Final Diagnosis --Lentigo Maligna (Atypical Lentiginous Hyperplasia)

FINAL DIAGNOSIS: LENTIGO MALIGNA (Atypical Lentiginous Hyperplasia).

DISCUSSION:

The overall incidence rate for cutaneous melanoma is increasing faster than for any other cancer (1). A review of data since the 1930s shows a consistent average annual increase in incidence of approximately 6%. Careful studies have shown that this increase is not due to changes in histologic criteria. It has been estimated that of the approximately one million Americans who will be diagnosed with skin cancer in 1997, an estimated 40,300 will have invasive melanoma, causing an estimated 7,300 deaths (2). This amounts to a current estimated lifetime risk for an American developing invasive melanoma of 1 in 87 (1 in 70 white men). Should the current rate of increase continue, lifetime risk would be 1 in 75 by the year 2000. Associated with this increased incidence, the mortality rate from melanoma also continues to rise, albeit more slowly. While accounting for only 3% of current estimated new cancer cases (2), melanoma is second only to adult leukemia in years of potential life lost, responsible for death in a disproportionately high number of relatively young and middle-aged adults (3). In fact, melanoma is the most frequent cancer in white women 25 to 29 years of age and second most frequent (after breast cancer) in white women 30 to 34 years of age (1). Early detection of melanoma in a premetastatic stage of development may prevent death (4,5). Unfortunatley, some cases of melanoma defy early recognition (6). Early recognition of suspicious lesions and histopathologic confirmation probably represent our best method of preventing death from melanoma. However, this task is not always easy.

Many non-pathologists have the misconception that the histopathlogic diagnosis of melanoma and its precursors is staightforward . On the contrary, the histopathologic diagnosis of melanoma may be extremely difficult (7). Numerous masqueraders of melanoma, lack of unanimity about criteria for histopathologic diagnosis and differentiation from other melanocytic tumors, complicates diagnosis. This difficulty is translated into a disproportionately high share of medicolegal cases concerning the diagnosis of melanoma (8). The diagnosis of lentigo maligna (LM), as illustrated in this case, poses an additional problem.

LM may be defined as a rather large, haphazardly pigmented macule on sun-damaged skin, usually in the elderly, consisting of a non-nested proliferation of variably atypical melanocytes within an atrophic epidermis (9). Other terms for LM include Hutchinson's freckle, senile freckle, circumscribed precancerous melanosis, lentigo malin des viellards, melanosis premaligna, melanosis circumscripta preblastomatosa, and precancerous non-nevoid melanocytoma. LM is important because of its developmental relationship to invasive melanoma. However, there has been much debate as to whether LM should be classified as intraepidermal (in situ) melanoma or a unique variety of intraepidermal melanocytic dysplasia (9, 10).

Dysplasia is a term used to describe a disorderly proliferation with loss in the uniformity of the individual cells as well as a loss in their architectural orientation. Dysplastic cells exhibit considerable pleomorphism and often possess hyperchromatic nuclei, which are abnormally large for the size of the cell. Mitotic figures are more abundant than usual, but are almost invariably conformed to normal patterns. When dysplastic changes are marked throughout the epithelium, the lesion is considered a preinvasive neoplasm and is referred to as carcinoma in situ. Although dysplastic changes are often found adjacent to foci of invasive carcinoma, dysplasia almost invariably antedates the appearance of cancer. Moreover, dysplasia does not necessarily progress to cancer. In fact, in some tissues mild to moderate changes that do not involve the entire thickness of epithelium may be reversible with removal of the putative inciting causes (11).

LM usually begins as a small, well-circumscribed, tan or light brown macule, that may remain stable or enlarge slowly or rapidly. Although no prospective natural history studies of LM exist, it is likely that the onset of LM precedes the diagnosis of melanoma arising in LM by many years in most cases , and it is not unusual to have a duration of 10 to 15 years or more before LM progresses to invasive melanoma (9). The true risk of invasive melanoma attributable to LM based on available information is difficult to assess. However, based on prevalence of LM and its contribution to melanoma case fraction (4%), it appears that the following are probably true: 1) risk of melanoma developing in LM may be estimated to be approximately 1 in 750 cases per year over the age of 45 years; 2) risk appears to increase with age; and 3)risk to age 75 years may be as high as 2.2 to 4.7 percent, depending on age at presentation (12).

The classification of melanomas into four major biologic variants has been suggested, based on clinical and histologic features (13). However, invasive cells of melanoma may appear histologically similar regardless of classification . In contrast to in situ melanoma and the intraepithelial components of invasive melanoma (see below), lesions of LM like the one in this case, show an almost contiguous presence of strikingly pleomorphic, variably atypical, single cell intraepidermal melanocytes (14). The melanocytes are crowded but spaced equidistant and located at the basal layer. Upward migration (ie. "pagetoid spread") of melanocytes is uncommon. Nest formation is also relatively uncommon, and should be of concern when present since it often presents simultaneously with an in situ and/or invasive component (15), and may require immunohistochemical staining to detect microinvasive disease. In addition, size of the lesion is also important. According to Wayte and Helwig (16), foci of invasion were detected in 50 percent of lesions > 1 cm in diameter and 75 percent of lesions > 5 cm in diameter originally thought to be LM clinically. Immunohistochemical staining with S100 and HMB-45 of the 1.2 cm lesion in this case failed to show invasion . Other features of LM, also seen in this case, include mutinucleated melanocytes located along the basal layer, usually having prominent dendritic processes, and eosinophilic non-pigmented cytoplasm (also seen in severely sun-damaged skin)(17, 18), a perivascular or band-like infiltrate of lymphocytes and melanin-laden histiocytes in the papillary dermis, epidermal atrophy and effacement of rete ridges, solar elastosis and periadnexal extension of atypical melanocytes (follicular outer root sheath and eccrine duct).

Although there is no generally accepted histologic definition of LM , the histologic criteria being suggested here for classification of LM, are based on observations described by Clark and Mihm (14) and Cohen (15). The fact that LM lacks many of the histopathologic characteristics ascribed to intraepidermal (in situ) melanoma (ie. in situ melanoma is characterized by the relatively monomorphic, nonequidistant, single cell and/or nested proliferation of melanocytes, cytologic atypia, pagetoid spread, asymmetry, poorly circumscribed lesion) and may remain stable for years, progress or even regress spontaneously (16), suggests that rather than being in situ melanoma it behaves like a precursor lesion or dysplasia. It should be mentioned however, that this classification of LM downgrades the diagnosis to a potential precursor lesion whose stability cannot be determined, and could play a significant part in choice of treatment options.

The differential diagnosis of LM includes solar lentigo, junctional nevomelanocytic nevus, seborrheic keratosis, pigmented superficial basal cell epithelioma, pigmented actinic keratosis and other varieties of lentigines (9). The differential diagnosis of LM should also include melanoma in situ, or foci thereof arising in association with LM, and invasive melanoma. The histologic findings in this case support this lesion being LM.

To further address the question posed by Ackerman and David (19), "is lentigo maligna a separate disease entity, a precursor of melanoma, or malignant melanoma … that is confined to epidermal and adnexal epithelium, that is, a malignant melanoma in situ," LM may be postulated as a unique variety of melanocytic dysplasia (for the reasons discussed above), induced by ultraviolet (UV) radiation, possibly arising from an abnormal clone of intraepidermal melanocytes. Compared with other varieties of melanoma, LM melanoma, is most strongly linked to the relative or absolute inability to tan in response to natural sunlight (20). Genetic factors may also play a role. LM melanoma was the predominant melanoma type in a case series of Xeroderma Pigmentosum (XP) patients from Japan (21). This suggests an association between this tumor subtype and the possibility of host susceptibility factors and sensitivity to UV radiation. The presence of UV radiation-induced atypical melanocytic proliferations in the form of solar lentigines in XP patients also supports the possibility that LM might develop from solar lentigo (22). In addition, morphological alterations induced in melanocytes by long-term solar radiation, or treatment with PUVA, are alterations present in LM (and LM melanoma), often making it difficult to distinguish atypical melanocytes in LM from pleomorphic, atypical melanocytes in sun damaged skin (16, 17, 23, 24, 25 and 26 ). Moreover, PUVA therapy for psoriasis, which may induce melanocytic tumors characterized by atypical melanocytic proliferations that persist even after PUVA therapy is discontinued, has been associated with a markedly increased melanoma risk (27). Thus, distinctive morphologic features appear to exist that suggest LM as a form of melanocytic dysplasia caused by UV radiation. However, these features only suggest a role for UV radiation in causation of this lesion, and further molecular studies are needed for support (28). Nevertheless, it appears that LM is a distinct clinical and histologic entity, and not merely "melanoma minus its intraepidermal component (ie. melanoma in situ)." Thus, reconition of LM is important because it may help to better understand the early stages in deveopment of melanocytic neoplasia. Occurring on sun-damaged skin, recognition of LM may also help to better understand the environmental contribution from sun-light to the development of melanocytic neoplasia, especially in susceptible individuals (29).


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Contributed by Samuel Ejadi, M.D.
The author thanks Arthur R. Rhodes, M.D. for his advice on preparation of this case.

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