Lentigo maligna melanoma

by Jason Wasserman MD PhD FRCPC
December 9, 2024

Lentigo maligna melanoma is a type of skin cancer that develops in areas of skin with significant sun damage, such as the face, neck, or arms. It begins as a non-invasive form of skin cancer called lentigo maligna, which is confined to the top layer of skin (the epidermis). Over time, lentigo maligna may progress to lentigo maligna melanoma when the cancer cells invade deeper layers of the skin. This type of melanoma is associated with chronic sun exposure and often occurs in older individuals with lighter skin tones.

Normal skin histology

What are the symptoms of lentigo maligna melanoma?

Lentigo maligna melanoma often starts as a flat or slightly raised patch or plaque on sun-damaged skin. Key features include:

  • Asymmetry: One side of the lesion looks different from the other.
  • Border irregularity: The edges are uneven or poorly defined.
  • Colour variation: The lesion may have multiple colours, including shades of brown, black, grey, red, or flesh tones.
  • Diameter: It grows larger over time, often exceeding 6 millimetres.
  • Evolution: Changes in size, shape, or colour are common.

Sometimes, lentigo maligna melanoma lacks pigmentation, appearing pink or red (amelanotic), making it resemble an inflammatory skin condition. Advanced lesions may show thickened areas, nodules, or ulceration, which can bleed. These changes signal deeper invasion into the skin.

What causes lentigo maligna melanoma?

Lentigo maligna melanoma is caused by long-term and excessive sun exposure that damages the DNA in melanocytes, the pigment-producing cells in the skin. This DNA damage leads to a high number of mutations in the affected cells. People with light skin who are more prone to sunburn and less able to tan are at greater risk. Lentigo maligna may sometimes appear next to solar lentigines (sunspots), but it is unclear whether these spots are precursors to melanoma or happen to be near the lesion.

How is this diagnosis made?

The diagnosis of lentigo maligna melanoma is made after a biopsy, where a sample of the suspicious lesion is removed and examined under a microscope. Pathologists look for abnormal melanocytes invading deeper layers of the skin, confirming the transition from lentigo maligna to melanoma. A dermatoscope, a tool that magnifies the skin, may also be used to identify subtle features of the lesion before the biopsy.

Microscopic features

Under the microscope, lentigo maligna melanoma shows the following features:

  • Epidermal changes: The tumour often has a poorly defined border and a thinning of the epidermis, with abnormal melanocytes (cells that produce pigment) spread along the bottom layer of the epidermis. These cells show moderate to severe irregularities in shape and size.
  • Patterns of growth: The in situ component (lentigo maligna) spreads widely along the epidermis, often involving hair follicles and sweat gland openings. The invasive component (lentigo maligna melanoma) grows downward into the dermis and may consist of atypical, spindle-shaped, or desmoplastic melanocytes.
  • Sun damage: Severe solar elastosis (damage to connective tissue caused by chronic sun exposure) is always present in the underlying dermis.
  • Variants: Some cases resemble other skin lesions, such as dysplastic nevi, and may require additional testing for confirmation.

Immunohistochemistry

Immunohistochemistry is a special test that uses antibodies to detect specific proteins in tumour cells. In lentigo maligna melanoma, this test can help identify subtle areas of invasion and confirm the presence of melanoma. Markers like S100, MelanA, and SOX10 highlight melanocytes and can show the extent of abnormal cell proliferation. However, pathologists interpret the results carefully, as some dermal cells may stain positive without being cancerous.

Another marker, PRAME, is sometimes used to evaluate surgical margins in lentigo maligna or lentigo maligna melanoma to ensure the entire lesion has been removed.

Tumour thickness

Lentigo maligna melanoma starts in the epidermis, a thin layer of tissue on the skin’s surface. As the tumour grows, the cells spread into the layers of tissue below the epidermis, including the dermis and subcutaneous adipose tissue. The spread of tumour cells in this way is called invasion. Tumour thickness (also known as Breslow’s thickness) is the distance from the epidermis to the deepest point of invasion. The tumour thickness is important because it determines the pathologic tumour stage (pT) and because thicker tumours are more likely to spread to other body parts, such as lymph nodes and the lungs.

Tumour thickness

Ulceration

Ulceration is a type of tissue damage that results in the loss of cells on the surface of a tissue. For skin tumours such as lentigo maligna melanoma, ulceration refers to the loss of cells in the epidermis over the tumour. Tumours that cause ulceration are associated with a worse prognosis. Ulceration is also used to determine the pathologic tumour stage (pT).

Mitotic rate

A mitotic figure (or mitosis) is a cell that is dividing to create two new cells. For tumours such as lentigo maligna melanoma, pathologists count the number of mitotic figures in a specified area of tissue (for example, 1 mm2), and the count is called the mitotic rate. The mitotic rate is important because tumours with a higher rate grow more quickly and are more likely to spread to other parts of the body.

Microsatellites

For lentigo maligna melanoma, a microsatellite is a group of tumour cells that have spread from the primary tumour (where the tumour started) to a nearby skin area. Another name for a microsatellite is cutaneous metastasis. Microsatellites are important because they increase the pathologic nodal stage (pT).

Tumour-infiltrating lymphocytes (TILs)

The term tumour-infiltrating lymphocytes (TILs) describes specialized immune cells called lymphocytes surrounding or spreading into the tumour. Current evidence shows that TILs can kill and remove tumour cells. For this reason, the more TILs seen, the better.

Most pathologists will categorize the number of tumour-infiltrating lymphocytes as follows:

  • No tumour-infiltrating lymphocytes were identified.
  • Non-brisk (very few tumour infiltrating lymphocytes).
  • Brisk (lots of tumour infiltrating lymphocytes).

Lymphovascular invasion

Lymphovascular invasion means cancer cells are seen inside a blood vessel or lymphatic vessel. Blood vessels are long, thin tubes that carry blood around the body. Lymphatic vessels are similar to small blood vessels except that they carry a fluid called lymph instead of blood. The lymphatic vessels connect with small immune organs called lymph nodes throughout the body. Lymphovascular invasion is important because cancer cells can use blood vessels or lymphatic vessels to spread to other body parts, such as lymph nodes or the lungs.

Lymphovascular invasion

Neurotropism

Neurotropism (also known as perineural invasion) is a term pathologists use to describe cancer cells attached to or inside a nerve. Nerves are like long wires made up of groups of cells called neurons. They are found all over the body and are responsible for sending information (such as temperature, pressure, and pain) between the body and brain. Neurotropism is important because cancer cells can use the nerve to spread into surrounding organs and tissues. This increases the risk that the tumour will regrow after surgery.

Tumour regression

Tumour regression is the gradual disappearance of tumour cells from an area where tumour cells were previously found. The tumour cells are often replaced by immune cells or scar tissue called fibrosis. Tumour regression is believed to be caused by immune cells that attack and kill the tumour cells. Invasive melanoma can show partial or complete tumour regression.

Lymph nodes

Lymph nodes are small immune organs located throughout the body that help fight infections and filter harmful substances. Cancer cells can spread through tiny lymphatic vessels from a tumour to nearby lymph nodes. When this happens, it is called a metastasis.

Lymph node

Lymph node removal and examination: Lymph nodes near the tumour are often removed and examined under a microscope to check for cancer cells. These are typically the first lymph nodes affected, but if there is concern about cancer spreading further, lymph nodes farther away may also be removed, especially if they are enlarged.

If lymph nodes are removed, the pathologist will examine them and include the following details in the pathology report:

  • The total number of lymph nodes examined.
  • Where the lymph nodes were located.
  • The number of lymph nodes containing cancer cells (if any).
  • The size of the largest focus or deposit of cancer cells

This information is important for determining the pathologic nodal stage (pN) and assessing the risk of cancer spreading to other body parts. Finding cancer in a lymph node may influence decisions about additional treatment, such as immunotherapy, chemotherapy, or radiation therapy.

Sentinel lymph node: The sentinel lymph node is the first to receive fluid drainage from the tumour. It is usually the first place where cancer cells spread.

Non-sentinel lymph nodes: Non-sentinel lymph nodes are the lymph nodes located after the sentinel lymph node. Cancer cells typically spread to these lymph nodes only after passing through the sentinel lymph node.

Extranodal extension: Lymph nodes are surrounded by a thin capsule of tissue. Extranodal extension occurs when cancer cells break through the capsule and spread into the surrounding tissue. This is significant because it increases the risk of the cancer regrowing in the same area after surgery and may lead to recommendations for additional treatments.

extranodal extension

Examining lymph nodes provides essential information about the extent of melanoma and helps guide treatment decisions. If you have questions about your pathology report or what the lymph node findings mean, your doctor can explain how this information applies to your care.

Margins

In pathology, a margin is the edge of a tissue cut when removing a tumour from the body. The margins described in a pathology report are very important because they tell you if the entire tumour was removed or if some of the tumour was left behind. The margin status will determine what (if any) additional treatment you may require.

Pathologists carefully examine the margins to look for tumour cells at the cut edge of the tissue. If tumour cells are seen at the cut edge of the tissue, the margin will be described as positive. If no tumour cells are seen at the cut edge of the tissue, a margin will be described as negative. Even if all of the margins are negative, some pathology reports will also measure the closest tumour cells to the cut edge of the tissue.

A positive (or very close) margin is important because it means that tumour cells may have been left behind in your body when the tumour was surgically removed. For this reason, patients with a positive margin may be offered another surgery to remove the rest of the tumour or radiation therapy to the area of the body with the positive margin.

 

Margin

Pathologic stage for lentigo maligna melanoma

The pathologic stage of lentigo maligna melanoma is determined using the TNM system, a standard classification system that describes the extent of cancer in the body. TNM stands for:

  • T (tumour): Describes the size and depth of the primary tumour.
  • N (nodes): Indicates whether cancer has spread to nearby lymph nodes.
  • M (metastasis): Refers to cancer in distant body parts.

Staging is critical for skin cancer because it helps doctors understand the extent of the disease, plan treatment, and estimate prognosis. Below is a summary of the T and N stages used to describe invasive melanoma.

T stages (tumour stages)

  • Tis: The melanoma is “in situ,” meaning it is confined to the top layer of skin and has not invaded deeper layers.
  • T1: The tumour is no more than 1 millimetre (mm) thick.
    • T1a: The tumour is no more than 1 mm thick and does not show ulceration.
    • T1b: The tumour is no more than 1 mm thick and shows ulceration or has a higher mitotic rate (a measure of cell division).
  • T2: The tumour is between 1 and 2 mm thick.
    • T2a: No ulceration is present.
    • T2b: Ulceration is present.
  • T3: The tumour is between 2 and 4 mm thick.
    • T3a: No ulceration is present.
    • T3b: Ulceration is present.
  • T4: The tumour is thicker than 4 mm.
    • T4a: No ulceration is present.
    • T4b: Ulceration is present.

N stages (lymph node stages)

  • N0: No cancer is found in nearby lymph nodes, and there are no signs of cancer in nearby skin (called in-transit, satellite, or microsatellite metastases).
  • N1: Cancer has spread to one nearby lymph node or nearby skin.
    • N1a: Cancer is found in one lymph node during a sentinel lymph node biopsy (a test to check for microscopic disease).
    • N1b: Cancer is found in one lymph node during a physical exam or imaging study (clinically detected).
    • N1c: No cancer is found in lymph nodes, but cancer is present in nearby skin or soft tissue.
  • N2: Cancer has spread to two or three nearby lymph nodes or nearby skin.
    • N2a: On sentinel lymph node biopsy, two or three lymph nodes are positive for cancer.
    • N2b: Cancer is found in two or three lymph nodes on physical exam or imaging.
    • N2c: Cancer is found in one lymph node and nearby skin or soft tissue.
  • N3: Cancer has spread to four or more lymph nodes or matted (connected) lymph nodes, or there is cancer in nearby skin with two or more lymph nodes involved.
    • N3a: Four or more lymph nodes are positive for cancer on sentinel lymph node biopsy.
    • N3b: Four or more lymph nodes are clinically detected, or any matted lymph nodes are present.
    • N3c: Cancer is found in two or more lymph nodes and nearby skin or soft tissue.

Cancer biomarkers for lentigo maligna melanoma

Cancer biomarkers are molecules found in tumour cells that provide important information about the biology of the cancer. In lentigo maligna melanoma, biomarkers help confirm the diagnosis, determine how aggressive the cancer may be, and guide treatment decisions. Pathologists test for these biomarkers in tumour tissue using specialized techniques, and the results are included in the pathology report. Below are key biomarkers for lentigo maligna melanoma and their significance.

BRAF mutations

  • What is it? BRAF is a gene that makes a protein involved in cell growth. Mutations in this gene, especially the V600E mutation, occur in about 50% of melanomas and can cause uncontrolled tumour growth.
  • Why is it important? A BRAF mutation makes the tumour eligible for targeted therapies, such as BRAF inhibitors (e.g., vemurafenib, dabrafenib) and MEK inhibitors, which can slow or stop tumour growth.
  • How is it tested? Pathologists test for BRAF mutations using methods like polymerase chain reaction (PCR), immunohistochemistry, or next-generation sequencing (NGS). The results are reported as “positive” (mutation detected) or “negative” (no mutation detected).

NRAS mutations

  • What is it? NRAS is another gene involved in cell signalling and growth. Mutations in NRAS are found in about 20% of melanomas and often occur in a mutually exclusive manner with BRAF mutations.
  • Why is it important? Although there are no approved targeted therapies specifically for NRAS-mutant melanoma, these mutations indicate a different tumour biology and may influence treatment strategies, including immunotherapy.
  • How is it tested? NRAS mutations are identified using genetic tests like PCR or NGS. The results specify whether an NRAS mutation is present and which type of mutation has been detected.

KIT mutations

  • What is it? KIT is a gene that helps regulate cell growth and survival. KIT mutations are found in less than 5% of melanomas, usually in specific subtypes such as acral (affecting hands or feet), mucosal, or chronically sun-damaged melanomas.
  • Why is it important? KIT mutations can make some tumours responsive to targeted therapies, such as imatinib or other tyrosine kinase inhibitors.
  • How is it tested? KIT mutations are tested using genetic sequencing or immunohistochemistry. If a mutation is found, its specific type (e.g., L576P or K642E) will be reported.

PRAME expression

  • What is it? PRAME is a protein that is abnormally expressed in some melanomas. Its presence may indicate a more aggressive tumour.
  • Why is it important? PRAME expression can help distinguish melanoma from benign lesions and may provide additional prognostic information.
  • How is it tested? PRAME is typically detected using immunohistochemistry, and the results are reported as positive or negative based on the intensity of staining in the tumour cells.

P16 loss

  • What is it? P16 is a tumour suppressor protein that helps regulate cell growth. Loss of P16 expression is common in invasive melanoma, especially in more advanced tumours.
  • Why is it important? Loss of P16 may indicate a more aggressive tumour that is more likely to grow and spread.
  • How is it tested? P16 is assessed using immunohistochemistry, and the results indicate whether the protein is present or absent in the tumour cells.

Cancer biomarker testing provides essential information for managing lentigo maligna melanoma. If you have questions about the biomarkers tested in your tumour, your doctor or pathologist can explain how the results influence your diagnosis and treatment plan.

What is the prognosis for someone diagnosed with lentigo maligna melanoma?

The prognosis for lentigo maligna melanoma is similar to that of other types of melanoma and depends on several factors:

  • Tumour thickness: Thinner tumours have a better prognosis.
  • Ulceration: The presence of ulceration worsens the prognosis.
  • Mitotic rate: A higher number of dividing cells in the tumour is associated with a worse outcome.
  • Lymphovascular or nerve invasion: The risk of spread is higher if cancer cells are found in blood vessels, lymphatic channels, or nerves.

Lentigo maligna melanoma generally progresses more slowly than other types of melanoma, but early detection and treatment are crucial to prevent spread. If you have been diagnosed with this condition, your doctor will discuss treatment options and monitor your recovery closely.

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