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

• Blue Nevus-like Melanoma
• Malignant Melanoma arising from a Blue Nevus
• MM arising in CBN

What is Melanoma arising from Blue Nevus? (Definition/Background Information)

• A melanoma is a type of cancer that develops from a certain type of cells called the melanocytes. Melanocytes are cells that produce melanin; the pigment that gives skin its color
• A blue nevus is a benign proliferation of melanocytes in the dermis or skin. In a cellular blue nevus, the number of melanocytes are greater in number than a regular blue nevus, and hence it is called ‘cellular’
• The transformation from a benign blue nevus/mole to a cancerous lesion is known to take place rapidly. This means that a longstanding blue nevus can suddenly become a melanoma in a short duration of time. Hence, careful and periodic monitoring of blue nevus is often recommended
• A Malignant Melanoma arising from a Blue Nevus is a very uncommon condition that is mostly observed in adults. The probability of a cellular blue nevus transforming into a malignant melanoma is greater than melanoma arising from a common blue nevus
• Melanoma arising from Blue Nevus is a highly-aggressive skin/cutaneous lesion with great tendency for local and distant metastasis. The tumor spread mostly involves the liver and lungs (in about 60% of the cases)
• Once a definitive diagnosis has been established, the tumor may be surgically removed (excised). Depending on how far the disease has progressed, additional modes of therapy may be needed. The prognosis of Melanoma arising from Blue Nevus is generally guarded due to the aggressive nature of the tumor

Who gets Melanoma arising from Blue Nevus? (Age and Sex Distribution)

• Only around 200 cases of Malignant Melanoma arising from a Blue Nevus has been reported in the medical literature. It is an extremely rare occurrence
• A wide age range of children and adults are known to be affected. But, the peak period is between 20-60 years with an average age of 44 years
• Both males and females are affected; some studies indicate a slight preference for females
• Cutaneous melanomas occur more frequently seen in Caucasians, as compared to individuals of other races. Few cases of dark-skinned individuals with Melanoma arising from Blue Nevus have also been recorded

What are the Risk Factors for Melanoma arising from Blue Nevus? (Predisposing Factors)

The following factors increase the risk of Melanoma arising from Blue Nevus:

• Presence of a blue nevus or a cellular blue nevus: While most nevi never become cancerous (or malignant), a small number of atypical/dysplastic nevi (moles with abnormal shape/borders/color) may turn cancerous
• Presence of an excessive number of melanocyte cells in skin, a condition called dermal melanocytosis, for a long duration of time. In rare cases, some infants have developed melanoma within a few months; while some children or adults have developed melanoma after a period of 1 year to 56 years, following onset of the blue nevus
• Treatment using light, or phototherapy, is observed to be a risk factor for melanoma developing from a cellular blue nevus
• Severe exposure to ultraviolet (UV) rays is a major risk factor. UV rays are present in sunlight, and also in tanning lamps and beds
• Fair-skinned individuals are at a higher risk; more so, individuals 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
• 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), medications (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 one’s 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 Melanoma arising from Blue Nevus? (Etiology)

The cause of Malignant Melanoma arising from Blue Nevus is unknown. The exact reason behind why some moles turn cancerous, while others do not, is still not understood.

The potential causes for Melanoma arising from Blue Nevus may include:

• Uncontrolled activity of oncogenes (rogue genes that promote rapid 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. Studies have found that tumors arising in blue nevus show some resemblance to genetic and chromosomal abnormalities observed in conventional skin melanomas and congenital melanocytic nevi
• 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 for cancer are passed on from one generation to the next

What are the Signs and Symptoms of Melanoma arising from Blue Nevus?

The melanoma typically arises from the skin component of the blue nevus/mole. A melanoma arising from a cellular blue nevus is over 3-times more common than a melanoma developing from a common blue nevus.

The signs and symptoms of a Malignant Melanoma arising from a Blue Nevus may include:

• Presence of a blue nevus on the hands and feet usually; or cellular blue nevus on the lower back and buttocks in most cases
• On the reported melanoma cases, the presence of blue nevus was observed in the following manner:
  • 35% of the blue nevus were seen congenitally
  • 15% formed during infancy and childhood
  • 43% formed during adulthood
• The melanoma is usually seen as a rapidly developing tumor at the site of the blue nevus/mole; an associated change in skin pigmentation is visible
• In a majority, the presence of a dark skin lesion or nodule is noted at the site of the blue mole
• Size of the primary tumor can range from 5 mm to 8 cm; average size of 2 cm
• Ulceration of the tumor
• Tiny satellite skin lesions at or around the primary tumor mass may be seen (this normally forms due to local spread of the melanoma). This condition is known as satellitosis, or the abnormal crowding of malignant tumor cells. This phenomenon that is frequently associated with blue nevus

How is Melanoma arising from Blue Nevus Diagnosed?

A thorough history and a complete physical exam by a physician are crucial for the diagnosis of Melanoma arising from Blue Nevus. 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 may 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, then possibly sutured. This is done when the lesion would require a large, possibly unnecessary surgery to remove the lesion in its entirety at the first surgery
  • Shave biopsy: After local anesthesia, a sharp blade is used to remove a thin section of the skin, only part of the way into the dermis. In some lesions, this is the preferred method. For deeper lesions, particularly pigmented lesions, it runs the risk of providing too superficial a specimen for the pathologist
  • Sentinel lymph node biopsy: It is performed to determine if the melanoma has spread to the 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 or MRI scans 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
• A differential diagnosis to exclude the following should be undertaken:
  • Atypical cellular blue nevus
  • Giant cellular blue nevus (large-plaque type)
  • Malignant melanoma that resembles blue nevus
  • Epithelioid melanocytoma (animal-type melanoma)

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 Melanoma arising from Blue Nevus?

The complications due to Melanoma arising in a Blue Nevus/Cellular Blue Nevus may include:

• Severe emotional and psychological stress
• Metastasis is frequently observed - the lymph nodes are affected in about 31% of the cases, and distant sites/organs in about 42% of the cases. Rarely, metastasis is known to occur after a few decades too
• The more advanced cases of melanoma metastasize beyond the skin, to the lymph nodes and other organs. Organs that are commonly involved in metastasis include:
  • Lung and liver - they account for nearly 60% of the cases
  • Brain (in 16% of the cases)
  • Skin (in 13% of the cases)
  • Bone (in 9% of the cases)
  • Other locations include the salivary glands, gastrointestinal tract, kidney, spleen, pancreas, adrenal gland, thyroid, and heart
• In advanced cases, dark-colored urine (melanuria) and excessive ‘whole body’ skin pigmentation (generalized melanosis), may be noted
• Tumor recurrence following surgery to remove the melanoma
• Side effects that arise from various treatment therapies

How is Melanoma arising from Blue Nevus Treated?

The choice of treatment for Melanoma arising from Blue Nevus 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 are 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: It is generally the treatment of choice.

• 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 surgery:
  • It is used by some surgeons as an alternative technique to standard excision of melanoma
  • A thin layer of skin is removed and checked for cancer. This process is the carried out continuously, until a cancer-free slice of skin is obtained
  • This procedure is rarely used as a surgical treatment option for melanoma
• Lymph node dissection, in cases where the melanoma has spread to involve the nodes: Lymph nodes help in the 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 are 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, depression, 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 the drugs vemurafenib and dabrafenib. The latter is combined with trametinib for the targets MEK and BRAF
  • For MEK alone, trametinib is used
  • For the target molecule PD-1, nivolumab and pembrolizumab are used
  • For CTLA-4, ipilimumab is used
• Research is progressing rapidly on targeted therapies. Checking with the physician on the most recent advances is always beneficial

Side effects of these therapies 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 health issues. Some medications area also known to increase the risk for certain skin carcinomas.

Radiation therapy:

• This uses high energy beams to kill the 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 Melanoma arising from Blue Nevus be Prevented?

Currently, it may not be possible to prevent Melanoma arising from Blue Nevus. However, the risk for melanoma may be lowered by considering the following factors:

• Undertake early (surgical) treatment if a benign blue nevus with atypical pigmentation is noted on the skin
• Avoid direct exposure to UV rays and remain in the shade, 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 Melanoma arising from Blue Nevus? (Outcomes/Resolutions)

• The prognosis of Melanoma arising from Blue Nevus is generally worse than other forms of cutaneous melanoma, since it is a very aggressive tumor with a high tendency for local and distant metastasis
• From among the reported cases (over 160 in total number), spread of the melanoma resulting in death was observed in about 35% of the cases. The average survival period following diagnosis of the melanoma was around 3.5 years
• 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

Additional and Relevant Useful Information for Melanoma arising from Blue Nevus:

• 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)