Obligate and Potential Precursors of Melanoma

In this issue, Olsen et al. (1) present a test of the hypothesis that melanoma in situ (ie, noninvasive) is an obligate precursor of invasive melanoma. They calculated the incidence rate ratio over time and compared the ages at diagnosis of these 2 conditions. In 3 populations (Queensland, Australia; United States White; and Scotland), the noninvasive to invasive melanoma ratio increased from less than 0.33 in 1980 to 1.95, 0.93, and 0.58, respectively. The mean age at diagnosis of noninvasive was the same or higher than invasive melanoma for most time periods and biopsy sites. These results were considered to be consistent with more indolent lesions coming to clinical attention than in previous eras, challenging the assumption that all or most noninvasive melanomas will ultimately become invasive.

As the authors also note (1), the incidence of invasive melanoma has risen steadily over the past 5 decades, whereas mortality has remained largely stable. One explanation for this trend could be that efforts in secondary prevention (screening and surveillance) have shifted the diagnosis toward earlier stages. This could be supported by evidence of an increasing incidence of noninvasive and “thin” (ie, good prognosis) melanomas relative to the potentially lethal “thick” melanomas over this time. However, the absolute incidence of the dangerous thick melanomas has not decreased as a result of these strategies (2).

Alternatively, widespread detection efforts are leading to overdiagnosis of melanoma, the diagnosis of indolent lesions that will not cause morbidity or death during a person’s lifetime (3). This latter hypothesis is compellingly supported by evidence that the incidence of invasive melanoma has dramatically increased while the mortality has remained almost stable (4). If obligate precursors of melanoma were being removed as a result of screening efforts, the incidence of the thicker, more lethal melanomas should decline, and thus mortality rates should also fall. Any argument that removal of these lesions identified by screening results in a global cure of them (likely true in individual cases) is challenged by the consideration that for any lesion identified and cured by such means, there must be an untold but undoubtedly large number of similar lesions remaining in the population, undetected by screening efforts, but fortunately remaining indolent.

The idea that noninvasive and thin invasive melanomas, the products or at least the targets of screening programs, are obligatory or at least high-risk precursors of more advanced and potentially lethal melanomas has led to aggressive screening programs whose utility has only recently come into question (5). With regard to melanoma in situ, its very name may suggest that it is at high risk of losing its protected status within the epidermis and becoming invasive and therefore a dangerous cancer. An earlier term, premalignant melanosis, also conveys this impression (6,7). However, during the time of this study, this has never been a universally accepted concept. In the middle of the last century, images of lesions that today would be unquestionably termed in situ melanoma were published under the term “active junctional nevus” by a major textbook author (8). About the same time, the term “atypical melanocytic hyperplasia” was proposed for these lesions because of concerns about patient anxiety, insurability, and overtreatment and lack of certainty that the nosology of these lesions warranted inclusion of the fearsome term melanoma (9,10). The term melanocytic intraepidermal neoplasia has also been proposed for similar reasons (11).

Melanoma in situ was first recognized as an adjacent component at the edges of invasive melanomas that, in most instances at that time, were high-risk lesions based on the then-emerging concepts of Clark’s level and Breslow thickness (8,12). It was subsequently recognized that changes seen in these adjacent components (proliferation of atypical melanocytes in the epidermis resembling those in the dermal tumors, with features such as pagetoid scatter and continuous basal lentiginous proliferation) were also seen in lesions that lacked invasion (8,12). This led to the concept, undoubtedly true in rare particular instances, that these lesions were precursors of the invasive lesions and therefore warranted the term melanoma in situ. Then it was considered that excision of these lesions would lead to a reduction in the incidence of progression to invasion and elimination of mortality from this disease (13). However, as briefly reviewed above, this prediction does not appear to have been borne out in practice, suggesting that progression in these lesions, although undoubtedly occurring in particular instances, must be an extremely rare event.

These considerations lead to the suggestion that melanoma in situ may represent a form of overdiagnosis in which the term melanoma should never have been applied to these indolent lesions. Classification of such a lesion, for example as a form of high-grade dysplasia, would better explain its significance as a potential precursor albeit with very low risk of individual progression of individual lesions (14,15). Beyond that, it is not clear that the comparison of noninvasive with invasive melanoma is the most appropriate one. The overdiagnosis literature is not based on in situ but on invasive melanoma and clearly demonstrates that there are subsets of invasive melanoma that lack competence for progression within the lifetime of the host.

One candidate for such overdiagnosed melanomas is the class of lesions that have been termed radial growth phase melanoma or microinvasive or nontumorigenic melanoma (16). The radial growth phase of melanoma is a clinical term that reflects an impression that melanomas expand along the radii of an imperfect circle in the skin. As defined by Clark and colleagues (17), the pure radial growth phase is a lesion that may contain melanoma cells that are in situ and also cells in the dermis that are invasive but lack the ability to form tumors and thus likely lack capacity for metastasis. In the next stage, vertical growth phase, lesional cells have the capacity not only to survive but also to proliferate and form tumors (in the traditional sense of a tumor being a lesion that forms a mass as opposed to a scattering of single cells or small nests).

It was hypothesized that melanomas that lack vertical growth might also lack capacity for metastasis because a metastasis is also a tumor mass, but one that occurs at a distant site remote from the primary tumor. This hypothesis was confirmed in an institutional database where the observed melanoma-specific survival of patients with invasive melanomas that lacked vertical growth was 100% over a period of 10 years of prospective follow-up (16) and in other datasets (18-20). Vertical growth phase as a prognostic attribute has not been adopted into databases, in part because of criticism that it is subjective and poorly reproducible. However, a formal reproducibility study found it to be about as reproducible as the measurement of Breslow thickness, the dominant prognostic variable for melanoma (21). Therefore, its inclusion has been recommended, at least for Clark level II lesions, most but not all of which lack vertical growth (18).

Given these considerations, it is time to propose changes in terminology for melanocytic tumors. In the common form of melanoma in the populations addressed here (1), there is clear evidence for a progression sequence from a benign nevus to a dysplastic or atypical nevus to noninvasive, then to invasive radial growth phase, and then to vertical growth phase melanoma. The question is always what is the risk of progression of each of these individual steps, which are clearly not obligatory. It is obvious that most nevi will never become melanomas, and the Olsen data suggest that the same is true for melanoma in situ (1). These lesions may be called potential precursors; however, clearly the vast majority of them will never realize this potential. On the other hand, studies of complex lesions that have adjacent actual precursors have clearly demonstrated that there is clonal continuity and clear evidence of genomic progression in these situations (22). Even so, in situ and invasive radial growth phase melanomas are indolent lesions, the vast majority of which will never progress to the much more lethal tumorigenic melanomas.

In other tumor systems where overdiagnosis has been identified, there have been nomenclature changes such as “papillary urothelial neoplasm” of the urothelial tract in place of terms such as papillary transitional cell carcinoma, which were used 50 years ago (23). The term melanocytic intraepithelial neoplasia is attractive but fails to encompass the indolent lesions that have invasion but lack tumorigenicity. One proposal could be to incorporate all of these lesions into categories of severe or high-grade melanocytic dysplasia. Another would be to adopt terminology similar to that from other neoplastic systems, such as “melanocytic neoplasm of low malignant potential” for those lesions currently called invasive melanoma but lacking the critical property of tumorigenicity (24).

Future studies directed at identifying the subsets of melanomas that lack competence for metastasis deserve substantial public health and national funding attention, ideally at least equivalent to the resources that have been devoted to the existing screening and surveillance system for melanoma.

Funding

No funding was used for this editorial.

Notes

Role of the funder: Not applicable.

Disclosures: The author has no disclosures.

Author contributions: DEE: writing—original draft, writing—review & editing.

Data Availability

No new data were generated or analyzed for this editorial.