Progression to invasive melanoma from malignant melanoma in situ, lentigo maligna type

We have previously hypothesized that lesions that have been termed lentigo maligna can be divided into 2 categories: 1 represents a pigmented lesion that is a precursor to melanoma, and the other melanoma in situ. We and others have hypothesized that there is a progressive acquisition of attributes in pigmented lesions that results in malignant melanoma. Based on these 2 hypotheses, we have predicted that the intraepidermal component of invasive malignant melanomas, lentigo maligna type, should be similar to those lesions that we have termed malignant melanoma in situ, lentigo maligna type rather than lentigo maligna. The intraepidermal component of 42 consecutive cases of invasive malignant melanoma, lentigo maligna type was evaluated by all of the authors. Malignant melanoma in situ, lentigo maligna type is characterized by pagetoid spread, confluence, and nesting of atypical melanocytes. All of the cases evaluated showed features diagnostic of malignant melanoma in situ, lentigo maligna type, in the epidermis overlying the invasive dermal component. We conclude that invasive lentigo maligna melanoma arises in association with those lesions that we have termed malignant melanoma in situ, lentigo maligna type, which may represent a step in the progression between atypical melanocytic hyperplasia (lentigo maligna) and invasive melanoma. This finding supports the distinction of these entities and may have therapeutic implications.     

Angiocentric invasion by lentigo maligna melanoma.

A case of angiocentric invasion by a lentigo maligna melanoma is reported. Pericapillary cuffing and permeative intimal expansion of veins by melanoma without luminal tumour cell emboli, thrombosis, or vascular destruction were associated with a lentigo maligna melanoma on the face of a 93 year old woman. This unusual infiltrative pattern suggests a specific interaction between melanoma cells and perivascular connective tissue elements, and may imply expression by tumour cells of receptors for molecules in the intima of blood vessels and in pericapillary stroma.     

Lentigo maligna and superficial spreading melanoma are different in their in situ phase: an immunohistochemical study

Clinical and pathologic observations have prompted the categorization of malignant melanoma into 4 subtypes. Although some authorities challenge the value of this classification, nevertheless it is generally accepted that lentigo maligna (LM), or melanoma on sun-damaged skin, has a different biological behavior than so-called superficial spreading melanoma (SSM), at least in the early stage of its evolution. To characterize some aspects of this different behavior, the in situ phase of SSM and LM was studied using immunohistochemical methods. Seventeen cases of SSM in situ and 13 cases of LM were chosen for the study. All cases qualified with strict histologic criteria. Sections from these lesions were stained with antibodies against HMB-45 antigen, basic fibroblast growth factor (bFGF), proliferating cell nuclear antigen (PCNA), and factor VIII. Semiquantitative analysis was performed. Cases classified as either LM or SSM corresponded well to the epidemiologic and clinical characteristics as described in the literature; that is, LM appeared in older patients and occurred mostly on the face, whereas SSM occurred mostly on the trunk and lower limbs. Although no difference in HMB-45 stain was observed, melanoctyes of SSM showed greater proliferative activity, as reflected by PCNA stain (P < 0.02) and higher levels of bFGF (P < 0.001), than melanocytes of LM. More blood vessels were counted under SSM than under LM (P < 0.05). These results are in accordance with the biological behavior of SSM and LM, that is, the longer in situ phase of the latter. bFGF is both a growth factor for melanocytes and an angiogentic factor. The differences in PCNA, a proliferation marker, and blood vessel count may be related to the bFGF effect. Thus this study reveals some of the biological differences between LM and SSM. Location and sun exposure habits may contribute to these differences, which already exist in the in situ phase.     

Immunohistochemical study of melanocytic differentiation antigens in cutaneous malignant melanoma. A comparison of six commercial antibodies and one non-commercial antibody in nodular melanoma, superficially spreading melanoma and lentigo maligna melanoma

In certain primary and metastatic malignant melanomas diagnostic problems may arise due to their cytologic features and/or absence of synthesis of melanin. As the "classic" combination of S-100 protein and HMB-45 may occasionally fail to stain cells of malignant melanoma, we have tested a series of commercially accessible antibodies which were so far not compared by other authors in the three most frequent subtypes of this tumor. In surgical specimens from 104 cutaneous malignant melanomas (40 nodular melanomas, 46 superficially spreading malignant melanomas and 18 lentigo maligna melanomas) the staining intensity and the proportion of neoplastic cells stained with antibodies to S-100 protein, HMB-45, NKI/C3, NKI/beteb, MART 1 (Melan A), KBA 62 and Mitf was semiquantitatively analysed. The use of this group of antibodies against melanoma-associated antigens revealed it to be a favourable supplement for the bioptical or cytological diagnosis of malignant melanoma in case the traditional/conventional combination of S-100 protein and HMB-45 antibody fails. According to the authors' experience the antibody against KBA 62 has shown to be the most effective antibody followed by the antibodies against MART-1 (Melan A) and NKI/C3.     

Dermal vascularity in lentigo maligna

Lentigo maligna (LM) may represent a tumour arrested in an in situ phase, lacking the angiogenic capacity and underlying dermal neovascularization required for invasive growth. The acquisition of an angiogenic phenotype might be associated with the development of lentigo maligna melanoma (LMM). To investigate this thesis, sections of formalin-fixed, paraffin-embedded tissue from 15 LMMs, and 11 LM excision specimens were stained with the vascular endothelial marker Ulex europaeus agglutinin I. Dermal vessels were counted and vascular morphometry was performed. In specimens in which LMM was present, dermal vascularity was significantly increased in LM compared with normal skin. The most significant increases were found for dermal vascular density (39 per cent increase, P=0.008) and for total vessel surface area (62 per cent increase, P=0.005). However, when no LMM was present, the vascular density underlying LM (79 ± 9 vessels/mm²) did not differ significantly from that of adjacent normal skin (67 + 6 vessels/mm²), although focal ‘hot spots’ of increased vascularity were present. We conclude that increased dermal vascularity is present beneath in situ LM and that this increased vascular density is closely associated with the presence of invasive LMM in the same specimen.     

Ultrastructure of lentigo maligna in the oral cavity

A rare case of lentigo maligna in the oral cavity was investigated by light and electron microscopy. Cutaneous lentigo malignas often develop to malignant melanomas. However, the electron microscopic examination revealed that even though there were a large number of melanosomes, most of them were late stage and had membrane structure, and positive staining with HMB-45 was not recognized. From our findings, it is difficult to conclude that oral lentigo malignas develop malignant melanomas, and thus further studies are needed.     

Lentigo maligna: Cytogenetic, ultrastructural, and phenotypic characterization of a primary cell culture

Lentigo maligna is an early cutaneous neoplastic lesion. This article presents the cytogenetic, ultrastructural, and phenotypic characterization of a primary cell culture obtained from a patient affected with lentigo maligna. Two cellular clones were identified, both characterized by chromosomal markers involving chromosome 10 with a breakpoint at 10q26.     

Malignant melanoma in situ: the flat, curable stage of malignant melanoma

Malignant melanoma can be diagnosed clinically and histologically when it is small, flat, and confined to the epidermis. The criteria for the diagnosis are described. The application of these criteria can lead to simple excision of the lesion and the prevention of the malignant melanoma from evolving into a neoplasm with the potential for metastasis.     

A retrospective histological study of 669 cases of primary cutaneous malignant melanoma in clinical stage I. The consequences of a reclassification of the original group of lentigo maligna melanomas.

A selected series of primary malignant melanoma of the skin, clinical stage I, was originally classified according to Clark's system. The consistency of this classification was tested by two Brisbane pathologists who indicated that we had misinterpreted some cases of superficial spreading malignant melanoma as lentigo maligna melanoma. We have therefore reclassified the original group of 86 lentigo maligna melanomas. This resulted in a total series of 37 (5.5%) lentigo maligna melanomas, 301 (45%) superficial spreading malignant melanomas, 194 (29%) nodular malignant melanomas (unchanged) and 137 (20.5%) unclassifiable malignant melanomas. The diagnosis of lentigo maligna melanoma was not made unless the epidermis was atrophic and dermal solar elastosis was present. The new group of lentigo maligna melanomas is dominated by cases on the head among patients over 50 years of age (especially women). This is in better agreement with other studies than our previous findings. The relationship with tumour cell type, pigmentation, mitotic count, atypia, transsectional profile, level of invasion, ulceration, vascular invasion, lymphocyte infiltration and prognosis shown by the new groups of lentigo maligna melanoma and superficial spreading malignant melanoma indicates that the cases by which the diagnosis has been changed are relatively benign. Our previous conclusions are still valid. The lentigo maligna melanoma is still the most benign type and nodular malignant melanoma still the most malignant type of melanoma. The superficial spreading malignant melanoma still represents an intermediate tumour type, although it has deviated in the benign direction.     

The diagnosis of Hutchinson's melanotic freckle (lentigo maligna) in Queensland

Following an increase in the reported incidence of melanoma of Hutchinson's melanotic freckle type (HMFM) in Queensland, a review of its histological diagnosis was undertaken. Ninety-nine pigmented lesions reported by 13 different pathology laboratories throughout Queensland as having an in-situ component of Hutchinson's melanotic freckle (HMF) were reviewed by 2 pathologists with an interest in malignant melanoma. This diagnosis was confirmed in 76 cases while in a further 3 the reviewers regarded the in-situ component as indeterminate. It would seem that the level of agreement among pathologists reporting HMF(M) should be considered in any assessment of incidence patterns of melanoma.     

Primary malignant melanoma of the esophagus with diffuse melanocytic atypia and melanoma in situ

Primary malignant melanoma is an unusual lesion in the esophagus that is not infrequently seen in association with melanosis. A case of esophageal invasive malignant melanoma with melanosis is described in which the melanosis exhibited melanocytic atypia extending through to melanoma in situ. The authors know of no previously reported such finding.     

Solar cycles and malignant melanoma.

There has been a sixfold increase in the incidence of malignant melanoma in the State of Connecticut during the past forty years. Superimposed on a steady incidence rise are cycles of markedly increased incidence rates which follow periods of maximum sunspot activity. We propose that the effect of sunspot cycles on human melanoma occurrence is mediated by modulation of stratospheric ozone and thus indirectly affects UV flux at the earth's surface. This hypothesis would predict a time lag in melanoma incidence cycles, relative to sunspot activity, with increasing distance from polar caps. This appears to be the case. The increase in melanoma incidence related to a given reduction in ozone depletion in this hypothesis, is in great excess of existing models relating anthropogenic ozone depletion and skin cancer.     

In situ analysis of the mononuclear cell infiltrate in primary malignant melanoma of the skin.

Monoclonal antibodies, directed against functionally different lymphocyte subsets, were applied on frozen sections of primary malignant melanomas and benign nevi. Positive reaction was identified by means of an immunoperoxidase method. It was found that lymphocytic infiltrate underneath and in between malignant melanoma is composed of approximately equal numbers of OKT4 positive helper and OKT8 positive suppressor/cytotoxic T cells. The majority of these lymphocytes also expressed HLA-Dr antigen, indicating an activated state. In addition HLA-Dr, OKT6 positive dendritic cells were present in the infiltrate and between the melanoma cells. Finally, melanoma cells expressed demonstrable amounts of HLA A, B, C antigens, whereas benign nevi did not. It is concluded that all ingredients for a successful immune reaction against primary malignant melanoma are on hand. This finding is in agreement with the relatively frequent occurrence of partial or even complete regression of primary malignant melanoma of the skin.     

Histological type and biological behavior of primary cutaneous malignant melanoma

Summary Primary cutaneous malignant melanomas are generally divided into 3 separate clinico-pathological variants, lentigo maligna melanoma (LMM), superficial spreading melanoma (SSM), and nodular melanoma (NM). Recently an additional variant, acral lentiginous melanoma (ALM), has been defined, occurring on acral regions, defined as plantar, palmar, and sub-/parungual areas. Histological examination of 86 primary melanomas on acral regions revealed 24 (28%) acral lentiginous melanomas (ALM), 23 (27%) superficial spreading melanomas (SSM), 18 (21%) nodular melanomas (NM), and 21 (24%) unclassifiable melanomas. No LMM was seen. The prognosis was found to be the same in patients with SSM and ALM. However, by correlating histological type with frequency of antecedent nevus, duration of melanoma and dominant invasive tumor cell, it was demonstrated that histologically typical ALM differed from histologically typical SSM by their infrequent origin from antecedent nevi, their lower local growth rate, and their more frequent content of spindle cells. These findings support ALM as a valid melanoma subtype only when clearly defined histologically.