IV.4. Early Evolution of Melanoma (Small-Diameter Melanoma)

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1 Chapter Early Evolution of Melanoma (Small-Diameter Melanoma) Robert J. Friedman, Melanie Warycha, Michele Farber, Dina Gutkowicz-Krusin, Harold Rabinovitz, David Polsky, Margaret Oliviero, Darrell S. Rigel, Lori Kels, Edward R. Heilman Contents.1 Introduction and Definition Clinical Features Dermoscopic Criteria Histopathology References Introduction and Definition Detecting melanomas in early stages of development is fundamental for preventing mortality from this disease. Prognosis for patients with melanoma is largely determined by early detection [17, 33], as 10-year survival rates have been reported as high as 99.5% for early melanomas <0.76 mm thick, but are only 48% for lesions >3 mm thick [17]. Early detection followed by appropriate treatment has led to considerable reduction in mortality from melanoma, from 60% for those diagnosed in 1960 to about 11% for those diagnosed in 2005 [39]; however, despite early detection efforts, incidence rates for melanoma have dramatically increased over time both in the United States and worldwide, the etiology of which could be attributed to changes in human behavior, the environment, or increased physician awareness [11, 32, 39]. It is estimated that in 2005 in the U.S. at least 62,000 cases of invasive melanoma will be diagnosed, ranking as the fifth leading cancer in men and the sixth in women [2]. Educational campaigns advocating routine self-examination of the skin have played a significant role in reducing deaths from melanoma [10, 16]. These efforts, coupled with the advent of novel techniques of melanoma detection, have led to the diagnosis of melanoma at earlier stages of development. Many patients now present to the dermatologist with much earlier lesions than had been encountered in the past [13]; thus, it is no surprise that recent reports have documented the existence of small-diameter melanomas, classified as lesions 6 mm [14, 21, 22]. Although there are only a limited number of studies which report on small melanomas of this size, the frequency of small melanomas reported ranges from less than 1% [35] to 17% [14], with the exception of one study conducted in Australia which reported that 31.1% of melanomas were 6 mm [36]. A recent survey of available literature on small melanomas estimated their frequency to be between 3 and 14% [1]. The aforementioned frequency of small melanomas is surely a gross underestimation, as most, if not all, melanomas have their origin as tiny, generally clinically unrecognizable pigmented macules of evolving melanoma in situ. Regardless of the true incidence of small-diameter melanomas, a more startling realization is the fact that some of these lesions are already invasive at presentation. Of 47 small-diameter melanomas diagnosed by Bono et al., 14 cutaneous melanomas were in situ, and 33 were invasive [14]. In reviewing published data, small-diameter melanoma tumor thickness has been reported to range from 0.11 to 1.5 mm, with a median thickness of approximately 0.7 mm [9, 21, 22, 36]. Since this thickness range generally corresponds to a favorable prognosis for small melanomas [7], targeting small melanomas for removal could potentially result in a marked reduction in mortality from melanoma.

2 214 R.J. Friedman, M. Warycha, M. Farber et al..2 Clinical Features Fig..1. A 4-mm-diameter macular pigmented lesion exhibiting lesion asymmetry, border irregularity, and play in color. The lesion was slowly growing over 9 months. A biopsy revealed melanoma, in situ Small melanomas can be clinically subtle, remaining a diagnostic challenge to even the most astute clinician. In order to promote recognition of early melanomas by both physicians and lay public alike, the ABCD criteria was devised in 1985, emphasizing the clinical features differentiating between thin melanomas and benign pigmented lesions [22]: Asymmetry, Border irregularity, Color variegation, and Diameter >6 mm [17]. This algorithm was later revised to include an E criterion for Evolving, which has been demonstrated as another key characteristic of melanoma and as a useful tool for differentiating between melanoma and atypical nevi [1]. Many small melanomas can be identified using the ABCD rule, exhibiting the asymmetry, border irregularity, and color variability characteristics of larger melanomas (Fig..1) [19, 22]; however, since all melanomas originate from one or more neoplastic melanocytes, not all of the ABCD criteria will be observable in earlier stages of development [19], but the combination of these criteria have been documented to increase diagnostic accuracy in clinical practice with adequate interobserver concordance [8, 28, 40]. Although no single criterion has been proven to have predictive value in decisions regarding biopsy management, emphasis has recently centered on the element of change in the evaluation of pigmented lesions. The concept of an evolving lesion, whether pertaining to changes in color, size, shape, elevation, surface, surrounding skin, sensation, and consistency [19], has been particularly useful in the identification of melanomas, especially in the subset of nodular and small-diameter melanomas ( 6 mm), which frequently fail to satisfy the ABCD rule [16, 23]. Further demonstrating the utility of the E criterion for small melanomas, these lesions were often removed because of a change or new discovery of the lesion in adulthood [9, 22] or occurrence of symptoms [9]. Other dermoscopists have also noted that a change of color was more frequently seen in small melanomas than in melanomas >6 mm [20]. Although patient recall is frequently hampered by subjectivity, its utility in differentiating melanoma from atypical nevi has become increasingly apparent. In addition to aiding physicians in diagnosing melanomas, the dynamic features of a pigmented skin lesion have been the most important indicators of malignancy perceived by the general public [6, 25]. Another important feature of small melanomas is that they tend to be found in patients at younger ages compared with melanomas >6 mm. While the majority of melanomas are found in patients of about 60 years of age or older [18], the average age of patients presenting with small melanomas has been reported to be between 39 and 42 years [9, 21, 22]; however, small melanomas have the same race, sex ratio, and anatomic distribution, including higher frequency on the lower extremity in females, as larger melanomas [22]; thus, the patient s history and physical examination plays a pivotal role in the detection of early melanoma. Change in a melanocytic lesion or development of a new pigmented lesion later in life (after age 40 years) should prompt suspicion for melanoma in physicians and patients alike [19]. Surveillance of high-risk patients using total-body imaging has also proved beneficial in identifying small and early tumors, whether as de-novo lesions or changes in pre-existing melanocytic lesions.

3 Early Evolution of Melanoma Chapter Dermoscopic Criteria Dermoscopy has been shown to improve diagnostic accuracy for identifying melanomas [24, 34, 38], although its diagnostic value depends on the experience of the dermoscopist [12]. One of the first dermoscopic features identified in the evolution of early melanoma is the appearance of an irregular and prominent pigment network. Histopathologically this correlates to the proliferation of atypical melanocytes along the dermo-epidermal junction. As these atypical melanocytes extend throughout the thickness of the epidermis, including the granular and cornified layers, the appearance of black dots in irregular distribution is evident. With the formation of confluent junctional nests of melanocytes accentuated toward the periphery of the lesion, irregular streaks appear (previously described as pseudopods and radial streaming). Irregular brown globules, which represent nests of melanocytes irregularly distributed throughout the dermo-epidermal junction and/or papillary dermis, can also be seen. Gray-blue areas are observed once melanocytes extend into the mid- and reticular dermis [3, 4]. Dermoscopic features (Fig..2,.6,.7) that can help identify early melanomas include: (a) a pigmented network with an abrupt margin [30, 34]; (b) depigmented scar-like areas; (c) a whitish veil; (d) colors of red, blue, gray, or white; (e) four or more colors; (f) border irregularity; and (g) multiple homogenous areas of variable size [34]. Although these features can aid the diagnosis of melanoma, it is important to note that certain characteristics are less frequently observable in earlier melanomas, notably depigmented areas and a whitish veil [34]. Results of a Consensus Net Meeting on Dermoscopy study found that three criteria were especially important in the identification of melanoma from benign pigmented lesions, including: (a) asymmetry; (b) atypical pigment network; and (c) blue-white structures [4]. Since then, this three-point checklist has been shown to be a valid and reproducible algorithm with high sensitivities for the diagnosis of melanoma, even when employed by non-experts [37]; however, it is important to be aware of the limitations of dermoscopy with particular regard to Fig..2. Dermoscopy image of 5.5-mm-diameter pigmented macule shows a melanocytic lesion with focal structureless areas, a non-uniform network, gray dots and granules, four colors, including light brown, dark brown, gray, and black, and a disorganized, reticular homogeneous network. These dermoscopy changes are suggestive of either a melanoma or an atypical melanocytic neoplasm. A diagnosis of melanoma was favored and a biopsy confirmed melanoma, in situ identifying smaller melanomas. The ABCD rule of dermoscopy may not be as useful in the identification of small melanomas, as studies have found barely sufficient interobserver agreement in evaluating the presence of each of the criteria in lesions 5 mm [31]. Furthermore, others determined that dermoscopy did not improve diagnostic performance for lesions 6 mm in diameter, even for those trained in dermoscopy [16]. These observations suggest a need for additional tools to help with the diagnosis of small melanomas. Promising new techniques, include computer-assisted imaging systems, are emerging (Fig..8)..4 Histopathology Approximately 75 83% of melanomas arise as de-novo lesions with the remainder developing in continuity with a variety of melanocytic lesions, the majority of which are compound or intradermal in type [18, 26]. Other potential precursor lesions include congenital melanocytic nevi, whose magnitude of risk correlates with increasing size of the nevus [27]. Melanomas have also been shown to originate infre-

4 216 R.J. Friedman, M. Warycha, M. Farber et al. Fig..3. Photomicrograph of a 1.3-mm-diameter tan macule. The patient requested a biopsy because of a prior history of melanoma and due to the fact that this was a new lesion. At lower-power magnification, there is a very subtle increase in the number of single melanocytes predominating mostly along the dermo-epidermal junction in a slightly asymmetric array. At higher magnification, a few single melanocytes are present slightly along the dermo-epidermal junction. Diagnosis: early melanoma, in situ, subtle, probable quently from dysplastic nevi, with higher risks of transformation in those nevi with more severe cytologic atypia [5, 29]. Regardless of subtype, it is hypothesized that melanomas evolve from single collections of melanocytes along the dermo-epidermal junction [18, 19]. Unfortunately, these early changes may not be easily discernible to the pathologist given the lack of reproducible histopathological criteria [19]. Moreover, this small focus of cytologically normal-appearing melanocytes (Fig..3) may not yet translate into clinical atypia, thus evading recognition during routine skin examination. At a diameter of only 1 2 mm, early melanoma may present simply as a small Fig..4. A 3.3-mm-diameter pigmented macule with a subtle play in color centrally. Microscopically, there is a proliferation of mostly single melanocytes at, and somewhat above, the dermo-epidermal junction. Diagnosis: early melanoma, in situ tan-brown macule, failing to exhibit the distinguishing features of larger melanomas. Over time, a few single atypical melanocytes emerge among the relatively normal-appearing melanocytes, confined initially to the dermoepidermal junction. Clinically this correlates to a slowly growing tan-brown macule which may display subtle abnormalities in symmetry and border. As the stages of melanoma progression advance, atypical melanocytes coalesce to form small nests at the dermo-epidermal junction with a prominent extension of scattered, solitary atypical melanocytes throughout the epidermis (Fig..4). At this phase, the melanoma in situ measures approximately 3 4 mm in diameter. As the lesion progresses, nests of atypical melanocytes develop along the lower portion of the epidermis, eventually spreading throughout the entire thickness of the epidermis and involving

5 Early Evolution of Melanoma Chapter 217 Fig..6. Dermoscopy image of an approximately 5-mm-diameter ill-defined pigmented lesion exhibits the ABCs. Dermoscopy shows a melanocytic lesion exhibiting branched streaks, focal structureless areas, asymmetrically distributed dots and globules, three colors, including light brown, dark brown, and gray, and a reticular globular homogeneous disorganized pattern. Overall impression on dermoscopy was melanoma. Diagnosis: melanoma, in situ Fig..5. A 4.1-mm-diameter pigmented macule with subtle clinical features of the ABCs and a change in D over the past few months ( ABCDE s). Microscopically, there are single and nested atypical melanocytes at and above the dermo-epidermal junction, including some melanocytes identified in the stratum corneum. Diagnosis: melanoma, in situ adnexal structures. It is at this stage where variations in color between tan and brown become more apparent, reflective of the presence of melanocytes at higher levels of the epidermis (Figs..5). Once they approach the cornified layer, pigment-laden melanocytes may lend to the dark brown or black appearance of some lesions. Melanomas are limited to the epidermis for a variable amount of time, likely contingent upon factors such as host immune response, chemical or humoral growth factors, genetic markers, etc. But for the majority of lesions, atypical melanocytes eventually descend into the papillary dermis. This typically occurs once the proportion of neoplastic melanocytes in nests surmounts those occurring as single atypical melanocytes, which can take months, years, or even decades Fig..7. Dermoscopy image of a 4.4-mm-diameter pigmented macule with featureless pattern. Ten experienced dermoscopists favored a benign diagnosis. Diagnosis: melanoma, in situ

6 218 R.J. Friedman, M. Warycha, M. Farber et al. Fig..8. A 5.4-mm-diameter pigmented macule shows nearly identical dermoscopy pattern with standard dermoscopy and machine vision computer-generated dermoscopy image. in some cases. Although melanocytes can descend from the epidermis into the subjacent dermis while the lesion is only 4 5 mm in diameter, melanomas can remain in situ until they are much larger in size, reaching 16 mm and possibly even 30 mm or more on the head and neck [19]. Once atypical melanocytes have invaded into the papillary dermis, the neoplasm tends to expand three-dimensionally. Neoplasms progress to involve deeper structures, including the reticular dermis and subcutaneous fat, with potential for development of clinically ulcerated and nodular components. The lesion may undergo regression and, in time, may develop multiple colors including red, white, or blue, in addition to those of brown, tan, or black. Presence of the latter features implies a more advanced lesion and as such is associated with a poor prognosis [8]. Eventually many of these neoplasms lead to regional and/or distant metastasis with dismal prognosis for survival. Maize and Ackerman briefly summarized the following histolopathogical features of melanoma regardless of size or anatomic site [26]: 1. Diameter typically >6 mm at time of biopsy 2. Asymmetric growth of atypical melanocytes (correlates to clinical asymmetry) 3. Poor circumscription atypical melanocytes arranged as solitary units extending above the most peripheral discrete nest of melanocytes within the epidermis 4. Increased number of single atypical melanocytes within the epidermis and epidermal adnexal structures, with single cells often predominating over nests 5. Scattered atypical melanocytes within upper levels of the epidermis (contributing to color variation) 6. Nests of melanocytes within the epidermis not equidistant (contributing to color variation) 7. Irregularity in the shape of nests of melanocytes 8. Confluence of nests of melanocytes (contributes to evolution of color in lesion)

7 C Core Early Evolution of Melanoma Chapter 219 With regard to early invasive melanomas, they noted the following [26]: 1. Failure of atypical melanocytes to mature with eventual descent into the dermis (contributes to elevation of a lesion) 2. Asymmetrical, patchy distribution of melanin within the neoplasm (contributes to color variation, including blue in more invasive lesions) 3. Extension of atypical melanocytes to epithelial adnexal structures 4. Asymmetrical distribution of inflammatory-cell infiltrates at the base of the neoplasm (contributes to color variation, including red, white, and blue) Common cytological features of melanoma also include atypical nuclei, necrosis of melanocytes, a greater number of melanocytes in mitosis, and pagetoid melanocytes within the epidermis. Available evidence indicates that melanomas 6 mm display many of these same histopathological atypia as larger melanomas. In a retrospective study of small proliferations <6 mm of atypical melanocytes within the dermis and epidermis, Kamino et al. [22] found that 19 of 30 melanomas showed evidence of all architectural and cytological features described by Maize and Ackerman [26], with the exception of the breadth criterion. Notably, poor circumscription was absent more often than all other criteria, although 87% of cases still evidenced poor circumscription. Messages As the incidence rates for melanoma continue to rise, detection in the earliest phases of tumor progression will become more essential. Regardless of size, melanomas confined entirely within the epidermis are 100% curable once subjected to complete removal. The majority of small-diameter ( 6 mm) melanomas can be identified using the ABCD(E) rule, with emphasis on the dynamic features of a lesion over time. Efforts to improve the diagnostic accuracy and sensitivity for melanoma have led to the development of new non-invasive techniques for melanoma detection, including dermoscopy and computerized image analysis systems. References 1. Abbasi NR, Shaw HM, Rigel DS, et al (2004) Early diagnosis of cutaneous melanoma: revisiting the ABCD criteria. J Am Med Assoc 292: American Cancer Society. Facts and figures Atlanta, GA: American Cancer Society 3. Argenziano G, Fabbrocini G, Carli P, et al (1997) Epiluminescence microscopy: criteria of cutaneous melanoma progression. J Am Acad Dermatol 37: Argenziano G, Soyer HP, Chimenti S, et al (2003) Dermoscopy of pigmented skin lesions: results of a consensus meeting via the Internet. J Am Acad Dermatol 48: Arumi-Uria M, McNutt S, Finnerty B (2003) Grading of atypia in nevi: correlation with melanoma risk. Mod Pathol 16: Baade PD, Balanda KP, Stanton WR, et al (1997) Community perceptions about the important signs of early melanoma. J Am Acad Dermatol 36: Balch CM, Soon S, Gershenwald JE, et al (2002) Prognostic factors analysis of 17,600 melanoma patients: validation of the American joint committee on cancer melanoma staging system. J Clin Oncol 19: Barnhill RL, Roush GC (1991) Correlation of clinical and histopathologic features in Clinically atypical melanocytic nevi. Cancer 67: Bergman R, Katz I, Lichtig C, et al (1992) Malignant melanomas with histologic diameters less than 6 mm. J Am Acad Dermatol 26: Berwick M, Begg CB, Fine JA, et al (1996) Screening for cutaneous melanoma by skin self-examination. J Natl Cancer Inst 88:17 23

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