Distribution of malignant melanoma on the body surface.

The distribution of malignant melanoma among the 4 major body sites (head, upper limb, lower limb and remainder (trunk) was investigated for 37 white populations. Although UV radiation is generally considered to be the major aetiological agent, it was found that approximately 75% of the tumours occurred on the relatively unexposed body sites. However, the sex differences in the incidence of melanoma at the various sites corresponded in direction and magnitude with the patterns of exposures of the sexes. The greatest difference between the sexes was the higher incidence on the female lower limb (the regular wearing of skirts results in a considerable exposure), and the next largest was the higher incidence on the male trunk (men can remove their shirts easily, but do not do so regularly). The results indicate that UV radiation is a major cause of malignant melanoma, but suggest that the mechanism of induction may be complex. Several hypotheses, as well as the types of additional evidence required, are discussed.     

Lactoperoxidase-catalysed iodination of surface proteins on human melanoma cells.

The cell-surface proteins of 6 different melanoma cell cultures have been labelled with 125I using lactaperoxidase-catalysed iodination. Fractionation of the proteins was achieved using 5--22.5% polacrylamide-gradient gel electrophoresis in the presence of sodium dodecyl sulphate (SDS) and the proteins were detected by autoradiography. Up to 24 labelled proteins were detected in the individual cell cultures, but the proteins labelled differed considerably in the 6 cultures examined. A possible reason for this, involving variation in the glycosylation of cell-surface glycoproteins is discussed. Cells of the same melanoma line had similar cell-surface proteins at different passage levels, but changes in the labelled proteins occurred when the culture conditions were altered. The cell-surface proteins of high molecular weight were cleaved by trypsin, but most of the low mol.-wt. proteins were resistant to trypsin. The "large external transformation sensitive" (LETS) protein detected as a major protein on fibroblasts in culture was not a dominant protein on the melanoma cells. It was detected on only 4/6 cell cultures. Possible relationships of the cell-surface proteins described in this study to morphology, immunological properties and proteolytic activity of human melanoma cells are discussed.     

Risk factors for melanoma by body site.

It has been hypothesized that cutaneous melanoma at different anatomic sites develops through divergent pathways. We examined this hypothesis prospectively. We followed 152,949 women and 25,204 men free of cancer at baseline for up to 14 years in three large prospective studies. We examined risk factors for melanoma by anatomic location (head or neck, trunk, upper extremity, and lower extremity). Polytomous logistic regression was used to test the difference among risk factors by location of melanoma. A total of 511 incident cases of invasive melanoma (49 head or neck, 188 trunk, 98 upper extremity, and 176 lower extremity) were included in the analysis. Compared with females, males had a higher risk of developing melanoma on the head or neck and trunk. History of severe and painful sunburn was most strongly related to melanoma of upper extremity; individuals with >10 burns had a 6.86-fold (95% confidence interval, 2.62-18.00) higher risk of melanoma of upper extremity compared with those with no burns (P for trend < 0.0001; P for difference by body site = 0.04). Number of moles was most strongly related to melanoma of the trunk; the multivariate relative risk for having >10 moles was 4.67 (95% confidence interval, 3.07-7.11) compared with having no moles (P for trend < 0.0001; P for difference by body site = 0.04). Age, family history of melanoma, and hair color did not statistically differ by anatomic site of the cancer. These data support divergent etiologic pathways of melanoma development by anatomic sites.     

Distribution of autologous tumor-specific cytotoxic T lymphocytes in human metastatic melanoma.

The study of specific immunity in human cancers has been hampered by the elusive distribution and heterogeneity of effector cells. In this study, we have investigated the distribution of autologous melanoma-specific cytotoxic T lymphocytes (CTLs) in 18 different distant metastases from melanomas (9 non-visceral and 9 visceral metastases). Uncultured cells from tumors were provided directly for the establishment of T-cell clones using limiting dilution analysis to avoid any possible effects of in vitro sensitization of T cells to coexisting tumor cells. Autologous tumor specific CTL clones were detected in 6 of 18 tumors (33%, 4 non-visceral and 2 visceral metastases). The majority of CTL clones (35 of 46 and 17 of 19) in 2 patients with HLA class-I A2 haplotype failed to lyse either A2+ or A2- allogeneic melanoma cells, although anti-class-I (monomorphic) MAb inhibited their cytotoxicity. The remaining 11 of 46 and 2 of 19 CTL clones showed A2-restricted cytotoxicity. Autologous tumor-specific cytotoxicity was also detected after polyclonal culture of these tumor-infiltrating lymphocytes (TILs) in 8 of 16 tumors (50%, 5 non-visceral and 3 visceral metastases). These results suggest that tumor-specific T cells exist at tumor sites in at least one-third of distant metastases of melanomas and could be induced by the addition of IL-2 in at least half of the tumors. Tumor-specific T cells were detectable more often in non-visceral than in visceral metastases.     

Demonstration of a well-characterized tumor-associated antigen on melanoma cell surface

We have isolated and characterized a melanoma tumor-associated antigen (TAA) from the spent culture medium of a melanoma cell line. Its presence has been detected in 72% of different melanoma specimens but not in normal tissues. Because tumor antigens may stimulate or perhaps block immune reactions to cancer cells, their presence on the cell surface may be a critical factor influencing tumor growth. Therefore, to define further the immunobiological characteristics of melanoma TAA, this antigen was investigated by membrane immunofluorescence. Serum from a melanoma patient known to have a high anti-TAA antibody titer was absorbed quantitatively with lymphoblastoid cells autologous to the target melanoma cells to remove non-anti-TAA antibodies. The absorbed serum was reacted with three cultured melanoma cell lines, UCLA-SO-10 (M10), UCLA-SO-14(M), and UCLA-SO-24 (M24). Of these cell lines, M10 and M14 are known to express the antigen as assessed by radioimmunoassay. Reaction of the antibody(s) to the antigen(s) on the melanoma cell surface was detected by fluorescein-conjugated goat anti-human IgG. The reactivity of the absorbed serum was inhibited by preincubation with purified melanoma TAA. These results clearly demonstrate that melanoma TAA is expressed on the cell surface of cultured melanoma cells.     

Identification and solubilization of iodinated cell surface human melanoma associated antigens.

To identify soluble cell surface melanoma-associated antigens (MAA), human melanoma cells in culture were radioiodinated by the lactoperoxidase technique and solubilized in non-ionic detergent (NP-40). Labelled MAA were identified by a quantitative double-antibody antigen binding assay and unrelated labelled macromolecules by trichloroacetic acid precipitation. Detergent solubilized 95% of the macromolecule-associated radioactivity. Approximately 8%, presumably MAA, was bound specifically by anti-melanoma serum. In contrast, anti-melanoma serum bound specifically only 0.5 to 1.5% of the acid precipitable radioactivity in control cells iodinated in a similar manner. Specificity was further studied by quantitative serum absorption. Two different melanoma lines were equally effective in inhibiting specific binding of iodinated melanoma lysate, whereas 50-100 times more normal fresh lymphocytes, liver and spleen cells, cultured HeLa or colon adenocarcinoma cells, and 8 times more cultured fetal cells were required to produce similar reductions in specific binding. These studies demonstrate that cell surface human melanoma antigens that differ qualitatively and/or quantitatively from those on normal or malignant allogeneic tissues can be solubilized and identified. These antigens are shared with other melanomas, and some are also present on fetal cells.     

Cell surface antigens of melanocytes and melanoma

One major focus of cancer immunology is the question of tumour-specific antigens, the existence of which has yet to be proven. The prime candidates for antigens that can be considered tumour-specific are the class 1 unique antigens that have been serologically defined on human malignant melanomas by antibodies from the tumour-bearing host. In addition to these antigens, intensive immunological, biochemical and genetic analyses of melanoma have permitted a rudimentary classification of other surface antigens expressed by this tumour type. Cell-surface antigens of melanoma can be grouped into three general classes: restricted antigens (i.e. antigens which are expressed by melanomas and astrocytomas) many of which are differentiation markers characterizing cells of neuroectodermal origin; antigens with intermediate distribution (i.e. antigens which are present on some cell tumour types but not on others and which show a limited distribution on normal tissues and cells); and antigens with broad distribution (i.e. antigens expressed by most human cells either malignant or normal). The detailed knowledge of the surface antigens (i.e. differentiation antigens and class 1 unique antigens) of melanoma cells has permitted a rational and coherent approach to assessing the possibility of immunological control of malignant melanoma in the clinic.     

Ciliary body melanoma treated with helium particle irradiation

Melanoma involving the ciliary body is a rare tumor which carries a poor prognosis when compared to all uveal melanoma. We have treated 54 patients with ciliary body melanoma using helium ions from 1978 to 1985. Because of the high rate of metastatic disease, the 5-year disease specific survival rate is only 59% despite a 5-year local control rate of 98%. The greatest diameter of the tumor was predictive of loss of vision and enucleation (p = .05, p = .04, respectively). Multivariate analysis showed that the greatest diameter of the tumor was the most important predictor of death from metastases. The incidence of neovascular glaucoma at 5 years is 43%. The 5-year actuarial rate of enucleation is 26%. Enucleation was done for pain and/or neovascular glaucoma. Univariate analysis showed treatment volume to be a statistically significant predictor for the development of neovascular glaucoma (p = .0017) and enucleation (p = .0078). Seventy percent of neovascular glaucoma occurred in patients with treatment volume greater than 5.5 cc. Seventy-four percent occurred in patients with an initial ultrasound height greater than 9.2 mm. Using this information, patients at high risk for neovascular glaucoma could be considered for prophylactic treatment with panretinal photocoagulation.     

Sex differences in numbers of nevi on body sites of young European children: implications for the etiology of cutaneous melanoma.

BACKGROUND: Since 1950, the greatest increase in cutaneous melanoma incidence in fair-skinned males took place on the trunk and on the head and neck, whereas in females, it took place on the limbs, mainly on the lower limbs. We examined the influence of sex on numbers and size of nevi on different body sites in white European schoolchildren.METHODS: Information about each holiday period since birth to interview was recorded from parents of six hundred twenty-eight 6- to 7-year-old children in four European cities (Brussels (Belgium), Bochum (Germany), Lyons (France), and Rome (Italy)). Number and anatomic location of small (2-4.9 mm) and large (>/=5 mm) nevi and individual susceptibility to sunlight were independently assessed.RESULTS: After adjustment for host characteristics, sun exposure, and sun protection habits, males had 7% [95% confidence interval (95% CI), -7 to 19] more small nevi than females. However, compared to females, numbers of small nevi were increased by 17% (95% CI, 1-31) on the head and neck and by 16% (95% CI, 2-27) on the trunk and shoulders. In contrast, in males, the number of small nevi on upper limbs was decreased by -5% (95% CI, -26 to 13), and on lower limbs by -8% (95% CI, -34 to 13). The number of large nevi was 6% higher in males than in females (95% CI, -26 to 30).CONCLUSIONS: The sex differences in small nevus distribution in schoolchildren reflect the sex differences in the anatomic distribution of melanoma in adults. Sex differences in sun exposure behaviors, dressing, and clothing would just add their effects to the sex-dependent inherited propensity to develop nevi on a given body site. These results reinforce the hypothesis by which childhood would be a decisive period for the occurrence of sun-induced biological events implicated in the genesis of cutaneous melanoma.     

Flexible, actin-based ridges colocalise with the beta1 integrin on the surface of melanoma cells

Using a combination of laser-scanning confocal microscopy and atomic force microscopy, we have identified flexible, actin-based structures on the surface of cells derived from the vertical growth phase of melanoma progression. These flexible structures, lacking on the surface of mature melanocytes, were observed on the surface of all four melanoma cell lines tested. Further investigation revealed that the beta1 integrin colocalises with these actin-based ridges on the cell surface, whereas beta1 integrin distribution in melanocytes did not correlate with actin-based structures. Fibronectin staining on the surface of melanoma cells was partially codistributed with the ridges. The combination of structural information derived from atomic force microscopy images and fluorescent imaging of the distribution of labelled proteins involved in invasion and metastasis has allowed us to identify a common feature that may be involved in disease progression, at the surface of vertical growth phase melanoma cells, despite the known variation in genetic composition of melanoma.     

不同部位贴敷芬太尼对晚期癌症病人镇痛效果比较

目的观察不同体表部位贴敷芬太尼对晚期癌症病人镇痛效果的比较,选出最佳部位。方法选择不同体表部位并分组,使用红外非接触体温计,记录及比较这些部位贴敷芬太尼前表面温度和敷贴后的起效时间,止痛时间,找出差异。结果横向比较后发现腋下、前胸、颈部、四肢和背部组的体表温度差异明显,其中颈部和腋下这两个温度较高的地方在起效时间上明显短于其它部位,二者P值均小于0．05,有显著的统计学意义,而且出现突发性疼痛的次数较其它为少。结论体表温度是影响该药物作用效果的因素之一,推荐腋下部位。     

Spatial density of primary malignant melanoma in sun-shielded body sites: A potential guide to melanoma genesis

UV radiation is a major factor in melanoma genesis, but non-UV linked factors are also operational, since primary malignant melanomas can emerge in body sites that never see the sun. The scarcity of melanomas in sun-shielded body sites reflects only the absolute number of melanomas, not the number of tumours per square unit of the surface in which they emerge. Studies on melanoma density conducted by us and others are here briefly reviewed. The access to reliable numbers along with measurable anatomical areas directed our choice of melanomas at the sun-shielded locations described here. Melanomas at the body surface. Calculations of surface areas bearing melanomas relative to the total body surface included sites on the vulva, subungual tissues, volar and palmar skin, and, for comparison melanomas of the face during the same period of time. The density of vulvar melanomas was identical to that in chronically sun-exposed facial skin. Subungual melanomas were almost nine times denser than expected whereas melanomas of palms and soles showed a lower density than expected. Melanomas beneath the body surface. The densities of melanomas in the vagina, anal canal and uvea, were calculated separately and compared to the average density of cutaneous melanomas (CMMs) during the same period of time. Melanomas of the anal canal displayed a density almost twice the average for CMMs, whereas the vaginal melanomas were similar in density to CMMs. In contrast, the density of the uveal melanomas was calculated as 50 and 41 times (men and women, respectively) the average density of CMMs. CONCLUSION: The high density of some melanomas in sun-shielded body areas indicates the presence of factors underlying the origins of these tumours that seem to be equivalent in strength to UV radiation and also implies that specific anatomical sites favour the emergence and proliferation of melanomas, independent of UV radiation.     

Metastatic melanoma of the gallbladder.

Metastatic involvement of the gallbladder in melanoma is rare, but constitutes the most common metastatic lesion involving this organ. Two cases of metastatic melanoma to the gallbladder with radiographic evidence of gallbladder abnormality prior to surgery are presented. These cases are compared to the nine previously reported cases of metastatic melanoma to the gallbladder with abnormal cholecystograms. All eleven cases presented with signs and symptoms compatible with cholecystitis. Nine of the eleven patients had a previous melanoma primary and most had other extrabiliary metastases. Associated cholelithiasis appeared to be only incidental. In addition, nine reported cases of "primary" biliary melanoma were reviewed. Clinical and pathologic presentations in the latter cases were similar to the former cases with metastases. Seventy-eight percent had extrabiliary sites of metastasis at some time in the course of their disease, tending to refute the impression of "primary" biliary melanoma. Melanoma in the gallbladder is much more likely to have metastasized from a regressed skin primary than to have arisen de novo. The two reported cases and the 18 cases from the literature indicate that the physician must consider gallbladder metastasis in melanoma patients presenting with symptoms compatible with cholecystitis.     

Cell surface glycoproteins of human tumor cell lines: unusual characteristics of malignant melanoma.

Cell surface glycoproteins of human tumor cell lines (melanomas and astrocytomas, and ovarian, bladder, stomach, cervical, laryngeal, and renal cancers) were studied by labelling with 1) neuraminidase-galactose oxidase-[3H]borohydride, 2) galactose oxidase-[3H]borohydride, and 3) dilute periodate-[3H]borohydride. The labeled components were examined by polyacrylamide gel electrophoresis and fluorography. Each tumor type had a distinctive pattern of labeled glycoproteins when the results from both procedures 1 and 2 were considered. Cell surface glycoproteins of malignant melanoma could not be labeled by procedure 2, whereas the other cell lines had at least two major glycoproteins that could be labeled by this method. Very similar profiles of melanoma glycoproteins were labeled by procedures 1 and 3. From these results the conclusion was reached that cell surface glycoproteins of melanomas are substituted with sialic acid so that their D-galactose and/or N-acetyl-D-galactosamine residues are available for oxidation by galactose oxidase only after neuraminidase treatment. An alternative explanation that these sugars are sterically accessible to galactose oxidase only after neuraminidase treatment also has to be considered. All melanoma lines studied were characterized by having two major cell surface glycoproteins with molecular weights of 110,000 and 90,000, respectively. Lines, however, varied considerably in their expression of other components. In particular, heterogeneity was shown in the expression of gp220, a component identified as fibronectin by immunoprecipitation with a specific antiserum, and in the expression of gp37/32, a pair of glycoproteins having the characteristics of la-like antigens. Of the other cell lines studied, astrocytomas most closely resembled melanoma in their glycoprotein profiles. The brain tumors, however, had two or three glycoproteins, including gp110, which could be labeled by galactose oxidase-[3H]borohydride without neuraminidase treatment.