What predicts prognosis of melanoma?

Melanoma is a type of skin cancer that develops from melanocytes, which are the pigment-producing cells of the skin. While melanoma accounts for only about 1% of skin cancer cases, it is responsible for the majority of skin cancer deaths, as it can be very aggressive and spread to other parts of the body quickly. Understanding the factors that predict melanoma prognosis is important for determining treatment and monitoring.

What is melanoma prognosis?

Melanoma prognosis refers to the likely course and outcome of the disease based on various clinical and pathological factors. It indicates a patient’s chance of recovery and survival. Good prognosis is associated with high chances of survival and recovery, while poor prognosis indicates higher risks of recurrence, metastasis (spread) and death.

Some factors that contribute to melanoma prognosis include:

Breslow thickness – the vertical thickness of the melanoma tumor measured in mm. Thicker tumors have worse prognosis.
Ulceration – presence of ulceration (break in the skin) in the tumor. Ulcerated tumors have worse prognosis.
Mitotic rate – the rate of cell division in the tumor. Higher rates indicate worse prognosis.
Lymph node spread – spread of melanoma to nearby lymph nodes. Worse prognosis if nodes are involved.
Distant metastasis – spread to distant organs like lungs, liver, brain or bones. Greatly worsens prognosis.
Elevated LDH – elevated blood levels of lactate dehydrogenase (LDH). Indicates worse prognosis.
Genetic factors – specific gene mutations in the tumor cells. Can influence prognosis.

Accurately determining melanoma prognosis is crucial for selecting proper treatment and management strategies. Patients with good prognosis may need less aggressive treatment, while those with poor prognosis require more intensive therapies.

TNM Staging system

The TNM system is the most commonly used staging method for melanoma prognosis. In this system:

– T stands for tumor thickness and ulceration
– N indicates spread to lymph nodes
– M represents distant metastasis

Based on these factors, melanoma is classified into different stages:

Stage 0 – Melanoma in situ, limited to the epidermis. Very early stage.

Stage I – Tumors < 1 mm thick without ulceration and no lymph node or distant spread. Favorable prognosis. Stage II – Tumors 1-2 mm thick, or <1 mm with ulceration. No cancer spread to lymph nodes or distant sites. Stage III – Tumors > 2 mm thick, or any thickness with nearby lymph node spread. Worse prognosis than earlier stages.

Stage IV – Distant metastasis to other organs. Worst prognosis.

Determining the TNM stage provides key information about prognosis and helps guide treatment options.

Breslow thickness

Breslow thickness, measured in millimeters (mm), is the most important factor predicting melanoma prognosis. It measures the vertical depth of tumor cells down through the layers of the skin.

In general, thicker tumors are associated with worse prognosis:

  • < 1 mm - 5 year survival rate is >90%
  • 1-2 mm – 5 year survival around 80%
  • 2-4 mm – 5 year survival 60-70%
  • > 4 mm – 5 year survival <50%

Breslow thickness directly correlates with risk of metastasis. Thinner tumors less than 1 mm rarely spread, while thicker tumors over 4 mm frequently metastasize to distant sites like the lung, liver or brain.

Microstaging of thin melanoma

For thin melanomas under 1 mm, additional microstaging factors can help refine prognosis:

  • Ulceration
  • Mitotic rate > 1/mm2
  • Lymphovascular invasion
  • Positive deep margins

Presence of these features in thin tumors indicates they may behave more aggressively, so patients require close monitoring and consideration of additional therapy.

Ulceration

Ulceration is another key factor predicting melanoma prognosis. It indicates breakdown of the skin overlying the tumor, which allows melanoma cells easier access to blood vessels and lymphatics to metastasize.

In the TNM system, any ulcerated tumor automatically gets classified into a higher risk category compared to a non-ulcerated tumor of the same thickness.

5-year survival rates by ulceration status:

  • Non-ulcerated melanoma – 90% survival
  • Ulcerated melanoma – 45-80% survival depending on thickness

Ulceration is also an important factor for microstaging of thin melanomas < 1mm thick. Ulcerated thin tumors have significantly worse prognosis than non-ulcerated tumors.

Mitotic Rate

The mitotic rate measures how rapidly melanoma tumor cells are dividing and proliferating. It is reported as number of mitoses (dividing cells) per mm2.

Higher mitotic rates are linked to worse prognosis:

  • Low mitotic rate (< 1/mm2) - 90% 5-year survival
  • High mitotic rate (≥ 1/mm2) – 60% 5-year survival

In microscopy, the pathologist will count the number of mitotic figures in the most proliferative area (“hot spot”) and report this as the mitotic rate.

It provides useful additional prognostic information, particularly in thin melanomas. High mitotic rate (>1/mm2) indicates worse prognosis in patients with < 1 mm thickness.

Lymph Node Status

Spread of melanoma to nearby lymph nodes (lymph node metastasis) worsens prognosis and indicates advanced disease. 5-year survival is:

  • Stage I/II with no lymph node involvement – 90% survival
  • Stage III with lymph node spread – 60% survival

Micrometastases detected by sentinel lymph node biopsy indicate increased risk of recurrence even in early stage I/II patients. Complete lymph node dissection is often required.

In stage III patients, the number of positive nodes and presence of ulceration in the primary tumor also affect prognosis. Higher number of positive nodes and ulcerated primaries lead to worse outcomes.

Distant Metastasis

Development of distant metastases in stage IV melanoma greatly worsens prognosis. 5-year survival is only 15-20% for stage IV patients.

Common sites of distant metastasis include:

  • Lung (common)
  • Brain (common)
  • Liver
  • Bones
  • GI tract

Patients with limited metastatic disease localized to a single organ have slightly better stage IV prognosis than those with widespread metastases in multiple locations.

Lactate Dehydrogenase (LDH)

Elevated blood LDH levels are linked to worse melanoma prognosis. LDH is an enzyme released by melanoma cells into the bloodstream.

High LDH indicates large tumor burden and aggressive disease. Patients can be categorized by LDH levels:

  • Normal LDH – 80% 5-year survival
  • Elevated LDH – 40% 5-year survival

LDH is now incorporated alongside TNM staging in the American Joint Committee on Cancer (AJCC) melanoma staging system. It serves as an important blood biomarker for prognosis.

Gene Expression Profile Testing

Gene expression profile (GEP) tests analyze a panel of gene mutations in melanoma tumors to help refine prognosis. Two common examples:

  • DecisionDx Melanoma – 23-gene expression profile test
  • Myriad myPath Melanoma – 31-gene expression profile test

These tests classify patients into low, moderate or high risk groups based on tumor genomics. High risk tumors have significantly worse 5-year survival:

GEP Class 5-year Survival
Low risk 97%
Moderate risk 80%
High risk 48%

GEP testing is often used for prognostic information in melanoma staging, particularly in early stage I-II patients. It can help guide treatment decisions and follow-up testing.

Sentinel Lymph Node Biopsy

Sentinel lymph node biopsy (SLNB) is a procedure that identifies the first lymph node(s) draining the melanoma tumor site. Pathologic analysis of the sentinel node(s) provides important staging and prognostic information:

  • Negative SLNB – no cancer detected. Excellent prognosis.
  • Positive SLNB – melanoma cells in lymph node. Worsens prognosis.

Positive SLNB indicates occult lymph node metastasis even if nodes feel normal on clinical exam. This microscopic spread indicates higher risk of recurrence in early stage patients.

Patients with positive SLNB often undergo complete lymph node dissection and may receive adjuvant therapy to lower recurrence risk. SLNB status is crucial for prognosis.

Blood Biomarkers

Certain blood biomarkers can provide prognostic information in melanoma:

Lactate dehydrogenase (LDH) – Elevated LDH indicates worse prognosis, as discussed earlier. Incorporated into current AJCC staging.

S100B – Protein secreted by melanoma cells. Higher levels indicate greater tumor burden and worse prognosis. Can be used for monitoring.

C-reactive protein (CRP) – Inflammatory marker elevated in advanced melanoma. Indicates worse prognosis.

Serum melanin – Pigment produced by melanoma tumor cells. Elevated levels predict poorer outcomes.

These circulating biomarkers allow serial blood testing to monitor disease status and treatment response. Rising levels generally indicate disease progression.

Patient Factors

Certain patient characteristics influence melanoma prognosis:

Age – Worse prognosis in older patients over 50 years old. More aggressive tumors and higher mortality.

Gender – Late stage melanoma has slightly higher 5-year mortality in males vs females. Reasons unclear.

Location – Melanomas on head/neck have higher local recurrence and worse survival vs. trunk or extremities.

Immune status – Immunosuppressed patients (e.g. transplant recipients) have higher recurrence risks and worse prognosis.

Accounting for these factors allows proper risk stratification and clinical decision making. Older male patients require particularly close surveillance.

Histologic Features

Certain microscopic features of the melanoma tumor affect prognosis:

Brisk TILs – Presence of many tumor infiltrating lymphocytes. Indicates activation of immune response against melanoma. Favorable prognostic factor.

Regression – Areas of tumor destruction by immune cells. Also indicates immune activation and better prognosis.

Vascular invasion – Tumor cells invading blood or lymphatic vessels. Allows easier spread so worse prognosis.

Neurotropism – Melanoma cells tracking along nerves. Increased risk of local recurrence after resection.

Evaluation of histology provides additional prognostic information beyond routine staging. It can help identify more aggressive tumors.

Oncogenic Driver Mutations

Presence of certain genetic mutations in melanoma tumors influences prognosis:

BRAF V600E – Occurs in ~50% of melanomas. Sensitive to BRAF inhibitor therapy. Overall neutral prognostic impact.

NRAS Q61 – Present in ~20% of melanomas. Associated with thicker primaries and worse prognosis.

KIT aberrations – Rare mutations. Higher risk of metastases and worse prognosis.

NF1 mutations – Related to worse prognosis. Indicated by desmoplastic melanoma subtype.

Testing for these mutations guides prognosis and selection of targeted therapies like BRAF/MEK inhibitors. Molecular testing is critical for optimal management.

Conclusion

Accurate assessment of melanoma prognosis is based on a combination of clinical, pathologic and genetic factors. Key determinants include Breslow thickness, ulceration, mitoses, lymph node spread, metastasis, LDH levels, GEP testing, sentinel node biopsy, blood biomarkers, patient factors, tumor histology and driver mutations.

Careful evaluation of all these parameters allows proper TNM staging and identifying patients at higher risk of recurrence or progression. Ongoing research continues to improve prognostic abilities and allow personalized therapy based on an individual tumor’s molecular makeup.

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