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Staging Workup, Sentinel Node Biopsy, and Follow-up Tests for Melanoma

Staging Workup, Sentinel Node Biopsy, and Follow-up Tests for Melanoma ObjectivesTo clarify and update workup and follow-up strategies based on fundamental principles and current data, and to discuss new and current concepts regarding sentinel lymph node biopsy (SLNB), particularly in relation to the staging workup.Data SourcesStudies conducted from 1995 to 2003 were identified by PubMed search. Additional searches included workup for reference lists of retrieved articles when applicable, and PubMed-related articles.Study SelectionContemporary studies with good design, conclusions based on sound methods, and results pertaining to staging workup, SLNB, and follow-up tests were critically reviewed.Data ExtractionData and conclusions based on the above studies were incorporated into a review.Data SynthesisRoutine tests have marginal to no efficacy and are not cost-efficient for detecting occult disease in asymptomatic patients with localized melanoma. The only staging test that has relatively high sensitivity and specificity and provides tissue diagnosis is SLNB; moreover, SLNB has revolutionized our understanding of lymphatic pathways. The concepts of interval nodes and unexpected lymphatic drainage pathways have been addressed by several recent reports. There are no data that demonstrate any significant difference in overall survival for detection of asymptomatic vs symptomatic stage IV melanoma.ConclusionsAn initial workup is useful for staging and prognosis to identify occult disease, with potential outcome benefit if treated early; and, by detecting distant occult disease (stage IV), to obviate the need for an extensive surgical procedure and thereby avoid associated increased morbidity. The foundation for the workup and follow-up remains thorough history taking and a physical examination, combined with a low index of suspicion for symptom-directed tests.MELANOMA IS THE FIFTH most common cancer in men and the seventh most common in women.Most patients diagnosed with melanoma present with localized disease, and most are asymptomatic and without clinical findings for regional and/or distant disease. Although melanoma management continues to progress and change with new and emerging discovery, much is yet to elucidate in the field of melanoma. Workup and follow-up guidelines have continued to change in the past several years. This review is designed to clarify and update current workup and follow-up strategies based on fundamental principles and current data. Current concepts regarding sentinel lymph node biopsy (SLNB) are also discussed, particularly in relation to the staging workup.WHY PERFORM ROUTINE TESTS?In an asymptomatic patient, the following questions should define both the workup strategy and recommendations following a diagnosis of melanoma: What tests are to be performed? What information will be obtained? How accurate will the information be? How will the information be used for clinical management? What will the benefit be with respect to both clinical significance and cost? An initial workup is beneficial for staging and prognosis to identify occult disease, with potential outcome benefit if treated early; and, by detecting distant occult disease (stage IV), to obviate the need for an extensive surgical procedure with associated increased morbidity.StagingWhy is staging important for melanoma management? Staging is necessary to group patients into similar prognostic and management cohorts. Staging guides the clinician to better counsel the patient with respect to prognosis and treatment. Accurate staging also groups patients with a highly heterogeneous disease into more homogeneous populations for potential entry into better clinical trials. The universal language of cancer staging developed by the American Joint Committee on Cancer (AJCC) uses the TNM classification. The AJCC staging classification has changed 4 times in the past 15 years because of the need to incorporate new information gained from numerous studies in an ever-changing field. The current AJCC staging system for melanoma, implemented in 2002, is based on outcome data from 17 600 patients with melanoma.With its several major revisions, the new AJCC staging classification represents a significant improvement. Breslow thickness and ulceration define the T (tumor) category, and Clark level further defines only thin T1 (≤1-mm) melanomas. The number of positive lymph nodes and the tumor burden—either subclinical (microscopic) or clinically apparent (macroscopic) nodal metastases, rather than nodal size—define the N category. Using tumor burden (microscopic/macroscopic) as a determinant of the N category allows incorporation of SLNB results into staging. Ulceration of the primary lesion upstages patients with localized and regional nodal disease. The M category is defined by the sites of distant metastases and the presence of elevated serum lactate dehydrogenase.What tests are indicated for a staging workup following diagnosis? The foundation of the initial workup is still thorough history taking and physical examination. The history should incorporate a melanoma-focused review of systems(Table 1). A complete mucocutaneous and lymphatic examination is indicated, with attention to the entire skin surface and regional nodal basin. Should imaging and hematologic tests be used for staging tumors in asymptomatic patients? In the past, these tests have been performed with the intent of detecting clinically occult distant disease. Unfortunately, presently available standard screening imaging and hematologic tests lack both high sensitivity and high specificity. The numerous reports providing collective data on thousands of patients demonstrate that these tests have marginal to no efficacy and are not cost-efficient for detecting occult disease in asymptomatic patients with melanoma.The true-positive rate of a baseline chest radiograph in large series of asymptomatic patients who have melanoma ranges from 0% to 0.5%.The cost of simply performing a baseline chest radiograph for patients with a new diagnosis of localized melanoma in the United States in 2003, at an estimated cost of $100 per radiograph, approaches $5 million. Specificity with presently available standard screening imaging and hematologic studies is also low, with false-positive rates as high as 8% to 15%.False-positive tests often lead to additional tests and increased patient anxiety.Table 1. Melanoma-Focused Review of Systems*SystemSign/SymptomConstitutionalWeight loss, malaise, decreased appetite, weakness, fatigue, feverRespiratoryCough, hemoptysis, pneumonia, pleurisy, chest pain, dyspneaSkin/lymphaticColor change, "swollen glands," nonhealing/bleeding skin lesions, easy bruisingHepaticAbdominal pain, jaundice, pain radiated to the scapula with deep inspirationMusculoskeletalBone pain (eg, rib, spine, hip)GastrointestinalCramping, abdominal pain, bleeding, nausea, anorexia, vomiting, constipationNeurologicHeadache, memory disturbances, depression, focal central nervous system symptoms, visual disturbances, seizures, balance problems, blackouts, local weakness, numbness, paralysis, mood swings*Adapted from Johnson et al.Lymph node sonography and positron emission tomography have been used for early detection of occult regional nodal disease.In fact, these modalities may represent the most sensitive noninvasive tests to identify small lymph node metastases in patients with melanoma. However, for the initial workup of the asymptomatic patient with clinically localized melanoma at significant risk for nodal involvement, SLNB is more sensitive and more specific in detecting subclinical lymph node disease than either sonography or positron emission tomography.The gold standard for diagnosis remains histopathologic confirmation, and SLNB is the only staging test that provides tissue diagnosis.Outcome BenefitUnfortunately, in 2003, there are no data that demonstrate any significant difference in overall survival between asymptomatic and symptomatic stage IV melanoma.Prognosis is dismal in stage IV melanoma but some patients may benefit from surgical and/or systemic intervention, which can provide significant remission periods following diagnosis. Quality of life may also be adversely impacted by asymptomatic detection of stage IV disease, however. Because there is no intervention known to increase overall survival despite earlier detection of asymptomatic stage IV melanoma, patient and family bear the psychosocial burden longer. Detection of occult regional disease (stage III) may result in higher survival rates.Stage III survival is primarily determined by the number of positive nodes, the microscopic and macroscopic tumor burden in the nodes, and the ulceration status of the primary lesion.Fewer Extensive Surgical ProceduresAlthough low in sensitivity and specificity, imaging and hematologic tests can detect distant occult disease (stage IV), and they may be performed to prevent patients from undergoing extensive surgical procedures with potentially high morbidity. For example, detection of occult distant disease would obviate the need for a complete lymphadenectomy following a positive SLNB result. If a patient has widespread visceral disease, systemic therapy rather than extensive surgical intervention may be warranted (Figure 1).Figure 1.Patient with newly diagnosed metastatic melanoma to the left inguinal lymph node basin, asymptomatic but with multiple significant comorbidities. A positron emission tomography scan, obtained prior to therapeutic lymphadenectomy, demonstrated widespread metastatic disease. The patient opted for hospice care.SENTINEL LYMPH NODE BIOPSYOne of the most significant advances in melanoma management over the last decade is SLNB. The procedure, which requires the expertise of 3 services—nuclear medicine, surgery, and histopathology—has been refined considerably over the past decade and continues to improve. It is now standard care for intermediate-thickness melanoma at every major melanoma center in the United States (Table 2). There are, however, reasons to do and not to do SLNB.Table 2. Guidelines for Initial Workup/Staging Tests in Asymptomatic Patients With MelanomaMelanomaNational Comprehensive Cancer Network*UM Multidisciplinary Melanoma ClinicLocal disease <1.0 mmNo routine testsNo routine tests. Consider SLNB for selected patients (see Table 3)Local disease ≥1.0 mmSLNB if indicated CR, serum LDH measurement (optional)SLNB if indicated CR, serum LDH measurement (optional for lesion >4 mm, or >2 mm with ulceration)Regional disease (stage III)CR, serum LDH measurement, pelvic CT scan if inguinal nodes are involvedCR, serum LDH measurement, pelvic CT scan if inguinal nodes are involvedOther imaging studies if clinically indicatedOther imaging studies if clinically indicatedDistant disease (stage IV)CR, serum LDH measurementCR, serum LDH measurementConsider chest, abdomen, and pelvis CT scan and/or head MRIConsider chest, abdomen, and pelvis CT scan and/or head MRIOther imaging studies if clinically indicated or per clinical trialOther imaging studies if clinically indicated or per clinical trialAbbreviations: CR, chest radiograph; CT, computed tomographic; LDH, lactase dehydrogenase; MRI, magnetic resonance imaging; SLNB, sentinel lymph node biopsy; UM, University of Michigan.*The complete guidelines are available at: http://www.nccn.org/physician_gls/f_guidelines.html. Accessed June 5, 2003.Reasons to Do SLNBWhy do SLNB? Reasons to consider performing SLNB include prognosis and staging, early therapeutic lymph node dissection, identification of similar patient populations for entry into clinical trials, and consideration of adjuvant treatment.Sentinel lymph node (SLN) status is the most powerful independent prognostic factor predicting survival.Prognostic information is invaluable for therapeutic guidance, patient counseling, and management of emotional distress, but the greatest known benefit of SLNB in 2003 is accurate staging.Data from the randomized World Health Organization Elective Lymph Node Dissection (ELND) trial suggest that early therapeutic node dissection in patients with microscopic nodal disease may offer a survival benefit.This trial prospectively randomized patients to ELND or observation. No significant difference in overall survival was detected between the ELND and observation groups. However, approximately 80% of the patients had a predicted negative nodal status based on tumor thickness. This finding resulted in low statistical power between the study and control groups to detect survival differences that may have existed between patients with positive nodes. However, subset analysis of the patients with positive nodes, with only 20 to 25 patients in each group, demonstrated a significant survival difference. The 5-year survival rate of patients with positive nodes in the ELND group (micrometastasis) was 48%, compared with the 5-year survival rate of the observation group (macrometastasis), which was 27% (P= .04). Although this subset was too small for definitive conclusions, these results formulate the basis for hypothesis-driven research to determine if there truly is a survival benefit for micrometastatic lymph node detection. With SLNB, there exists a minimally invasive procedure to identify patients with microscopic nodal disease who may benefit from early therapeutic lymph node dissection while sparing those with negative nodes the morbidity of ELND.Sentinel lymph node biopsy facilitates the identification of more homogeneous cohorts of high-risk patients with stage IIB, IIC, or III disease for entry into adjuvant therapy clinical trials. Advancement in the area of adjuvant therapy depends on rigorous clinical trials with more homogeneous populations to better distinguish between natural disease course and therapeutic intervention. Adjuvant interferon alfa therapy is Food and Drug Administration-approved for high-risk melanoma but controversy remains regarding survival benefit. Better adjuvant therapies with fewer side effects are needed. Yet, SLNB results can help patients and oncologists in making the decision to initiate adjuvant interferon therapy.Reasons Not to Do SLNBThere are also reasons not to do SLNB. First, if the probability of a positive SLN is low, SLNB is not indicated because of minimal staging benefit, and because of a higher surgical risk and cost compared with wide local excision alone. Most melanomas, which have a thickness less than 1.0 mm, fall within this category.Second, no randomized prospective trials so far have demonstrated that SLNB improves survival, but an ongoing multicenter trial with 1600 patients randomized to wide local excision alone or wide local excision and SLNB is likely to answer this question. It can be argued that, even without survival benefit, SLNB is the best current staging test for patients appropriately selected, and that it is more cost-efficient than other staging tests for melanoma.Third, SLNB may not be indicated in patients with significant medical comorbidities, or whose risk in general anesthesia or potential need for therapeutic lymphadenectomy are higher than the benefit of staging information. Observation, with intervention following early clinical detection, is indicated in this population.Last, the accuracy of SLNB may be compromised following wide local excision of a primary melanoma, particularly in an ambiguous drainage location or following a flap for wound closure.Ideally, the wide local excision is performed in conjunction with SLNB.New ConceptsThe SLNB procedure has been extensively reviewed elsewhere. Several new and evolving concepts are worth mentioning. The utility and accuracy of SLNB for head and neck melanoma have been verified.The SLN identification rate and average number of SLNs harvested are similar for head and neck, trunk, and extremities. However, the head and neck region presents special challenges. It is 3-dimensional, and often contains SLNs deep under muscle, in the parotid basin, and/or adjacent to vital nerves. Facial nerve injury is a risk, but no facial nerve injuries were reported in a large series.Unlike in the trunk and extremities, SLNs in the head and neck region are often in close proximity to the primary cutaneous melanoma. Therefore, a wide local excision is usually performed prior to SLN harvest to prevent radioactive "shine through" from the primary melanoma site and obscure identification of the SLN. Radiocolloid is used preferentially to blue dye in the head and neck region. Recent reports have also demonstrated that SLNB can be performed with high accuracy in pediatric patients and for melanoma in unusual locations such as the eyelid and vulva.Sentinel lymph node biopsy has revolutionized our understanding of lymphatic pathways. The concepts of interval nodes and unexpected lymphatic drainage pathways have been addressed by several recent reports.Unusual lymphatic drainage pathways occur in unexpected locations (Figure 2). Interval nodes, which are located between the primary lesion and the primary nodal basin, occur in up to 12% of truncal melanomas (Figure 3). Interval SLNs contain metastatic disease with a frequency similar to that of SLNs in conventional basins. A preoperative lymphoscintogram identifies aberrant lymphatic drainage pathways and interval nodes. Thus, results from previous ELND trials can be questioned given the occurrence of dissecting the incorrect basin, missing interval nodes, and not using immunohistochemistry, which is standard for SLNB.Figure 2.A healthy 68-year-old woman presented with a melanoma 5.5 mm in depth at the deep margins, greater than 3 cm in diameter, and with ulceration on the left side of her back. A, Dynamic lymphoscintigraphy scan demonstrates multiple lymphatic drainage pathways in the axilla bilaterally, more prominent in the right than in the left side (posterior view). B, This 18-minute anterior view reveals bilateral sentinel lymph nodes. One of 4 sentinel lymph nodes in the right axilla were positive and 2 of 2 in the the left axilla were negative. A chest radiograph and measurement results for serum lactate dehydrogenase concentration ordered at another institution were normal. There was unusual drainage with metastasis from a primary lesion on the left side of the back to the right axilla.Figure 3.Melanoma, 1.43 mm in depth, on the right dorsal foot of a 35-year-old man. Preoperative lymphoscintogram demonstrates 2 lymphatic channels to both the popliteal (interval node) and inguinal basins. Four sentinel lymph node biopsy specimens from the popliteal basin and groin were negative. This case highlights the finding of interval nodes.Who should be counseled regarding SLNB? All studies to date verify that the probability of a positive SLN increases with increasing tumor thickness. The probability of a positive SLNB for melanomas less than 1.0 mm thick is less than 5%. The rate of SLN positivity increases to 10% for melanomas thicker than 1.5 mm, and to 30% to 50% for melanomas thicker than 4 mm.Other factors have been variably reported to be correlated with an increased probability of a positive SLNB. Ulceration status of the primary melanoma is the other best documented predictor of a positive SLNB. Some centers consider SLNB for lesions less than 1 mm thick if the Clark level is IV or higher. Younger age and higher mitotic rate have also been shown to be associated with a higher probability of a positive SLNB.Performing SLNB may be considered for melanomas less than 1 mm thick with ulceration, extensive regression to 1 mm in depth, young age of patient, and a higher mitotic rate in young patients (Table 3). Criteria for appropriate candidates for SLNB will certainly be refined and modified in the future, with new studies performed and additional information gained through molecular profiling and polymerase chain reaction. Following a positive SLNB result, a complete lymph node dissection is indicated. An average of 20% to 25% of patients with a positive SLN will have other positive nonsentinel nodes.Table 3. Indications for Consideration of Sentinel Lymph Node Biopsy in Patients With Clinically Localized Melanoma*Lesion ≥1.0 mmLesion <1.0 mm (0.75-1.0 mm) with any of the following:UlcerationExtensive vertical regression to at least 1.0 mmYoung patient ageHigh mitotic rate particularly in younger age*Primary melanoma location and location or number of predicted draining nodal basins should not be used as exclusion criteria. Older patient age is not a contraindication in the case of high-risk lesions.MELANOMA FOLLOW-UPThe patient with melanoma is at risk for local, regional, and distant recurrence and for additional primary melanoma. The risk of recurrence is primarily dependent on the stage of the disease. Any melanoma, including, very rarely, melanoma in situ, may metastasize.The cornerstone for melanoma follow-up is thorough history taking and physical examination, including a complete skin and lymph node examination with attention to the regional nodal basin. The skin is palpated for cutaneous and subcutaneous metastases, with focus between the primary site and regional lymph node basin and a high index of suspicion for lesions clinically appearing to be a "cyst" or "blue nevus." Approximately 5% to 10% of patients develop multiple primary melanomas, and a significant percentage of patients develop subsequent lesions decades after initial diagnosisand approximately 75% of these occur in a different anatomic region.Therefore, patients with melanoma need lifetime surveillance with total body skin examinations.Patients with cancer have significant psychosocial issues and those with melanoma are no exception. The largest series examining distress levels in 670 patients with stage I to III melanoma, showed approximately 30% of patients with moderate to high levels of distress independent of stage of disease.In addition to assessing psychosocial well-being and referring to appropriate support services, follow-up visits are an important opportunity for patient education. This includes review of monthly self-examination of skin and lymph nodes, sun protection strategies, the ABCD and 7-point checklist criteria, and the early signs and symptoms of melanoma (change in size, shape, or color, or persistent itching).Like initial workup, tests should be ordered based on findings from history taking and physical examination, and symptom-directed tests should be based on a low index of suspicion. Follow-up frequency guidelines vary but intervals generally range between 3 and 12 months (Table 4). More frequent visits may be warranted for patients with many atypical nevi or patients who have difficulty performing self-examinations. A team approach with a dermatologist and a primary care physician, internist, or medical oncologist can be beneficial.Table 4. Guidelines for Follow-up of Patients With MelanomaMelanomaNational Comprehensive Cancer Network*UM Multidisciplinary Melanoma ClinicIn situPeriodic skin examination for lifeSkin and node examination every 6 mo for 1 y, then annuallyLocal disease <1.0 mmSkin and node examination every 3-12 moSkin and node examination every 6 mo for 1 y, then annuallyLocal disease ≥1.0 mm with a negative SLNBSkin and node examination every 3-6 mo for 3 y, then every 4-12 mo for 2 y, then annuallySkin and node examination every 6 mo for 1 y, then annuallyCR, serum LDH, CBC every 3-12 mo (optional); CT scans as clinically indicatedLocal disease ≥1.0 mm with unknown SLN statusSkin and node examination every 3-6 mo for 3 y, then every 4-12 mo for 2 y, then annuallySkin and node examination every 6 mo for 3 y, then annuallyCR, serum LDH, CBC every 3-12 mo (optional); CT scans as clinically indicatedRegional disease (stage III)Skin and node examination every 3-6 mo for 3 y, then every 4-12 mo for 2 y, then annuallySkin and node examination every 6 mo for 3 y, then annuallyCR, serum LDH, CBC every 3-12 mo (optional); CT scans as clinically indicatedTests only if clinically indicated based on history and examinationDistant disease (stage IV)Per clinical trial protocol or at the discretion of the medical oncologistPer clinical trial protocol or at the discretion of the medical oncologistAbbreviations: CBC, complete blood cell count; CR, chest radiograph; CT, computed tomographic; LDH, lactase dehydrogenase; MRI, magnetic resonance imaging; SLNB, sentinel lymph node biopsy; UM, University of Michigan.*The complete guidelines are available at: http://www.nccn.org/physician_gls/f_guidelines.html.THE FUTURE OF MELANOMA STAGINGThe future of melanoma staging—which will determine workup and follow-up guidelines—will unfold at the molecular/genetic level (ultrastaging) using gene expression profiling. The first report of molecular profiling for melanoma, in 31 stage III and IV melanomas, examined the expression of approximately 8000 genes.Cluster analysis grouped melanomas with similar genetic profiles and 19 melanomas were identified as having similar gene expression. Analysis suggested a prognostic correlate, as most early patient deaths occurred in the nonclustered group of 12 melanomas. These results, while preliminary, offer a glimpse of the power of gene expression profiling to predict outcome and response to treatment and provide additional information for staging. Gene expression profiling has already advanced the management of some cancers such as oligodendroglioma, for which it is now standard care because it determines treatment and prognosis.The management of melanoma is evolving and will be propelled by advances in molecular biology and the search to unravel the genetic phenomena determining biologic behavior.SUMMARYBased on the existing knowledge in the field, the initial workup should be guided by cost-efficient tests with high sensitivity and high specificity for staging and prognosis. In 2003, SLNB, which fulfills these criteria, is the best staging test for patients at significant risk for occult nodal involvement. Furthermore, SLNB detects occult nodal disease and allows early intervention, which may have outcome benefit. Lymph node sonography and positron emission tomography may also detect occult potentially curable stage III disease, but they are less effective than SLNB. Survival benefit following therapeutic intervention has not been demonstrated in cases of asymptomatic or symptomatic stage IV melanoma. This argues against performing standard screening imaging and hematologic tests for occult distant metastases for survival purposes. Screening tests may be indicated in an attempt to detect occult distant disease (stage IV) prior to extensive, high-morbidity surgical procedures. 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Johnson, MD, University of Michigan Health System, 1910 Taubman Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0314 (e-mail: timjohn@med.umich.edu).Accepted for publication June 16, 2003.This work was presented at the annual meeting of the American Academy of Dermatology; March 21, 2003; San Francisco, Calif. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Dermatology American Medical Association

Staging Workup, Sentinel Node Biopsy, and Follow-up Tests for Melanoma

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American Medical Association
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Copyright 2004 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
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2168-6068
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2168-6084
DOI
10.1001/archderm.140.1.107
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14732667
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Abstract

ObjectivesTo clarify and update workup and follow-up strategies based on fundamental principles and current data, and to discuss new and current concepts regarding sentinel lymph node biopsy (SLNB), particularly in relation to the staging workup.Data SourcesStudies conducted from 1995 to 2003 were identified by PubMed search. Additional searches included workup for reference lists of retrieved articles when applicable, and PubMed-related articles.Study SelectionContemporary studies with good design, conclusions based on sound methods, and results pertaining to staging workup, SLNB, and follow-up tests were critically reviewed.Data ExtractionData and conclusions based on the above studies were incorporated into a review.Data SynthesisRoutine tests have marginal to no efficacy and are not cost-efficient for detecting occult disease in asymptomatic patients with localized melanoma. The only staging test that has relatively high sensitivity and specificity and provides tissue diagnosis is SLNB; moreover, SLNB has revolutionized our understanding of lymphatic pathways. The concepts of interval nodes and unexpected lymphatic drainage pathways have been addressed by several recent reports. There are no data that demonstrate any significant difference in overall survival for detection of asymptomatic vs symptomatic stage IV melanoma.ConclusionsAn initial workup is useful for staging and prognosis to identify occult disease, with potential outcome benefit if treated early; and, by detecting distant occult disease (stage IV), to obviate the need for an extensive surgical procedure and thereby avoid associated increased morbidity. The foundation for the workup and follow-up remains thorough history taking and a physical examination, combined with a low index of suspicion for symptom-directed tests.MELANOMA IS THE FIFTH most common cancer in men and the seventh most common in women.Most patients diagnosed with melanoma present with localized disease, and most are asymptomatic and without clinical findings for regional and/or distant disease. Although melanoma management continues to progress and change with new and emerging discovery, much is yet to elucidate in the field of melanoma. Workup and follow-up guidelines have continued to change in the past several years. This review is designed to clarify and update current workup and follow-up strategies based on fundamental principles and current data. Current concepts regarding sentinel lymph node biopsy (SLNB) are also discussed, particularly in relation to the staging workup.WHY PERFORM ROUTINE TESTS?In an asymptomatic patient, the following questions should define both the workup strategy and recommendations following a diagnosis of melanoma: What tests are to be performed? What information will be obtained? How accurate will the information be? How will the information be used for clinical management? What will the benefit be with respect to both clinical significance and cost? An initial workup is beneficial for staging and prognosis to identify occult disease, with potential outcome benefit if treated early; and, by detecting distant occult disease (stage IV), to obviate the need for an extensive surgical procedure with associated increased morbidity.StagingWhy is staging important for melanoma management? Staging is necessary to group patients into similar prognostic and management cohorts. Staging guides the clinician to better counsel the patient with respect to prognosis and treatment. Accurate staging also groups patients with a highly heterogeneous disease into more homogeneous populations for potential entry into better clinical trials. The universal language of cancer staging developed by the American Joint Committee on Cancer (AJCC) uses the TNM classification. The AJCC staging classification has changed 4 times in the past 15 years because of the need to incorporate new information gained from numerous studies in an ever-changing field. The current AJCC staging system for melanoma, implemented in 2002, is based on outcome data from 17 600 patients with melanoma.With its several major revisions, the new AJCC staging classification represents a significant improvement. Breslow thickness and ulceration define the T (tumor) category, and Clark level further defines only thin T1 (≤1-mm) melanomas. The number of positive lymph nodes and the tumor burden—either subclinical (microscopic) or clinically apparent (macroscopic) nodal metastases, rather than nodal size—define the N category. Using tumor burden (microscopic/macroscopic) as a determinant of the N category allows incorporation of SLNB results into staging. Ulceration of the primary lesion upstages patients with localized and regional nodal disease. The M category is defined by the sites of distant metastases and the presence of elevated serum lactate dehydrogenase.What tests are indicated for a staging workup following diagnosis? The foundation of the initial workup is still thorough history taking and physical examination. The history should incorporate a melanoma-focused review of systems(Table 1). A complete mucocutaneous and lymphatic examination is indicated, with attention to the entire skin surface and regional nodal basin. Should imaging and hematologic tests be used for staging tumors in asymptomatic patients? In the past, these tests have been performed with the intent of detecting clinically occult distant disease. Unfortunately, presently available standard screening imaging and hematologic tests lack both high sensitivity and high specificity. The numerous reports providing collective data on thousands of patients demonstrate that these tests have marginal to no efficacy and are not cost-efficient for detecting occult disease in asymptomatic patients with melanoma.The true-positive rate of a baseline chest radiograph in large series of asymptomatic patients who have melanoma ranges from 0% to 0.5%.The cost of simply performing a baseline chest radiograph for patients with a new diagnosis of localized melanoma in the United States in 2003, at an estimated cost of $100 per radiograph, approaches $5 million. Specificity with presently available standard screening imaging and hematologic studies is also low, with false-positive rates as high as 8% to 15%.False-positive tests often lead to additional tests and increased patient anxiety.Table 1. Melanoma-Focused Review of Systems*SystemSign/SymptomConstitutionalWeight loss, malaise, decreased appetite, weakness, fatigue, feverRespiratoryCough, hemoptysis, pneumonia, pleurisy, chest pain, dyspneaSkin/lymphaticColor change, "swollen glands," nonhealing/bleeding skin lesions, easy bruisingHepaticAbdominal pain, jaundice, pain radiated to the scapula with deep inspirationMusculoskeletalBone pain (eg, rib, spine, hip)GastrointestinalCramping, abdominal pain, bleeding, nausea, anorexia, vomiting, constipationNeurologicHeadache, memory disturbances, depression, focal central nervous system symptoms, visual disturbances, seizures, balance problems, blackouts, local weakness, numbness, paralysis, mood swings*Adapted from Johnson et al.Lymph node sonography and positron emission tomography have been used for early detection of occult regional nodal disease.In fact, these modalities may represent the most sensitive noninvasive tests to identify small lymph node metastases in patients with melanoma. However, for the initial workup of the asymptomatic patient with clinically localized melanoma at significant risk for nodal involvement, SLNB is more sensitive and more specific in detecting subclinical lymph node disease than either sonography or positron emission tomography.The gold standard for diagnosis remains histopathologic confirmation, and SLNB is the only staging test that provides tissue diagnosis.Outcome BenefitUnfortunately, in 2003, there are no data that demonstrate any significant difference in overall survival between asymptomatic and symptomatic stage IV melanoma.Prognosis is dismal in stage IV melanoma but some patients may benefit from surgical and/or systemic intervention, which can provide significant remission periods following diagnosis. Quality of life may also be adversely impacted by asymptomatic detection of stage IV disease, however. Because there is no intervention known to increase overall survival despite earlier detection of asymptomatic stage IV melanoma, patient and family bear the psychosocial burden longer. Detection of occult regional disease (stage III) may result in higher survival rates.Stage III survival is primarily determined by the number of positive nodes, the microscopic and macroscopic tumor burden in the nodes, and the ulceration status of the primary lesion.Fewer Extensive Surgical ProceduresAlthough low in sensitivity and specificity, imaging and hematologic tests can detect distant occult disease (stage IV), and they may be performed to prevent patients from undergoing extensive surgical procedures with potentially high morbidity. For example, detection of occult distant disease would obviate the need for a complete lymphadenectomy following a positive SLNB result. If a patient has widespread visceral disease, systemic therapy rather than extensive surgical intervention may be warranted (Figure 1).Figure 1.Patient with newly diagnosed metastatic melanoma to the left inguinal lymph node basin, asymptomatic but with multiple significant comorbidities. A positron emission tomography scan, obtained prior to therapeutic lymphadenectomy, demonstrated widespread metastatic disease. The patient opted for hospice care.SENTINEL LYMPH NODE BIOPSYOne of the most significant advances in melanoma management over the last decade is SLNB. The procedure, which requires the expertise of 3 services—nuclear medicine, surgery, and histopathology—has been refined considerably over the past decade and continues to improve. It is now standard care for intermediate-thickness melanoma at every major melanoma center in the United States (Table 2). There are, however, reasons to do and not to do SLNB.Table 2. Guidelines for Initial Workup/Staging Tests in Asymptomatic Patients With MelanomaMelanomaNational Comprehensive Cancer Network*UM Multidisciplinary Melanoma ClinicLocal disease <1.0 mmNo routine testsNo routine tests. Consider SLNB for selected patients (see Table 3)Local disease ≥1.0 mmSLNB if indicated CR, serum LDH measurement (optional)SLNB if indicated CR, serum LDH measurement (optional for lesion >4 mm, or >2 mm with ulceration)Regional disease (stage III)CR, serum LDH measurement, pelvic CT scan if inguinal nodes are involvedCR, serum LDH measurement, pelvic CT scan if inguinal nodes are involvedOther imaging studies if clinically indicatedOther imaging studies if clinically indicatedDistant disease (stage IV)CR, serum LDH measurementCR, serum LDH measurementConsider chest, abdomen, and pelvis CT scan and/or head MRIConsider chest, abdomen, and pelvis CT scan and/or head MRIOther imaging studies if clinically indicated or per clinical trialOther imaging studies if clinically indicated or per clinical trialAbbreviations: CR, chest radiograph; CT, computed tomographic; LDH, lactase dehydrogenase; MRI, magnetic resonance imaging; SLNB, sentinel lymph node biopsy; UM, University of Michigan.*The complete guidelines are available at: http://www.nccn.org/physician_gls/f_guidelines.html. Accessed June 5, 2003.Reasons to Do SLNBWhy do SLNB? Reasons to consider performing SLNB include prognosis and staging, early therapeutic lymph node dissection, identification of similar patient populations for entry into clinical trials, and consideration of adjuvant treatment.Sentinel lymph node (SLN) status is the most powerful independent prognostic factor predicting survival.Prognostic information is invaluable for therapeutic guidance, patient counseling, and management of emotional distress, but the greatest known benefit of SLNB in 2003 is accurate staging.Data from the randomized World Health Organization Elective Lymph Node Dissection (ELND) trial suggest that early therapeutic node dissection in patients with microscopic nodal disease may offer a survival benefit.This trial prospectively randomized patients to ELND or observation. No significant difference in overall survival was detected between the ELND and observation groups. However, approximately 80% of the patients had a predicted negative nodal status based on tumor thickness. This finding resulted in low statistical power between the study and control groups to detect survival differences that may have existed between patients with positive nodes. However, subset analysis of the patients with positive nodes, with only 20 to 25 patients in each group, demonstrated a significant survival difference. The 5-year survival rate of patients with positive nodes in the ELND group (micrometastasis) was 48%, compared with the 5-year survival rate of the observation group (macrometastasis), which was 27% (P= .04). Although this subset was too small for definitive conclusions, these results formulate the basis for hypothesis-driven research to determine if there truly is a survival benefit for micrometastatic lymph node detection. With SLNB, there exists a minimally invasive procedure to identify patients with microscopic nodal disease who may benefit from early therapeutic lymph node dissection while sparing those with negative nodes the morbidity of ELND.Sentinel lymph node biopsy facilitates the identification of more homogeneous cohorts of high-risk patients with stage IIB, IIC, or III disease for entry into adjuvant therapy clinical trials. Advancement in the area of adjuvant therapy depends on rigorous clinical trials with more homogeneous populations to better distinguish between natural disease course and therapeutic intervention. Adjuvant interferon alfa therapy is Food and Drug Administration-approved for high-risk melanoma but controversy remains regarding survival benefit. Better adjuvant therapies with fewer side effects are needed. Yet, SLNB results can help patients and oncologists in making the decision to initiate adjuvant interferon therapy.Reasons Not to Do SLNBThere are also reasons not to do SLNB. First, if the probability of a positive SLN is low, SLNB is not indicated because of minimal staging benefit, and because of a higher surgical risk and cost compared with wide local excision alone. Most melanomas, which have a thickness less than 1.0 mm, fall within this category.Second, no randomized prospective trials so far have demonstrated that SLNB improves survival, but an ongoing multicenter trial with 1600 patients randomized to wide local excision alone or wide local excision and SLNB is likely to answer this question. It can be argued that, even without survival benefit, SLNB is the best current staging test for patients appropriately selected, and that it is more cost-efficient than other staging tests for melanoma.Third, SLNB may not be indicated in patients with significant medical comorbidities, or whose risk in general anesthesia or potential need for therapeutic lymphadenectomy are higher than the benefit of staging information. Observation, with intervention following early clinical detection, is indicated in this population.Last, the accuracy of SLNB may be compromised following wide local excision of a primary melanoma, particularly in an ambiguous drainage location or following a flap for wound closure.Ideally, the wide local excision is performed in conjunction with SLNB.New ConceptsThe SLNB procedure has been extensively reviewed elsewhere. Several new and evolving concepts are worth mentioning. The utility and accuracy of SLNB for head and neck melanoma have been verified.The SLN identification rate and average number of SLNs harvested are similar for head and neck, trunk, and extremities. However, the head and neck region presents special challenges. It is 3-dimensional, and often contains SLNs deep under muscle, in the parotid basin, and/or adjacent to vital nerves. Facial nerve injury is a risk, but no facial nerve injuries were reported in a large series.Unlike in the trunk and extremities, SLNs in the head and neck region are often in close proximity to the primary cutaneous melanoma. Therefore, a wide local excision is usually performed prior to SLN harvest to prevent radioactive "shine through" from the primary melanoma site and obscure identification of the SLN. Radiocolloid is used preferentially to blue dye in the head and neck region. Recent reports have also demonstrated that SLNB can be performed with high accuracy in pediatric patients and for melanoma in unusual locations such as the eyelid and vulva.Sentinel lymph node biopsy has revolutionized our understanding of lymphatic pathways. The concepts of interval nodes and unexpected lymphatic drainage pathways have been addressed by several recent reports.Unusual lymphatic drainage pathways occur in unexpected locations (Figure 2). Interval nodes, which are located between the primary lesion and the primary nodal basin, occur in up to 12% of truncal melanomas (Figure 3). Interval SLNs contain metastatic disease with a frequency similar to that of SLNs in conventional basins. A preoperative lymphoscintogram identifies aberrant lymphatic drainage pathways and interval nodes. Thus, results from previous ELND trials can be questioned given the occurrence of dissecting the incorrect basin, missing interval nodes, and not using immunohistochemistry, which is standard for SLNB.Figure 2.A healthy 68-year-old woman presented with a melanoma 5.5 mm in depth at the deep margins, greater than 3 cm in diameter, and with ulceration on the left side of her back. A, Dynamic lymphoscintigraphy scan demonstrates multiple lymphatic drainage pathways in the axilla bilaterally, more prominent in the right than in the left side (posterior view). B, This 18-minute anterior view reveals bilateral sentinel lymph nodes. One of 4 sentinel lymph nodes in the right axilla were positive and 2 of 2 in the the left axilla were negative. A chest radiograph and measurement results for serum lactate dehydrogenase concentration ordered at another institution were normal. There was unusual drainage with metastasis from a primary lesion on the left side of the back to the right axilla.Figure 3.Melanoma, 1.43 mm in depth, on the right dorsal foot of a 35-year-old man. Preoperative lymphoscintogram demonstrates 2 lymphatic channels to both the popliteal (interval node) and inguinal basins. Four sentinel lymph node biopsy specimens from the popliteal basin and groin were negative. This case highlights the finding of interval nodes.Who should be counseled regarding SLNB? All studies to date verify that the probability of a positive SLN increases with increasing tumor thickness. The probability of a positive SLNB for melanomas less than 1.0 mm thick is less than 5%. The rate of SLN positivity increases to 10% for melanomas thicker than 1.5 mm, and to 30% to 50% for melanomas thicker than 4 mm.Other factors have been variably reported to be correlated with an increased probability of a positive SLNB. Ulceration status of the primary melanoma is the other best documented predictor of a positive SLNB. Some centers consider SLNB for lesions less than 1 mm thick if the Clark level is IV or higher. Younger age and higher mitotic rate have also been shown to be associated with a higher probability of a positive SLNB.Performing SLNB may be considered for melanomas less than 1 mm thick with ulceration, extensive regression to 1 mm in depth, young age of patient, and a higher mitotic rate in young patients (Table 3). Criteria for appropriate candidates for SLNB will certainly be refined and modified in the future, with new studies performed and additional information gained through molecular profiling and polymerase chain reaction. Following a positive SLNB result, a complete lymph node dissection is indicated. An average of 20% to 25% of patients with a positive SLN will have other positive nonsentinel nodes.Table 3. Indications for Consideration of Sentinel Lymph Node Biopsy in Patients With Clinically Localized Melanoma*Lesion ≥1.0 mmLesion <1.0 mm (0.75-1.0 mm) with any of the following:UlcerationExtensive vertical regression to at least 1.0 mmYoung patient ageHigh mitotic rate particularly in younger age*Primary melanoma location and location or number of predicted draining nodal basins should not be used as exclusion criteria. Older patient age is not a contraindication in the case of high-risk lesions.MELANOMA FOLLOW-UPThe patient with melanoma is at risk for local, regional, and distant recurrence and for additional primary melanoma. The risk of recurrence is primarily dependent on the stage of the disease. Any melanoma, including, very rarely, melanoma in situ, may metastasize.The cornerstone for melanoma follow-up is thorough history taking and physical examination, including a complete skin and lymph node examination with attention to the regional nodal basin. The skin is palpated for cutaneous and subcutaneous metastases, with focus between the primary site and regional lymph node basin and a high index of suspicion for lesions clinically appearing to be a "cyst" or "blue nevus." Approximately 5% to 10% of patients develop multiple primary melanomas, and a significant percentage of patients develop subsequent lesions decades after initial diagnosisand approximately 75% of these occur in a different anatomic region.Therefore, patients with melanoma need lifetime surveillance with total body skin examinations.Patients with cancer have significant psychosocial issues and those with melanoma are no exception. The largest series examining distress levels in 670 patients with stage I to III melanoma, showed approximately 30% of patients with moderate to high levels of distress independent of stage of disease.In addition to assessing psychosocial well-being and referring to appropriate support services, follow-up visits are an important opportunity for patient education. This includes review of monthly self-examination of skin and lymph nodes, sun protection strategies, the ABCD and 7-point checklist criteria, and the early signs and symptoms of melanoma (change in size, shape, or color, or persistent itching).Like initial workup, tests should be ordered based on findings from history taking and physical examination, and symptom-directed tests should be based on a low index of suspicion. Follow-up frequency guidelines vary but intervals generally range between 3 and 12 months (Table 4). More frequent visits may be warranted for patients with many atypical nevi or patients who have difficulty performing self-examinations. A team approach with a dermatologist and a primary care physician, internist, or medical oncologist can be beneficial.Table 4. Guidelines for Follow-up of Patients With MelanomaMelanomaNational Comprehensive Cancer Network*UM Multidisciplinary Melanoma ClinicIn situPeriodic skin examination for lifeSkin and node examination every 6 mo for 1 y, then annuallyLocal disease <1.0 mmSkin and node examination every 3-12 moSkin and node examination every 6 mo for 1 y, then annuallyLocal disease ≥1.0 mm with a negative SLNBSkin and node examination every 3-6 mo for 3 y, then every 4-12 mo for 2 y, then annuallySkin and node examination every 6 mo for 1 y, then annuallyCR, serum LDH, CBC every 3-12 mo (optional); CT scans as clinically indicatedLocal disease ≥1.0 mm with unknown SLN statusSkin and node examination every 3-6 mo for 3 y, then every 4-12 mo for 2 y, then annuallySkin and node examination every 6 mo for 3 y, then annuallyCR, serum LDH, CBC every 3-12 mo (optional); CT scans as clinically indicatedRegional disease (stage III)Skin and node examination every 3-6 mo for 3 y, then every 4-12 mo for 2 y, then annuallySkin and node examination every 6 mo for 3 y, then annuallyCR, serum LDH, CBC every 3-12 mo (optional); CT scans as clinically indicatedTests only if clinically indicated based on history and examinationDistant disease (stage IV)Per clinical trial protocol or at the discretion of the medical oncologistPer clinical trial protocol or at the discretion of the medical oncologistAbbreviations: CBC, complete blood cell count; CR, chest radiograph; CT, computed tomographic; LDH, lactase dehydrogenase; MRI, magnetic resonance imaging; SLNB, sentinel lymph node biopsy; UM, University of Michigan.*The complete guidelines are available at: http://www.nccn.org/physician_gls/f_guidelines.html.THE FUTURE OF MELANOMA STAGINGThe future of melanoma staging—which will determine workup and follow-up guidelines—will unfold at the molecular/genetic level (ultrastaging) using gene expression profiling. The first report of molecular profiling for melanoma, in 31 stage III and IV melanomas, examined the expression of approximately 8000 genes.Cluster analysis grouped melanomas with similar genetic profiles and 19 melanomas were identified as having similar gene expression. Analysis suggested a prognostic correlate, as most early patient deaths occurred in the nonclustered group of 12 melanomas. These results, while preliminary, offer a glimpse of the power of gene expression profiling to predict outcome and response to treatment and provide additional information for staging. Gene expression profiling has already advanced the management of some cancers such as oligodendroglioma, for which it is now standard care because it determines treatment and prognosis.The management of melanoma is evolving and will be propelled by advances in molecular biology and the search to unravel the genetic phenomena determining biologic behavior.SUMMARYBased on the existing knowledge in the field, the initial workup should be guided by cost-efficient tests with high sensitivity and high specificity for staging and prognosis. In 2003, SLNB, which fulfills these criteria, is the best staging test for patients at significant risk for occult nodal involvement. Furthermore, SLNB detects occult nodal disease and allows early intervention, which may have outcome benefit. Lymph node sonography and positron emission tomography may also detect occult potentially curable stage III disease, but they are less effective than SLNB. 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profiling.Nature.2000;406:536-540.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10952317&dopt=AbstractJGCairncrossKUekiMCZlatescuSpecific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas.J Natl Cancer Inst.1998;90:1473-1579.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9776413&dopt=AbstractCLNuttDRManiRABetenskyGene expression-based classification of malignant gliomas correlates better with survival than histological classification.Cancer Res.2003;63:1602-1607.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12670911&dopt=AbstractCorresponding author: Timothy M. Johnson, MD, University of Michigan Health System, 1910 Taubman Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0314 (e-mail: timjohn@med.umich.edu).Accepted for publication June 16, 2003.This work was presented at the annual meeting of the American Academy of Dermatology; March 21, 2003; San Francisco, Calif.

Journal

JAMA Dermatology – American Medical Association

Published: Jan 1, 2004

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