Does This Patient Have a Mole or a Melanoma?

A patient presenting to your office informs you that he is concerned about a mole on his arm. Although he's not sure how long the mole has been present, he tells you that recently it has enlarged and looks different. As you begin the examination, you also notice the presence of several other moles and ask yourself, "Is this lesion a benign mole or a malignant melanoma?"

The incidence rate of malignant melanoma, once considered a rare malignancy, has increased dramatically in recent decades. In 1930, the lifetime risk of an individual in the United States developing melanoma was 1 in 1500. Estimates placed the lifetime risk in 1996 at 1 in 87 with a projected risk of 1 in 75 by the year 2000.¹ This increased incidence is important because, unlike the more common nonmelanoma skin cancers (basal cell carcinoma and squamous cell carcinoma), melanoma is much more likely to cause death. Six of 7 skin cancer deaths are from melanoma.² While risk generally increases with age, melanoma often occurs in young adulthood. In fact, it is the most common reported malignancy in whites between ages 25 and 29 years.³ The median age of onset for superficial spreading melanoma, which is by far the most common type of melanoma, is 44 years.⁴ Thus, a deadly melanoma can strike during early adulthood resulting in decades of potential life lost.

Metastatic potential and death from melanoma are related to the tumor's level of invasion. The prognosis of melanoma is approximated by relating it to the thickness of the tumor at the time of excision. Melanoma that is confined to the epidermis (in situ) is greater than 99% curable.⁵ Patients with thin lesions (thickness <0.75 mm) have a 5-year survival rate of greater than 98%, whereas those with thicker lesions (>4 mm) have a less than 50% survival rate.⁶ The prognosis is grim for metastatic disease. Nodal metastatic disease has a 36% 5-year survival rate, which decreases to only 5% with the presence of distant metastases.⁷ Thus, the importance of the physical examination is clear; if thin melanomas are detected and excised, a cure is likely, whereas undetected progression of the tumor markedly decreases a patient's chance of survival.

Benign moles and melanoma arise from a cell normally present in the basal layer of the epidermis called a melanocyte. The melanocyte produces melanin, which results in skin pigmentation. Alterations in melanin production result in different pigmentary characteristics.

While melanocytes normally exist as solitary units, in moles or nevi they exist as collections of cells. These include junctional nevi, which are grouped collections of epidermal melanocytes, compound nevi, which are epidermal and dermal collections of melanocytes, and intradermal nevi, which are dermal collections of melanocytes. There also exists a spectrum of nevi that have a variable degree of atypia termed atypical or dysplastic nevi.

Melanomas, because of their loss of normal growth controls, have changing features and tend to grow in an irregular manner leading to asymmetry, irregular borders, and haphazard coloration. This contrasts with benign nevi that are characteristically more stable, tend to be symmetric, have well-defined borders, and have even-color distribution. However, these features are not absolute and caution is warranted particularly when change has been noted.

History plays an important role in the examination of the skin for melanoma. Patients should be asked whether they have noted any lesions of concern, particularly any new moles or a change in size, shape, color, or sensation of a preexisting mole. This is critical information since approximately one half of melanomas are initially discovered by the patient.⁸ Changes in size and/or color are the 2 most common patient-reported features of melanoma.^{9 - 11} Bleeding, tenderness or pain, and itching are also reported, although these features occur in more invasive lesions.⁹ Patients should also be asked about a personal or family history of melanoma. The results of previous skin biopsies and any history of nonmelanoma skin cancer should also be assessed. The patient's tendency to burn and history of prior sunburns may also help assess risk. The presence of focal or systemic symptoms or the presence of any lumps or bumps under the skin should be addressed, particularly in a patient with a history of a cutaneous malignancy.

To examine for melanoma, the entire skin surface should be inspected. Melanoma can occur anywhere on the skin and may develop in sun-protected areas. Patients who undergo complete cutaneous examinations are 6.4 times more likely to have a melanoma detected than patients receiving only a partial examination.¹² The patient should be examined head to toe in a well-lit room. A gown may be used and removed incrementally to evaluate various regions of the patient's entire body surface. The examination of the patient's scalp may be aided by sequentially parting the hair or by the use of a handheld hair dryer. The oral mucosa, genital area, nails, and the skin between the toes should be included in the inspection for evidence of pigmented lesions.

When examining the patient, it is also important to make a global assessment of his or her skin. For example, if your patient has multiple nevi, those nevi may have relatively uniform characteristics. However, if 1 of the moles has unusual features that are dissimilar to other nevi, that lesion should be more closely examined. In the same manner, a single pigmented lesion occurring in a patient without other nevi should be evaluated with an increased level of concern. Patients at high risk for melanoma appear to be those with numerous nevi, those with nevi with atypical features, and particularly those with a family history of melanoma.^{13 - 15} In patients with an increased risk of melanoma, regular skin examinations may result in melanoma detection at an earlier, thinner stage.^{16 - 19}

In the United States, the ABCD checklist for detecting cutaneous melanoma is recommended as a means for distinguishing benign lesions from melanoma.²⁰ The criteria making up the ABCD checklist are all physical examination features: (1) if the lesion is bisected one half is not identical to the other half, asymmetry (A); (2) when the border is uneven or ragged as opposed to smooth and straight, border irregularity (B); (3) when more than 1 shade of pigment is present, color variegation (C); and (4) when the diameter is greater than 6 mm, diameter (D).

Lesions that have these features are considered to potentially represent a melanoma. Although not incorporated into the ABCD checklist, Friedman et al²⁰ state that historical features of a changing, preexisting pigmented nevus or the development of a new pigmented lesion should alert the physician to the possibility of malignant melanoma. An amendment to the checklist that adds an E, representing an elevation above the skin surface, has been proposed.²¹ However, since many benign nevi are elevated and elevation may not be apparent in early melanoma, this criterion is often excluded.

A second checklist is the revised 7-point checklist used in the United Kingdom.²² Three major criteria, all historical features, and 4 minor criteria, primarily physical examination features, are used to evaluate lesions suggestive of melanoma. The checklist was developed mainly for use by primary care physicians to assist them in making referral decisions. The major criteria are change in size, shape, and color; the minor criteria are inflammation, crusting or bleeding, sensory change, and a diameter greater than or equal to 7 mm.

One interpretation of this guideline states that the major criteria are the basis for determining referral decisions.²² Any patient with at least 1 major sign should be referred to a dermatologist. The revised 7-point checklist has also been given a slightly different interpretation with change in shape replaced by irregular shape (or appearance of irregularity in an old lesion), change in color replaced by irregular color, and a greater importance placed on the minor criteria.^{23 - 24} A scoring system assigns 2 points for each major criteria and 1 point for each minor criteria. If a score of 3 points or more is noted then a referral for lesion evaluation was suggested.

The gold standard for the diagnosis of melanoma is the histopathological evaluation of excised tissue.

A literature search was performed using MEDLINE for the years 1966 through 1996. Medical subject heading terms melanoma and skin neoplasms were combined with physical examination, sensitivity, specificity, observer variation, mass screening, and self-examination, yielding approximately 713 citations. In addition, a MEDLINE search was performed with the search strategy developed for this series of articles, which yielded 659 citations. Titles, abstracts, and relevant articles were reviewed in their entirety. Current Contents was reviewed using the terms melanoma, skin cancer, and mass screening to search for more current manuscripts. References for manuscripts found by the search strategy and other manuscripts pertaining to melanoma were systematically reviewed for additional literature sources.

The quality of the published articles was evaluated as previously described.²⁵ For studies that assessed accuracy, 20 articles were reviewed. The 95% confidence intervals (CIs) reported here, when not reported in the original articles, were calculated from the available data when possible for test performance characteristics. Studies were included if the level of evidence was graded as C or above. Lack of independence between the reference standard and the test, leading to verification bias, occurs in the existing literature. Another methodological issue relates to the nature of the reference standard, namely histological tissue obtained by biopsy. The decision to perform a skin biopsy requires clinical judgment since a biopsy specimen is not obtained for all patients with skin lesions. This requires utilizing follow-up examinations, multiple examiners, or even consensus opinion to ascertain the diagnosis. No existing studies were given a quality score of A or B; thus, all 12 studies graded as C were included.

Two studies have evaluated examiners' precision for specific features of benign pigmented lesions, which include 4 of the features found in the ABCD(E) checklist. Physicians examining the most atypical pigmented lesion found on patients recently diagnosed as having malignant melanoma displayed a moderate level of interobserver agreement.²⁶ Among 3 examiners (medical oncologist, internist/epidemiologist, and dermatologist/dermatopathologist) the intraclass correlation coefficient was highest for degree of macularity, corresponding with elevation (E) at 0.56, asymmetry (A) at 0.46, haphazard color (C) at 0.44, and border irregularity (B) at 0.40. A second study assessed interobserver and intraobserver agreement among 3 physicians using photographs of melanocytic nevi.²⁷ After establishing criteria to be assessed for each feature, the level of agreement was similar to that found in the first study, although less precision was noted for rating asymmetry. Interobserver agreement for physician pairs, as measured by the κ statistic, ranged from 0.41 to 0.55 for macular vs papular lesions (E), 0.38 to 0.53 for color variegation (C), 0.29 to 0.53 for border irregularity (B), and 0.05 to 0.26 for contour irregularity (A). The level of intraobserver agreement was, overall, similar to interobserver agreement. However, intraobserver agreement was measured based on a 4-point scale, which graded the degree of each feature, rather than the presence or absence of each feature.

Precision estimates among physicians for 4 features of the ABCD(E) checklist found that benign pigmented lesions are considered fair to moderate.²⁸ Since only benign pigmented lesions were assessed, observer agreement for these features found in actual malignant melanoma lesions may be higher than reported in these studies. Precision estimates for global assessments of the presence or absence of melanoma are not available.

Two studies have assessed accuracy of the ABCD(E) checklist (Table 1). Different features of the checklist were assessed, and the interpretation of a positive test result was not the same in both studies. Features of the ABCD(E) checklist were prospectively recorded for patients with pigmented lesions who had been referred to a pigmented lesion clinic.²⁹ A total of 65 histologically confirmed melanomas were included in the analysis. Only 5 lesions were not identified by the ABCD(E) portion of the checklist, resulting in a sensitivity of 92% (95% CI, 82%-96%). The ABCD(E) checklist was considered positive when a lesion had 1 or more of the 5 features. Specificity was not reported.

A second study utilized a retrospective design to assess 3 features of the ABCD checklist; border irregularity (B), color variegation (C), and diameter (D).³⁰ The checklist was applied by reviewing charts and pathology reports among patients who had undergone biopsies of pigmented lesions over a 1-year period. Pigmented lesion biopsy specimens determined by dermatologists to have a clinical diagnosis of rule-out dysplasia, lentigo maligna, or malignant melanoma on the pathology submission form were included. All 6 histologically confirmed melanomas had all 3 features on the checklist. The sensitivity was, therefore, 100% (95% CI, 54%-100%). Only 3 lesions that were benign had all 3 features, resulting in a specificity of 98% (95% CI, 95%-99%).

In the study by Healsmith et al,²⁹ all 5 of the melanomas that were not identified had a diameter of less than 6 mm, although a change in size was noted.²⁹ Because of concerns that requiring lesions to be larger than 6 mm may lower the sensitivity of the ABCD checklist resulting in missed lesions, 1150 melanomas that underwent biopsy over a 27-month period in Australia were retrospectively analyzed for their size.³¹ Three hundred fifty-eight (31%) of 1150 of the melanomas were 6 mm or less in diameter. This indicates that requiring a diameter of greater than 6 mm in this sample of lesions would have lowered the sensitivity considerably.

More data exist for differentiating benign lesions from melanoma with the revised 7-point checklist than with the ABCD checklist (Table 2). The revised 7-point checklist was also analyzed against the 65 histologically confirmed melanomas that were found over a 38-month period in the aforementioned prospective analysis by Healsmith et al.²⁹ This same checklist was applied to 100 randomly selected benign pigmented lesions—68 were considered benign based on clinical characteristics and 32 were histologically confirmed to be benign. The sensitivity of the revised 7-point checklist was 100% (95% CI, 94%-100%), since all melanomas had at least 1 major feature. The specificity was lower at only 37% (95% CI, 28%-46%).

A second study reported the sensitivity of the revised 7-point checklist applied to 100 patients with histologically proven malignant melanoma to be 79% (95% CI, 70%-85%).²³ In this study, the alternative interpretation of the revised 7-point checklist was used; features of the checklist were assigned scores, 2 points for each major feature and 1 point for each minor feature present. A score of 3 or more was considered a lesion that should be referred to a dermatologist because of its malignant potential. The checklist was prospectively applied to patients presenting to a pigmented lesion clinic with lesions suggestive of melanoma.

The specificity of the revised 7-point checklist, again using the scoring system, was estimated by applying it to a consecutive series of 100 histologically benign lesions.²⁴ Seventy of the benign lesions achieved a score indicative of malignancy resulting in a specificity of 30% (95% CI, 21%-39%). This is the only study that has assessed accuracy of patient assessments, reporting a specificity comparable to the physician evaluations of 32% (95% CI, 23%-41%).

Studies assessing accuracy of the checklists have not applied and interpreted the gold standard independently with the checklists and should be interpreted with some discretion. Additionally, both the revised 7-point checklist and the ABCD checklist have been subject to varying interpretations of the requirements for a positive and negative test result. With that in mind, existing evidence suggests that both checklists result in a sensitive diagnostic test. A highly sensitive test is desirable for a disease like melanoma that, left undetected, can result in death. When using the ABCD checklist, requiring a lesion to be greater than 6 mm in diameter may lower the sensitivity, which could result in missed lesions. It appears that the checklists' high sensitivity may come at the expense of low specificity, especially when using the revised 7-point checklist. No conclusions can be drawn about the specificity of the ABCD checklist from the available data.

Accuracy measurements for global assessments for detecting melanoma's presence or absence used 2 methods of examination: (1) actual patient examination and (2) image evaluation through the use of pictures, slides, or digitized images of lesions. Accuracy assessments have included dermatologist and nondermatologist examiners.

Dermatologists have primarily been the examiners in studies utilizing patient examinations. Estimates for sensitivity range widely from 50% to 97%, while specificity estimates have been more consistent ranging from 96% to 99% (Table 3).^{32 - 36} Data from existing studies generally do not allow for calculation of likelihood ratios. However, the positive predictive value, although influenced by prevalence, is often reported. In the largest series of patients followed after completion of a screening skin examination, the positive predictive value was found to be 17%.³⁷ Other estimates of the positive predictive value vary greatly from 35% to 86%.^{33 - 35 ,38}

Lesions presented as pictures, slides, and digitized computer images rather than patient evaluations have been an alternative mode of evaluation used to assess accuracy and have often been used to compare nondermatologists' examinations to those performed by dermatologists (Table 4 and Table 5). One study presented melanoma lesions in both a 35-mm slide and digitized computer image format to nondermatologists (general internal medicine and family practice residents) and dermatologists (resident and attending physicians).³⁹ Nondermatologists provided the correct diagnosis 60% of the time compared with dermatologists who correctly diagnosed the lesions 74% of the time, a difference that was statistically significant. The correct treatment option (defined as recognition of the need for a biopsy and the type of biopsy required) was selected by nondermatologists significantly less often (52%) than by dermatologists (67%). The correct diagnosis and treatment options were determined by biopsy results and consensus opinion of 2 dermatologists. In another study that compared nondermatologist examiners (first-year internal medicine residents and practicing physicians) to dermatologists (third-year residents and practicing dermatologists), 100% of the dermatologists correctly identified at least 3 of the 6 melanoma lesions compared with 70% of the nondermatologists.⁴⁰ An additional study that compared practicing primary care physicians and internal medicine residents with dermatology faculty, 88% of the nondermatologists correctly identified melanoma compared with 100% of the dermatologist examiners.⁴¹ General practitioners in Australia that were shown pictures, which included 2 early melanoma lesions and 1 late melanoma lesion, correctly identified all 3 as melanoma 41% of the time.⁴² However, they made the correct decision to perform a biopsy on the lesion 83% of the time. Another study of similar design from New Zealand found that a high proportion of correct diagnoses and biopsy decisions were made by general practitioners.⁴³ A correct diagnosis was made by general practitioners in 81% of cases compared with 90% by dermatologists. Recognizing the need for a biopsy was similar for both groups, with the correct biopsy decision being made greater than 95% of the time.

Specificity is high, at least among dermatologist examiners, when patient populations are examined for melanoma. The sensitivity of patient examinations for melanoma is less clear, and better study designs are needed to provide more accurate sensitivity assessments. Studies that have used images of lesions rather than patient examinations have indicated that nondermatologists' examinations are less sensitive than examinations performed by dermatologists. Studies utilizing examinations on patient populations, with rigorous application of the test and classification of the disease state, which include dermatologists and nondermatologists as examiners, are needed to provide better assessments of operating characteristics.

Returning to the clinical scenario, a concerned patient presents with an enlarging mole on his arm that has changed in appearance. Based on the existing literature, the usefulness of the ABCD checklist or revised 7-point checklist to distinguish melanoma from benign lesions is not fully established. If a positive test result does not require that all 4 features of the ABCD checklist be present, misdiagnosing a melanoma as a benign lesion appears to be unlikely. The accuracy of using the ABCD checklist to predict the disease state when a positive test result requires the presence of all 4 features has not been described. However, early melanoma lesions may be small (<6 mm in diameter), and requiring a lesion to be greater than 6 mm in diameter when using the checklist may result in some early lesions to be falsely classified as benign. It is unclear how often benign lesions would be considered to have malignant potential when using the ABCD checklist. The patient's report of the lesion enlarging and changing in appearance incorporate the primary criteria used in the revised 7-point checklist. When using the revised 7-point checklist, misdiagnosing a melanoma as benign would also be unlikely, although it appears the checklist may classify many benign lesions as malignant.

In summary, malignant melanoma is an increasingly common malignancy with an incidence rate that is projected to continue to rise. The history and physical examination play a unique role in the secondary prevention of cutaneous malignant melanoma. It is the sole means of identifying lesions that require excision for histopathological evaluation. Because of the growth characteristics of melanoma, examinations that detect earlier stages of melanoma can result in a better prognosis. The utility of the ABCD and revised 7-point checklists for distinguishing melanoma from benign skin lesions is not conclusively described. The ABCD checklist (when a positive test result does not require all 4 features to be present) and the revised 7-point checklist appear to be sensitive diagnostic aids when evaluating individual lesions and, therefore, rarely classify a melanoma as a benign lesion. However, the revised 7-point checklist lacks specificity resulting in benign lesions being classified as potentially malignant. The specificity of the ABCD checklist is less well described. A change in lesion characteristics is frequently reported by patients with melanoma and is an important feature to assess during an examination. Better study designs are necessary to define the operating characteristics of physicians' examinations for detecting the presence or absence of melanoma. Existing evidence suggests that examinations are highly specific, at least among dermatologist examiners, but sensitivity estimates are less clear. Data regarding nondermatologists' examinations suggest that their examinations are less sensitive than those performed by dermatologists.