Staging of Melanoma

• The melanoma staging system continues to evolve in parallel with our understanding of this complex disease
• Some key features of the 8th Edition staging system include:
  • Modifications to the T1 subcategory
  • More granular incorporation of satellite, in-transit, and microsatellite disease into the N category
  • Refinement and expansion of the M1 subcategories
• T Category:
  • Breslow tumor thickness and tumor ulceration:
    • Remain the dominant prognostic factors in the T category
  • Breslow tumor thickness:
    • Measured in millimeters and reported to the nearest tenth of a millimeter in the 8th Edition:
      • Is determined by using an ocular micrometer to measure the total vertical height of the melanoma:
        • From the granular layer to the area of deepest penetration
    • Historically, Clark level of invasion:
      • Was determined by assessing the extent of penetration into the dermis
    • Prospective data support that measurement of Breslow tumor thickness:
      • Is more reproducible than measurement of Clark level and that Breslow tumor thickness is the more accurate predictor of outcome
    • The AJCC Melanoma Expert Panel:
      • Continues to use Breslow tumor thickness cut-points of:
        • 1 mm for the T categories
        • 2 mm for the T categories
        • 4 mm for the T categories
      • However, in the 8th Edition of the AJCC staging system:
        • A tumor thickness stratum of 0.8 mm plays a key prognostic role:
          • In subcategorizing T1 tumors:
            • In contrast to previous incorporation of mitoses (as a dichotomous variable only:
              • i.e., < 1 mitosis/mm² vs. at least 1 mitosis/mm²:
                • Contributed to the definition of T1a and T1b, respectively in the 7th Edition
        • Specifically, in the 8th Edition, primary melanomas:
          • With a tumor thickness < 0.8 mm without ulceration are:
            • Designated T1a
          • Whereas primary melanomas 0.8 to 1.0 mm or those < 0.8 mm with ulceration are:
            • Categorized as T1b
      • Despite its removal from the T category for thin melanomas:
      • The AJCC recognizes the prognostic importance of mitotic rate in all T1 to T4 lesions:
        • Notes that this important covariate should be recorded (as number of mitoses/mm²), as it will likely be included in the development of clinical tools and contemporary prognostic models
• Melanoma may also present as metastasis to a regional nodal basin, or even with distant metastatic disease:
  • Yet without evidence of a primary lesion:
    • When there is no evidence of a primary tumor (i.e., unknown primary or completely regressed melanoma) or when thickness cannot be assessed:
      • The AJCC (8th Ed.) categorizes these as T0 and TX, respectively
• Primary tumor ulceration:
  • Is histopathologically defined:
    • As the absence of an intact epidermis overlying a portion of the primary tumor
  • Importantly, ulcerated melanomas are associated with a:
    • Significantly worse prognosis than nonulcerated melanomas of the same thickness
  • In the T category of the AJCC staging system, ulcerated tumors are designated by b following the numerical T:
    • An exception to this rule is for a nonulcerated primary melanoma with a tumor thickness 0.8 to 1 mm:
      • It is also designated by a “b” (T1b)

• N Category:
  • The N category refers to melanoma metastases to:
    • Regional lymph node basins and other intralymphatic manifestations of melanoma metastasis (e.g., in-transit, satellite, and microsatellite disease)
  • Regional nodal tumor burden:
    • Is the most important predictor of survival in patients without distant disease
  • Overall, there is significant heterogeneity in prognosis among patients with regional disease
  • Multiple studies have demonstrated that the number of pathologically involved lymph nodes:
    • Is a dominant and independent predictor of outcome in patients with melanoma
  • The 8th Edition AJCC staging system N category continues to use:
    • 1, 2 to 3, and 4 or more regional lymph nodes to generate N subcategories
  • The presence of primary tumor ulceration has also been shown to be an independent adverse prognostic factor:
    • Among patients with regional nodal disease:
      • Leading to its continued incorporation into the melanoma staging system
  • In the 8th Edition:
    • Both primary tumor thickness and ulceration are used to define N stage groups
  • Aside from the number of tumor-involved lymph nodes:
    • It is important to distinguish the:
      • Burden of nodal disease as well as the presence or absence of in-transit, satellite, and/or microsatellite disease
    • Previous empiric definitions such a microscopic and macroscopic regional nodal disease:
      • Have been replaced by “clinically occult” or “clinically detected” regional nodal disease, respectively:
        • Patients who have clinically negative regional lymph nodes but pathologically documented nodal metastases (i.e., a positive sentinel node):
          • Are defined as having “clinically occult” nodal metastases:
            • Designated by the letter a in the N category
      • In contrast, patients with clinical evidence of regional nodal metastases that is confirmed on pathologic examination are defined as having “clinically detected” nodal metastases:
        • Designated by the letter b in the N category
          • Overall, survival for patients with clinically detected nodal disease is worse than for patients with clinically occult nodal disease
  • Additional components of the N category include:
    • Satellite, in-transit, or microsatellite disease
    • Presence of at least one of these types of metastasisis coded by a suffix “c” in the 8th Edition N category and further stratified according to the number of tumor-involved regional lymph nodes:
      • N1c, N2c, or N3c
    • Satellite and in-transit metastases are classically defined:
      • As skin or subcutaneous lesions:
        • Within 2 cm of the primary tumor or more than 2 cm from the primary melanoma, respectively:
          • But generally not beyond the regional nodal basin, and are types of non-nodal regional metastasis
    • Microsatellites are defined as:
      • Any foci of metastatic tumor cells adjacent or deep to, and discontinuous from the primary tumor
      • It is important that there be an element of normal interposition tissue, that is, if only fibrosis and/or inflammation separate a suspected microsatellite from its primary, one should query where this represents regression of this intervening region
      • Microsatellites are also included in the N category staging system

• M Category:
  • The M category refers to:
    • Melanoma distant metastasis and is classified as stage IV
  • Within the M category:
    • There is only one stage, M1
      • In contrast to the three M subcategories in the 7th Edition (M1a, M1b, and M1c)
    • There are four subcategories in the 8th Edition AJCC melanoma staging system
  • Distant metastases to the skin, subcutaneous tissue, or distant lymph nodes:
    • Are designated M1a:
      • They are associated with a better prognosis than metastases to other anatomical sites
  • Metastases to the lungs:
    • Are associated with an intermediate prognosis:
      • Are designated M1b
  • Visceral metastases are associated with a worse prognosis:
    • Are designated M1c
  • New to the 8th Edition is the addition of a subcategory for CNS metastasis (i.e., brain, spinal cord, and/or leptomeningeal disease):
    • Designated M1d
      • This category of disease is generally associated with worse survival compared to the other M categories
  • M1c now includes patients with non-CNS visceral metastasis
  • The subcategories reflect survival differences among patients with metastatic disease:
    • Depending on the anatomic sites of metastases.
  • Serum lactate dehydrogenase (LDH) level also continues to be included in the M category:
    • An elevated LDH has been shown to adversely influence survival across patients with stage IV disease
    • LDH level is denoted with:
      • The suffix (0) in patients without elevation, or (1) for those with an elevated LDH (i.e., M1a(1) …M1d(1))
    • In patients in whom LDH level is unknown or unspecified, no suffix is added

• Clinicopathologic Staging (c/pTNM)
  • Clinical staging includes:
    • Above-noted features of the primary tumor:
      • As well as lesions and clinical and/or radiologic studies
  • Pathological staging involves incorporating all variables of microstaging of the primary tumor:
    • As well as information from the surgical specimen, including treatment effect and margin status
    • Lymph node status is confirmed by both identification and quantification of sentinel and/or regional nodal basin involvement
    • Formal pathological staging is crucial to both proper classification and prognostication of patient outcome

• EXTENT OF DISEASE EVALUATION
  • In addition to physical examination, several adjuncts are used to determine the extent of disease
  • The National Comprehensive Cancer Network (NCCN) provides guidelines to evaluate for possible metastatic melanoma with imaging
  • For melanoma in situ:
    • Imaging studies are not recommended
  • For stages I–II melanoma:
    • Imaging is recommended only if there are specific signs or symptoms that need evaluation
  • For stage III melanoma:
    • It is my general practice to obtain baseline imaging with a:
      • Chest x-ray, computed tomographic scan, PET/CT, and/or magnetic resonance imaging (MRI) of the brain
      • Ultrasonography with fine-needle aspiration of the associated lymph node basins may be useful in detecting metastatic disease in lymph nodes:
        • Excisional biopsy and/or formal resection of suspicious nodes solely for diagnostic purposes is discouraged
  • Patients who present with suspected stage IV are generally staged with:
    • Computed tomography (CT) of the chest, abdomen, and pelvis ± positron emission tomography (PET) as well as MRI of the brain:
      • Image-guided percutaneous biopsy of concerning lesions can be used to confirm disease
      • Excisional biopsy of suspected metastatic lesions is rarely indicated for diagnostic purposes

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