There is no clear consensus on the best means of detecting melanoma, particularly recurrence of melanoma. Physical examination remains paramount, but other means have been recommended also. This article provides a survey of these means.
Initial evaluation of the patient suspected of having a melanoma consists of a thorough physical examination. If a suspicious lesion is identified, palpation of the nearby regional lymph node basins should be performed to assess for clinical adenopathy. For lesions on an extremity, the ipsilateral axillary (upper extremity) or inguinal (lower extremity) should be examined. For lesions in the head and neck, the parotid and cervical nodes should be evaluated. For lesions on the trunk, bilateral axillary and inguinal nodal basins should be examined, as multiple studies have demonstrated that the first draining node for a cutaneous area is not necessarily the closest nodal basin by distance, and multiple nodal basins may drain a cutaneous area.
The American Joint Committee on Cancer (AJCC) groups primary tumor (T) staging based on thickness of the tumor and ulceration. Surveillance recommendations by the AJCC by stage are as follows:
Stage 0—patient education, follow-up with primary doctor annually as part of any patient’s annual physical examination
Stage 1—patient education; baseline chest radiograph; baseline complete blood cell count (CBC), liver function test (LF),T and lactate dehydrogenase (LDH); history and physical examination every 6 to 12 months for 3 years, then annually thereafter; further imaging studies or laboratory studies as indicated
Stage 2A—patient education; baseline CBC, LFT, and LDH and then annually for life; baseline chest radiograph; history, physical examination and chest radiograph every 6 to 12 months for 3 years, then annually; further imaging and laboratory testing as indicated
Stage 2B/C—patient education; baseline CBC, LFT, and LDH and then every 6 months for 5 years, then annually for life; baseline chest radiograph and then every 6 to 12 months for 3 years then annually; history and physical examination every 6 months for 5 years then annually; baseline computed tomography (CT) chest/abdomen/pelvis; further imaging and laboratory testing as indicated
Stage 3—patient education; baseline CBC, LFT, LDH, with surveillance labs every 6 months for 5 years, then annually for life; baseline chest radiograph, then every 6 months for 5 years, then annually; history and physical examination every 6 months for 5 years then annually thereafter; baseline CT chest/abdomen/pelvis; Further imaging and laboratory testing as indicated
Stage 4—individualized
For ulcerated lesions, the measured distance from the base of the ulcer to the deepest point of invasion is recorded as the thickness of the lesion; one should not construct an imaginary line to represent the superficial limit of the lesion before ulceration or alter the actual measured thickness in any manner. Lesions without ulceration and less than or equal to 1.0 mm thick are characterized further by Clark’s level ; such lesions that abut the junction of the papillary and reticular dermis but have not violated the reticular dermis are classified as T1A. Invasion into the reticular dermis or ulceration for lesions less than or equal to 1.0 mm changes the classification to T1B. Lesions 1.01 to 2.0 mm, 2.01 to 4.0 mm, and greater than 4.0 mm are placed into T2, T3, and T4 groups, respectively. For T2 to T4 lesions, the presence of ulceration changes the T classification to subgroup b (eg, a 1.5 mm ulcerated lesion would be characterized as T2B), whereas nonulcerated lesions are in subgroup A. Clark’s level has no impact on T staging for lesions greater than 1.0 mm thick.
In the AJCC system, patients then are staged based on initial tumor, nodal status, and metastatic disease. Patients are staged both clinically at the initiation of treatment, and later pathologically, based on microscopic evaluation of sentinel lymph node(s) or completion lymph node dissection specimens. Clinical stage 3 disease groups all patients with nodal disease together, whereas pathologic staging stratifies stage 3 patients based on the number of positive nodes and whether these nodes are clinically identifiable as involved or only by microscopic Hematoxylin and Eosin (H&E) assessment. Patients with fewer nodes that are only identifiable by microscopic assessment have better survival than those with more positive nodes or clinically identifiable lymph node disease. Patients with distant metastases, those with skin, subcutaneous, or distant lymph node disease (M1) were noted to have better survival with those with lung (M2) or other visceral sites of disease (M3). Elevation of serum LDH was noted to be a poor prognostic indicator regardless of location of the metastasis, and patients with this finding also are included in the M3 group. A complete discussion of the AJCC staging of melanoma is beyond the scope of this article.
Evaluation of the primary lesion
Initial pathologic assessment of the primary lesion is performed by full-thickness biopsy. It is imperative that any lesion suspicious for melanoma be biopsied in a full-thickness fashion. Shave biopsies that demonstrate melanoma often have positive deep margins, and it may not be possible to obtain a proper full-thickness biopsy once shave biopsy has been performed. Staging for these patients, assuming node and metastases assessment is negative, becomes impossible because of an inability to obtain accurate assessment of the lesion’s thickness. This problem is completely avoidable by obtaining a full-thickness initial biopsy. For patients with localized melanoma, tumor thickness and ulceration were the two most powerful predictors of outcome.
Whenever possible, excisional biopsy is ideal for evaluating pigmented lesions. If the lesion is negative for melanoma, treatment is complete. If positive for melanoma, width of the re-excision depends on depth of the lesion. In cosmetically sensitive areas, or areas where primary closure of an excisional biopsy would not be possible, incisional biopsy is an appropriate alternative. For any such initial biopsy, the surgeon should plan the incision with local geography (relaxed skin tension lines, facial aesthetic subunits) and possible future treatments in mind.
Patients with no evidence of distant disease by history or clinical examination and in situ or T1a disease require close clinical follow-up, but most authors do not advocate further intervention. Multiple studies have demonstrated no benefit to serologic or radiographic evaluation in these patients. Patients should be re-examined at least annually for the rest of their lives. Multiple studies have advocated sentinel node biopsy for T1A lesions if the lesion has certain characteristics on light microscopy.
Sentinel lymph node biopsy
Sentinel lymph node (SLN) biopsy is generally advocated for patients with clinical stage 1B or 2 disease. Further evaluation for patients with palpable adenopathy or distant disease will be discussed later. SLN identification is performed in the standard manner with radiolabeled tracer before surgery and a colored lymphatic tracer intraoperatively. Multiple studies have demonstrated near 100% ability to identify one or more SLNs. Because up to 80% of patients with stage 1B or 2 disease do not have positive SLN, these patients can be spared the morbidity of lymph node dissection that would not be expected to provide them any benefit. Zogakis and colleagues reported disease-free survival and overall survival of 88% and 93% respectively in 773 patients with negative SLN biopsies. The subset of patients with thick, ulcerated primary lesions in the head and neck did notably poorer than the overall group.
Patients who have at least one SLN typically then undergo completion lymph node dissection for therapeutic benefit. Interestingly, a large, multi-institutional series failed to demonstrate any detriment to recurrence risk or survival in patients with positive SLN biopsy who did not undergo completion dissection. In addition, several authors caution against the risk of false-positive SLN biopsy if the immunohistochemical staining results are not well correlated with the H&E assessment, or if the results are not evaluated in the context of the clinical picture.
The clinical utility of SLN biopsy in patients with melanomas greater than or equal to 4 mm thick but no clinical adenopathy or distant disease (stages 2B and C) is somewhat controversial. Multiple studies, however, have demonstrated value of SLN assessment for prognosis and directing further treatment.
Sentinel lymph node biopsy
Sentinel lymph node (SLN) biopsy is generally advocated for patients with clinical stage 1B or 2 disease. Further evaluation for patients with palpable adenopathy or distant disease will be discussed later. SLN identification is performed in the standard manner with radiolabeled tracer before surgery and a colored lymphatic tracer intraoperatively. Multiple studies have demonstrated near 100% ability to identify one or more SLNs. Because up to 80% of patients with stage 1B or 2 disease do not have positive SLN, these patients can be spared the morbidity of lymph node dissection that would not be expected to provide them any benefit. Zogakis and colleagues reported disease-free survival and overall survival of 88% and 93% respectively in 773 patients with negative SLN biopsies. The subset of patients with thick, ulcerated primary lesions in the head and neck did notably poorer than the overall group.
Patients who have at least one SLN typically then undergo completion lymph node dissection for therapeutic benefit. Interestingly, a large, multi-institutional series failed to demonstrate any detriment to recurrence risk or survival in patients with positive SLN biopsy who did not undergo completion dissection. In addition, several authors caution against the risk of false-positive SLN biopsy if the immunohistochemical staining results are not well correlated with the H&E assessment, or if the results are not evaluated in the context of the clinical picture.
The clinical utility of SLN biopsy in patients with melanomas greater than or equal to 4 mm thick but no clinical adenopathy or distant disease (stages 2B and C) is somewhat controversial. Multiple studies, however, have demonstrated value of SLN assessment for prognosis and directing further treatment.
Positive SLN biopsy and clinical adenopathy
Patients with positive SLN biopsy typically undergo completion dissection of the involved nodal basin(s). Patients with palpable lymph nodes, particularly if the primary melanoma is thin or nonulcerated, present a clinical dilemma, as the adenopathy may not be related to the melanoma. Multiple authors have advocated ultrasound-guided fine needle aspiration (FNA) to evaluate these nodes. The presence of melanoma in these nodal aspirations mandates completion nodal dissection. Open biopsy of palpable nodes is also an option for patients with clinically palpable adenopathy to determine if completion node dissection is necessary. After nodal assessment is completed (either by SLN biopsy, or completion dissection, if performed), patients with stage 3 clinical disease will be placed into subgroups (A to C) based on the number of nodes or if macroscopic disease is present.
A major reason for the interest in reducing the frequency of completion lymph node dissection is the significant morbidity associated with the procedure. Completion lymph node dissection is performed much less frequently since the introduction of SLN evaluation for melanoma. Patients are at risk for several complications from this procedure, including wound problems and lymphedema. Sabel and colleagues found that risk of lymphedema (42% vs 24%) and major wound problems (28% vs 14%) was notably higher for patients undergoing completion lymph node dissection for clinically palpable disease than for positive SLN, although no increased risk of nodal recurrence was identified for the clinically palpable group. Serpell and colleagues noted a higher complication rate (71% vs 47%) for inguinal node dissection than for axillary node dissection. Roaten and colleagues reported a 19.5% overall complication rate for patients undergoing completion lymph node dissection, although 5.9% of their SLN biopsy patients had complications including seroma and transient nerve injury. They correlated removal of two or more nodes and placement of a closed suction drain with increased complications in the sentinel lymph node biopsy group.
Imaging and laboratory evaluation
Multiple studies have been evaluated for the evaluation of distant disease in melanoma patients. Chest radiograph has been evaluated by multiple studies as a screening tool for metastatic disease. All of the previously mentioned studies demonstrated no survival benefit for chest radiograph evaluation in asymptomatic melanoma patients. These studies also demonstrated notably high incidences of false-positive findings (abnormal findings that did not represent metastatic melanoma). Further evaluation of these chest radiograph findings led to significant cost and heightened anxiety in the patients evaluated.
Other imaging modalities, including positron emission tomography (PET) and CT scanning also have been evaluated as staging tools for melanoma, both for distant metastases and for occult lymph node disease. Multiple studies have demonstrated poor sensitivity and high cost for these techniques as screening tools.
Serologic evaluation also has been considered for melanoma patients to evaluate for occult distant disease and to detect recurrence. Nonspecific markers such as LDH have been shown not to be of benefit in identifying occult distant disease. Melanoma-specific markers such as tyrosinase and Melanoma Antigen Recognized by T-cells-1 have shown promise in identifying occult disease and detecting disease progression. A large, prospective, multi-institutional study of molecular staging of melanoma with these markers, however, did not demonstrate any additional prognostic benefit to patients. There are no established guidelines regarding which patients, what time points, and which markers should be used; these serologic markers remain purely investigational tools at this time.
Although melanoma patients presenting without symptoms to suggest distant disease should not undergo imaging or serologic workup routinely, those patients presenting with symptoms suggestive of distant disease should be worked up as appropriate for the organ system in question. In this patient population, distant disease may be identified by symptom-directed workup. These patients may be eligible for medical or surgical treatment of their distant disease, which may prolong their survival.
Postoperative surveillance of patients with cutaneous malignant melanoma
Postoperative surveillance of patients who have been treated for melanoma is clearly important as evidenced by the frequent reoccurrence of primary melanomas or the development of additional primary melanomas. Early detection of melanoma and recurrence thereof is the most important factor in regards to overall prognosis.
Despite extensive research on the topic, there is little agreement as to what optimal surveillance is. Many questions remain as to how frequently patients should be examined, for how long they should be followed, and to what extent laboratory tests and imaging studies should be used. The specific staging of a melanoma patient also will impact the degree of surveillance needed to adequately follow a patient. Melanoma incidence is increasing; optimal surveillance can offer several advantages not only for patients, but also for the health care system.
Impact of staging on surveillance
It generally is agreed upon that patients with a melanoma in situ have low risk with regards to local, regional, or distant spread. High-risk patients, however, are those who have been diagnosed with invasive melanoma (AJCC stage 1 or higher) or those with a sporadic or familial dysplastic nevus syndrome. These are the patients in need of surveillance. Lifelong follow-up is needed for these patients, but there is no consensus on the frequency of follow-up or the methods of surveillance.
The most common sites of distant spread in patients with melanoma are: distant skin, subcutaneous tissue or lymph nodes (42% to 59%), lungs (18% to 36%), liver (14% to 20%), brain (12% to 20%), bone (11% to 17%) and gastrointestinal (GI) system (1% to 7%). Christianson and Anderson reported that the overall 3-year survival rate in patients with AJCC stage 1 or 2 was 76% for those whose metastases were discovered early, as opposed to 38% for those whose metastases were discovered late. For stage 3 patients, the survival rate was 60% versus 18% for early versus late discovery of metastases, respectively. Most recurrences and metastases occur within the first 3 years. Mooney and colleagues reported that most recurrences occur in the first 2 years and that most are local or regional and not systemic. They went on to suggest that systemic surveillance such as chest radiographs should not be used more frequently than every 6 months for the first 2 years for better cost-effectiveness. Further, Mooney and colleagues recommended that surveillance cease after 5 to 10 years if the patient remains disease-free. Recurrence after 10 years is infrequent (about 3%) and occurs with approximately equal frequency between local, regional, and distant involvement. Christianson and Anderson reported the median time intervals and ranges between initial visits and diagnosis of recurrences according to AJCC staging:
Stage 1 had a median recurrence of 22 months (range of 2.0 to 60.5 months).
Stage 2 had a median recurrence of 13.2 months (range of 2.0 to 71.0 months)
Stage 3 had a median recurrence of 10.6 months (range 2.3 to 53.8 months).
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