What are the key prognostic factors to consider when evaluating a patient with melanoma?

Prognostic Factors for Melanoma: Hierarchical Rating by Disease Stage

Primary Melanoma (Stages I-II): Localized Disease

For localized melanoma, Breslow thickness and ulceration status are the two most critical prognostic factors that directly predict survival and guide treatment decisions. 1

Tier 1: Essential Prognostic Factors (Highest Impact)

• Breslow Thickness: The single most important prognostic factor, demonstrating the closest correlation with survival and serving as the foundation for staging, surgical margin determination, and sentinel lymph node biopsy decisions 2, 1

  • Specific thresholds: ≤1 mm, 1-2 mm, 2-4 mm, >4 mm each carry distinct prognostic implications 2
  • Directly determines 5-year survival rates ranging from >90% for thin melanomas (≤1 mm) to 50-90% for thicker lesions 1

• Ulceration Status: The second most important characteristic, independently predicting worse outcomes across all thickness categories 1

  • Presence of ulceration upstages thin melanomas from IA to IB 1
  • Remains prognostically significant in stage III disease alongside nodal burden 1

• Mitotic Rate: Now replaces Clark level as a primary staging criterion for thin melanomas (≤1 mm) 1

  • Any mitotic activity (≥1/mm²) upstages T1 melanomas from IA to IB 1
  • Mitotic rate >6/mm² represents an independent poor prognostic factor, with >11/mm² conferring particularly poor prognosis (84% 5-year survival in node-negative patients) 3, 4
  • Must be measured using the "hot spot" technique and reported as mitoses per mm² 3
  • Serves as an independent predictor of sentinel lymph node positivity alongside Breslow thickness 1

Tier 2: Important Additional Factors

• Microscopic Satellitosis: Defines a high-risk subgroup with prognosis similar to stage III disease, indicating regional and systemic failure risk 1

  • Must be documented when present 1

• Clark Level: Retains prognostic value only for thin melanomas (<1 mm) when mitotic rate cannot be determined 1

  • No longer an independent predictor when mitotic rate is available 1
  • Should be reported for non-ulcerated lesions ≤1.0 mm if mitotic rate is unavailable 1

• Margin Status: Deep and peripheral margin positivity affects local recurrence risk and requires re-excision 1

Tier 3: Optional but Helpful Factors

• Vertical Growth Phase: Recommended by AAD task force but not mandatory for reporting 1

• Tumor-Infiltrating Lymphocytes (TIL): Not recommended for routine reporting due to poor reproducibility and lack of independent prognostic significance 5

  • Wide observer variation in classification (absent, non-brisk, brisk) limits clinical utility 5

• Regression: May be documented but lacks standardized prognostic impact 1

Special Considerations for Localized Disease

• Pure Desmoplastic Melanoma: Has very low incidence of nodal involvement; sentinel lymph node biopsy is not routinely indicated 1

  • Mixed desmoplasia behaves like conventional melanoma and requires standard evaluation 1

• Lymphovascular Invasion: Represents an adverse feature that increases metastatic risk 1

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Stage III Disease: Regional Metastases

For patients with regional disease, sentinel lymph node status is the single most important prognostic factor, followed by the number and clinical characteristics of involved nodes. 1

Tier 1: Critical Nodal Factors

• Sentinel Lymph Node Status: The most important prognostic factor among patients with localized melanoma undergoing biopsy 1

  • Positive sentinel node roughly halves survival rates compared to node-negative disease 1

• Number of Metastatic Nodes: The most important predictor of survival in stage III disease 1

  • 5-year survival ranges from 20-70% depending primarily on nodal tumor burden 1

• Clinical Nodal Status: Nonpalpable versus palpable nodes significantly impacts prognosis 1

  • Clinically positive (palpable) nodes indicate worse prognosis than microscopic sentinel node disease 1

Tier 2: Additional Stage III Factors

• Primary Tumor Ulceration: Remains prognostically significant even in the presence of nodal metastases 1

• Extranodal Tumor Extension: Presence indicates worse prognosis and may warrant consideration of adjuvant radiation therapy 1

  • Should be documented in pathology reports 1

• Size and Location of Metastatic Melanoma in Sentinel Nodes: Affects prognosis and should be recorded 1

  • Larger deposits and multiple positive nodes indicate higher risk 1

• Total Number of Nodes Examined: Important for accurate staging and prognostic assessment 1

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Stage IV Disease: Distant Metastases

For metastatic melanoma, the site of metastasis is the most significant predictor of outcome, with elevated lactate dehydrogenase serving as an independent poor prognostic indicator. 1

Tier 1: Critical Metastatic Factors

• Site of Metastasis: The most significant predictor of outcome in stage IV disease 1

  • Different metastatic sites (lung, liver, brain, bone, soft tissue) carry distinct prognoses 1
  • Number of metastatic sites correlates with survival 6

• Serum Lactate Dehydrogenase (LDH): Independent predictor of poor outcome, incorporated into AJCC staging 1

  • Elevated LDH at diagnosis of stage IV disease indicates worse prognosis 1
  • Should be measured and documented at stage IV diagnosis 1

Tier 2: Additional Stage IV Factors

• Tumor Burden: Higher disease burden correlates with worse outcomes, particularly relevant for targeted therapy selection 7

• Time Interval from Primary to Metastases: Longer disease-free intervals suggest more indolent biology 2

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Clinical and Demographic Factors (All Stages)

Lower-Impact but Recognized Factors

• Age: Younger age is an independent predictor of positive sentinel lymph node, though no specific threshold has been established 1

  • Older age generally associated with poorer survival 7
  • Age alone is not sufficient indication for sentinel lymph node biopsy 1

• Gender: Male gender associated with poorer survival, but prognostic value is low compared to histopathological factors 2, 7

• Anatomic Site: Axial location (trunk, head/neck) carries worse prognosis than extremity melanomas 7, 8

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Critical Pathology Reporting Requirements

The NCCN Melanoma Panel mandates specific reporting elements based on disease stage to ensure accurate prognostication and treatment planning. 1

For All Primary Melanomas:

• Breslow thickness 1
• Ulceration status 1
• Mitotic rate (ideally for all lesions) 1
• Deep and peripheral margin status 1
• Satellitosis if present 1
• Clark level for non-ulcerated lesions ≤1.0 mm when mitotic rate unavailable 1

For Stage III Disease:

• Number of positive nodes 1
• Total number of nodes examined 1
• Presence or absence of extranodal tumor extension 1
• Size and location of tumor in positive sentinel nodes 1

For Stage IV Disease:

• All sites of metastatic disease 1
• Serum LDH at diagnosis 1

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Common Pitfalls to Avoid

• Do not rely on Clark level when mitotic rate is available—it has been replaced as a staging criterion except in specific circumstances 1

• Do not perform sentinel lymph node biopsy on confirmed pure desmoplastic melanoma due to very low nodal involvement rates 1

• Do not use tumor-infiltrating lymphocytes for prognostic stratification or treatment decisions due to poor reproducibility 5

• Do not omit mitotic rate from pathology reports—it is emerging as an independent predictor of outcome and should be reported for all lesions 1, 3

• Young age alone is not a sufficient indication for sentinel lymph node biopsy despite being a predictor of positive nodes 1