Protocol for the Examination of Specimens From Patients With Melanoma of the Skin

The College of American Pathologists offers these protocols to assist pathologists in providing clinically useful and relevant information when reporting results of surgical specimen examinations. The College regards the reporting elements in the “Surgical Pathology Cancer Case Summary” section of the protocols as essential elements of the pathology report. However, the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice.The College developed these protocols as an educational tool to assist pathologists in the useful reporting of relevant information. It did not issue the protocols for use in litigation, reimbursement, or other contexts. Nevertheless, the College recognizes that the protocols might be used by hospitals, attorneys, payers, and others. Indeed, effective January 1, 2004, the Commission on Cancer of the American College of Surgeons has mandated the use of the checklist elements of the protocols as part of its Cancer Program Standards for Approved Cancer Programs. Therefore, it becomes even more important for pathologists to familiarize themselves with the document. At the same time, the College cautions that use of the protocols other than for their intended educational purpose may involve additional considerations that are beyond the scope of this document.This protocol applies to invasive melanoma of cutaneous surfaces only. It is based on the 6th edition of the American Joint Committee on Cancer/International Union Against Cancer TNM classification system for the staging of melanomas of the skin.Optimal evaluation of melanocytic lesions requires complete excision that incorporates the full thickness of the involved lesion removed intact. “Shave” procedures should be avoided.Older patient age and male sex have been shown to be adverse prognostic factors in some studies, but the effect of these factors, independent of other strong adverse prognostic factors with which they correlate, is unclear.Data from selected treatment centers indicate that the average patient age at diagnosis ranges from about 48 to 59 years.1–5 A correlation between advanced age (ie, age greater than the median at diagnosis) and decreased survival has been suggested by several studies.346–8 However, some multivariate analyses have failed to support an independent effect of age.9–12 In other studies, correlative trends have been noted between advanced age and increased melanoma thickness at diagnosis, which is a very strong adverse prognostic factor, suggesting that this interrelationship may account for the apparent prognostic effect of age.9 In more recent multivariate analyses of data from melanoma centers worldwide, a strong independent relationship between age and outcome was demonstrated.1Male sex also has proven to be an adverse prognostic factor in many studies, many using multivariate analysis of results.1–3679111314 However, anatomic site of origin, tumor ulceration, and tumor stage (see notes C, D, and H) are very strong prognostic factors in cutaneous melanoma, and all of these factors correlate with sex. That is, males are more likely than females to develop melanomas in unfavorable sites, to have ulcerated tumors, and to have a higher stage of disease presentation.1For cutaneous melanoma, location on the extremities is associated with a better survival compared with location on the trunk or head and neck.1 Sublocation analyses have indicated that location on the upper extremities is associated with a slightly better survival than location on the lower extremities. In the head and neck region, location on the face or neck is associated with a survival advantage compared to location on the scalp.2Ulceration is a dominant prognostic factor in cutaneous melanoma without metastasis. It is defined as the absence of an intact epidermis over any part of the primary tumor based on microscopic observation of histologic sections.1516 The presence or absence of ulceration must be confirmed on microscopic examination. Ulcerated melanomas typically show invasion through the epidermis, whereas nonulcerated melanomas tend to lift the overlying epidermis. Thus, ulceration is widely regarded as an indication of biological aggressiveness in cutaneous melanoma, and clinical data strongly support this interpretation.Ulceration has been shown repeatedly to be among the most powerful adverse prognostic factors in stage I and II melanomas (see note H below for stage definitions), and in several studies, it has proven to be the single most important feature predicting outcome.12 Overall, for patients with stage I and II melanomas, the 10-year survival rate is 50% if the tumor is ulcerated and 78% if the tumor is not ulcerated.2 In almost every Cox regression analysis of prognostic factors in cutaneous melanoma that includes ulceration, a significantly worse prognosis and a higher risk of metastatic disease have been demonstrated for ulcerated versus nonulcerated tumors of equivalent thickness.11516There is a positive correlation between ulceration and thickness. For ulcerated tumors, the median thickness has been shown to be about 3 mm; for nonulcerated tumors, it is about 1.3 mm. Nevertheless, the adverse prognostic significance of melanoma ulceration has been shown to be independent of tumor thickness. For thin melanomas (≤1.0 mm thick), level of invasion is more predictive of survival outcome than ulceration. For all melanomas greater than 1.0 mm, ulceration is clearly more predictive than thickness.1Data from numerous studies have suggested that an elevated serum level of LDH is a stage-independent prognostic factor for decreased survival in melanoma. In these studies, pretreatment LDH elevation has been variably defined as serum levels greater than 200 to 225 U/L or levels elevated above the normal levels of the reference laboratory.1211 It is recommended that any elevation above normal should be checked by repeat LDH testing after at least 24 hours. For stage IV melanoma, a decreased serum albumin level (≤3.5–4.0 g/dL) has also been shown to be an independent adverse prognostic factor.1211The use of frozen sections in biopsies or excisions of pigmented lesions is discouraged. Optimal histologic evaluation of cutaneous melanoma requires formalin fixation.The classification of variants of malignant melanocytic neoplasms17 of the skin includes the following:Other terms for variants not included in the above-cited classification18 include:The prognostic significance of histologic type is less significant than the growth patterns and depth of infiltration displayed by those histologic types. For example, superficial spreading melanomas, by definition, demonstrate prominent radial growth and have a better prognosis than nodular melanomas, which predominantly demonstrate vertical growth.9Tumor demonstrates a uniform cytologic appearance and is generally wider than it is deep. The present or absence of a radial growth phase should be noted because the information may be used clinically to plan the extent of the re-excision.Tumor exhibits at least 2 cytologically distinct clones of tumor cells microscopically and shows an inconstant relationship between width and depth. Nodular melanomas are by definition vertical growth phase tumors. The presence or absence of a vertical growth phase should be noted. If a vertical growth phase is present, the character of the cells may also be noted as follows: epithelioid, spindled, or small. Vertical growth phase is an adverse prognostic factor for cutaneous melanoma.The TNM Staging System of the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) recommended by this protocol is shown below.1920 In the sixth editions of the AJCC and the UICC staging manuals, the staging system for melanoma of the skin has been completely changed, using different criteria for T, N, and M. Thus, the current staging system cannot be directly compared with previous TNM classifications.Pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial or complete lymphadenectomy. Pathologic stage 0 or stage 1A patients are exceptions; they do not require pathologic evaluation of their lymph nodes.19In virtually all studies of cutaneous melanoma, tumor thickness has been shown to be a dominant prognostic factor1516 and forms the basis for the stratification of pT. Clark levels are also commonly used to indicate depth of invasion of the primary tumor.19–22By AJCC/UICC convention, the designation “T” refers to a primary tumor that has not been previously treated. The symbol “p” refers to the pathologic classification of the TNM, as opposed to the clinical classification, and is based on gross and microscopic examination. pT entails a resection of the primary tumor or biopsy adequate to evaluate the highest pT category, pN entails removal of nodes adequate to validate lymph node metastasis, and pM implies microscopic examination of distant lesions. Clinical classification (cTNM) is usually carried out by the referring physician before treatment, during initial evaluation of the patient or when pathologic classification is not possible.Pathologic staging is usually performed after surgical resection of the primary tumor. Pathologic staging depends on pathologic documentation of the anatomic extent of disease, regardless of whether the primary tumor has been completely removed. If a biopsied tumor is not resected for any reason (eg, when technically unfeasible) and if the highest T and N categories or the M1 category of the tumor can be confirmed microscopically, the criteria for pathologic classification and staging have been satisfied without total removal of the primary cancer.* Clinical T classification (cT) is usually not possible for melanoma, and pathologic (microscopic) assessment of the primary tumor is required for proper staging. Therefore, excision of the primary tumor, rather than punch or other incisional biopsy, is always advised. The T classification of melanoma is based on the thickness of the primary tumor, its anatomic level of invasion, and the presence or absence of ulceration. Maximal thickness is measured with an ocular micrometer at a right angle to the adjacent normal skin. The upper point of reference is the granular layer of the epidermis of the overlying skin or, if the lesion is ulcerated, the base of the lesion (ulcer). The lower reference point is the deepest point of tumor invasion (ie, the leading edge of a single mass or an isolated group of cells deep to the main mass). Ulceration is a strong adverse prognostic factor116 (see note D).† Clark levels are defined as follows:* The regional lymph nodes are the most common sites of metastasis. The widespread use of cutaneous lymphoscintigraphy, lymphatic mapping, and sentinel lymph node biopsies has greatly enhanced the ability to identify the presence of lymph node metastasis.19 By convention, the term regional lymph nodal metastasis refers to disease confined to 1 nodal basin or 2 contiguous nodal basins, as in patients with nodal disease in combinations of femoral/iliac, axillary/supraclavicular, cervical/supraclavicular, axillary/femoral, or bilateral axillary or femoral metastases.† Isolated Tumor Cells, Micrometastases, and Sentinel Lymph Nodes.2021—Use of published guidelines for definitions of nodal metastasis is recommended.2021 Accordingly, any histologically identified focus of tumor (ie, seen on routine hematoxylin-eosin stain) greater than 0.2 mm in size is classified as nodal involvement. However, tumor measuring 0.2 mm or less or identified only by immunohistochemistry or nonhistologic methods should be classified as pN0, as described in the following list, with a comment on the finding in the pathology report (see below).The biologic significance of minute amounts of tumor (isolated tumor cells [ITCs]) in regional lymph nodes or distant metastatic sites is unproven at present. Isolated tumor cells are defined as single cells or small clusters of cells not more than 0.2 mm in greatest dimension.2021 They are always clinically occult, but when seen on routine histologic examination are classified as pN0. Lymph nodes or distant sites that are histologically negative but contain ITCs found by either special morphologic (immunohistochemistry) or nonmorphologic techniques (eg, flow cytometry, DNA analysis, polymerase chain reaction amplification of a specific tumor marker) also should be classified as N0 or M0, respectively. Specific denotation of the assigned N category is suggested as follows for cases in which ITCs are the only evidence of possible metastatic disease.Sentinel lymph node identification and evaluation may be included in the surgical approach to cutaneous melanoma. A sentinel lymph node is defined as the first node to receive lymphatic drainage from a primary tumor. There may be more than 1 sentinel node for some tumors. The clinical rationale for sentinel lymph node identification and separate evaluation is based on the assumption that metastatic involvement of a sentinel node increases the likelihood that other more distant nodes may also contain metastatic disease. Conversely, if sentinel nodes are negative, other regional nodes would be less likely to contain metastasis. Like other regional lymph nodes, sentinel lymph nodes that contain histologically identified tumor that is greater than 0.2 mm are classified as pN1. Sentinel lymph nodes that are histologically negative for true metastasis but have been examined for ITCs by any approach are denoted as follows:‡ In almost all studies using Cox regression analysis, either the number of regional lymph nodes containing metastases or the percentage of regional nodes containing metastases more strongly predicted outcome than the size of metastasis.141516 Patients with 1 involved lymph node have longer survival times compared to patients with any combination of 2 or more involved nodes, regardless of the size of the metastasis. In their review of reported studies, the AJCC Melanoma Staging Committee found no compelling evidence that the gross dimension of lymph node metastases was an independent predictor of outcome.22§ The presence of in-transit metastasis between the primary tumor and the regional lymph nodes portends a poor prognosis. In-transit metastasis is defined arbitrarily as intralymphatic tumor in skin or subcutaneous tissue more than 2 cm from the primary tumor but not beyond the nearest regional lymph node basin.‖ The presence of clinical or microscopic satellite lesions around a primary melanoma and in-transit metastases both portend a poor prognosis, and an analysis of the available data by the AJCC Melanoma Staging Committee revealed no significant difference in survival for these 2 entities.1516 They both are associated with a prognosis equivalent to multiple lymph node metastases.1516Note that for cutaneous melanoma, clinical and pathologic stage groupings differ for stage III. The complete clinical stage groupings are shown below for comparison.For identification of special cases of TNM or pTNM classifications, the “m” suffix and “y,” “r,” and “a” prefixes are used. Although they do not affect the stage grouping, they indicate cases needing separate analysis.The “m” suffix indicates the presence of multiple primary tumors in a single site and is recorded in parentheses: pT(m)NM.The “y” prefix indicates those cases in which classification is performed during or following initial multimodality therapy (ie, neoadjuvant chemotherapy, radiation therapy, or both chemotherapy and radiation therapy). The cTNM or pTNM category is identified by a “y” prefix. The ycTNM or ypTNM categorizes the extent of tumor actually present at the time of that examination. The “y” categorization is not an estimate of tumor prior to multimodality therapy (ie, before initiation of neoadjuvant therapy).The “r” prefix indicates a recurrent tumor when staged after a documented disease-free interval and is identified by the “r” prefix: rTNM.The “a” prefix designates the stage determined at autopsy: aTNM.Residual Tumor (R)Tumor remaining in a patient after therapy with curative intent (eg, surgical resection for cure) is categorized by a system known as the R classification, as follows.For the surgeon, the R classification may be useful to indicate the known or assumed status of the completeness of a surgical excision. For the pathologist, the R classification is relevant to the status of the margins of a surgical resection specimen. That is, tumor involving the resection margin on pathologic examination may be assumed to correspond to residual tumor in the patient and may be classified as macroscopic or microscopic according to the findings at the specimen margin(s).Vessel InvasionBy AJCC/UICC convention, vessel invasion (lymphatic or venous) does not affect the T category indicating local extent of tumor unless specifically included in the definition of a T category. In all other cases, lymphatic and venous invasion by tumor are coded separately as follows:Lymphatic Vessel Invasion (L)Venous Invasion (V)Perineural invasion may be seen in melanomas, particularly desmoplastic-neuroid subtypes.23 Although still debated, this feature may correlate with an increased risk for local recurrence. It is suggested that the presence of perineural infiltration be noted in surgical pathology reports on melanomas.At least one study24 has suggested that vascular invasion by melanomas correlates independently with worsened overall survival. We suggest that this parameter be recorded if it is present.A paucity of TILs is an adverse prognostic factor for cutaneous melanoma.25 Although a precise numerical characterization of that finding has not been made, a recent study26 has shown good to excellent overall interobserver agreement in the classification of TILs as brisk, nonbrisk, or absent according to Clark,27 using the guidelines that follow.26 To qualify as TILs, lymphocytes needed to surround and disrupt tumor cells of the vertical growth phase.No lymphocytes present, or lymphocytes present but do not infiltrate tumor at all.Lymphocytes infiltrate melanoma only focally or not along the entire base of the vertical growth phase.Lymphocytes diffusely infiltrate the entire invasive component of the melanoma or the entire base of the vertical growth phase.Regression of 75% or more of the lesion (defined by replacement of tumor cells by lymphocytic inflammation, with or without dermal melanophages and fibrosis) carries adverse prognostic importance in invasive melanomas.28A mitotic rate of one or more mitotic figures per square millimeter is an adverse prognostic factor for cutaneous melanoma.29 For a ×25 objective with a field diameter of 0.59 mm, the field area is 0.274 mm2. For a ×40 objective with a field diameter of 0.44 mm, the field area is 0.152 mm2.Microscopically measured distances between tumor and labeled lateral or deep margins are appropriately recorded for melanoma because these neoplasms may demonstrate clinical “satellitosis,” as discussed in note H. A comment on margins is necessary only for excisional biopsies or formal resections. If a lateral margin is involved by tumor, it should be stated whether the tumor is in situ or invasive.Pathologic examination of lymph nodes has become increasingly important in cutaneous melanoma.1930 Therefore, a comment may be needed that documents the clinical nodal (cN substage) versus pathologic (pN substage) status in assigning the stage grouping for the tumor. It is strongly recommended that patients with clinically negative nodes undergo pathologic staging using the sentinel lymph node technique or complete regional lymph node dissection. This is especially important for patients being considered for clinical trials.Removal of sentinel lymph nodes may be performed for patients with primary localized vertical growth phase cutaneous melanomas with a thickness of 1 mm or greater, and recent data indicate that removal also may be justified for lesions less than 1 mm thick (incidence of sentinel lymph node metastasis is about 6% in so-called thin melanomas vs about 15% for melanomas ≥1 mm thick).31 Frozen section analysis of sentinel lymph nodes is not advised. Review of hematoxylin-eosin–stained slides from multiple (6 to 10) levels through sentinel lymph nodes increases the sensitivity of detecting microscopic melanoma metastasis; routine analysis (hematoxylin-eosin–stained sections of the cut surfaces of a simply bisected lymph node) may lead to a false-negative rate of 10% to 15%. The use of (eg, for or also increases the sensitivity of of microscopic melanoma metastases and may also be considered in the examination of sentinel lymph However, should not be used in of histologic histologic whether for sentinel node analysis or routine regional lymph node evaluation (see note the entire node should be lymph nodes may be bisected or at whereas nodes may be histologic metastatic tumor measuring greater than 0.2 mm is classified as pN1.

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