Immunohistochemical characterization of Spitz's nevus: differentiation from common melanocytic nevus, dysplastic melanocytic nevus and malignant melanoma

Recently it has been reported that Spitz's nevus possesses a deranged melanogenesis with formation of the spherical melanosomes also seen in superficial spreading melanoma (SSM) and dysplastic melanocytic nevus (DMN). To characterize the nature of Spitz's nevus, immunohistochemical studies were carried out in 9 cases of this condition using monoclonal antibodies (MoAbs) which identify (a) human melanosome-associated antigen (HMSA-1 and HMSA-2), (b) S-100 protein (α and β subunits), (c) Leu-7 (HNK-1), (d) β2 microglobulin (B2MG), and (e) neuron specific enolase (NSE). In contrast to SSM and DMN, none of the 9 cases showed any significant reactivity with MoAbs HMSA-1 and HMSA-2. Similar to cutaneous malignant melanoma (CMM) and DMN, and unlike common melanocytic nevus (CMN), anti-S-100 protein α subunit MoAb reacted from moderately to intensely with Spitz's nevus, and anti-S-100 protein β subunit MoAb reacted weakly. Anti-B2MG MoAb was reactive with 8 of 9 cases. Only one case showed cytoplasmic reactivity to anti-Leu-7 MoAb. Polyclonal NSE was found in 7 cases at varying intensities. Our immunohistochemical study indicates the distinct, benign neoplastic nature of Spitz's nevus which has immunoreactivities differing from those of CMM, DMN and CMN.     

Association of melanoma and neurocutaneous melanocytosis with large congenital melanocytic naevi--results from the NYU-LCMN registry

BACKGROUND: Large congenital melanocytic naevi (LCMN), which develop in utero and are present in approximately one in 20,000 newborns, are associated with markedly increased risks of cutaneous melanoma, leptomeningeal melanoma and neurocutaneous melanocytosis (NCM). OBJECTIVES: This study examined clinical characteristics associated with melanoma and NCM among patients with LCMN, and estimated the risk of developing melanoma and NCM in these patients. METHODS: Two hundred and five LCMN patients enrolled in the New York University registry were studied. One hundred and seventy of these patients were followed prospectively. The remaining 35 patients had either melanoma at the time of entry into the registry (n = 6), or had insufficient follow-up information (n = 29). The outcome measures were the occurrence of melanoma and NCM. The associations between these outcomes and the clinical covariates (anatomical location of the LCMN, size of the LCMN, number of satellite lesions, family history of melanoma, patient sex and treatment) were assessed. RESULTS: Four of 170 (2.3%) prospectively followed patients developed melanomas, representing a standardized morbidity ratio of 324. Among the entire cohort (n = 205), there were associations between increasing numbers of satellite naevi and the occurrence of melanoma (P = 0.04), and the presence of NCM (P = 0.06). Compared with patients who did not develop these diseases, median LCMN diameters were larger among patients who developed melanoma (49 vs. 39 cm) and NCM (55 vs. 46 cm). CONCLUSIONS: In LCMN patients, increasing numbers of satellite lesions and larger LCMN diameters are associated with melanoma and NCM.     

Malignant melanoma with preserved hairs: A snap shot could suggest the development from an acquired melanocytic nevus

A 63-year-old man presented with a dome-shaped, black nodule on his right forehead, where hairs were preserved. The black surface tone measured 7 mm in diameter and spread irregularly from the periphery of the nodule. He had been conscious of the preceding, black macule for approximately 50 years. A snap shot of the patient in adolescence showed a tiny, black macule, which was a few millimeters in diameter. Histological examination demonstrated irregular proliferation of melanoma cells from the epidermis to the dermis. Partially, there were well-circumscribed, oval nests composed of nevus cells in the acanthotic epidermis and follicles. Nevus cells were also seen in the dermal component, presenting a burnt-out appearance. In this case, the small final size, the preserved hairs and the snap shot suggested a preceding, acquired melanocytic nevus. Malignant melanoma could arise from acquired melanocytic nevus.     

Presence of high-risk mucosal human papillomavirus genotypes in primary melanoma and in acquired dysplastic melanocytic naevi

BACKGROUND: Some studies have shown that cutaneous and mucosal melanoma biopsy specimens harbour human papillomavirus (HPV), suggesting that this virus may play a role in development and progression of the tumour. OBJECTIVES: To investigate the presence of HPV DNA and the prevalence of different high-risk mucosal HPV genotypes in primary melanoma (PM) and in acquired dysplastic melanocytic naevi (ADMN). METHODS: Fifty-one PMs from 18 men and 33 women (median age 55.5 years), 33 ADMN from 15 men and 18 women (median age 35.1 years) and 20 control skin samples from nine men and 11 women (median age 43.5 years) were studied. All diagnoses were made after histological analysis. HPV DNA analysis was made using two different polymerase chain reaction-enzyme-linked immunosorbent assay (PCR-ELISA) methods, namely MY-PCR and GP-PCR. RESULTS: Using GP-PCR, mucosal HPVs were detected in 14 PMs (27%; P = 0.0166) and eight ADMN (24%; P = 0.0367), while with MY-PCR, mucosal HPVs were found in 11 PMs (22%; P = 0.04) and five ADMN (15%; P not significant). All control skin samples were negative for mucosal HPVs with both DNA amplification procedures. CONCLUSIONS: Using our PCR-ELISA methods, the detection of mucosal high-risk HPV genotypes in 24% of precursor lesions (ADMN) and in 27% of PMs adds to the body of evidence indicating a colocalization of mucosal HPV and tumoral melanocytic pathologies.     

Melanoma and melanocytic nevi in decorative tattoos: three case reports

Background: In response to the demands of style and fashion, the number of decorative tattoos has been increasing worldwide. This has been paralleled by a rising incidence of melanocytic proliferations, including melanoma. The coincidence of various dermatological diseases and skin tumors with tattoos has been documented with some frequency, but reports of melanoma associated with tattoos are exceedingly rare. To date, only 13 cases have been documented in the English language literature. The possibility of an association between melanocytic proliferations and tattoos remains an area for further study. Observations: This report presents two cases of melanocytic nevi and one of melanoma occurring in association with a decorative tattoos. Conclusions: At present, the pathogenesis of melanoma developing in a tattoo is unknown. Mere coincidence cannot be ruled out. However, trauma, ultraviolet light exposure, a photoallergic effect, or an inflammatory reaction may promote malignant transformation. Clinicians and histopathologists should be aware of the clinical and pathological features if they are to make a correct diagnosis. Varga E, Korom I, Varga J, Kohán J, Kemény L, Oláh J. Melanoma and melanocytic nevi in decorative tattoos: three case reports.     

A rational approach to melanoma follow-up in patients with primary cutaneous melanoma. Scottish Melanoma Group

From the Scottish Melanoma Group database for south-east Scotland we evaluated 5-year follow-up in patients with cutaneous malignant melanoma excised between 1979 and 1994 and devised an 'evidence-based' review protocol. Of the 1568 with stage I melanoma, 293 (19%) developed a recurrence, 32 had a second primary melanoma and 97 had an in-situ melanoma. The disease-free interval shortened progressively with increasing tumour thickness. Overall, 80% of recurrences were within the first 3 years, but a few patients (< 8%) had recurrences 5 or 10 years after the initial surgery. In-situ melanomas did not recur. Almost half (47%) the recurrences were noted first by the patient, and only 26% were detected first at a follow-up clinic. One hundred and thirty-nine patients (89%) were still under review when their recurrences were detected, and 102 (65%) had been seen within the previous 3 months. Questionnaires were completed by 120 patients: sun protection and avoidance, and mole examination were more likely after melanoma excision. We recommend 3-monthly review of patients with invasive lesions for the first 3 years. Thereafter, those with lesions >/= 1.0 mm need two further annual reviews. Patients with in-situ lesions should be reviewed once, to confirm adequate excision (0.5 cm margins) and to give appropriate education. Surveillance beyond 5 years is only justified if there are special risk factors.     

Aggressive melanoma in an infant with congenital melanocytic nevus syndrome and multiple,NRAS and BRAF mutation‐negative nodules

We report the case of a newborn boy with multinodular NRAS and BRAF mutation‐negative congenital melanocytic nevi and cerebral lesions compatible with congenital intraparenchymal melanosis. Histopathology from skin lesions showed atypical nodular melanocytic proliferation with marked melanocytic atypia and a large number of mitoses and apoptosis, indicating aggressive proliferation. The child developed several new subcutaneous tumors and multiple internal lesions, which were confirmed to be metastases, and died at 5 months of age. This case may represent an infantile melanoma developing from a giant congenital melanocytic nevus or a congenital melanoma.     

Case–control study to identify melanoma risk factors in the Belgian population: the significance of clinical examination

BACKGROUND: Although numerous studies have evaluated risk factors associated with cutaneous malignant melanoma (CMM), no such study has been carried out in Belgium. OBJECTIVES: To identify individuals who are at high risk of developing malignant melanoma in Belgium, which could enhance the efficacy of screening interventions and avoid unnecessary skin inspections. STUDY DESIGN/SETTING/SUBJECTS: We prospectively included patients who were diagnosed with invasive malignant melanoma between 1998 and 2001 at the Department of Dermatology in a case-control study. Controls were selected from the outpatient dermatology clinic. Participants were interviewed and clinically examined by a dermatologist. We asked questions concerning most known risk factors associated with malignant melanoma such as phenotypical and skin characteristics, and environmental and lifestyle exposures. To adjust for confounding variables and to estimate odds ratios (ORs) and 95% confidence intervals (CIs), a multivariate model was used. RESULTS: Although sunburn in childhood and substantial occupational solar exposure were modestly, but significantly, associated with malignant melanoma risk, clinical examination yielded several stronger risk factors. In a multivariate model, which adjusted for age, gender and skin phototype, phenotypical characteristics such as skin, hair and eye colour were significantly associated with the development of malignant melanoma. In the multivariate model, people with three or more atypical naevi were at more than 10-fold risk of developing a malignant melanoma (> or = 3 atypical naevi; adjusted OR = 11.40, 95% CI = 4.79-17.53) compared to those without an atypical naevus. The presence of one or more palpable naevi on the upper extremities or having solar lentigines increased the odds of developing malignant melanoma at least twofold. CONCLUSIONS: In Belgium, risk factors associated with malignant melanoma appear to be in accordance with previous studies. To assess peoples' risk profile, clinical skin examination is likely to yield the most important sporadic malignant melanoma risk factors. Therefore, focusing screening campaigns on individuals with predefined findings on skin self-examination may increase its efficacy.     

Novel LRRFIP2-RAF1 fusion identified in an acral melanoma: A review of the literature on melanocytic proliferations with RAF1 fusions and the potential therapeutic implications

A small subset of cutaneous melanomas harbor oncogenic gene fusions, which could potentially serve as therapeutic targets for patients with advanced disease as novel therapies are developed. Fusions involving RAF1 are exceedingly rare in melanocytic neoplasms, occurring in less than 1% of melanomas, and usually arise in tumors that are wild type for BRAF, NRAS, and NF1. We describe herein a case of acral melanoma with two satellite metastases and sentinel lymph node involvement. The melanoma had a concomitant KIT variant and LRRFIP2-RAF1 fusion. This constellation of molecular findings has not been reported previously in melanoma. We review the existing literature on melanocytic neoplasms with RAF1 fusions and discuss the potential clinical implications of this genetic event.     

Evaluation of heparanase and matrix metalloproteinase-9 in patients with cutaneous malignant melanoma

Elevated heparanase and matrix metalloproteinase (MMP)-9, frequently found in human cancer, is a major cause of degradation of the extracellular matrix (ECM) and basement membrane (BM), thus facilitating tumor cell migration and invasion. Although a lot of work has been done, the role of heparanase and MMP-9 has not been delineated in skin cancer progression. The purpose of this study was to do such an exploration. To investigate the role of heparanase and MMP-9 in cutaneous malignant melanoma (CMM) development, we performed immunohistochemical analysis to detect the alternation of these two factors in paraffin-embedded biopsy specimens of normal skin, junctional nevi and CMM. It is interesting to note that the expression profile of heparanase and MMP-9 was similar. Contrary to negative staining in normal skin, overexpression of heparanase and cytoplasmic MMP-9 was observed in as many as 70% of CMM, whereas only 10% of the junctional nevi exhibited faint staining (P = 0.0005, P = 0.0000). Considering the lymph node (LN) metastasis, the expression of the two factors is significantly higher in LN-positive lesions than that in LN-negative lesions (P = 0.0295, P = 0.0013). Meanwhile, there was positive correlation between the expression of MMP-9 and heparanase (r = 0.689, P = 0.003). The first expression of MMP-9 and heparanase occurs at benign lesions. However, the significantly increased expression in advanced CMM stages, particularly in LN-positive metastasis lesions, might synergistically contribute to degradation of ECM and BM, therefore promoting carcinogenesis and metastasis.     

The risk for cutaneous malignant melanoma, melanoma in situ and intraocular malignant melanoma in relation to tobacco use and body mass index

BACKGROUND: The incidence of cutaneous malignant melanoma (CMM) and melanoma in situ (MIS) has been increasing during the last 50 years. Malignant melanoma (MM) is also the most common intraocular malignancy (IMM). Besides ultraviolet radiation, the cause of these tumours is largely unknown. OBJECTIVES: We designed a study to examine the effect of body mass index (BMI) and tobacco use on the risk for MM and MIS. METHODS: Analyses were performed on a nationwide cohort of 339 802 Swedish construction workers. Exposure information was collected prospectively by questionnaires combined with personal interviews. RESULTS: Follow up yielded a total of 7 663 400 person-years during which 1639 workers developed MM/MIS. The risk for MM/MIS was reduced in current or previous smokers compared with those who had never smoked, both when analysing all smoking tobacco products combined and when analysing cigarette and pipe smokers separately. The risk was further diminished with longer duration of smoking and greater quantity of tobacco smoked. The effect was more evident in CMM/MIS than in IMM. Snuff taking conferred a decreased risk for CMM/MIS, and a BMI over normal weight range conferred an increased risk for CMM. CONCLUSIONS: Tobacco smoking was found to be inversely associated with the risk for CMM and MIS. The mechanism of action is unknown but it has been suggested to be due to the immune suppressive effect that tobacco exerts which would be protective against deleterious immune reactions caused by, for example, the sun. Neither is the mechanism behind the higher risk for CMM due to being overweight known. One hypothesis is that it is an effect of a hormonal imbalance. Further studies are required to elucidate these mechanisms.     

Melanoma arising in a nevus of Ito: novel genetic mutations and a review of the literature on cutaneous malignant transformation of dermal melanocytosis

Dermal melanocytosis refers to a spectrum of benign melanocytic proliferations that includes Mongolian spot, nevus of Ota and nevus of Ito. These lesions most commonly occur in persons of Asian or African descent and are often present at birth or develop during childhood. Very rarely, dermal melanocytoses undergo malignant transformation. There have been only 13 reports in the literature of primary cutaneous melanoma arising in dermal melanocytoses. We report a case of a Chinese woman with melanoma arising in a congenital nevus of Ito. We performed targeted next‐generation sequencing of the tumor which revealed mutations of GNAQ and BAP1, suggesting that alterations in these two genes led to malignant transformation of the nevus of Ito. We also provide a summary of reports in the literature regarding primary cutaneous melanoma arising in the context of dermal melanocytosis.     

Increase in and stabilization of incidence and mortality of primary cutaneous malignant melanoma in Western Netherlands, 1980-95

In summer 1989, a skin cancer campaign was organized in the coastal area of western Netherlands. In order to assess the impact of this and future campaigns on detection rates for melanomas of various thicknesses, a frame of reference for the epidemiology of cutaneous melanoma was established. We performed a retrospective investigation of all melanomas diagnosed in this region in the period 1980-95. A total of 3705 (2967 invasive and 738 in situ melanomas) cases was analysed. During the 1980s the age-adjusted incidence of invasive melanoma steadily increased (from five in 100,000 to 11 in 100,000 for men and from nine in 100,000 to 14 in 100,000 for women). Since 1988/89 the rate has remained stable for men and has increased only slightly among women. Detection rates for in situ melanomas followed the same pattern. Mortality rates remained largely unchanged for both sexes (European standard rates are about 2.6 in 100,000 for men and 2.2 in 100,000 for women). The median Breslow thickness decreased from 1.2 to 1.1 mm for men and from 1.1 to 0.8 mm for women. A marked increase occurred in the proportion of thin melanomas in comparison with intermediate and thick tumours, particularly among women. The female/male ratio declined in the period studied from 2.0 to 1.5. Directly after the campaign in 1989 a temporary increase occurred in the total number of melanomas diagnosed, largely due to more thin melanomas (相似文献   

Congenital nevi versus metastatic melanoma in a newborn to a mother with malignant melanoma – diagnosis supported by sex chromosome analysis and Imaging Mass Spectrometry

A 37‐year‐old pregnant woman presented with a 2‐cm irregular reddish nodule on her left upper arm during pregnancy. A biopsy from the lesion showed a 2.2‐mm thick malignant melanoma with intravascular invasion, 25 mitosis/mm² and no ulceration. Following induction of labor, the patient underwent re‐excision with sentinel lymph node biopsy. This showed no residual melanoma and no lymph node metastasis. The newborn boy had multiple pigmented lesions on the trunk, some of which were large and irregular. Two were biopsied and histologic examination showed dense dermal proliferation of medium sized melanocytes with multiple mitotic figures and no maturation with their descent into the dermis, raising suspicion of transplacental metastases. Examination of the placenta failed to show metastatic lesions. Multiplex polymerase chain reaction (PCR)‐based genotyping, including testing for amelogenin locus for sex chromosome determination, demonstrated the presence of Y chromosome material in the melanocytes of the newborn's lesions excluding maternal origin. A diagnosis of congenital nevi was rendered. Subsequently, Imaging Mass Spectrometric analysis of the mother's lesion showed proteomic signature expression indicative of malignant melanoma, whereas the two lesions in the newborn showed changes indicative of nevi. This case demonstrates the utility of genotyping and Mass Spectrometry analysis in this challenging clinical scenario     

CDKN2A mutations in Scottish families with cutaneous melanoma: results from 32 newly identified families

BACKGROUND: Up to 5% of patients with melanoma have a family history of a first-degree relative also being affected. OBJECTIVES: To study such families for germline mutations, to help clarify the gene-environment interaction in melanoma aetiology. METHODS: Thirty-two families in Scotland with melanoma in two or more first-degree relatives are reported for the first time. Peripheral blood DNA was extracted, and denaturing high-performance liquid chromatography analysis performed on exons 1alpha and 2 of the CDKN2A gene and their splice junctions. The coding sequences and splice junctions of these exons were sequenced in all samples as confirmation of the chromatographic pattern observed. RESULTS: Seven of the 32 melanoma families (22%) have CDKN2A mutations. One mutation, H83N, which has not previously been described in melanoma families, was found in one family. In addition, two families have R112G mutations, one family has a G67R mutation, one has an exon 1alpha 24-bp duplication where bases 9-32 are duplicated between bases 32 and 33, and two families have M53I mutations, bringing the total of known Scottish families with the M53I mutation to six. CONCLUSIONS: This study brings the total of Scottish families investigated for germline mutations to 48, and strongly suggests that the M53I mutation originated in Scotland.     

Sentinel lymph node biopsy in patients with primary cutaneous melanoma: study of 455 cases

BACKGROUND: The role of elective lymph node dissection in the treatment of patients with primary melanoma is a debated topic in surgical oncology. However, recent data assure a survival improvement with this technique only for patients harbouring nodal metastases. The emergence of a new procedure of lymphatic mapping permits the identification of the sentinel lymph node (SLN), the first draining node from the site of cutaneous melanoma, which has demonstrated to be predictive of staging of the entire regional lymphatic basin and useful in selecting for lymph node dissection only those patients who have early micrometastases. OBJECTIVES: To verify in a large series of cases whether a combination of preoperative lymphoscintigraphy and intraoperative mapping with both vital blue dye and a hand-held gamma probe would permit an increase of the rate of successful SLN localization up to 100%; to check the utility of a wider application of SLN biopsy in patients with thin melanomas owing to a favourable risk-benefit ratio; to determine the predictive value of SLN biopsy by performing regional lymphadenectomy in patients who have pathological evidence of metastases in the SLN; to observe whether the use of SLN technique and selective lymphadenectomy might improve the clinical evolution of patients and favour low rates of recurrence. METHODS: In 425 AJCC stage I or II melanoma patients, preoperative lymphoscintigraphy by intracutaneous injection of Tc99m-labelled albumin nanocolloids around the tumour or the tumour's excision scar was combined with the intraoperative use of a hand-held gamma probe and patent blue V mapping technique, in order to identify and harvest the SLN. In five cases the blue dye was voluntarily not used because of previous allergic reactions. In other 25 preliminary cases the procedure was performed using the blue dye alone (10 cases) or combined with a preoperative lymphoscintigraphy (15 cases). A wide excision of the primary site was then undertaken in all cases. SLNs were sent to the pathologist for serial sectioning and permanent preparations with histological and immunohistochemical examination. Patients with pathological evidence of metastatic disease in SLN returned for regional lymphadenectomy. RESULTS: The combined use of lymphoscintigraphy, blue dye and gamma probe allowed us to identify one or more SLNs in all cases except for two (99.5% rate of success). In 70 melanomas less than 0.76 mm thick, SLNs were negative for metastases, whereas in 380 patients with thicker tumours micrometastases were demonstrated in 75 cases (19.7%). In patients with SLN metastases who underwent regional lymph node dissection, no other metastases were found three times out of four. After a median follow-up period of 18 months the rate of recurrence of the disease in 335 patients with SLN free of metastasis was low (5.4%) with a very low regional nodal recurrence (1.2%). Moreover, the worsening of the disease did not exceed 18.5% of cases with metastasis in SLN. CONCLUSIONS: Our data confirm in a large series of cases that the SLN biopsy is extremely selective and useful to find early micrometastases and to identify patients needing regional lymphadenectomy and adjuvant immunotherapy. Patients with intermediate thickness melanoma (0.76-4.0 mm) should be informed on the availability of such a revolutionary procedure, which represents a new opportunity in primary melanoma surgery.