Melanoma Cells that Pass through Lymph More Likely to Spread

September 30, 2020,
by NCI Staff

Melanoma cells can spread from the primary tumor through the bloodstream and lymphatic system to form new tumors.

Credit: © Terese Winslow

Melanoma, the most aggressive form of skin cancer, is often incurable once the cancer has spread from the original site of the tumor to distant organs and tissues.

Doctors have known for decades that melanoma and many other cancer types tend to spread first into nearby lymph nodes before entering the blood and traveling to distant parts of the body. But the implications of this detour through the lymph nodes have remained unclear.

Now, an NCI-funded study may provide some answers, raising the possibility of new treatment approaches that could help keep melanoma from spreading, or metastasizing, the study investigators said.

The study, published September 3 in Nature, shows that melanoma cells that pass through the lymphatic system before entering the bloodstream spread and form new tumors more readily than cells that directly enter the bloodstream.

In studies in mice, a team led by Sean Morrison, Ph.D., director of the Children’s Medical Center Research Institute at UT Southwestern, found that melanoma cells that travel through the lymphatic system are more resistant to a form of cell death called ferroptosis.

“This knowledge uncovers tremendous therapeutic potential, since enhancers and inhibitors of ferroptosis are being developed,” said Konstantin Salnikow, Ph.D., of NCI’s Division of Cancer Biology, who was not involved in the study.

However, further work is needed before such drugs could be tested in people with melanoma, Dr. Salnikow said.

Mouse Models Mimic Metastasis of Human Melanoma

Metastasis is a highly inefficient process in that “the vast majority of cancer cells that try to migrate [to distant sites] die before they ever have an opportunity to form a tumor,” Dr. Morrison said.

Dr. Morrison’s team found previously that one factor limiting the survival of melanoma cells circulating in the blood is that the cells experience a high level of oxidative stress. Oxidative stress—an imbalance between free radicals and antioxidants in the body—causes chemical reactions that can damage proteins, DNA, and lipids (fats) in cells and disrupt normal cell processes. However, precisely how oxidative stress kills circulating melanoma cells was not known.

For their studies, the team used a mouse model of metastasis created by transplanting melanoma cells from humans beneath the skin of specially bred mice with weakened immune systems. These mice were used to avoid having the transplanted human cells seen as foreign and attacked by the immune system. The team also used a second mouse model created by transplanting mouse melanoma cells into mice with normal immune systems.

Comparing these two mouse models let the researchers control for potential effects of the immune system on the spread of melanoma, Dr. Salnikow explained.

The study was supported in part by NCI’s Patient-Derived Models of Cancer program, which promotes the development of animal models that more closely mirror how tumor cells behave in humans.

Comparing Metastatic Melanoma Cells in Lymph Versus Blood

Most studies of cancer cell metastasis in people have focused on cells circulating in the blood. That’s because it’s much easier to collect patient blood samples than it is to collect samples of lymph, the clear fluid that carries immune cells through vessels of the lymphatic system, Dr. Morrison said.

Dr. Morrison’s team found that human melanoma cells injected into lymph nodes in the mice were more likely to form distant tumors than melanoma cells injected into blood.

To study the role of lymph in metastasis, lead investigator Jessalyn Ubellacker, Ph.D., a postdoctoral researcher in Dr. Morrison’s lab, figured out how to collect melanoma cells from lymph in mice. This allowed the team to do the first side-by-side comparison of melanoma cells spreading through lymph and through blood in the same animal, Dr. Morrison said.

Next the team found that melanoma cells in lymph experienced less oxidative stress than melanoma cells in blood. “That offered a potential explanation for why melanoma cells from lymph nodes were surviving better and better able to form a tumor,” Dr. Morrison said.

Further experiments showed that melanoma cells in blood are vulnerable to ferroptosis—a form of cell death that occurs when lipids damaged by oxidative stress build up in the outer membrane of a cell. By contrast, melanoma cells from lymph nodes were protected from ferroptosis.

As added support of lymph’s protective effects, the team found that when they collected melanoma cells from lymph nodes and from a primary tumor beneath the skin of one mouse and injected them into the blood of other mice, the lymph-dwelling cells were better able to survive and form metastatic tumors than those from the primary tumor.

A detailed analysis of melanoma cells collected from blood and lymph of the same mice showed that the cells in lymph had much higher levels of a fatty acid called oleic acid, Dr. Morrison said. The oleic acid was being incorporated into the outer membranes of melanoma cells in lymph, the team found.

Treating melanoma cells grown in the laboratory with oleic acid protected the cells from oxidative stress and from ferroptosis. And pretreatment with oleic acid increased the cells’ ability to form tumors after they were injected into the bloodstream of mice.

When lipids in the cell membrane are damaged by oxidative stress, “the membrane gets leaky and then the cells eventually die,” Dr. Salnikow explained. But if those damaged lipids are replaced by oleic acid, the cell is protected from oxidative damage and ferroptosis.

In other words, Dr. Morrison concluded, “The melanoma cells load up on oleic acid in the lymph, and then once they go into the blood, they’re bulletproof and can survive to grow at a distant site.”

Lymph Nodes as a Stopover on a Cancer Cell’s Journey

Movement of melanoma cells into lymph nodes “is not necessarily an endpoint, but rather a stopover on the cells’ journey elsewhere,” wrote Barbara Grüner, Ph. D., of University Hospital Essen in Germany, and Sarah-Maria Fendt, Ph.D., of the Leuven Center for Cancer Biology in Belgium, in an accompanying commentary.

“These results provide a first step towards understanding the protective environment of lymph,” Drs. Grüner and Fendt wrote. “To what extent [the] findings apply to tumor types other than melanoma, and to humans, remains to be determined. If the results are relevant to human disease, innovative ways must be found for them to have a therapeutic impact.”

Dr. Morrison’s team is already looking into existing drugs that might make cancer cells more vulnerable to ferroptosis and block the protective effects of lymph, he said. The idea would be to see if such a drug could be given early in the disease course of melanoma to prevent it from spreading.

“If we can find a therapy that blocks disease progression in mice, then we would go into clinical trials to see if it works in humans,” he added.

Dr. Salnikow said multiple approaches will likely be needed to prevent the spread of melanoma, because different biological factors may be important for metastasis in different people.

In fact, a previous study by Dr. Morrison’s team showed that melanoma cells from patients with tumors that spread more efficiently have higher levels of a transporter molecule called MCT1, which increases a cell’s ability to manage oxidative stress. They showed further that an experimental drug that blocks the activity of MCT1 reduced the number and size of metastatic tumors that formed in mice implanted with melanoma cells from these patients.

“One of the interesting questions to answer is whether MCT1 is also helping to protect these melanoma cells [that are] metastasizing through lymph, and we’re doing those experiments now,” Dr. Morrison said.

Metastatic Melanoma Stage 3 and 4 Symptoms, Survival Rate

This page was reviewed under our medical and editorial policy by

Maurie Markman, MD, President, Medicine & Science.

This page was updated on June 20, 2022.

Melanoma is cancer in specific pigmented cells in your body called melanocytes. These cells are found in your skin, mucous membranes and the eye. When a tumor develops from one of these cells, it’s called a melanoma.

This article will cover:

• What is metastatic melanoma?
• Causes and risk factors for metastatic melanomas
• Metastatic melanoma symptoms
• Diagnosis of metastatic melanoma
• Metastatic melanoma stages
• Treatment of metastatic melanoma
• Metastatic stage 3 and 4 melanoma survival rate

Metastatic melanoma is a disease that occurs when the cancerous cells from the original tumor (primary tumor) get loose, spread by traveling through the lymph or blood circulation, and start a new tumor (metastatic tumor) somewhere else. Once it spreads, or metastasizes, the disease is known as metastatic melanoma. This type of melanoma may typically occur during stage 3 or stage 4. Common melanoma metastasis sites include the lymph nodes, lungs, liver, bones and brain.

About 97,610 adults in the United States will be diagnosed with melanoma in 2023, according to the American Cancer Society. Approximately 4 percent of people are diagnosed with melanomas that have spread to distant parts of the body, according to the ASCO. This is the most advanced stage of metastatic melanoma.

The percentage of people diagnosed with melanoma that has spread to nearby lymph nodes is 8.5 percent, according to the National Cancer Institute (NCI). These cases have a slightly better prognosis.

From 2014 to 2018, the incidence rate of melanoma that had spread to distant parts of the body was 0.9 per 100,000 people, according to the NCI.

Melanoma tumors that have metastasized to other parts of the body are still considered melanoma. For example, melanoma found in the lungs is called metastatic melanoma of the lung or melanoma with lung metastases.

Like other skin cancers, melanoma is typically caused by exposure to ultraviolet (UV) rays, which can damage the DNA of cells in the skin, causing them to grow out of control and form cancerous tissue. The sun and tanning beds are the most common sources of damaging UV rays. Metastatic melanoma develops when melanoma cells spread to other areas of the body.

You cannot get metastatic melanoma without first having melanoma, though the primary melanoma may be so small it’s undetectable. Major risk factors for melanomas include:

• Light skin, light-colored hair (blond, red) or light-colored eyes (blue, green)
• Skin prone to burning easily
• Multiple blistering sunburns as a child
• Family history of melanoma
• Frequent exposure to sun or ultraviolet (UV) radiation (from tanning beds, for example)
• Certain genetic mutations
• Exposure to environmental factors, such as radiation or vinyl chloride

Other factors have been connected with increased metastasis. In a 2018 study in the Anais Brasileiros de Dermatologia and a 2019 study in the Journal of the National Cancer Institute, the following factors were associated with higher levels of metastasis:

• Male gender
• Primary tumor thickness of more than 4 mm
• Nodular melanoma, which is a specific subtype that a care team would identify (it typically appears as a raised, hard bump on the skin)
• Ulceration of the primary tumor (broken down skin over the melanoma)

Melanoma usually is found in early stages, before it’s become metastatic. If you notice any abnormal moles or discolorations on your skin, don’t hesitate to reach out to your doctor. This is especially important for those with many risk factors. Melanoma is more treatable at early stages, so early identification may prevent metastatic melanoma from developing.

Though a primary tumor is typically found, it’s possible that metastatic melanoma is detected elsewhere in the body and causes symptoms without any signs of a primary tumor.

Metastatic melanoma symptoms and signs may include:

• Fatigue
• Swollen or painful lymph nodes
• Weight loss
• Loss of appetite
• Trouble breathing or a cough that doesn’t go away
• Bone pain
• Headaches
• Seizures
• Swelling of the liver

Symptoms vary depending on where the metastasis spreads in the body.

If melanoma spreads to the lungs, specific symptoms may include:

• Coughing, with or without blood
• Chest pain
• Shortness of breath
• Fluid around the lungs

If melanoma spreads to the brain, specific symptoms may include:

• Headache
• Paralysis in the arms or legs
• Sleepiness
• Problems with remembering things
• Changes in emotions or behavior
• Difficulties hearing, seeing or swallowing
• Seizures
• Nausea or vomiting

If melanoma spreads to the bones, specific symptoms may include:

• Bone aches and pains
• Back pain or numbness
• Easily fractured bones
• Changes in calcium levels, from bones being broken down, which may cause sleepiness, confusion or changes in bowel habits

If melanoma spreads to the liver, specific symptoms may include:

• Loss of appetite
• Fatigue or lethargy
• Jaundice (yellowing of the skin or whites of eyes)
• Swelling in the abdomen or legs
• Itchiness

Your care team may use several tests to diagnose metastatic melanoma.

If there’s evidence of a primary tumor, a biopsy may be taken. For this, a small section of suspected cancerous skin is removed with a razor, scalpel or small punch tool. The removed tissue is examined under a microscope to determine whether it’s melanoma.

Additional tests are needed to determine whether the cancer is metastatic melanoma, or if there’s no visible primary tumor. To test for metastatic melanoma, or melanoma that has spread to lymph nodes or distant parts of the body, your care team may perform the following tests.

• Lymph node mapping and sentinel lymph node biopsy (SLNB): Your doctor may perform a physical exam of your lymph nodes and check for swelling or physical masses. If no tumors are found (because they may just be too small to see or feel), an SLNB may be done. For an SLNB, a radioactive dye is injected to locate the primary tumor. Then, the doctor will remove the lymph nodes that the dye traveled to and check them for melanoma.
• Computed tomography (CT) scan, positron emission tomography (PET) scan, magnetic resonance imaging (MRI) scan or ultrasound exam: Each of these scans is a noninvasive way to look inside your body and check for tumors.
• Blood chemistry studies: Cancer may cause elevated or abnormal levels of certain substances in your blood. A laboratory test can identify if your blood chemistry shows signs of a cancerous tumor.

Your melanoma is given a stage depending on how much the cancer has progressed upon diagnosis. Melanoma staging uses the TNM system, which classifies a melanoma’s stage based on three main factors.

• T is for tumor, and takes into consideration a tumor’s thickness and whether the skin is decaying around the tumor.
• N is for nodes, and considers whether the cancer has spread to nearby lymph nodes.
• M is for metastasis, or whether the cancer has spread or not.
• Stages are labeled from 0 to 4.

Stages 0, 1 and 2 are melanoma. Stage 3 (some cases) and stage 4 melanomas are considered metastatic melanomas.

Metastatic stage 3 melanoma

Stage 3 is broken down into several subcategories.

• Stage 3A
  • These tumors are no more than 2 mm thick, and small tumors have spread to one to three nearby lymph nodes. The primary tumor may be ulcerated.
• Stage 3B includes two presentations:
  • There’s no sign of a primary tumor, but cancer has spread to one nearby lymph node, or to small areas of nearby skin and close lymph channels.
  • The cancer is no more than 4 mm thick and has spread to one to three lymph nodes or small areas of nearby skin. The primary tumor may be ulcerated.
• Stage 3C includes four possible presentations:
  • There’s no sign of a primary tumor. Cancer has spread to two or more nearby lymph nodes (with at least one being so big it can be seen without a microscope), or it’s spread to small areas of skin and reached nearby lymph nodes, or it’s spread to nearby clumped lymph nodes.
  • The primary tumor is no more than 4 mm thick. It’s either spread to more than four lymph nodes or to clumped lymph nodes, or it’s spread to small nearby areas of skin and into nearby lymph nodes.
  • The primary tumor is 2 to 4 mm and ulcerated, or more than 4 mm and not ulcerated. It’s spread to one or more nearby lymph nodes or has spread to small areas of nearby skin and lymph channels.
  • The primary tumor is more than 4 mm thick and is ulcerated. It’s spread to one to three nearby lymph nodes, or has spread to small areas of nearby skin and lymph channels.
• Stage 3D
  • The tumor is thicker than 4 mm and is ulcerated. It’s either spread to small areas of the skin and at least two nearby lymph nodes, to lymph nodes that are clustered together, or to four or more nearby lymph nodes.

Metastatic stage 4 melanoma

Once a melanoma has spread to distant parts of the body, such as the lungs, liver or other areas of skin, it’s considered stage 4. This cancer can be any thickness and may or may not have spread to nearby lymph nodes.

Stage 4 can be further staged based on where the cancer has spread:

• M1a: Cancer has metastasized to skin that’s far from the original site and/or to areas with soft tissue.
• M1b: Cancer has extended to the lungs.
• M1c: Cancer has spread to a location other than your central nervous system (CNS).
• M1d: There is cancer spread to your CNS. This includes your brain, spinal cord and/or cerebrospinal fluid.

Metastatic melanomas can be difficult to treat. The five-year survival rate for people diagnosed with melanoma that has spread to nearby lymph nodes is 66 percent, according to the American Cancer Society. When cancer has spread to distant parts of the body, there may also be other metastases too small to detect by scans. For people diagnosed with stage 4 melanoma, or melanoma that has spread to distant parts of the body, the five-year survival rate is 27 percent.

For stage 3 and 4 melanomas, the following treatments may be used:

• Surgery removes the tumor with scalpels or other instruments. Local numbing is typically used to allow for complete removal of the primary tumor. Usually, surgery also removes all lymph nodes near the site of the primary tumor, though this may carry some risks. You and your care team can decide whether lymph node dissection is right for you. Surgery may also be used to remove metastatic tumors (for example, in the brain or lungs), which may extend life span and help control symptoms of cancer. If surgery isn’t possible, other options may be used to shrink the size of metastatic melanomas.
• Targeted therapies are drugs that kill cells with specific mutations. Some melanomas have particular mutations that make them good candidates for these drugs, and these targeted therapies can destroy the tumor and its metastases selectively.
• Immunotherapy medications train your immune system to recognize and attack cancer cells. They may be more successful in shrinking metastatic melanomas.
• Radiation therapy uses high-energy beams to kill cancer cells. Radiation may be used after surgery to prevent recurrence of cancer. It also may help manage symptoms of metastases, such as bone aches and pains.
  Chemotherapy is a cancer treatment that uses various drugs to kill the tumor.
• Chemotherapy isn’t as likely to be used as treatment due to the increasing success rates of targeted therapy and immunotherapy drugs.
• Clinical trials are studies researching new therapies. New drugs are always being developed and tested, and some may be able to treat your cancer.

Multiple therapies can be used at any given time, and your care plan is a dynamic process. You and your care team should discuss all the options and decide on a treatment plan. Each treatment has different side effects, and it’s important to feel fully informed of all the associated risks. Other medications and options may help manage the symptoms of your cancer treatment, so you can live the highest quality of life possible throughout the course of your treatment and disease.

When doctors talk about cancer survival, they typically speak of the five-year survival rate—or how many cancer patients are estimated to be alive five years after being diagnosed or starting treatment. These are estimates based on groups of previous patients and older treatments. Statistics may give you and your care team information, but keep in mind that everyone’s response to treatment is different.

According to the American Cancer Society, the five-year survival rate for people diagnosed with stage 3 melanoma that has spread to nearby lymph nodes or structures (regional spread) is 66 percent. For patients diagnosed with stage 4 melanoma (distant spread), the five-year survival rate is 27 percent.

Another measure that helps estimate the outcome of cancer is the prognosis, meaning your chances of recovery or recurrence. People with stage 3 melanoma have an intermediate to high risk for recurrence. Stage 4 melanoma has a high likelihood of recurring and is considered difficult to treat.

Treatments for melanoma are improving every day, and the most current treatments are more targeted, which also means fewer side effects. As a result, a patient’s prognosis and survival rates for advanced-stage melanomas are expected to improve as well.

early to late

What is melanoma staging?

Determining the stage of a tumor is called melanoma staging. The conclusion is based on the size, thickness, rate of mitosis, how often and severely the neoplasm ulcerates, whether it has affected the lymph nodes or other organs.

The stage of melanoma is determined by the results of a comprehensive examination:

• medical examination by a dermatologist-oncologist;
• with a dermatoscope;
• histology;
• blood biochemistry;
• diagnostic methods (CT – computed tomography, MRI – magnetic resonance imaging, ultrasound – ultrasound, radiography).

Cancer staging is very important because it gives doctors the opportunity to choose the most effective treatment for different degrees of melanoma.

Melanoma staging methods

In fact, there are two main methods for determining the stage of melanoma development: clinical, which is based on an examination by a specialist and the results of a biopsy (morphological examination of a cell sample), and histological (a microscopic method for examining tissues, organs and body systems, including biopsy and surgical material). Histology, which is done after a biopsy, is often higher than the clinical stage. For example, a biopsy showed stage III, the results of histology may be more serious – stage 4 skin cancer.

Melanoma stage	Characterization of the spread of melanoma
Stage 0	Tis, N0, M0: Melanoma in situ, meaning that it is in the epidermis but has not spread to the dermis (underlying layer).
Stage IA	T1a, N0, M0: Melanoma thinner than 1 mm. It is not ulcerated and the rate of mitosis is less than 1/mm 2 . It was not found in the lymph nodes or distal organs.
Stage IB	T1b or T2a, N0, M0: Melanoma is thinner than 1 mm and ulcerated, or its mitosis rate is less than 1/mm 2 , or its thickness is between 1.01 and 2.0 mm and it is not ulcerated. It was not found in the lymph nodes or distal organs.
Stage IIA	T2b or T3a, N0, M0: Melanoma is between 1.01 and 2.0 mm thick and is ulcerated, or melanoma is between 2.01 and 4.0 mm thick and is not ulcerated. It was not found in the lymph nodes or distal organs.
Stage IIB	T3b or T4a, N0, M0: The melanoma is between 2.01 and 4.0 mm thick and ulcerated, or the melanoma is greater than 4.0 mm thick and not ulcerated. It was not found in the lymph nodes or distal organs.
Stage IIC	T4b, N0, M0: Melanoma thicker than 4 mm with ulceration. It was not found in the lymph nodes or distal organs.
Stage IIIA	T1a to T4a, N1a or N2a, M0: Melanoma may be of any thickness but not ulcerated. The melanoma is spread to 1-3 lymph nodes near the affected area of ​​the skin, but the nodes are not enlarged and the melanoma is found only when viewed under a microscope. There is no distant distribution.
Stage IIIB	One of the following applies: T1b to T4b, N1a or N2a, M0: Melanoma can be of any thickness and is ulcerated. The melanoma is spread to 1-3 lymph nodes near the affected area of ​​the skin, but the nodes are not enlarged and the melanoma is found only when viewed under a microscope. There is no distant distribution. T1a to T4a, N1b or N2b, M0: Melanoma may be of any thickness but not ulcerated. Spread to 1-3 lymph nodes near the affected area of ​​skin. The nodes are enlarged due to melanoma. There is no distant distribution. T1a to T4a, N2c, M0: Melanoma may be of any thickness but not ulcerated. Spread to small patches of nearby skin or lymphatic channels around the original tumor, but the nodes do not contain melanoma. There is no distant distribution.
Stage IIIC	One of the following applies: T1b to T4b, N1b or N2b, M0: Melanoma can be of any thickness and is ulcerated. Spread to 1-3 lymph nodes near the affected area of ​​skin. The nodes are enlarged due to melanoma. There is no distant distribution. T1b to T4b, N2c, M0: Melanoma can be of any thickness and is ulcerated. Spread to small patches of nearby skin or lymphatic channels around the original tumor, but the nodes do not contain melanoma. There is no distant distribution. Any T, N3, M0: Melanoma can be of any thickness and may or may not be ulcerated. Melanoma has spread to 4 or more nearby lymph nodes that are crowded together, or it has spread to nearby skin or lymph channels around the original tumor and nearby lymph nodes. The nodes are enlarged due to melanoma. There is no distant distribution.
Stage IV	Any T, any N, M1(a, b, or c): Stage 4 melanoma has spread beyond the original skin area and nearby lymph nodes to other organs such as the lungs, liver, or brain, or to distant skin, subcutaneous tissues, or distant lymph nodes. Neither spread to nearby lymph nodes nor thickness is considered at this stage, but melanoma is usually thick and also spread to lymph nodes.

Melanoma classification

In modern oncology, several classifications are used to determine the stage of skin cancer – melanoma (according to Clark, according to A. Breslow, mitotic index). The most commonly referred to is the TNM system, which was developed by the AJCC (American Society for the Study of Cancer). The name TNM contains key factors for determining the degree of skin cancer: Tumor – a tumor, Lymph Node – a lymph node, Metastasis – metastases.

Category T

denotes the thickness of the tumor (measured according to the Breslow system). In addition, the rate of mitosis is taken into account (it makes it possible to predict how quickly the cancer will spread to other tissues and organs), whether or not there are ulcerations (damages, tears in the upper layer of the skin over the tumor). In the description of the medical history, one can find, for example, such values ​​of the T category: T1a (typical for skin cancer in the first stage) or T4b (such an index is more common in the last stage of skin cancer).

Category N

indicates if there is a tumor in the lymph nodes that the cancer first affects. This marking is used based on the results of the biopsy. The early stage of melanoma is characterized by the designation N0 (the tumor did not metastasize to regional lymph nodes), for the later stages – N3 (there are 2-3 metastases in the nearby lymph nodes), N2b (the pathological enlargement of the lymph nodes is visible without a microscope).

Category M

indicates whether the melanoma has spread to other organs and which ones, as well as how much the level of the LDH enzyme (lactate dehydrogenase, takes part in glycolysis) has changed. In the early stages of skin cancer, the tumor usually does not metastasize.

Melanoma stages

Melanoma stages	Stage characteristic
0	Melanoma so far only in the epidermis (in situ). Non-invasive, does not spread into deep layers and other parts of the body.
I (available A and B)	At an early stage, the thickness of the malignant neoplasm is up to 1 mm. She does not bleed, there are no ulcers and peeling. Low rate of cell division. Surgical removal of the cancer is usually all that is required in the first stage of melanoma. Metastasis in lymph nodes and distant organs is not observed.
II (can be A, B, C)	The tumor grows deep, its thickness increases to 2. 0 mm (4.0 mm), the surface of the malignant formation is hypertrophied, flaky, covered with ulcers, sometimes bleeding. At this stage, cancer cells have not yet invaded the lymph nodes and distant organs.
III (can be A, B, C)	Cancer cells reach the lymph nodes. They increase or stay the same. The tumor becomes thicker, grows deep into the tissue. Ulcerations may or may not be present. To combat the disease, surgical methods, radiation and chemotherapy are used.
IV	The last stage of melanoma, when the tumor has metastasized to the internal organs (lungs, liver or brain), certain areas of the skin or distant lymph nodes. Therapy at this stage is complex and lengthy, it is possible to cope with the tumor surgically (skin lesions are also removed, if possible, metastases from internal organs).

Methods of treatment

Treatment for melanoma depends on the stage of the tumor. The early stages of skin cancer respond well to therapy, since only the skin is affected, and the tumor has not grown into the deep layers, has not touched the lymph nodes and other organs. In the second and third stages, surgical excision plus immune therapy is also performed. Melanoma at 4 stages extends to the internal organs and the skeletal system, the treatment of the disease is complex (surgical intervention, taking anticancer drugs, radiation therapy).

There is a generally accepted protocol for the treatment of melanoma of the skin, which is followed in different countries:

In situ stage: wide excision of the tumor, treatment with immunomodulators.

Stage I: surgical removal of the tumor and healthy skin around it. Biopsy of the sentinel (sentinel) lymph node, if necessary – removal. Medical therapy.

Stage II: Surgical removal of the melanoma and healthy skin around it. Biopsy of the sentinel (sentinel) lymph node, if necessary – removal. Drug therapy to prevent recurrence of the disease.

Stage III: surgical removal of melanoma and a healthy skin area around it, as well as a sentinel lymph node, if necessary, regional and other areas where malignant cells are found. Immuno-, chemo- and targeted (molecular targeted) therapy.

Stage IV: immune and targeted therapy, radiation method, signal transduction inhibitors, palliative care.

After removal of the tumor, the patient is regularly examined for three years, when the risk of melanoma recurrence is high.

Survival predictions

According to WHO, more than 132 thousand cases of melanoma are diagnosed annually in the world. Women get sick more often than men. Melanoma can be inherited – about 10% of cases. However, thanks to early diagnosis and new developments in the field of medicine, overall survival (up to 5 years) of patients has increased in the last 10 years. Melanoma at an early stage is characterized by a positive prognosis in treatment and stable remission in more than 90% of patients. Statistical data on five-year survival rate: I degree (up to 92%), II degree (53–81%), III degree (40–78%), IV degree (15–20%).

Sometimes the prognosis for grade IV melanoma is even better than, for example, grade II or III, since cancer cells metastasize to distant skin areas and lymph nodes, “bypassing” important organs and systems. In addition, the prognosis must take into account the level of LDH – if it is normal, then the chances that the disease will recede increase even more.

The prognosis of survival is influenced by the age of patients. So, in older people, the chances are slightly less than in young people, and regardless of the stage of melanoma. White-skinned people are more likely to suffer from skin cancer, but if a dark-skinned person is diagnosed with the disease, his chances of survival are lower. Those who have undergone organ transplants, have HIV, serious chronic diseases, also have a worse prognosis for recovery.

Signs of melanoma

Melanoma is a dangerous form of cancer that develops imperceptibly, but rapidly, quickly metastasizes to the lymph nodes, then moving to the internal organs and tissues. That is why timely diagnosis is so important, which increases the patient’s chances of recovery. Skin cancer at the initial stage has characteristic symptoms. The ABCD rule is the main marker for melanoma:

• A (Asymmetry) – asymmetry: the edges of the mole or nevus are not symmetrical;
• B (Border) – borders: the edges of the neoplasm are uneven, indistinct, jagged;
• C (Color) – color: the color of the mole is uneven, there are shades of brown, gray, sometimes there are blotches of pink, red or white spots;
• D (Diameter) – diameter: the diameter of the formation is more than 6 mm and gradually increases in size.

The initial stage of melanoma of the skin can be manifested by such symptoms: itching, burning, soreness, bleeding, the appearance of scales and ulcers on the surface of the neoplasm. The most important sign is that the spot stands out strongly from other moles. For any warning signs, you should contact an oncologist.

Materials used in the preparation of the article

You can learn about melanoma, early diagnosis of the disease, as well as the classification of stages from the following sources:

http://www.cancerresearchuk.org/about-cancer/melanoma/stages-types

https://www.cancer.net/cancer-types/melanoma/stages

https://www.medicinenet.com/melanoma/article.html

https://www.medicalnewstoday.com/articles/154322.php

https://www.cancer.org/cancer/melanoma-skin-cancer/detection-diagnosis-staging/melanoma-skin-cancer-stages.html

Melanoma: treatment, symptoms, diagnosis, removal

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Melanoma

Melanoma is a malignant tumor that develops from pigment-forming cells (melanocytes), characterized by intense color and capable of producing melanin pigment. Melanoma is more common on exposed areas of the body that are exposed to sunlight. At the same time, in women it is more often located on the skin of the lower extremities, in men – on the trunk. Sometimes melanoma can form in other parts of the body: the retina, mucous membranes, anus and vagina. Also on the skin of the lower extremities, torso and face, melanoma shows symptoms. Tumor treatment depends on the stage of the disease. It should be noted that not every type of nevus is equally prone to malignancy. Melanoma can also occur on a clean area of ​​skin. Early diagnosis of melanoma is essential and significantly increases the patient’s chances of recovery.

Melanoma can occur in people of any age, including teenagers. This is a dangerous disease that requires immediate treatment. In most cases, a malignant formation is localized on the skin, it is not difficult to identify it in the initial stage, when a cure is possible.

Diagnosis

The first stage of diagnosis is an examination by an oncologist or dermatologist. When making a diagnosis, methods such as dermatoscopy, biopsy and histological examination are used. To study the prevalence of the process, studies of the “sentinel” lymph node are carried out, as well as additional studies (computed tomography, ultrasound, etc.).

These techniques are widely used by LISOD specialists, which makes it possible to accurately diagnose the extent of the disease with the subsequent amount of therapy.

Treatment

Melanoma treatment depends on the stage of the disease. In the presence of a primary focus without metastases, surgical treatment with a wide excision of the primary focus is used. Sometimes, after such an excision, rather large defects are formed, requiring closure with complex skin flaps from other parts of the body. This is especially true of functionally active zones – limbs and face. In LISOD, this step is performed by an experienced plastic surgeon.

In the presence of melanoma metastases in regional lymph nodes, excision of regional lymph nodes is additionally performed, treatment with antitumor agents is combined with immunotherapy. To determine if the lymph nodes are affected, if there are no clear indications, it is possible to perform a procedure to identify the “sentinel” lymph node. This lymph node is the first to receive lymph from the tumor area and is the first in which metastases develop. If no metastases are found in the “sentinel” node, then the probability of their spread to other lymph nodes does not exceed 2-3%. Thus, by examining the state of the “sentinel” lymph node, we can judge the state of all other lymph nodes with a very high degree of certainty and save many patients from traumatic operations and possible complications associated with them.

If surgical treatment is not possible, modern chemotherapy methods, which are widely used in LISOD, are an alternative. The chemotherapy regimen for patients is selected purely individually, taking into account all the criteria. The number of chemotherapy courses depends on the course of the disease and the patient’s tolerance to therapy. After a minimum number of cycles, the patient undergoes a follow-up examination, such as computed tomography or PET-CT, based on the results of which the effectiveness of therapy is evaluated.

Radiation therapy is also used in the treatment of melanomas. The use of linear accelerators with the involvement of computed tomography and complex computer programs makes it possible to obtain a three-dimensional image of the tumor and healthy organs. In this case, the necessary dose of radiation is supplied to the tumor, while the radiation practically does not extend to the surrounding organs and tissues. This can significantly reduce the incidence of side effects and complications of radiation therapy.

Symptoms

Clinically, the transition from a benign pigmented spot to a malignant melanoma is characterized by the following symptoms:

• spot growth and hardening;
• increased pigmentation or, conversely, weakening it;
• the appearance of redness and congestion around the base of the spot;
• the development of pigmented or non-pigmented radiant growths extending from the pigment spot in different directions.

Sometimes the first symptom of growing melanoma is enlargement of regional lymph nodes , while a long-standing pigmented spot or papilloma does not show signs of visible increase or sometimes even slightly decreases in size and intensity of pigmentation. An increase in the pigment spot (papilloma) and its compaction are the first and most constant signs of a malignant transformation of birthmarks.

Often, next to the increasing pigment spot, other small nodules appear, more often pigmented, less often not pigmented.

Another initial sign, sometimes coinciding with the first or appearing independently of them, is an increase or decrease in pigmentation . Particular importance is attached to pigmented or non-pigmented radial growths that diverge from the primary tumor in different directions and carry with them the spread of the process into the surrounding normal skin and neighboring tissues.

Finally, a fairly significant group of tumors appear for no apparent reason – first in the form of a benign induration, papilloma, pigmented formation, sometimes remaining without visible growth for a long time.

Risk factors

The most significant factors affecting the occurrence of melanoma are:

• increased solar radiation;
• sunburn.

Most skin cancers, including melanoma, are caused by excessive ultraviolet radiation. Under the influence of UV radiation, the likelihood of genetic disorders in cells increases, which can lead to the formation of a tumor. Only timely treatment of skin melanoma can help the patient.

Risk groups

• The risk of melanoma is significantly increased if a similar diagnosis has already been made or any other skin cancer has been identified.
• Family history. If the next of kin (especially 2 or more) have already encountered this disease, then the risk of melanoma increases significantly.
• Old age. Melanoma is much more common in older people.
• Traumatization. Nevus injury (both single and multiple).

Prevention

The main prevention is to avoid excessive UV exposure.

Questions and Answers

Questions from patients and answers from our specialists are published in this section. Each person’s question concerns a specific problem related to their disease. Israeli clinical oncologists and the head doctor of LISOD, MD, Professor Alla Vinnitskaya answer the patients.

The answers of specialists are based on knowledge of the principles of evidence-based medicine and professional experience. The answers correspond solely to the information provided, are for informational purposes only and do not constitute medical advice.

The main purpose of section is to provide information to the patient and family so that they can decide with their doctor about the type of treatment. The tactics of treatment offered to you may differ from the principles set forth in the answers of our specialists. Feel free to ask your doctor about the reasons for the differences. You must be sure that you are receiving the correct treatment.

Good afternoon, my mother had melanoma, we had two surgeries, please. Protongasio sorgi. Mi$ melanoma in the inguinal lymph nodes on the right.
22.03. Іb.operation: removal of the tumor of the perianal vein. Histological report No. 13823-32 (01.04.16.) – pigmented melanoma with superior horizontal growth, after Clark III, with superior, mild lymphatic infiltrate along the periphery of the urethra. CT scan (of the head, OGK, o.p. and pelvis on 25.04.16.) – a sign of secondary injury on the vein of obstruction was not detected, a cyst of the right tibia (protocol of obstruction on the hands). Global blood test: Er-4.0 -1012/l, Hb-122 g/l, KP-0.9, L-83’109/l (e-1%, n-5%, s-71%, l-17%, m-6%), SHOE- 11 mm/year. Biochemical blood analysis: zag.bіlіrubіn-11.9µmol/l, zag.bіlok- 79.5 g/l, glucose-6.0 mmol/l, creatinine-48 µhol/l, AST-21od/l (PM<37od/l), ALT-20od/l ( 14.<41 od'l), amylase-98 od/l (PM< 100 od'l). Coagulogram: prothrombin hour-13.4", prothrombin index-97%, zag.fibrinogen -3.7 g/l, fibrinogen "B"-1+, ethanol test-weakly positive, ITCHK-0.79. Blood gr. B(ІІІ)III+ ECG-no pathology Ultrasound: in the right inguinal dilatation there are clusters of hypoechoic heterogeneous oval-shaped well-contoured inclusions сі~1. 0; 2.5; 2.65; 4.5 cm – enlargement of lymph nodes. 14 .07.16 Duquesne operation on the right. i pіd ambulatory care proctologist.

Hello. The patient needs a more detailed examination to clarify the extent of the spread of the disease. A visit to a clinical oncologist is required.

Good afternoon I am 33 years old, 1.5 years after the birth of my second child, I noticed that a mole on my lower leg had grown (from the usual it turned into something incomprehensible, more like a “goose”). I went to the doctor, recommended removal, the analysis showed melanoma. Immunohistochemical study with antibodies to: Myogenin (F5D), CD177, S-100 protein, HMB45, Ki 67 (MIB-1). Tyrosinase (T311), Desmin (D33). A skin tumor of a characteristic alveolar structure from atypical melancytes with a characteristic expression of S-protein, HMB45, vertical spread to the upper layers of the epidermis and the reticular layer of the dermis, reaching the sweat glands, the presence of atypical mitoses in the nuclei and nuclear expression of Ki 67 in about 10% of tumor cells. There is a minimal intra- and extracellular pigment content and a meager perifocal reactive lymphoid infiltrate. Total: melanoma, nodular form, 4th level of invasion, thickness 2.2 mm. An operation was performed to excise the skin around the mole, and no tumor growth was detected in the results. Treatment was prescribed for a year with laferobion or immunofan. Tell me, is that enough?

For melanoma, with the characteristics you specified ((T3) and no distant metastases), it is recommended to perform a wide excision of the tumor (2 cm of the incision margin) and study of the “sentinel” lymph node (usually inguinal, in your case). If there are no metastases in this node, then surgical treatment is limited to this, if there is, the entire group of inguinal lymph nodes is removed. Given the high risk of recurrence, metastasis and young age, it is customary to recommend prophylactic interferon therapy.

Hello! I am 35 years old. In April 2012, I was diagnosed with melanoma of the skin of the right thigh according to histology, the mole was removed according to the principle of an extensive biopsy without any preliminary examination. Further it turned out that there are mts in the inguinal lymph nodes. The Duken operation was performed on July 3, after which a course of interferons was prescribed at 40 million IV according to the 5-2 scheme for 2 months. As soon as the dose was reduced to 6, a repeated CT scan revealed lymph nodes in the right groin and iliac region. On November 30, an intrapelvic ileo-obturator right-sided lymph node dissection was performed, right-sided inguinal lymph node node dissection T3N1MO stage 3 gr 2. After the operation, chemotherapy was prescribed, but only from January 21, 2013 (while everything was healing). A repeat CT scan from January 2013 revealed new nodes along the right iliac vessels and inguinal nodes on the left.