What are the other Names for this Condition? (Also known as/Synonyms)

• Cutaneous Nodular Melanoma
• Malignant Melanoma of Skin, Nodular Type
• NM of Skin

What is Nodular Melanoma of Skin? (Definition/Background Information)

• A melanoma is a type of cancer that develops from cells, called melanocytes. Melanocytes are cells that produce melanin, the pigment that gives skin its color
• Nodular Melanoma (NM) of Skin is the second-most common subtype of cutaneous melanoma that usually arises from the head and neck region or the torso. It is the most aggressive form of melanoma of skin
• This type of melanoma is present in older adults; some studies indicate a propensity for males. Nodular Melanoma of Skin is typically observed as a solitary skin lesion that exhibits rapid growth
• They are usually brown or black in color. Although these can occur anywhere on the body, common sites of occurrence include:
  • Head and neck
  • Chest, back, and abdomen
  • Legs
• Nodular Melanoma of Skin is diagnosed with the help of a biopsy. Once a definitive diagnosis has been made, it is surgically removed (excised)
• Depending on how far the disease has progressed, additional modes of therapy may be needed. The outcome of Nodular Melanoma of Skin is generally guarded due to the aggressive nature of the tumor

Who gets Nodular Melanoma of Skin? (Age and Sex Distribution)

• Nodular Melanoma of Skin can occur in young as well as old individuals; although, in comparison to some forms of melanoma, Nodular Melanoma of Skin is mostly observed in older adults
• Both males and females are affected; some studies indicate a male predominance
• Cutaneous melanomas occur more frequently seen in Caucasians, as compared to other races
• Between 10-15% of all melanomas diagnosed in fair-skinned Caucasians belong to this type

What are the Risk Factors for Nodular Melanoma of Skin? (Predisposing Factors)

The following factors increase the risk for Nodular Melanoma of Skin:

• Severe exposure to ultra violet (UV) rays is a major risk factor. UV rays are present in sunlight, and also in tanning lamps and beds
• Nevus (medical term for mole) is a non-cancerous pigmented tumor. While most nevi never become cancerous (or malignant), a small number of atypical/dysplastic nevi (moles with abnormal shape/borders/color) may turn cancerous. When such dysplastic nevi run in families, the condition is called dysplastic nevus syndrome. Individuals with this condition have a 10% increased risk of developing melanoma. Despite the above and irrespective of the condition, whether the nevi are present since birth, or are normal or atypical, more moles indicate more melanoma risk
• Fair-skinned individuals are at a higher risk; more so those with freckles, or those who develop sunburns easily
• Individuals with light or red hair color and those with blue eyes also have a higher risk
• Previous history of melanoma or a history of melanoma in parents/siblings; 6-14% of the individuals with melanoma are found to have someone with melanoma in their family
• An inherited condition called xeroderma pigmentosum, where the ability of the cells to repair sun-induced damage to genetic material is impaired
• Weakened immune system, as a result of infections (such as HIV infection), drugs (chemotherapy or immunosuppressants), and due to the presence of cancers (such as lymphoma)

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Nodular Melanoma of Skin? (Etiology)

The exact reason behind, why some moles turn cancerous and others do not, is still not exactly known. In the case of Nodular Melanoma of Skin, the cancer is not generally known to arise from a preexisting mole; a spontaneous ‘new’ skin lesion is observed to be the origin of this melanoma type.

The potential causes for Nodular Melanoma of Skin may include:

• Uncontrolled activity of oncogenes (rogue genes that promote cell growth and division) or depressed action of tumor suppressor genes (genes that normally keep a check on cell growth and division) is thought to play a role in the development of melanomas
• About 50% of all melanomas have a mutation (change) involving the BRAF oncogene
• UV-radiation induces damage to DNA (genetic material that determines all of our traits and functions), which in turn may turn-on oncogenes, or turn-off tumor suppressor genes
• In families with inherited melanomas, gene mutations that increase the risk of cancer are passed on from one generation to the next. About 1 in 5 individuals with a positive family history of melanoma, show mutations in the CDKN2A gene

What are the Signs and Symptoms of Nodular Melanoma of Skin?

Nodular Melanoma of Skin typically appears as a new and rapidly-expanding spot/growth. The signs and symptoms may include:

• The common location for the skin lesions include the face, head and neck region, the lower limbs, and the body or trunk. However, NM of Skin may be present at any location
• The lesion appears as a nodule, or as a papule/plaque, and shows a rapid increase in size
• Some tumors appear like polyps or are suspended from a stalk-like structure on the skin (pedunculated)
• Most skin lesions are pigmented blue or black, while some show hardly any skin color change (called amelanotic melanomas)
• Amelanotic melanomas may show a subtle color or a pigmented peripheral ring (on the boundary of the mole)
• Most skin lesions are regular and symmetric; the edges are also well-defined; some tumors are asymmetrical with a raised skin surface (like a bump)
• During diagnosis, most lesions are observed to be around 1 cm in size on an average
• The nodule/papule/plaque may show redness or itching (due to inflammation). Such areas may also be scaly, exhibit some oozing of fluid, or bleeding following ulceration
• Ulceration, bleeding, and crust formation may be a chronic repetitive event

How is Nodular Melanoma of Skin Diagnosed?

A thorough history and a complete physical exam by a physician are crucial for the diagnosis of Nodular Melanoma of Skin. This is followed by some tests which include:

• Biopsy of skin: A sample of the skin, from any suspected area found on physical examination, is taken and examined under a microscope for signs of cancer by a pathologist. The types of biopsy performed include:
  • Excisional biopsy: After numbing the area with a local anesthetic, the entire mole is removed with a small border of surrounding skin. Where possible, this is the generally preferred method
  • Punch biopsy: After numbing the area with a local anesthetic, a circular blade is pressed into the skin around the suspicious area, and a round piece of skin removed. This type of biopsy is carried out, when the lesion (the suspicious area) is large in size
  • Incisional biopsy: After numbing the area with a local anesthetic, a portion of the tumor is removed using a scalpel
  • Sentinel lymph node biopsy: Performed to determine if the melanoma has spread to nearby lymph nodes. A dye is injected into the area from where the melanoma is removed. The first lymph node that takes up the dye is biopsied and examined for cancer cells, under a microscope
• Sometimes, biopsy of other large lymph nodes in the area near the melanoma may be performed using fine needle aspiration cytology (FNAC) technique. In this, a sample of cells is removed from the mass, using a syringe with a hollow needle and then examined under a microscope
• If the melanoma is suspected to have metastasized (spread) to internal organs, imaging tests, such as X-ray, CT scan or MRI of the affected areas, may be carried out
• In rare cases, biopsies of areas other than skin may have to be done, when the primary source/origin of the tumor cannot be determined

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Nodular Melanoma of Skin?

Early stage melanomas include melanoma in situ (confined to just the upper skin layer called epidermis) or locally invasive melanomas that have spread to the deeper layers of the skin. The more advanced cases of Nodular Melanoma of Skin metastasize beyond the skin, to lymph nodes and other organs. Organs that are commonly involved in metastasis include:

• Lung
• Liver
• Brain
• Bone
• Gastrointestinal tract

How is Nodular Melanoma of Skin Treated?

The choice of treatment for Nodular Melanoma of Skin depends on how far the cancer has progressed. This is estimated through staging of the tumor. Some of the factors taken into consideration during staging include:

• The thickness of the melanoma (also called Breslow’s measurement): Tumors can be thin, intermediate, or thick, depending on how deep into the skin they have penetrated. The thinner the tumor, the better the chances of a cure
• Presence of any ulceration (open sores) over the tumor.
• Spread of melanoma to lymph nodes or other internal organs

The melanoma is sorted into one of four stages depending on how far it has progressed, with I and II being early stages, III and IV being later stages, where melanoma has spread to sites beyond the skin. While early stage melanomas can be treated by surgery alone, the later stages of the disease often require a combination of treatment measures.

Treatment options for melanoma include:

Surgery:

• Simple excision of the tumor along with some normal, non-cancerous skin at the edges (called margin). The width of the margin is based on the thickness of the tumor; as the thickness of the melanoma increases, the margin required increases as well
• Mohs micrographic assisted surgery:
  • It is used as an alternative technique to standard excision of melanoma
  • An excision is made at the margin of the clinically apparent nodular melanoma. Another excision of a thin section of skin is done, with careful attention to the site of removal. Immunohistochemical stains are done to help a pathologist determine whether the margins are clear. If NM of skin is detected at the margin, another layer is excised at only the site of residual tumor. This process is then carried out continuously, until a cancer-free defect is obtained. The staining techniques required for melanoma take about 24 for hours, so the surgery sometimes require several days. Each day, one short surgical session is performed under local anesthetic, then the skin bandaged until the slides are examined to determine if further specimens are required. When the cancer is completely removed, a reconstructive plan is formulated
• Sentinel node biopsy is generally performed
• Lymph node dissection, in cases where the melanoma has spread to involve the nodes: Lymph nodes help in drainage of tissue fluid (lymph). However, removal of these nodes may therefore lead to a build-up of lymph causing swelling (lymphedema)

Chemotherapy:

• Drugs are used to kill the tumor cells, which may be given as oral pills, or injected into veins
• Side effects of chemotherapy may include nausea, vomiting, hair loss, loss of appetite, diarrhea, and fatigue, increased risk of infection, mouth sores, or easy bruising, depending on the drug used
• In cases, where the melanoma is advanced, but remains confined to an arm or leg; chemotherapy is only circulated through the affected the limb, by a process called isolated limb perfusion

Immunotherapy:

• This therapy stimulates the immune system and involves the use of substances produced naturally by the body or such similar synthetics, made in a laboratory
• Drugs used include, synthetic immune proteins and proteins that boost the immune system, called cytokines- interferon alpha or interleukin-2
• Side effects of cytokines may include chills, fatigue, fever, headaches and muscle aches; while synthetic immune proteins may cause the immune system to start attacking other parts of the body

Targeted therapy:

• Involves the use of drugs tailored to target the differences in a melanoma cell, as compared to a normal cell
• Half of all melanomas involve a mutation in the BRAF gene. This is targeted by a drug vemurafenib
• Side effects may include nausea, joint pain, fatigue, rash, itching, hair loss, sensitivity to the sun, and rarely heart rhythm problems, liver problems, severe allergic reactions, and severe skin or eye problems

Radiation therapy:

• This uses high energy beams to kill cancer cells
• Generally, this method is not used to treat the original melanoma, but often to relieve symptoms, when the melanoma has spread to other organs; or following lymph node dissection, where many nodes were found to be cancerous
• The most common side effect is fatigue, but this gets resolved, once the treatment is complete

How can Nodular Melanoma of Skin be Prevented?

A few steps to prevent of Nodular Melanoma of Skin may include:

• Avoid direct exposure to UV rays and remain in the shade, as and when possible
• When heading out into the sun:
  • Slip on a shirt
  • Slop on some sunscreen. Sunscreens with SPF values higher than 30, and those offering broad spectrum protections (against UV-A and UV-B rays), are recommended. Apply an ounce to all exposed areas, 30 minutes before heading outdoors. Reapply every two hours, and also after excessive sweating
  • Slap on a hat
  • Wrap on sunglasses

This is encapsulated as the “Slip! Slop! Slap! Wrap” method for skin cancer prevention. (Source: The American Cancer Society, Atlanta)

• Avoid tanning beds and sun lamps
• Perform self-examination of your skin, from head to toe, once a month
• Get a professional skin exam from a healthcare provider, once a year
• All patients with melanoma should undergo skin examinations regularly even after treatment, at least once a year throughout their lives

What is the Prognosis of Nodular Melanoma of Skin? (Outcomes/Resolutions)

• The prognosis of Nodular Melanoma of Skin is generally worse that other forms of cutaneous melanoma, since it is a very aggressive tumor
• In general, the prognosis depends upon a set of several factors, which include:
  • Stage of tumor: With lower-stage tumors, when the melanoma is confined to site of origin, the prognosis is usually excellent with appropriate therapy. In higher-stage cancers, such as those with metastasis, the prognosis is poor
  • Overall health of the individual: Individuals with overall excellent health have better prognosis compared with those with poor health
  • Age of the individual: Older individuals generally have poorer prognosis than younger individuals
  • The size of the melanoma: Individuals with small-sized melanomas fare better than those with large-sized ones
  • Individuals with bulky disease have a poorer prognosis
  • Involvement of vital organs may complicate the condition
  • The surgical resectability of melanoma of skin (meaning if the melanoma can be removed completely)
  • Whether the cancer is occurring for the first time, or is recurrent. Recurring cancers have worse prognosis compared to those that do not recur
  • Response to treatment: Melanomas that respond well to treatment have better prognosis compared to melanomas that do not respond to treatment
  • Progression of the condition makes the outcome worse (progressive cutaneous melanoma)
• An early diagnosis and prompt treatment of the condition generally yields better outcomes than a late diagnosis and delayed treatment
• The factors that affect the outcome include:
  • Ulceration of the lesion and cell division rate, both influenced by tumor thickness, are known to be significant prognostic factors
  • For thin melanomas (less than 1 mm), the level of invasion
• The factors that negatively affect the outcome include:
  • The tumor displays an increased vascularity (including vascular invasion)
  • Invasion of local lymphatic vessels
  • The presence of tiny or microscopic satellite lesions
  • Older age and male gender
  • Lesions on the back, chest, head and neck region
  • Number of lymph nodes being affected; if the affected lymph nodes are visible (on the surface) or not
  • If tumor ulceration is observed
  • If organ metastasis is noted

Additional and Relevant Useful Information for Nodular Melanoma of Skin:

• Melanoma is the most common form of cancer in young adults, aged 25-29 years. 1 in 50 Americans, have a lifetime risk of developing melanoma
• The ‘Slip-Slop-Slap campaign’ was initially launched in Australia, by Cancer Council Victoria in the 1980s, to promote awareness about skin cancer and methods for its prevention. This was then adopted in New Zealand as the ‘Slip-Slop-Slap-Wrap campaign’ (Source: The Wikipedia)