Biopsy

Patients presenting with a suspicious pigmented lesion optimally should undergo an excisional biopsy, preferably with 1- to 3-mm margins. The orientation of the excisional biopsy should always be planned with definitive treatment in mind (e.g., a longitudinal orientation in the extremities). With the increasing use of lymphatic mapping and sentinel node biopsy, biopsies should also be planned so they will not interfere with this procedure. In this regard, wider margins for the initial diagnostic procedure should be avoided.

Excisional biopsy may be inappropriate for certain sites (including the face, palmar surface of the hand, sole of the foot, ear, distal digit, or subungual lesions) or for very large lesions. In these instances, a full-thickness incisional or punch biopsy of the clinically thickest portion of the lesion is an acceptable option, rather than a shave biopsy. These procedures should provide accurate primary tumor microstaging, without interfering with definitive local therapy. If the incisional biopsy is inadequate to make a diagnosis or accurately microstage the tumor (based on evaluation by a dermatopathologist) for treatment planning, rebiopsy with narrow margin excision should be considered.

Pathology Report

In the revised American Joint Committee of Cancer (AJCC) staging system, patients with melanoma are categorized into 3 groups: localized disease with no evidence of metastases (stage I–II), regional disease (stage III), and distant metastatic disease (stage IV).^7,8 Breslow tumor thickness, ulceration, and mitotic rate are the 3 most important characteristics of the primary tumor predicting outcome in patients with localized melanoma (stage I or II).

Mitotic rate is an indicator of tumor proliferation and is measured as the number of mitoses per mm². The latest AJCC staging manual recommended the “hot spot” technique for calculating the mitotic rate.⁸ Barnhill et al.⁹ compared the relative importance of mitotic rate with ulceration as major prognostic factors in localized melanoma. In a multivariate analysis including mitotic rate and ulceration, tumor thickness and mitotic rate (< 1, 1–6, > 6) emerged as the most important independent prognostic factors. Several other studies have also confirmed the prognostic importance of mitotic rate in patients with primary cutaneous melanoma.^10–12 In the evidence-based derivation of the 2010 AJCC staging system, mitotic rate greater than or equal to 1 per mm² was independently associated with worse disease-specific survival, especially in patients with melanoma less than or equal to 1.0-mm thick. Therefore, mitotic rate has replaced Clark level as a criterion for upstaging patients with melanomas less than or equal to 1.0 mm in thickness from IA to IB. In multivariate analyses, mitotic rate and younger age were identified as independent predictors of a positive sentinel lymph node (SLN), in addition to Breslow thickness.^13,14 In contrast to mitotic index, no threshold of age has been determined to be an independent predictor of a positive SLN. Young age alone is not a sufficient cause for performing sentinel lymph node biopsy (SLNB).

The American Academy of Dermatology (AAD) task force recommends including mitotic rate in the biopsy report, along with other additional optional factors, such as vertical growth phase, tumor-infiltrating lymphocytes, and regression.¹⁵ Microscopic satellitosis, if present, should also be recorded, because this defines a patient subgroup at high risk for regional and systemic failure, prognostically similar to stage III. Clinicians should also note cases of pure desmoplastic melanoma (as opposed to mixed desmoplasia with spindle cell and/or epithelioid cells), because these have a very low incidence of nodal involvement that does not support the routine use of SLNB.^16–18 Mixed desmoplasia has a similar rate of lymph node spread to that of conventional melanoma. When pure desmoplastic melanoma is suspected, the entire lesion should be examined by an experienced dermatopathologist; SLNB should not be performed on confirmed pure desmoplasia.

Some melanocytic proliferations can be diagnostically challenging. Examples are atypical melanocytic proliferation, melanocytic tumor of uncertain malignant potential, superficial melanocytic tumor of uncertain significance, atypical Spitz tumor, and atypical cellular blue nevus. These lesions are more frequently seen in younger patients, and when suspected, referral to a pathologist with expertise in atypical melanocytic lesions is recommended. When melanoma is in the differential diagnosis, the report should include prognostic elements as for melanoma. Comparative genomic hybridization (CGH) or fluorescence in situ hybridization (FISH), if available, should be considered to detect the presence of selected gene mutations for histologically equivocal lesions. CGH is a more comprehensive technique than FISH, which may offer higher sensitivity and specificity in identifying relevant copy number changes, as suggested by a recent small study on atypical Spitz tumors.¹⁹

Among patients with localized melanoma undergoing SLNB, the status of the sentinel node is the most important prognostic factor.²⁰ Among patients with nodal metastases (stage III), the number of metastatic nodes and clinical nodal status (nonpalpable vs. palpable) are the most important predictors of survival, followed by the presence or absence of primary tumor ulceration. Other prognostically relevant factors include the presence of extranodal tumor extension and, in patients with positive sentinel nodes, the size and location of the metastatic melanoma in the sentinel nodes.

The site of metastasis is the most significant predictor of outcome among patients with distant metastases (stage IV). Elevated lactose dehydrogenase (LDH) is also an independent predictor of poor outcome in patients with stage IV disease and has been incorporated into the AJCC staging system.^20,21

NCCN Recommendations: The NCCN Melanoma Panel recommends including Breslow thickness, ulceration status, mitotic rate, deep and peripheral margin status (positive or negative), satellitosis (if present), and Clark level for nonulcerated lesions 1.0 mm or less when mitotic rate is not determined in the pathology report. Ideally, mitotic rate should be reported for all lesions, because it is emerging as an independent predictor of outcome. The panel agreed that recording of the parameters identified by the AAD task force would be helpful but not mandatory.

For patients with stage III disease, the panel recommends reporting the number of positive nodes, the total number of nodes examined, and the presence or absence of extranodal tumor extension. In addition, the panel recommends recording the size and location of tumor present in a positive sentinel node.

For patients with stage IV disease, the panel recommends reporting all sites of metastatic disease and the serum LDH at diagnosis of stage IV.

Preliminary Workup

After the diagnosis of melanoma has been confirmed, a history and physical examination (H&P) and complete dermatologic examination are recommended. Preliminary workup of patient presenting with melanoma or dysplastic nevi should include a detailed personal and family history, including any history of melanoma or dysplastic nevi removal.³ In the physical examination of patients with invasive melanoma, physicians should pay special attention to the locoregional area and lymph node drainage basins of the established melanoma.

Wide Excision

Surgical excision is the primary treatment for melanoma. Several prospective randomized trials have been conducted in an effort to define optimal surgical margins for primary melanoma.

An international prospective study conducted by the WHO randomized 612 patients with primary melanomas not thicker than 2.0 mm to wide excision with either 1.0- or 3.0-cm margins.^37,38 At a median follow-up of 90 months, local recurrence and disease-free and overall survival rates were similar in both groups.

The National Intergroup Trial randomized 468 patients with melanomas 1.0 to 4.0 mm in thickness to wide excision with either 2.0- or 4.0-cm margins. At a median follow-up of 10 years, no differences were seen in local recurrence and disease-free and overall survivals.^39,40 Prospective randomized trials from Sweden have confirmed that satisfactory local control and melanoma-specific survival are not compromised by narrower margins.^41,42

In a more recent prospective randomized trial comparing 1.0-versus 3.0-cm margins for melanomas thicker than 2.0 mm, wider margins were associated with a slightly lower rate of combined local/regional/nodal recurrence, but not improvement in local recurrence alone or melanoma-specific survival.⁴³ A systematic review and meta-analysis also reported that surgical excision margins no more than 2.0 cm are adequate, and that surgical margins should not be less than 1.0 cm around primary melanoma.⁴⁴

Management of lentigo maligna and in situ melanoma may present unique problems because of the characteristic, yet unpredictable, subclinical extension of atypical junctional melanocytic hyperplasia, which may extend several centimeters beyond the visible margins. Various approaches to achieve complete surgical excision with meticulous margin control have shown high local control rates and are used at some NCCN Member Institutions, although they are not universally accepted.^45,46

NCCN Recommendations: The clinical/surgical margins discussed in this section refer to those taken at surgery and do not necessarily correlate with gross pathologic/histologic margins measured by pathologists.

For in situ melanoma, a measured margin of 0.5 cm around the visible lesion should be obtained. For large in situ lentigo maligna melanoma, surgical margins greater than 0.5 cm may be necessary to achieve histologically negative margins. In the absence of prospective clinical trials, this margin is recommended based on panel consensus.

For patients with stage IA melanoma (≤ 1.0 mm), wide excision with a 1.0-cm margin is recommended (category 1). For patients with melanomas measuring 1.01 to 2.0 mm in thickness, wide excision with a 1.0- to 2.0-cm margin is recommended (category 1). For melanomas measuring more than 2.0 mm in thickness, wide excision with 2.0-cm margins is recommended (category 1 for tumors ≤ 4.0 mm in thickness; category 2A for tumors > 4.0 mm in thickness). Surgical margins may be modified to accommodate individual anatomic or cosmetic considerations. The panel recognized that 1.0- to 2.0-cm margins might be acceptable in anatomically difficult areas in which a full 2.0-cm margin would be difficult to achieve.

Although surgical excision remains the standard of care for in situ melanoma, it is sometimes not feasible because of comorbidity or cosmetically sensitive tumor location. Topical imiquimod has emerged as a treatment option, especially for lentigo maligna.^47–51 However, long-term comparative studies are still needed. Radiotherapy (RT) has also been used selectively for lentigo maligna. In a retrospective review by Farshad et al.,⁵² a 5% crude local failure rate occurred with definitive radiation, with a mean time to recurrence of 45.6 months. Of the 5 recurrences, 4 were at the edge of the radiation field, and the authors suggested targeting a margin of at least 10 mm around the visible lesion.

Sentinel Lymph Node Biopsy

SLNB is a minimally invasive staging procedure developed to identify patients with subclinical nodal metastases at higher risk of recurrence who could be candidates for complete lymph node dissection or adjuvant systemic therapy.⁵³ MSLT-I, an international multicenter phase III trial conducted by the Multicenter Selective Lymphadenectomy Trial Group, was initiated to evaluate the accuracy, morbidity, and use of lymphatic mapping and SLNB for staging patients with early-stage melanoma.⁵⁴ In a preliminary publication, Morton et al.⁵⁴ reported an initial sentinel node identification rate of 95%. SLNB was also associated with low false-negative and complication rates.

Recently, Morton et al.⁵⁵ published data from the third interim analysis of results from the MSLT-I trial. Among patients with intermediate thickness primary melanoma (1.2–3.5 mm), those undergoing wide excision with SLNB (and completion lymph node dissection if their sentinel nodes were positive) showed no significant improvement in melanoma-specific survival rates compared with those undergoing initial wide excision and nodal observation, and delayed therapeutic lymphadenectomy if necessary. However, an improvement was seen in the estimated 5-year disease-free survival rate in the SLNB group (78% after SLNB vs. 73% after observation; P = .009), at least partly because of the higher nodal relapse rate in the observation group. Among patients undergoing SLNB, sentinel node status was the most important prognostic factor for disease-specific survival. Furthermore, among all patients with nodal metastases, those who had immediate lymph node dissection following lymphatic mapping and positive SLNB had higher survival rates than those who underwent delayed lymphadenectomy for clinical disease (72% vs. 52%). This difference was largely attributed to a lower nodal tumor burden in patients with positive SLNs compared with in those with clinically positive nodes. These results confirm that SLNB is of prognostic value and that the procedure can identify patients with low-volume nodal metastases whose survival is superior to that of patients whose nodal metastases are detected on clinical examination.

The value of SLNB for patients with thin melanomas (≤ 1.0 mm) and thick melanomas (≥ 4.0 mm) was not addressed specifically in the MSLT-I trial. Because patients with thin melanoma have a generally favorable prognosis, the role of SLNB in this cohort is unclear.⁵⁶ A review by Andtbacka and Gershenwald⁵⁷ reported an overall SLN metastasis rate of 2.7% in patients with melanoma thinner than 0.75 mm from 7 studies. In patients with melanoma 0.75 to 1.0 mm thick, 6.2% of patients undergoing SLNB were found to have a positive SLN. Factors predicting an increased probability of a positive SLN in patients with thin melanomas include increasing Breslow thickness and, less consistently, Clark level, higher mitotic rate, and younger age. However, with relatively short follow-up, only one center showed any convincing evidence that the SLN status was predictive of outcome in this low-risk group of patients.⁵⁸ Larger series and longer-term follow-up are required to assess the prognostic value of the SLN in patients with thin melanoma.^59–61

The probability of a positive sentinel node in patients with thick melanoma (≥ 4 mm) is 30% to 40%. Almost every retrospective series has shown that SLN status is a strong independent predictor of outcome in patients with thick melanoma.^62–64 Thus, in these high-risk patients, offering SLNB would seem reasonable to help define prognostically homogeneous groups for participation in clinical trials of adjuvant therapy.

The significance of tumor regression is debatable, with more recent studies reporting no association between the presence of regression and the incidence of SLN positivity.^65,66

Meticulous pathologic examination of all sentinel nodes is mandatory. Serial sectioning and immunohistochemical staining should be performed. Because the presence of even scattered clusters of melanoma cells in a sentinel node is clinically relevant, the AJCC was unable to determine a sentinel node tumor burden too low to report as metastatic disease. However, the presence of bland or benign-appearing melanocytes should be interpreted with caution; these nodal nevi can masquerade as metastatic disease. In the presence of any doubt, review by an experienced dermatopathologist is recommended.

NCCN Recommendations: SLNB may be offered to appropriate patients with localized melanoma for pathologic staging. The panel does not recommend SLNB for patients with in situ melanoma (stage 0) or stage IA melanoma that is 1.0 mm or less with no adverse features. Discussion of SLNB should be considered for patients with stage IA thin melanomas (≤ 1.0 mm) with adverse prognostic features, such as thickness greater than 0.75 mm, positive deep margins, lymphovascular invasion, or young age (although no threshold of young age alone is sufficient to recommend SLNB). Because the yield of a positive SLNB in patients with stage IA melanoma is low and the clinical significance of a positive SLN in these patients remains unclear, these factors should be discussed with patients considering the procedure. For patients with stage IB or II melanoma (≤ 1.0 mm thick with ulceration or mitotic rate ≥ 1 per mm²; or > 1.0 mm thick), SLNB should be discussed and offered. SLNB may also be considered for patients with resectable solitary in-transit stage III disease. However, although SLNB is a useful staging tool, its impact on the overall survival of these patients remains unclear. In patients who would be candidates for SLNB, the decision to not perform SLNB may be based on significant patient comorbidities or patient preference.

The validity of SLNB in accurately staging patients after prior wide excision is unknown. Therefore, wide excision before planned SLNB is discouraged, although patients may be considered for the procedure on an individual basis if they present after initial wide excision.

The panel discussed the appropriate management of clinically negative lymph nodes in patients at risk for regional metastases in the event that SLNB is unavailable. Based on the results of 3 prospective randomized trials, the panel does not recommend routine elective lymph node dissection for this group. Wide excision alone or referral to a center where lymphatic mapping is available are both acceptable options in this situation.

The panel discussed at length the absolute lower limit of probability of sentinel node positivity that should prompt a discussion of SLNB. They agreed that the procedure should be considered for patients with high-risk stage IA melanoma, and should be discussed and offered to patients with stage IB–IIC melanomas. For patients with stage IA or IB melanoma at very low risk for either positive sentinel lymph node or melanoma recurrence (≤ 0.5 mm thick and mitotic rate < 2 per mm²), there is nonuniform panel consensus that it would be appropriate to omit SLNB unless other specific adverse features are present (category 2B). In the absence of firm data, the decision about SLNB in this setting should be left to the patient and the treating physician.

Lymph Node Dissection

Among patients with a positive sentinel node, published studies have reported additional positive nonsentinel nodes in approximately 15% to 20% of these complete lymph node dissection specimens.^67,68 However the impact of completion lymph node dissection on regional control and survival in this setting has not been clearly shown. MSLT-II is an ongoing trial in which patients with sentinel node metastases are randomized to undergo either completion lymph node dissection or observation. This trial should resolve the issue of whether complete lymph node dissection has an impact on outcome (Clinical-Trials.gov identifier: NCT00297895). Complete lymph node dissection consists of an anatomically complete dissection of the involved nodal basin. The extent of complete lymph node dissection is often modified according to the anatomic area of lymphadenopathy. In the absence of clinical or radiologic evidence, patients with melanoma metastatic to inguinal nodes are at risk for pelvic node involvement and are candidates for elective pelvic lymph node dissection when more than 3 superficial nodes are involved, when the nodes are clinically positive, or when Cloquet’s node is positive.^69–71

NCCN Recommendations: If the sentinel node is negative, regional lymph node dissection is not indicated. Patients with stage III disease based on a positive SLN should be offered a complete lymph node dissection of the involved nodal basin, either as standard care or in the context of a clinical trial evaluating alternative strategies (such as close monitoring with nodal basin ultrasound). Participation in MSLT-II, assessing the option of nodal observation in patients with positive sentinel nodes, is encouraged if available. Nodal basin observation for these patients has not been studied sufficiently to be recommended as a standard option.

Patients presenting with clinically positive nodes without radiologic evidence of distant metastases should undergo wide excision of the primary site (if present) and complete lymph node dissection of the involved nodal basin. In the setting of inguinal lymphadenopathy, a pelvic dissection is recommended if the PET/CT or pelvic CT scan reveals iliac and/or obturator lymphadenopathy, or if a positive Cloquet’s lymph node is found intraoperatively (category 2B). Pelvic dissection also should be considered for clinically positive nodes or if more than 3 superficial nodes are involved (category 2B).

One measure of the completeness of a regional lymph node dissection is the number of lymph nodes examined. However, the panel believed that available retrospective evidence was insufficient to mandate that a specific number of nodes be required to deem a lymph node dissection adequate for any designated lymph node basin. As a measure of quality control to ensure adequacy of lymphadenectomy, the panel recommended that the operative note should fully describe the anatomic boundaries of the lymph node dissection.

Low- and Intermediate-Dose Interferon

The first major randomized trial of adjuvant interferon for completely resected stage III melanoma conducted by the WHO⁷² showed no improvement in overall survival (35% for the interferon group vs. 37% for those assigned to observation alone). In the French Cooperative Group trial evaluating adjuvant interferon in patients with melanoma larger than 1.5 mm thick and clinically negative nodes, after a median follow-up of 5 years, adjuvant interferon therapy showed a significant relapse-free survival benefit and a nonsignificant trend toward increased overall survival.⁷³ In another prospective randomized study, adjuvant interferon prolonged disease-free survival for patients with resected stage II melanoma at a median follow-up of 41 months.⁷⁴

Two other randomized clinical trials (EORTC 18952 and the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglyceride and Impact on Global Health Outcomes [AIM HIGH] study) compared adjuvant interferon with observation in patients with resected stage IIB and stage III melanoma. In the AIM HIGH study, low-dose interferon alfa-2a did not improve either overall or recurrence-free survivals.⁷⁵ EORTC 18952 reported no significant improvement in progression-free survival for intermediate-dose interferon alfa-2b.⁷⁶

High-Dose and Pegylated Interferon

High-dose interferon has been evaluated in 3 randomized clinical trials. ECOG 1684 compared high-dose interferon alfa-2b with observation in patients with stage IIB (≥ 4.0 mm with no evidence of lymph node involvement) and III melanomas with either regional lymph node disease or in-transit metastases. Median follow-up of 6.9 years showed a statistically significant improvement in relapse-free and overall survival for patients in the interferon group. However, at 12.6 years of follow-up, overall survival was not significantly different between the groups, although a significant benefit was seen in relapse-free survival.⁷⁷

The results of a larger follow-up trial, ECOG 1690, also showed a relapse-free survival advantage but none for overall survival.⁷⁸ ECOG 1694 compared high-dose interferon alfa-2b with an experimental vaccine, GM2-KLH21. At approximately 2 years’ median follow-up, the interferon alfa-2b group showed better relapse-free and overall survivals than the vaccine group. More recently, concerns have been raised concerning the vaccine control group used in ECOG 1694. The randomized phase III trial of adjuvant GM2-KLH21 in 1314 patients with stage II melanoma (EORTC 18961) was closed early by the data monitoring committee because of inferior survival in the vaccine arm.⁷⁹

A recent retrospective review of 200 patients with melanoma (stage IIB, IIC, or III) reported that those who had autoantibodies or clinical manifestations of autoimmunity after treatment with high-dose interferon alfa-2b had improved relapse-free and overall survivals compared with patients who did not show manifestation of autoimmunity.⁸⁰

Review of data combined from the randomized controlled trials found that adjuvant interferon alfa was not associated with improved overall survival in patients with melanoma who were at increased risk for recurrence.⁸¹ A pooled analysis of E1684, E1690, and E1694 confirmed an improvement in relapse-free survival in patients with high-risk resected melanoma (2-sided log-rank P value = .006) but found no significant improvement in overall survival.⁸²

The ECOG studies included patients with stage IIB (≥ 4.0 mm with no evidence of lymph node involvement) and III melanomas with either regional lymph node disease or in-transit metastases. In a recent systematic review, Verma et al.⁸³ concluded that although high-dose interferon alfa is associated with improved disease-free survival in patients with high-risk primary melanomas, the role of adjuvant interferon for those with intermediate- to high-risk melanoma remains undefined. Adjuvant high-dose interferon is a toxic therapy that is decreasingly being used in most institutions, but panelists agree that it still may have a role in community practice.

The EORTC protocol (18991) randomized 1256 patients with completely resected stage III melanoma to either observation or pegylated interferon alfa treatment for an intended duration of 5 years. Four-year relapse-free survival was significantly better in the interferon group compared with the observation group (45.6% vs. 38.9%); however, no significant effect of pegylated interferon was seen on overall survival.⁸⁴ Based on these data, pegylated interferon alfa received approval by the FDA in 2011 as an option for adjuvant therapy in patients with melanoma with nodal involvement. The panel included pegylated interferon as an adjuvant option for completely resected nodal disease.

A recent post hoc analysis of 2 large randomized phase III trials (EORTC1892 and EORTC18991) indicated that a reduction in risk for recurrence and death in patients treated with adjuvant interferon was observed primarily in patients with ulcerated primary melanomas.⁸⁵ The clinical and biologic significance of this observation remains unclear.

Adjuvant Radiation Therapy

Adjuvant RT is rarely necessary for excised local melanoma. One exception may be desmoplastic neurotropic melanoma (DNM), which tends to be locally aggressive. In a retrospective series of 128 patients with DNM (84% stage II), patients who did and did not receive adjuvant radiation had a similar incidence of local failure (7% with RT vs. 6% without) despite worse prognostic features in the radiated group (thicker tumors, deeper Clark level invasion, and narrower excision margins).⁸⁶ The authors concluded that radiation should be considered for patients with inadequate margins, which in this series occurred predominately in the head and neck region.

Radiation has a role in controlling nodal relapse in patients at risk. The largest retrospective review investigating the role of RT was performed by Agrawal et al.,⁸⁷ who evaluated 615 patients who met the specific criteria portending a high risk of regional nodal relapse based on lymph node number, size, location, and extracapsular extension. At a median follow-up of 5 years, regional recurrence occurred in only 10.2% of the radiated patients versus 40.6% of the nonradiated patients. Adjuvant radiation was associated with improved locoregional control on multivariate analysis (P < .0001). Notably, treatment-related morbidity was significantly increased with RT (5-year rate of 20% vs. 13%; P = .004), particularly lymphedema. A prospective randomized trial of adjuvant nodal basin RT versus observation in patients at risk for nodal relapses has been completed in Australia,⁸⁸ and preliminary results have been reported in abstract form. In this phase III trial, 250 patients with an isolated lymph node field melanoma relapse that was completely resected received either adjuvant radiation to the nodal basin or observation. Eligible patients included those with 1 or more parotid, 2 or more cervical or axillary, or 3 or more groin nodes; maximum node diameter of 3 cm or larger in neck or axilla or 4 cm or larger in the groin; or nodal extracapsular extension. Lymph node field recurrence was significantly less frequent in the adjuvant radiation group (hazard ratio [HR], 1.77; 95% CI, 1.02–3.08; P < .041), but no improvement was seen in overall survival. Postoperative radiation with various fractionation schemes has been used in other clinical studies.^89–91

Publication of trial results is anticipated soon. Hypofractionated RT seems as equally effective as standard fractionation. Although particular concern for toxicity should be exercised when using higher doses per fraction, all studied regimens seem well tolerated.

NCCN Recommendations: Most patients with in situ or early-stage melanoma will be cured with primary excision alone. However, patients who have desmoplastic lesions with extensive neurotrophism are at high risk for local recurrence, especially if margins are suboptimal. Adjuvant radiation after surgery may be considered to improve local control. If positive margins remain after optimal surgery, topical imiquimod (for melanoma in situ) or RT may be considered in selected patients (category 2B). For patients with nodenegative early-stage melanoma who are at risk for recurrence (stage IB or II; ≤ 1.0 mm thick with ulceration or mitotic rate ≥ 1 per mm²; or > 1.0 mm thick), adjuvant treatment options include a clinical trial or observation. For patients with node-negative stage IIB or IIC disease, adjuvant treatment options include clinical trial, observation, or high-dose interferon alfa. For patients with stage III melanoma, adjuvant treatment options include clinical trial (preferred), observation, or interferon alfa. Pegylated interferon alfa is an alternative to high-dose interferon in completely resected stage III disease with either positive sentinel nodes or clinically positive nodes, but not for stage III in-transit disease. Adjuvant RT to the nodal bed should be considered for high-risk nodal disease: multiple positive nodes, large nodes, or macroscopic extranodal soft tissue extension, with a lower threshold for using RT in the cervical lymph node location.

Treatment with adjuvant high-dose or pegylated interferon alfa is currently a category 2B recommendation in all of the cases described because of low benefit-to-risk ratio. Decisions about the appropriateness of adjuvant interferon alfa-2b treatment for patients should be made on an individual basis after discussion with the patient, which should include an explanation of the potential benefits and side effects of interferon therapy.

In all patients who have been rendered free of disease by surgery, after initial treatment for recurrent regional or distant metastatic disease (stage III in-transit metastases or stage IV), consideration of adjuvant treatment is appropriate. No evidence supports the use of adjuvant interferon alpha for completely resected stage IV disease, and the panel does not recommend it as an option in that setting. Therefore, the main option for adjuvant therapy in this setting is participation in a clinical trial. See next section on Treatment of Metastatic Melanoma and Treatment of Recurrence section on page 394.

Local Treatment for In-Transit Disease

Many different treatment options, mostly local/regional, are available for patients presenting with stage III in-transit metastases. Treatment is based on the size, location, and number of tumor deposits, but evidence is limited and no consensus exists on the best approach. Excision to clear margins is the mainstay for resectable tumors in small numbers. Although in-transit disease has a high probability of occult nodal involvement, and a positive sentinel node in the presence of in-transit metastasis portends a more ominous prognosis, the impact of SLNB on outcome remains unproven.⁹²

Several nonsurgical regional approaches are being used. Isolation limb perfusion or infusion is a method to administer high doses of chemotherapy to an affected extremity while avoiding systemic drug exposure.^93,94 Melphalan is the drug widely used for this technique. Isolation limb infusion has been reported by Thompson et al.⁹⁵ to be a simpler technique, with response rates comparable to those of limb perfusion. A recent study of isolated limb infusion in 128 patients showed a complete response rate of 31%.⁹⁶ However, a modified hyperthermic isolated limb perfusion procedure was associated with a higher complete response rate of 63%, with 5-year survival observed in 38% of patients.⁹⁷

Other therapies include intralesional local injections with bacillus Calmette-Guérin (BCG)⁹⁸ or interferon alfa, laser ablation, and topical imiquimod.⁹⁹ Imiquimod may have some activity for small superficial dermal lesions but not for subcutaneous disease.¹⁰⁰ RT is sometimes used; however, patients with satellitosis are at risk for recurrence in the radiated field. In a series of high-risk patients who received adjuvant radiation, the only risk factor associated with in-field locoregional recurrence was satellitosis.⁹⁰

Systemic Therapy

Traditional Chemotherapy: Metastatic melanoma is associated with a poor prognosis. Common agents currently being used in community practice include dacarbazine,^101,102 temozolomide,¹⁰² high-dose interleukin-2,^103–106 and paclitaxel with or without cisplatin or carboplatin.^107–111 These have shown modest response rates of less than 20% in first- and second-line settings. Little consensus exists regarding standard chemotherapy for patients with metastatic melanoma, which most likely reflects the low level of activity of older FDA-approved agents.^112,113 However, the therapeutic landscape for metastatic melanoma is rapidly changing with the recent development of novel agents.

Novel Therapies: Ipilimumab, a monoclonal antibody directed to the immune checkpoint receptor termed cytotoxic T lymphocyte antigen-4 (CTLA-4), received FDA approval for treatment of metastatic melanoma in March 2011. Approval was based on a randomized phase III trial of 676 patients with unresectable metastatic disease that progressed during systemic therapy.¹¹⁴ Patients received ipilimumab plus a glycoprotein 100 peptide vaccine (gp100), ipilimumab alone, or gp100 alone in a 3:1:1 ratio. Overall survival was significantly longer in patients receiving the combination (10.0 months; HR, 0.68 compared with gp100 alone; P < .001) or ipilimumab alone (10.1 months; HR, 0.66 compared with gp100 alone; P = .003) compared with those receiving gp100 only (6.4 months). Notably, 15 of 23 patients experienced partial response or stable disease after reinduction.

Ipilimumab stimulates T cells and is associated with substantial risk of immune-related reactions. Patients with underlying autoimmune disorders may be especially susceptible to serious reactions. In this pivotal trial, immune-related events were recorded in 60% of patients treated with the agent. Of treated patients, 10% to 15% experienced grade 3 or 4 events. Diarrhea was the most common immune-related reaction; severe cases were treated with high-dose corticosteroids. In all, 7 deaths were attributed to immune-related toxicity in the trial.

In a second phase III study, 502 patients with previously untreated metastatic melanoma were randomly assigned to ipilimumab plus dacarbazine or dacarbazine plus placebo.¹¹⁵ The primary end point was reached with the ipilimumab arm, showing longer overall survival than the control arm (11.2 vs 9.1 months). The 3-year survival rates were 20.8% and 12.2% for patients receiving ipilimumab and placebo, respectively (HR, 0.72; P < .001). A 56% incidence of grade 3 or 4 adverse events was recorded in the ipilimumab arm, but no drug-related deaths occurred.

Approximately 45% of patients with metastatic melanoma harbor an activating mutation of the intracellular signaling kinase, BRAF. Vemurafenib is a specific inhibitor of signaling by mutated BRAF.¹¹⁶ A randomized phase III trial compared vemurafenib with dacarbazine in 675 patients with previously untreated metastatic melanoma containing a V600 mutation of BRAF.¹¹⁷ Vemurafenib was associated with improved overall and progression-free survival (relative risk [RR] of death, 0.37; RR of death or progression, 0.26; P < .001). At 6 months, 84% and 64% of patients were alive in the vemurafenib and dacarbazine groups, respectively. Overall, 38% of patients receiving vemurafenib required dose modification because of adverse events. Skin complications were frequently associated with the agent: 18% of vemurafenib-treated patients developed cutaneous squamous cell carcinoma or keratoacanthoma that required simple excision, whereas 12% experienced grade 2 or 3 photosensitivity skin reactions. Arthralgia was the most common (21%) noncutaneous side effect.

Based on the results of this randomized study, vemurafenib was approved by the FDA in August 2011 for the treatment of metastatic or unresectable melanoma with the BRAF mutation. The Cobas 4800 BRAF V600 mutation test, a companion diagnostic test to determine the tumor mutational status, received approval along with the agent. The panel added vemurafenib to the list of available systemic treatments for patients with a documented V600 E or K mutation of the BRAF gene. Mutational status should be tested by an FDA-approved test or a facility approved by Clinical Laboratory Improvement Amendments (CLIA).

Although approval of ipilimumab and vemurafenib has significantly altered the initial management of patients with stage IV melanoma, each agent has unique limitations. Ipilimumab is associated with the potential for serious autoimmune toxicity, clinical responses may take months to become apparent, and the overall response rate is less than 20%. However, when responses are seen, they can be durable. Vemurafenib, on the other hand, is associated with a 40% to 50% response rate in patients with a V600-mutated BRAF gene, and responses may be seen days to weeks after starting the drug. Unfortunately, the median duration of response is only 5 to 6 months.

The success of these 2 agents has prompted a new wave of questions regarding their use in the adjuvant setting, augmenting response through combining them with cytotoxic chemotherapy, and defining mechanisms of drug resistance.

The pace of change underscores the importance of participating in a clinical trial whenever possible; this remains the preferred choice of management for unresectable metastatic disease in these guidelines.

Biochemotherapy: Biochemotherapy is the combination of chemotherapy and biologic agents. In single-institutional phase II trials, biochemotherapy (cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2) produced overall response rates of 27% to 64% and complete response rates of 15% to 21% in patients with metastatic melanoma.^118–120 In a small phase III randomized trial comparing sequential biochemotherapy (dacarbazine, cisplatin, vinblastine with interleukin-2 and interferon alfa administered on a distinct schedule) versus dacarbazine plus cisplatin and vinblastine (CVD), response rates were 48% and 25%, respectively, and median survival was 11.9 versus 9.2 month, respectively.¹²¹ In a phase III randomized intergroup trial (E3695), biochemotherapy (cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alpha-2b) produced a slightly higher response rate and progression-free survival than CVD alone, but it was not associated with improvement in either quality of response or overall survival.¹²² Biochemotherapy was substantially more toxic than CVD. Additional attempts to decrease toxicity of biochemotherapy through administering subcutaneous outpatient interleukin-2 did not show a substantial benefit of biochemotherapy versus chemotherapy alone.^123–125 A recent meta-analysis also showed that although biochemotherapy improved overall response rates, it was not associated with a survival benefit in patients with metastatic melanoma.¹²⁶

Palliative Radiation Therapy: Contrary to common perception that melanoma is radioresistant, RT often achieves good palliation of symptomatic metastatic disease. Studies have shown a 39% and 68% to 84% incidence of significant symptom relief for CNS and non-CNS metastasis, respectively.^127,128 The reported clinical complete response rate ranges from 17% to 69%, with 49% to 97% of patients experiencing either a partial or complete response.^91,129,130 In a single-institutional review of 121 patients receiving palliative RT, overall and complete response rates of 49% and 17% were observed in the stage IV group.¹³⁰ The brain metastases response rate was 54%. For nodal or in-transit metastases, a 77% overall response was reported, including 44% with a complete response.

NCCN Recommendations

Stage III: In-Transit Metastases: For patients with a single or a small number of in-transit metastases, complete surgical excision with histologically negative margins is preferred, if feasible (category 2B). In patients undergoing curative resection of a solitary in-transit metastasis, SLNB can be considered (category 2B).

In patients who have a limited number of intransit metastases, particularly dermal lesions, which are not amenable to complete surgical excision, intralesional local injections with BCG or interferon alfa, or topical imiquimod, can be used. Laser ablation or RT may be given to selected patients. For patients with multiple, regional, in-transit metastases, regional chemotherapy by hyperthermic perfusion or infusion is an option. All of these treatments are category 2B recommendations. Other alternatives include systemic therapy (particularly after failure of local and/or regional therapy) or treatment in the context of a clinical trial.

Distant Metastatic Disease (Stage IV): Treatment of stage IV metastatic melanoma depends on whether disease is limited (resectable) or disseminated (unresectable).

Resection, if feasible, is recommended for limited metastatic disease. In selected patients with a solitary site of visceral metastatic melanoma, a short period of observation or systemic treatment followed by repeat scans may be appropriate to rule out the possibility that the visceral metastasis is the first of many metastatic sites and to better select patients for surgical intervention.

After observation, patients with resectable solitary sites of disease should be assessed for surgery. Patients who undergo resection can be offered adjuvant treatment in a clinical trial. There is panel consensus that adjuvant interferon alpha monotherapy outside of a clinical trial is inappropriate for resected stage IV disease. Alternatively, limited metastatic disease can be treated with systemic therapy either in the context of a clinical trial (preferred) or as standard care. Residual disease after incomplete resection for limited metastases is treated as described here for disseminated disease.

Disseminated disease is treated based on the presence or absence of brain metastases. For patients without brain metastases, options for systemic therapy include:

• Clinical trial (preferred)

• Ipilimumab (category 1)

• Vemurafenib (category 1) if BRAF mutation documented

• Dacarbazine, temozolomide, or high-dose interleukin-2

• Combination chemotherapy or biochemotherapy (dacarbazine or temozolomide-based, including cisplatin and vinblastine, with or without interleukin-2, interferon alfa; category 2B)

• Paclitaxel-based chemotherapy (single-agent or in combination with cisplatin or carboplatin; category 2B)

Close monitoring of potentially lethal immune-related events in patients receiving ipilimumab is essential, and panelists strongly recommend participation in the risk evaluation and mitigation strategy (REMS) program during the course of ipilimumab treatment. Patients treated with ipilimumab who experience stable disease of 3 months’ duration after week 12 of induction or partial or complete response, who subsequently experience progression of melanoma, may be offered reinduction with up to 4 doses of ipilimumab at 3 mg/kg every 3 weeks. For patients on vemurafenib, the panel recommends regular dermatologic evaluation with referral to a dermatologist as indicated to monitor for skin complications.

Caution is warranted in the administration of high-dose interleukin-2 or biochemotherapy because of the high degree of toxicity reported. Some patients may attempt biochemotherapy for palliation or to achieve a response that may render them eligible for other therapies. In any case, if this therapy is considered, the panel recommends patients receive treatment at institutions with relevant expertise. Contraindications for interleukin-2 include inadequate organ reserve, poor performance score, and untreated or active brain involvement.

The recommendation for first-line systemic therapy of melanoma is based on several factors, including the BRAF mutation status, the tempo of disease, and the presence or absence of cancer-related symptoms. Patients with low-volume, asymptomatic metastatic melanoma may be good candidates for immunotherapy (ipilimumab or interleukin-2), because there will hopefully be time for an antitumor immune response to emerge. Patients with BRAF-mutant melanoma who have symptomatic disease or who have progressed despite immunotherapy should be considered for vemurafenib. Clinical trials are underway to address unanswered questions regarding the optimal sequencing and/or combination of these agents.

For patients who are intolerant to or experiencing relapse after first-line systemic therapy, additional systemic therapy may be indicated in those with an ECOG performance status of 0 to 2 or a Karnofsky status of 60 or greater. Options for second-line therapy include clinical trial (preferred) or treatment with a different agent from the list of first-line options indicated earlier.

For patients with brain metastases, the treatment of the CNS disease usually takes priority in an effort to delay or prevent intratumoral hemorrhage, seizures, or neurologic dysfunction. Treatment for patients with brain metastases is based on symptoms, number of lesions present, and location of the lesions, as described in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Central Nervous System Cancers (to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org). Stereotactic radiosurgery and/or whole-brain radiotherapy may be administered either as the primary treatment or as an adjuvant following resection. In addition to systemic therapy, surgical resection and/or radiation may be considered for palliation or management of symptoms, such as gastrointestinal bleeding or obstruction, painful or ulcerated soft tissue cutaneous metastases, or bulky adenopathy. Best supportive care is an alternative for these patients.

In patients with both brain and extracranial metastases, therapy as outlined in the preceding paragraph may be administered during or after treatment of the CNS disease, with the exception of high-dose interleukin-2, which has low efficacy in patients with previously untreated brain metastases and may worsen edema surrounding the untreated metastases. Disagreement exists on the value of interleukin-2 therapy in patients with small brain metastases but no significant peritumoral edema; interleukin-2 may be considered in selected cases (category 2B).

NCCN Recommendations

Skin examination and surveillance at least once a year for life is recommended for all patients with melanoma, including those with stage 0 in situ melanoma. All patients who had stage IA to IV melanoma should be educated about posttreatment monthly self-examination of their skin and lymph nodes. Specific signs or symptoms are indications for additional radiologic imaging.

For patients with stage IA to IIA melanoma and no evidence of disease, comprehensive H&P with specific emphasis on the regional nodes and skin should be performed every 3 to 12 months for 5 years and annually thereafter as clinically indicated. The consensus of the panel is that routine blood testing or imaging is not useful for these patients.

For patients with stage IIB–IV melanomas and no evidence of disease, comprehensive H&P should be performed every 3 to 6 months for 2 years, then every 3 to 12 months for 3 years, and annually thereafter, as clinically indicated. The surveillance interval should be tailored to substage. Although not recommended at baseline, chest radiograph, CT, MRI, and/or PET/CT every 6 to 12 months can be considered to screen for recurrent or metastatic disease at the discretion of the physician (category 2B). Routine blood testing to detect recurrence is not recommended for these patients.

Because most recurrences manifest within the first 5 years, routine imaging is not recommended beyond this period.

NCCN Recommendations

Local Scar Recurrence: The panel recognized the distinction between true local scar recurrence after inadequate initial excision (which most likely represents locally persistent disease) and local recurrence after adequate initial excision (which likely represents dermal lymphatic disease appearing close to the wide excision scar). In the former situation, the prognosis after re-excision is much better, whereas the latter scenario is prognostically similar to recurrent regional disease.

For true local scar recurrence after inadequate primary therapy, the workup should be similar to that of the primary tumor based on lesion thickness. Re-excision to appropriate margins is recommended, with or without lymphatic mapping and SLNB, appropriate to the microstaging of the recurrence.

Local, Satellite, and/or In-Transit Recurrence: For a local recurrence after adequate prior wide excision, baseline imaging (chest radiograph, CT and/or PET/CT or MRI) should be considered for staging and to evaluate specific signs or symptoms. In the absence of extraregional disease, surgical excision with negative margins is recommended for local recurrence after initial adequate wide excision. Lymphatic mapping with SLNB may be considered in these patients on an individual basis. Adjuvant treatment options following complete resection of a local recurrence after adequate primary therapy include clinical trial, observation, or interferon alfa (category 2B).

For patients with in-transit recurrence, the clinical diagnosis should be confirmed through biopsy (FNA or excision). The workup is similar to that previously outlined for patients presenting with intransit disease. A surgically resectable recurrence should be excised with negative margins; SLNB may be considered in these patients on an individual basis.

Unresectable in-transit recurrence could be treated with any one of the following options: intralesional injections with BCG or interferon-alfa, topical imiquimod (for small dermal lesions), laser ablation therapy, or hyperthermic limb perfusion or infusion. All of the local treatment options are category 2B recommendations. Alternatively, patients can be treated in the context of a clinical trial or with systemic therapy. In unusual circumstances, RT may be effective in achieving regional control (category 2B).

After complete response to any of these modalities, options include a clinical trial or observation, or high-dose interferon alfa (category 2B).

Regional Nodal Recurrence: For patients presenting with regional nodal recurrence, the clinical diagnosis should be confirmed preferably with biopsy (FNA or excision). The workup is similar to the one previously outlined for patients with clinically positive lymph nodes.

For patients who have not undergone prior lymph node dissection or had an incomplete lymph node dissection, a complete lymph node dissection is advised. If the patient underwent a previous complete lymph node dissection, excision of the recurrence to negative margins is recommended if possible. After complete resection of nodal recurrence, options for adjuvant treatment include a clinical trial, observation, or, in patients not previously treated, high-dose or pegylated interferon alfa (category 2B). Adjuvant radiation may also be considered (category 2B). Options for patients with incompletely resected nodal recurrence include radiation and/or clinical trial, systemic therapy, or observation. Those with unresectable disease may participate in a clinical trial or receive systemic therapy or RT.

Distant Recurrence: For patients presenting with distant recurrence, the workup and treatment options are similar to those outlined previously for patients presenting initially with stage IV metastatic disease.