in diameter. They have an extremely low chance of developing into melanoma. They can be raised or flat, and often occur in photo-exposed areas
  • Congenital Melanocytic Nevi
    Congenital melanocytic nevi (melanocytic nevi present at birth or within first few months of life) have a 40 cm). (3)
  • Atypical Nevi (also known as Dysplastic Nevi)
    Atypical nevi are benign acquired melanocytic neoplasms that have many similarities to neoplasms. They are potential precursors for melanoma. They are generally multiple shades of brown or red-brown, greater than 6 mm in diameter, irregular in shape, have a pebbly or centrally raised surface, and have an irregular border.

Lentigo Maligna

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)

Genetic Background

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).

  • Familial atypical multiple mole melanoma (FAMMM) syndrome
    FAMMM syndrome is characterized by 10-100 multiple melanocytic nevi mainly on the trunk, buttocks or lower limbs. It is inherited in an autosomal dominant fashion with incomplete penetrance.
  • Xeroderma pigmentosum
    Xeroderma pigmentosum is a condition where skin cannot repair sun damage. DNA repair mechanisms are altered and thus skin is hypersensitive to UV radiation. It is inherited in an autosomal recessive fashion.
  • Werner Syndrome
    Werner Syndrome is a rare condition characterized by the appearance of premature aging. In these individuals, skin ages prematurely and is at a higher risk of developing into melanoma. It is inherited in an autosomal recessive fashion.

Personal History of Melanoma

  • Risk is highest in the first year after initial diagnosis
  • Risk varies depending on age and lesion site. Younger patients and patients with head or neck melanoma are at higher risk for developing additional lesions
  • Previous non-melanoma skin cancers are also associated with higher risk of melanoma

Immunosuppression

Immunosuppressed individuals, such as organ transplant recipients, lymphoma patients or HIV patients, are at a higher risk of melanoma

Tools for Determining Risk

Melanoma Risk Assessment Tool

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:

  • An inspection of the back for moles
  • Questions about complexion type and history of sun exposure

Patient Survey

The survey assesses a patient’s awareness of typical and atypical nevi. It is to be completed before a clinical encounter.

Prevention

Screening

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

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.

UV Protection

Patients should be educated on wearing proper clothing and hats, avoiding direct sunlight, avoiding indoor tanning and wearing sunscreen.

Skin Self Examination and the ABCDEs of melanoma

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.

Pathophysiology

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 Exposure

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.

Nevi Development

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.

Classification

There are 4 major subtypes of invasive cutaneous melanoma based on their histological differences.

Superficial spreading

  • Most common subtype, about 65% of all malignant melanomas. Majority are de novo, while 25% are associated with a pre-existing nevus (such as a dysplastic or congenital nevus).
  • Occurs at any age after puberty.
  • Has a predilection for the back in men and lower extremities in women.
  • Appears as a flat, variably pigmented plaque with an irregular border, a few mm to several cm in diameter. Often fits the ABCDE criteria for diagnosis.
  • Usually undergoes a slow change over 1 to 5 years and becomes more irregular, asymmetric, varied in color, and depigmented over time. Starts with outward radial growth and spreads across the surface of the skin. Progresses to downward vertical growth.
  • Histologically, appears poorly circumscribed, and lacks cellular maturation.
Superficial Spreading Melanoma

Nodular Melanoma

  • Second most common type of melanoma, 15 to 30% of melanomas.
  • Most difficult to diagnose at early stage.
  • Often found on the chest, back, head or neck.
  • Raised or dome shaped. Appears stuck to skin. Darkly pigmented (often black or blue in color but some are amelanotic/flesh-coloured), pedunculated (attached to the base tissue by a slender stalk) or polypoid nodule.
  • Vertical growth phase melanomas (no identifiable radial growth phase). Grows more quickly than other types of melanomas and easily spreads if not removed.
  • Histologically, dermal growth occurs in isolation or with epidermal component.
Nodular Melanoma

Lentigo Maligna Melanoma

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).

  • About 5% of melanomas.
  • Most often seen in sun damaged skin of older individuals, more common in women than men, commonly on the head and neck.
  • Appears as large and flat lesions. Begins as a freckle like tan brown macule and gradually enlarges and develops dark asymmetric foci over time. Has irregular borders with notching and indentation.
  • Transformation from intraepidermal lesions to lentigo maligna melanoma is slow.
  • Histologically, neoplastic melanocytes are seen along the dermal-epidermal junction in a lentiginous pattern. Epidermal atrophy and solar elastosis is also seen.
Lentigo Maligna Melanoma

Acral Lentiginous

  • Rare. About 5% of melanomas in Caucasians, 35-60% of melanomas in African-Americans, Asians and Hispanics.
  • Commonly on palmar, plantar (soles of feet), subungual (under the nails) and mucosal surfaces. Often looks like subungual hematoma or plantar hematoma.
  • Dark brown to black unevenly pigmented patch. Foci of grey or white discoloration indicates areas of regression. Subungual melanomas present as a brown or black streak under the nail bed and may be misdiagnosed as hematoma.
  • Like nodular melanoma, lesion may grow aggressively, changing quickly from radial to vertical growth.
  • Histologically, lentiginous arrays of atypical melanocytes line the dermal epidermal junction and foci of confluent melanocytic growth area seen. Atypical cells are large and hyperchromatic angulated melanocytes with scant cytoplasm.
Acral Lentiginous Melanoma

Other Types

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.

Diagnosis

History

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:

  • Signs and symptoms –characterize the skin lesion of note and ask questions related to the potential areas of spread (i.e. swelling in lymph node basins, general constitution, pain etc)
  • Personal History – melanoma or other skin cancer, UV exposure, tanning bed use, immunosuppression, type and number of nevi, sun sensitivity and ability to tan
  • Family History – melanoma or other types of cancer, genetic risk factors

Physical Examination

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

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.

Revised Glasgow 7 Point Checklist

Scores equal or greater to 3 points suggest referral. (1)

Major features (2 points each)
  • Change in size or new lesion
  • Change in shape
  • Change in colour
Minor features (1 point each)
  • Diameter greater or equal to 7 mm
  • Inflammation
  • Crusting or bleeding
  • Sensory change

British Association of Dermatologist Indications for Referral

The British Association of Dermatologists suggest the following indications for referral:

  • ‍A new mole appearing after the onset of puberty which is changing in shape, color, or size
  • A longstanding mole which is changing in shape, color, or size
  • Any mole which has three or more colors or has lost its symmetry
  • A mole which is itching or bleeding
  • Any new persistent skin lesion, especially if growing, pigmented, or vascular in appearance, and if the diagnosis is not clear
  • A new pigmented line in a nail, especially where there is associated damage to the nail
  • A lesion growing under a nail

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

Evaluation of Skin Lesions

Dermoscopy

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.

Biopsy

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.

Staging of Melanoma

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.

Laboratory Tests

Lactate Dehydrogenase

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

Imaging can be done to assess the extent of the disease for higher risk lesions.

Ultrasound

Ultrasound can be used to monitor or check the lymph nodes for metastasis.

Chest X Ray

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.

CT

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.

Magnetic Resonances Imaging (MRI)

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.

Positron Emission Tomography (PET)

PET can be used to evaluate metastases to lymph nodes or other organs for high risk melanomas.  It is not done routinely.

Staging

TNM Staging (AJCC 8th Edition)

Tumor:
Nodal:
Metastasis:

Overall Staging

AJCC Prognostic Staging

cTNM Staging

pTNM Staging

Breslow’s Method

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.

Clark’s Method

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

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.

Survival

Survival by Thickness

Depth (mm)
<0.85
0.85 to 1.69
1.70 to 3.64
>3.65
5 Year Survival
99%
94%
78%
42%

Survival by Stage

Treatment

Carcinoma in Situ (Stage 0) or Clinically Localized (Stage I or II)

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 [1].

Desmoplastic Melanoma

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.

Resectable Stage III or IV

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:

  1. CT chest/abdomen/pelvis or whole-body FDG PET/CT (may be omitted at clinician's discretion for stage IIIA).
  2. CT neck if clinically indicated (symptoms or clinical findings).
  3. Brain MRI for stage IIIC or IV disease.
  4. Consider BRAF V600 mutation testing.

Management of resectable stage III-IV melanoma generally entails two parts: resection and adjuvant therapy.

Local Management

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 [1]. 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 [8]. If margins are positive, local therapies may improve both local control as well as induce a distant response. These include T-VEC [9], IL-2 injections [10, 11], BCG injections [12], rose bengal injections [13], 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.

Adjuvant 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 [14] and adjuvant pembrolizumab [15] 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 [16], 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.

Advanced Unresectable 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 [19]. 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 [1].

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 [1]. Combinations with established efficacy include vemurafenib/cobimetinib [21], dabrafenib/trametinib [22], and encorafenib/binimetinib [23]. As with adjuvant therapy, no prospective comparisons exist between targeted therapy and anti-PD-1 agents.

Follow-up

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.

Stage I-IIA

History and physical examination, with particular attention to skin and nodes, every 6–12 months for 5 years. Then annually as clinically indicated.

Stage IIB-IV
  1. 1History and physical examination, with particular attention to skin and nodes, every 3–6 mo for 2 years. Then every 3–12 months for 3 additional years and annually thereafter as clinically indicated.
  2. Nodal surveillance for patients with positive SLNB who do not undergo complete nodal dissection. These patients should undergo ultrasound at least every 4 months during the first 2 years and every 6 months in the next 3 years.
  3. There is no consensus on the indications for imaging surveillance. Consider surveillance with chest radiographs, CT chest/abdomen/pelvis, whole body PET, and/or MRI brain every 3-12 months. Special consideration should be given to patients with previous brain metastases who should be followed closely by MRI brain.

Virtual Patient Case

References

Anatomy


1) Wiener C. Harrison's principles of internal medicine. New York: McGraw-Hill,
Medical Pub. Division; 2008.

2) Shah A. Essentials of clinical oncology. 2nd ed. Vancouver, BC: Somerset Publishing;
2008.

3) www.cancer.ca. Canadian Cancer Society [Internet]. 2015
[cited 29 June 2015]. Available from:

4) Liu
V, Mihm M. Pathology of malignant melanoma. Surgical Clinics of North America. 2003;83(1):31-60.

Epidemiology

1) Canadian Cancer Society. Canadian Cancer Statistics. Toronto, ON: Canadian Cancer Society; 2015.

2) Shah A. Essentials of clinical oncology. 2nd ed. Vancouver, BC: Somerset Publishing; 2008.

3) www.bccancer.bc.ca. Melanoma [Internet]. 2015 [cited 29 June 2015]. Available from: http://www.bccancer.bc.ca/health-professionals/professional-resources/cancer-management-guidelines/skin/melanoma

4) Autier P, Doré J, Eggermont A, Coebergh J. Epidemiological evidence that UVA radiation is involved in the genesis of cutaneous melanoma. Current Opinion in Oncology. 2011;23(2):189-196.

5) Gilchrest B. The Pathogenesis of Melanoma Induced by Ultraviolet Radiation. New England Journal of Medicine. 1999;341(10):766-767.

6) Cooke K, Fraser J. Migration and death from malignant melanoma. International Journal of Cancer. 1985;36(2):175-178.

7) Holman C, Armstrong B. Cutaneous malignant melanoma and indicators of total accumulated exposure to the sun: an analysis separating histogenetic types. Journal of the National Cancer Institute. 1984;73(1):75.

8) Colantonio S, Bracken M, Beecker J. The association of indoor tanning and melanoma in adults: Systematic review and meta-analysis. Journal of the American Academy of Dermatology. 2014;70(5):847-857.e18.

9) Stern R. The risk of melanoma in association with long-term exposure to PUVA. Journal of the American Academy of Dermatology. 2001;44(5):755-761.

10) Curiel-Lewandrowski C. Risk factors for the development of melanoma [Internet]. Uptodate.com. 2015 [cited 29 June 2015]. Available from: http://www.uptodate.com/contents/risk-factors-for-the-development-of-melanoma

11) Wiener C. Harrison’s principles of internal medicine. New York: McGraw-Hill, Medical Pub. Division; 2008.

12) www.cancer.ca. Canadian Cancer Society [Internet]. 2015 [cited 29 June 2015]. Available from: https://www.cancer.ca/en/cancer-information/cancer-type/skin-melanoma/melanoma

Prevention

1) Autier
P, Doré J, Eggermont A, Coebergh J. Epidemiological evidence that UVA radiation
is involved in the genesis of cutaneous melanoma. Current Opinion in Oncology.
2011;23(2):189-196.

2) Geller
A, Swetter S. Screening and early detection of melanoma [Internet]. Uptodate.com.
2015 [cited 30 June 2015]. Available from:
http://www.uptodate.com/contents/screening-and-early-detection-of-melanoma

3) Wiener
C. Harrison's principles of internal medicine. New York: McGraw-Hill, Medical Pub.
Division; 2008.

4) Shah
A. Essentials of clinical oncology. 2nd ed. Vancouver,
BC: Somerset
Publishing; 2008.

Pathophysiology

1) Noonan F, Zaidi M,
Wolnicka-Glubisz A, Anver M, Bahn J, Wielgus A et al. Melanoma induction by
ultraviolet A but not ultraviolet B radiation requires melanin pigment. Nat
Comms. 2012;3:884.

2) Premi S, Wallisch S, Mano C,
Weiner A, Bacchiocchi A, Wakamatsu K et al. Chemiexcitation of melanin
derivatives induces DNA photoproducts long after UV exposure. Science.
2015;347(6224):842-847.

3) Kalia S. Skin Cancer. Lecture
presented at; 2014; UBC.

Classification

1) Canadian Cancer Society.
Canadian Cancer Statistics. Toronto,
ON: Canadian Cancer Society;
2015.

2) Shah
A. Essentials of clinical oncology. 2nd ed. Vancouver,
BC: Somerset
Publishing; 2008.

3)
www.cancer.ca. Canadian Cancer Society [Internet]. 2015 [cited 29 June 2015].
Available from: https://www.cancer.ca/en/cancer-information/cancer-type/skin-melanoma/melanoma

4) Geller A, Swetter S. Screening
and early detection of melanoma [Internet]. Uptodate.com. 2015 [cited 30 June
2015]. Available from: http://www.uptodate.com/contents/screening-and-early-detection-of-melanoma

5) www.bccancer.bc.ca. Melanoma
[Internet]. 2014 [cited 30 June 2015]. Available from:
http://www.bccancer.bc.ca/health-professionals/professional-resources/cancer-management-guidelines/skin/melanoma#Diagnosis

Diagnosis

1) Shah A. Essentials of clinical oncology. 2nd ed. Vancouver, BC: Somerset Publishing; 2008.

2) Walter F, Prevost A, Vasconcelos J, Hall P, Burrows N, Morris H et al. Using the 7-point checklist as a diagnostic aid for pigmented skin lesions in general practice: a diagnostic validation study. British Journal of General Practice. 2013;63(610):345-353.

3) Donohoe K. Imaging studies in melanoma [Internet]. Uptodate.com. 2013 [cited 6 July 2015]. Available from: http://www.uptodate.com/contents/imaging-studies-in-melanoma

4) www.bccancer.bc.ca. Melanoma [Internet]. 2015 [cited 29 June 2015]. Available from: http://www.bccancer.bc.ca/health-professionals/professional-resources/cancer-management-guidelines/skin/melanoma

5) Cancer.org. How is melanoma skin cancer diagnosed? [Internet]. 2015 [cited 6 July 2015]. Available from: http://www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-diagnosed

6) Kantarjian H, Koller C, Wolff R. The M.D. Anderson manual of medical oncology. New York: McGraw-Hill, Medical Pub.; 2006.

Staging

1)
www.bccancer.bc.ca. Melanoma [Internet]. 2015 [cited 29 June 2015]. Available
from: http://www.bccancer.bc.ca/health-professionals/professional-resources/cancer-management-guidelines/skin/melanoma

2) Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, et al. (Eds.). AJCC Cancer Staging Manual (8th edition). Springer International Publishing: American Joint Commission on Cancer; 2017.

3)
www.cancer.ca. Canadian Cancer Society [Internet]. 2015 [cited 29 June 2015].
Available from:

Prognosis

1) www.cancer.ca. Canadian Cancer
Society [Internet]. 2015 [cited 29 June 2015]. Available from: 

2) Shah A. Essentials of clinical
oncology. 2nd ed. Vancouver, BC:
Somerset Publishing;
2008.

Treatment

1) National Comprehensive Cancer Network. Cutaneous Melanoma (Version 3.2019). https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf. Accessed November 10, 2019.

2) Oliver DE, Patel KR, Switchenko J, et al. Roles of adjuvant and salvage radiotherapy for desmoplastic melanoma. Melanoma Res. 2016;26(1):35-41. 

3) Guadagnolo BA, Prieto V, Weber R, Ross MI, Zagars GK. The role of adjuvant radiotherapy in the local management of desmoplastic melanoma. Cancer. 2014;120(9):1361-8.

4) Chen JY, Hruby G, Scolyer RA, et al. Desmoplastic neurotropic melanoma: a clinicopathologic analysis of 128 cases. Cancer. 2008;113(10):2770-8.

5) Strom T, Caudell JJ, Han D, et al. Radiotherapy influences local control in patients with desmoplastic melanoma. Cancer. 2014;120(9):1369-78.

6) Faries MB, Thompson JF, Cochran AJ, et al. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Engl J Med. 2017;376(23):2211-2222.

7) Leiter U, Stadler R, Mauch C, et al. Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2016;17(6):757-767.

8) Nelson DW, Fischer TD, Graff-baker AN, et al. Impact of Effective Systemic Therapy on Metastasectomy in Stage IV Melanoma: A Matched-Pair Analysis. Ann Surg Oncol. 2019;26(13):4610-4618.

9) Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol. 2015;33(25):2780-8.

10) Weide B, Derhovanessian E, Pflugfelder A, et al. High response rate after intratumoral treatment with interleukin-2: results from a phase 2 study in 51 patients with metastasized melanoma. Cancer. 2010;116(17):4139-46.

11) Byers BA, Temple-oberle CF, Hurdle V, Mckinnon JG. Treatment of in-transit melanoma with intra-lesional interleukin-2: a systematic review. J Surg Oncol. 2014;110(6):770-5.

12) Cohen MH, Jessup JM, Felix EL, Weese JL, Herberman RB. Intralesional treatment of recurrent metastatic cutaneous malignant melanoma: a randomized prospective study of intralesional Bacillus Calmette-Guerin versus intralesional dinitrochlorobenzene. Cancer. 1978;41(6):2456-63.

13) Thompson JF, Agarwala SS, Smithers BM, et al. Phase 2 Study of Intralesional PV-10 in Refractory Metastatic Melanoma. Ann Surg Oncol. 2015;22(7):2135-42.

14) Weber J, Mandala M, Del vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med. 2017;377(19):1824-1835.

15) Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. 2018;378(19):1789-1801.

16) Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med. 2017;377(19):1813-1823.

17) Agrawal S, Kane JM, Guadagnolo BA, Kraybill WG, Ballo MT. The benefits of adjuvant radiation therapy after therapeutic lymphadenectomy for clinically advanced, high-risk, lymph node-metastatic melanoma. Cancer. 2009;115(24):5836-44.

18) Henderson MA, Burmeister BH, Ainslie J, et al. Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial. Lancet Oncol. 2015;16(9):1049-1060.

19) Wolchok JD, Chiarion-sileni V, Gonzalez R, et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017;377(14):1345-1356.

20) Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26):2521-32.

21) Ascierto PA, Mcarthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17(9):1248-60.

22) Robert C, Grob JJ, Stroyakovskiy D, et al. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. N Engl J Med. 2019;

23) Dummer R, Ascierto PA, Gogas HJ, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(5):603-615.

Followup

1) National Comprehensive Cancer Network. Cutaneous Melanoma (Version 3.2019). https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf. Accessed November 10, 2019.

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