Lentigo maligna melanoma = ميلانوم الشامة الخبيثة |
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Lentigo Maligna Melanoma
Lentigo maligna, previously referred to as melanosis circumscripta preblastomatosa of Dubreuilh and also as melanotic freckle of Hutchinson [or Hutchinson's melanotic freckle (HMF), a term used currently in Australia for this condition], accounts for about 10% of melanomas and typically occurs on the chronically exposed cutaneous surfaces of the elderly, most commonly on the face, and occasionally on the back, the forearms, or the lower legs . The term "lentigo maligna" may be regarded as synonymous with "lentigo maligna melanoma in situ" for most purposes. It is controversial whether lentigo maligna should be regarded as a form of melanoma in situ in all cases or whether some cases should be regarded as precursor lesions (lentigo maligna) of in situ melanoma (melanoma in situ, lentigo maligna type) . In any case, these lesions, like other melanomas in situ, do not metastasize after complete excision, although they may persist and recur if not adequately excised. The lesion evolves slowly over many years, starting as an unevenly pigmented macule that gradually extends peripherally and may attain a diameter of several centimeters. It has an irregular border and, as long as it remains in situ or microinvasive, shows no induration. While extending in some areas, it may show spontaneous regression in others, resulting in irregular depigmented areas. The color varies from light brown to brown with minute darkbrown or black flecks. Fine reticulated lines are usually also present and help in distinguishing the lesions from actinic lentigines. In contrast to superficial spreading melanoma, the border is usually impalpable and indistinct. For this reason, the accurate clinical delineation of the border of a lentigo maligna melanoma can be problematic, and this not uncommonly results in unexpected positive or close margins in resection specimens. Occasionally, a lesion of lentigo maligna lacks melanin pigmentation . The clinical appearance then resembles that of a solar keratosis or Bowen's disease or of an inflammatory patch, such as lupus.
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It has been suggested that the risk of progression from lentigo maligna to invasive lentigo maligna melanoma may be about 5% , although some cases may progress rapidly . After adjustment for tumor thickness and other factors, lentigo maligna melanoma (LMM) has the same prognosis as other forms of melanoma . However, its demographics and associations differ from those of the most common form of melanoma, superficial spreading melanoma (SSM). For example, patients with LMM have fewer nevi but more actinic keratoses than patients with SSM, consistent with a hypothesis of chronic sun exposure in the etiology of LMM . In addition, especially in older individuals, lesions that lack nesting and pagetoid scatter of melanocytes-criteria similar to those described for lentigo maligna melanoma-are less likely to be associated with BRAF or NRAS mutations than when these attributes are present, as in SSMs . In contrast, the oncogene KIT has been found to be mutated in 28% of melanomas on chronically sun-damaged skin . These evolving genetic data will lead to refinement of the clinicopathologic melanoma classification system in the near future.
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Histopathology
Architectural Features. In its earliest stage, lentigo maligna may show at its periphery only hyperpigmentation with slight melanocytic proliferation, mainly in the basal cell layer. Toward the center of the lesion, there is a more pronounced increase in the concentration of basal melanocytes and some irregularity in their arrangement. Until there is contiguous proliferation of lesional melanocytes, these changes are not specific and may overlap with those of actinic lentigines. The epidermis is frequently flattened, in contrast to SSM, in which it is irregularly thickened and thinned, or actinic lentigines, in which there is elongation of the rete. This feature, although of diagnostic importance, is less prominent than in superficial spreading melanoma . Noteworthy is the tendency of the basal layer of follicular infundibula to also be involved by the lentiginous proliferation of atypical melanocytes
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in lentigo maligna. Some nesting of melanocytes in the basal layer may be seen, but this is not usually pronounced until invasion of the dermis is developing . The atypical melanocytes within the nests usually retain their spindled shape, and they often "hang down" like rain droplets from the interface . Except in areas of nesting, the melanocytes tend to retain their dendritic processes. If the melanocytes are heavily melanized, some dendrites may be visible even in sections stained with hematoxylin-eosin; otherwise, staining with silver demonstrates the dendrites.
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The upper dermis, which almost always shows severe elastotic solar degeneration, contains numerous melanophages and a rather pronounced, often bandlike, inflammatory infiltrate. Invasion may be demonstrable in these areas of dermal inflammation. Because invasion in a lentigo maligna melanoma (as in other melanomas) is a focal process, one should ensure that the specimen is adequately grossed and sectioned in order not to miss such areas. The presence or absence
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of tumorigenic vertical growth phase is recognized using criteria already presented. The possibility of a desmoplastic vertical-growth-phase component (see later section) should be kept in mind because this may be a subtle finding. In case of doubt, an S100 stain can be crucial in demonstrating the lesion.
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Cytologic Features. In fully evolved lesions of lentigo maligna, the lesional melanocytes in the epidermis show a marked increase in concentration, so that they come to lie in contiguity with one another, and their number in some areas exceeds that of the basal keratinocytes. Many of them are elongated and spindle shaped. Their nuclei appear atypical, being enlarged, hyperchromatic, and pleomorphic. However, the chromatin pattern is often not as open or "vesicular" as that seen in the more epithelioid cells of superficial spreading melanoma in its radial phase of growth. Frequently, atypical melanocytes extend along the basal cell layer of hair follicles, often for a considerable distance, frequently extending to the base of a shave biopsy specimen. Usually, the proliferating melanocytes contain moderate melanin, and melanin is present also in keratinocytes. There is usually some upward pagetoid extension of atypical melanocytes.
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In summary, the properties of contiguous proliferation and uniform cytologic atypia in a broad, poorly circumscribed lesion are clearly of major importance in the diagnosis of in situ or microinvasive lentigo maligna melanoma. These features are shared with superficial spreading melanoma, whereas focal pagetoid melanocytosis, although often present, is less prominent. It should also be remembered that some individuals with chronic sun damage may show diffuse, clinically covert, noncontiguous lentiginous proliferation of somewhat atypical melanocytes within the epidermal basal cell layer, and thus correlation with clinical appearance may be critical to determining the biological significance of low-grade atypical melanocytic hyperplasias. Mitotic figures are uncommonly present in the epidermal compartment of lentigo maligna melanoma; if present in the dermis, they are indicative of vertical growth phase. When tumorigenic vertical growth supervenes, it is often of the spindle cell type, including the desmoplastic and neurotropic variants.
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Pathogenesis.
As an explanation for the somewhat distinctive behavior of lentigo maligna, the theory has been offered that it is derived from spindle-shaped junctional melanocytes and thus represents a melanocyte-derived melanoma, in contrast to the superficial spreading melanoma that is derived from rounded junctional nevus cells and can be regarded as a nevus cell-derived melanoma . Electron microscopy provides some support for this concept. The melanocytes of lentigo maligna are large, synthetically active cells with many dendrites. The
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melanosomes are essentially normal, except that they appear somewhat more elongated than those present in normal melanocytes . This is in contrast to superficial spreading melanomas, in which the melanosomes show considerable abnormalities. In a study of several immunohistochemical markers comparing lentigo maligna and superficial spreading melanomas, melanocytes of the latter showed greater proliferative activity, as reflected by PCNA staining, higher levels of basic fibroblast growth factor, and more blood vessels. In addition, staining for p53, considered to be a marker of chronic solar damage, is significantly greater in lentigo maligna than in superficial spreading melanomas (452). These results were considered to be in accordance with the biological behavior of superficial spreading and lentigo maligna melanomas, that is, the longer in situ phase of the latter . Although progression of lentigo maligna is often slow, some cases progress more rapidly, and complete excision of these lesions is recommended to prevent the development of a more dangerous melanoma .
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Differential Diagnosis of Lentigo Maligna.
Lentigo maligna may be associated with fields of atypical lentiginous melanocytic proliferation that in a small biopsy may not permit an outright diagnosis. Recognition of this fact is important in suggesting the potential utility of additional sampling, particularly for clinically suspicious lesions. Lentigo maligna with junctional nest formation may also be mistaken for a superficial dysplastic nevus, especially in a partial biopsy specimen. It is important in such lesions to note the occurrence of the proliferation in an atrophic epidermis devoid of elongation of rete ridges, the uniform (rather than random) atypia of the lesional cells, and, if present, the presence of follicular extension by the atypical melanocytes. As mentioned, invasion in lentigo maligna melanoma may be extremely subtle, particularly when the involved cells exhibit desmoplastic or small-cell (nevoid) features. Close attention to subtle yet uniform atypia, aided by immunohistochemical approaches to support melanocytic (e.g., versus fibroblastic) lineage, may be helpful in such problematic lesions.
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