IV.4.1 Introduction and Definition Detecting melanomas in early stages of develop- ment is fundamental for preventing mortality from this disease. Prognosis for patients with melanoma is largely determined by early detec- tion [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, de- spite 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 diag- nosed, 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 sig- nificant role in reducing deaths from melanoma
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
IV.4
Contents
IV.4.1 Introduction and Definition . . . .213
IV.4.2 Clinical Features . . . 214
IV.4.3 Dermoscopic Criteria . . . .215
IV.4.4 Histopathology . . . .215
References . . . .219
[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 pres- ent to the dermatologist with much earlier le- sions than had been encountered in the past [13]; thus, it is no surprise that recent reports have documented the existence of small-diam- eter 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 re- ported ranges from less than 1% [35] to 17% [14], with the exception of one study conducted in Australia which reported that 31.1% of melano- mas were ≤6 mm [36]. A recent survey of avail- able 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, gener- ally clinically unrecognizable pigmented mac- ules of evolving melanoma in situ.
Regardless of the true incidence of small-di-
ameter 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 cutane-
ous melanomas were in situ, and 33 were inva-
sive [14]. In reviewing published data, small-di-
ameter 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 re-
duction in mortality from melanoma.
IV.4
IV.4.2 Clinical Features
Small melanomas can be clinically subtle, re- maining a diagnostic challenge to even the most astute clinician. In order to promote recogni- tion of early melanomas by both physicians and lay public alike, the ABCD criteria was devised in 1985, emphasizing the clinical features differ- entiating between thin melanomas and benign pigmented lesions [22]: Asymmetry, Border ir- regularity, 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 characteris- tic of melanoma and as a useful tool for differ- entiating between melanoma and atypical nevi [1]. Many small melanomas can be identified us- ing the ABCD rule, exhibiting the asymmetry, border irregularity, and color variability char- acteristics of larger melanomas (Fig. IV.4.1) [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 com- bination of these criteria have been documented to increase diagnostic accuracy in clinical prac- tice 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 cen- tered on the element of change in the evaluation of pigmented lesions. The concept of an evolv- ing lesion, whether pertaining to changes in color, size, shape, elevation, surface, surround- ing skin, sensation, and consistency [19], has been particularly useful in the identification of melanomas, especially in the subset of “nodu- lar” 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 dermosco- pists have also noted that a change of color was more frequently seen in small melanomas than in melanomas >6 mm [20]. Although patient re-
call is frequently hampered by subjectivity, its utility in differentiating melanoma from atypi- cal nevi has become increasingly apparent. In addition to aiding physicians in diagnosing melanomas, the dynamic features of a pigment- ed skin lesion have been the most important in- dicators of malignancy perceived by the general public [6, 25].
Another important feature of small melano- mas 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 pivo- tal 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 melano- ma in physicians and patients alike [19]. Surveil- lance of high-risk patients using total-body im- aging has also proved beneficial in identifying small and early tumors, whether as de-novo lesions or changes in pre-existing melanocytic lesions.
Fig. IV.4.1. 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
IV.4.3 Dermoscopic Criteria
Dermoscopy has been shown to improve diag- nostic 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 appear- ance of an irregular and prominent pigment network. Histopathologically this correlates to the proliferation of atypical melanocytes along the dermo-epidermal junction. As these atypi- cal melanocytes extend throughout the thick- ness 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 (previ- ously described as pseudopods and radial streaming). Irregular brown globules, which represent nests of melanocytes irregularly dis- tributed throughout the dermo-epidermal junc- tion 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. IV.4.2, IV.4.6, IV.4.7) that can help identify early melanomas include: (a) a pigmented network with an abrupt margin [30, 34]; (b) depigmented scar-like ar- eas; (c) a whitish veil; (d) colors of red, blue, gray, or white; (e) four or more colors; (f) border ir- regularity; 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 fre- quently observable in earlier melanomas, nota- bly depigmented areas and a whitish veil [34].
Results of a Consensus Net Meeting on Der- moscopy study found that three criteria were especially important in the identification of melanoma from benign pigmented lesions, in- cluding: (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]; how- ever, it is important to be aware of the limita- tions of dermoscopy with particular regard to
identifying smaller melanomas. The ABCD rule of dermoscopy may not be as useful in the iden- tification 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 de- termined that dermoscopy did not improve di- agnostic performance for lesions ≤6 mm in di- ameter, even for those trained in dermoscopy [16]. These observations suggest a need for ad- ditional tools to help with the diagnosis of small melanomas. Promising new techniques, include computer-assisted imaging systems, are emerg- ing (Fig. IV.4.8).
IV.4.4 Histopathology
Approximately 75–83% of melanomas arise as de-novo lesions with the remainder developing in continuity with a variety of melanocytic le- sions, the majority of which are compound or intradermal in type [18, 26]. Other potential precursor lesions include congenital melano- cytic nevi, whose magnitude of risk correlates with increasing size of the nevus [27]. Melano- mas have also been shown to originate infre-
Fig. IV.4.2. Dermoscopy image of 5.5-mm-diameter
pigmented macule shows a melanocytic lesion with fo-
cal structureless areas, a non-uniform network, gray dots
and granules, four colors, including light brown, dark
brown, gray, and black, and a disorganized, reticular–ho-
mogeneous network. These dermoscopy changes are sug-
gestive of either a melanoma or an “atypical melanocytic
neoplasm.” A diagnosis of melanoma was favored and a
biopsy confirmed melanoma, in situ
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quently from dysplastic nevi, with higher risks of transformation in those nevi with more se- vere cytologic atypia [5, 29].
Regardless of subtype, it is hypothesized that melanomas evolve from single collections of melanocytes along the dermo-epidermal junc- tion [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. IV.4.3) 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
tan-brown macule, failing to exhibit the distin- guishing features of larger melanomas.
Over time, a few single atypical melanocytes emerge among the relatively normal-appearing melanocytes, confined initially to the dermo- epidermal 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, soli- tary atypical melanocytes throughout the epi- dermis (Fig. IV.4.4). At this phase, the melano- ma in situ measures approximately 3–4 mm in diameter.
As the lesion progresses, nests of atypical me- lanocytes develop along the lower portion of the epidermis, eventually spreading throughout the entire thickness of the epidermis and involving
Fig. IV.4.3. 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 junc- tion in a slightly asymmetric array. At higher magnifica- tion, a few single melanocytes are present slightly along the dermo-epidermal junction. Diagnosis: early mela- noma, in situ, subtle, probable
Fig. IV.4.4. 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 some- what above, the dermo-epidermal junction. Diagnosis:
early melanoma, in situ
adnexal structures. It is at this stage where vari- ations in color between tan and brown become more apparent, reflective of the presence of me- lanocytes at higher levels of the epidermis (Figs. IV.4.5). 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 melano- cytes eventually descend into the papillary der- mis. 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. IV.4.5. 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. Diagno- sis: melanoma, in situ
Fig. IV.4.6. Dermoscopy image of an approximately 5-mm-diameter ill-defined pigmented lesion exhib- its the ABCs. Dermoscopy shows a melanocytic lesion exhibiting branched streaks, focal structureless areas, asymmetrically distributed dots and globules, three col- ors, including light brown, dark brown, and gray, and a reticular–globular–homogeneous disorganized pattern.
Overall impression on dermoscopy was melanoma. Di- agnosis: melanoma, in situ
Fig. IV.4.7. Dermoscopy image of a 4.4-mm-diameter
pigmented macule with featureless pattern. Ten experi-
enced dermoscopists favored a benign diagnosis. Diag-
nosis: melanoma, in situ
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in some cases. Although melanocytes can de- scend from the epidermis into the subjacent dermis while the lesion is only 4–5 mm in diam- eter, 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 in- vaded into the papillary dermis, the neoplasm tends to expand three-dimensionally. Neo- plasms progress to involve deeper structures, including the reticular dermis and subcutane- ous fat, with potential for development of clini- cally 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 me- tastasis with dismal prognosis for survival.
Maize and Ackerman briefly summarized the following histolopathogical features of mel- anoma regardless of size or anatomic site [26]:
1. Diameter typically >6 mm at time of biopsy
2. Asymmetric growth of atypical melano- cytes (correlates to clinical asymmetry) 3. Poor circumscription – atypical melano-
cytes 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 (contribut- ing to color variation)
6. Nests of melanocytes within the epider- mis 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)
Fig. IV.4.8. A 5.4-mm-diameter pigmented macule shows nearly identical dermoscopy pattern with standard der-
moscopy and “machine vision” computer-generated dermoscopy image.
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 (contrib- utes to color variation, including blue in more invasive lesions)
3. Extension of atypical melanocytes to epithelial adnexal structures
4. Asymmetrical distribution of inflamma- tory-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 histopatho- logical atypia as larger melanomas. In a retro- spective 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 circumscrip- tion was absent more often than all other crite- ria, although 87% of cases still evidenced poor circumscription.
C
