Do hormones influence melanoma? Facts and controversies

The issue of whether hormones influence malignant melanoma (MM) has been controversial for many years. Although early case reports demonstrated a negative effect of hormones, recent evidence has not supported a potential role for hormones in MM. We address whether exogenous and endogenous hormones influence a woman's risk for MM or affect her prognosis if diagnosed with MM. Multiple epidemiologic studies show the use of oral contraceptives or hormone replacement therapy does not appear to increase a woman's risk for MM. Pregnancy does not appear to influence a woman's risk of MM, nor does pregnancy appear to affect prognosis in the woman diagnosed with MM. When counseling the woman who is diagnosed with MM during pregnancy or during the childbearing years, future use of oral contraceptives or hormone replacement therapy is not contraindicated; counseling concerning future pregnancies should be done on a case-by-case basis, with emphasis placed on established prognostic factors for MM.     

Melanocytic nevi, melanoma, and pregnancy

Malignant melanoma is among the malignant tumors whose incidence has risen markedly in recent decades. For many years the medical community debated the potential adverse effects of female hormones (whether of exogenous or pregnancy-related endogenous origin), on melanocytic nevi and malignant melanoma. Given that women have been delaying pregnancy until their thirties or forties and that the incidence of malignant melanoma increases in those decades, the likelihood of this tumor developing during pregnancy has increased. Recent clinical and experimental evidence has suggested that pregnancy does not affect prognosis in malignant melanoma and that it does not seem to lead to significant changes in nevi. This review examines the relationship between malignant melanoma and hormonal and reproductive factors. Evidence was located by MEDLINE search (in PubMed and Ovid) for articles in English and Spanish for the period from 1966 to March 2010; additional sources were found through the reference lists of the identified articles.     

Hormones, nevi, and melanoma: an approach to the patient

For many years, clinicians have been concerned about a potential adverse effect of pregnancy-associated hormones and exogenous hormones on melanocytic nevi and malignant melanoma. Today, these issues are more significant as women have delayed childbearing into their 30's and 40's, and the likelihood of diagnosis with melanoma during pregnancy is enhanced. More recent clinical, epidemiologic, and laboratory studies have shed some light on the relationship among hormones, nevi, and melanoma in pregnancy.     

对色素痣恶变几个问题的探讨

收集７０例有完整记录的ＭＭ临床及病理资料，对哪些色素痣易恶变？普通后天性痣（ＡＮ）是否易恶变以及组织病理对诊断色素痣恶变的意义等进行探讨。我们认为：１．色素痣恶变的诊断有赖于对病史的正确采集和分析，仅根据病理上有痣细胞的证据，尚不足以正确判断部分ＭＭ是否源于色素痣；２．除已获一致意见的先天性巨痣、发育不良性痣易恶变外，先天性小痣（ＣＳＮ）也易恶变；３．ＡＮ恶变尚缺乏确切资料。     

Melanocytic nevi in pregnancy: histologic features and Ki‐67 proliferation index

Background: Changes in the clinical appearance of benign dermal nevi during pregnancy may be concerning for malignant transformation. Because the hormonal milieu of pregnancy has not proven to alter their banal behavior, histologic characterization is needed to prevent over‐diagnosis and unnecessary treatment. Methods: Dermal nevi excised from pregnant women (n = 16) were compared with nevi from location‐ and aged‐matched control patients (n = 15). Histologic features and Ki‐67 proliferation index were evaluated. Results: Nevi in pregnancy were more likely to have dermal mitotic figures (62.5% vs. 13.3%, p = 0.028) and higher mitotic rates (1.44 vs. 0.20 mitoses/mm², p = 0.0027) than control nevi. A distinctive histologic entity, termed superficial micronodules of pregnancy (SMOPs), was observed more frequently in the nevi of pregnancy (81.3% vs. 26.7%, p = 0.040), and showed consistent immunoreactivity for HMB45. There was a trend toward higher Ki‐67 proliferation index in the nevi of pregnancy (3.0% vs. 1.0%, p = 0.073). Prominent multinucleated melanocytes were seen only in controls. There was no significant difference in pigmentation or irritation changes between groups. Conclusions: Dermal nevi removed during pregnancy show characteristic histologic features including increased dermal mitoses, superficial micronodules of pregnancy (SMOPs), and trend toward increased Ki‐67 proliferation index. Chan MP, Chan MM, Tahan SR. Melanocytic nevi in pregnancy: histologic features and Ki‐67 proliferation index.     

先天性小痣的超微病理改变

在透射电镜下观察16例先天性小痣(CSN),并以18例恶性黑素瘤(MM)、3例先天性巨痣(CGN)及10例后天性痣(AN)作对照,以探讨CSN的超微结构特点及在MM发病中的地位。结果显示:先天性痣尤其是巨痣,胞核及核仁多大于AN,小于MM;CSN胞核中假包涵体常见,1例CGN和2例3个CSN中,尚发现被认为是MM超微结构特征的异常黑素小体。结果提示:1.CSN较AN易于恶变,2.异常黑素小体并非只限于MM。     

Estrogen receptor beta expression in nevi during pregnancy

Abstract:  Estrogen levels increase during pregnancy and clinical evidence has long suggested that melanocytes are estrogen-responsive. We hypothesized that nevi from pregnant patients would exhibit increased expression of estrogen receptor β (ERβ) and thus enhanced potential to respond to altered estrogen levels. Normal, dysplastic and congenital nevi ( n  = 212) were collected from pregnant and non-pregnant women ranging from 18 to 45 years of age. Immunohistochemical staining was performed on these nevi using antibodies specifically directed against estrogen receptor α (ERα) and ERβ. ERα was not observed in any lesions; thus, ERβ was the predominant estrogen receptor in melanocytic cells from all types of nevi. Enhanced positivity for ERβ in normal nevi during pregnancy was noted, compared with non-pregnant controls including nevocytes residing in both the epidermal and dermal micro-environments ( P  = 0.005 and P  = 0.001 respectively). Nevi with increasingly melanocytic atypia showed increased ERβ in nevocytes nested within the epidermis. No additional increase in ERβ in atypical nevi was observed during pregnancy. For normal and congenital nevi, regardless of pregnancy status, dermally associated nevocytes tended to have greater ERβ immunoreactivity. Significant decreases in ERβ immunoreactivity were observed in congenital nevi from pregnant women compared with normal and dysplastic nevi from pregnant women. Our data suggest that nevi possess the capacity to be estrogen-responsive. Factors such as pregnancy and degree of atypia are associated with enhanced ERβ with the exception of congenital nevi where the melanocytes were unique in their response to pregnancy.     

The number and distribution of nevus cell nevi in patients with malignant melanoma

Total-body cutaneous examination of 211 patients with malignant melanoma (MM) and 157 controls showed that patients with MM had significantly more nevi. Among MM patients, men had more nevi on the trunk than women, and women had more nevi on the lower extremities than men. Men had an MM distribution that was similar to their nevus distribution. Women, however, had proportionately more MM on the legs and fewer MM on the neck. The "nevus density," defined as the number of nevi per unit surface area of skin, was higher in male MM patients. The nevus density was highest on the head and neck, and lower on the lower extremities and anterior trunk. Patients with nodular melanoma had more nevi than those with superficial spreading melanoma. MM patients with a family history of many nevi had more nevi than those without such a history. Patients with a family history of MM did not show an increased number of nevi, but they had larger numbers of suggestive nevi removed than those without a family history of MM. We believe that many of these observations are consistent with the view that MM is caused by a genetic predisposition to an overactive melanocytic system in combination with an external stimulant, such as UV radiation.     

Immunohistochemical expression of cyclooxygenage-2 in melanocytic skin lesions

Background Several reports have shown expression of cyclooxygenase‐2 (COX‐2) in malignant skin tumors. COX‐2 has also recently been reported as a marker of malignant melanoma (MM). Objective Our aim was to investigate whether there is a difference in the immunohistochemical expression of COX‐2 between malignant and benign melanocytic lesions of the skin. Methods We selected 40 archival cases of MM including 10 cases of superficial spreading melanoma, 10 of lentigo maligna melanoma, 10 of nodular melanoma, and 10 of acral lentiginous melanoma. For comparison, we also selected 35 benign melanocytic lesions, which included 15 nonatypical nevi and 10 atypical nevi. The remaining 10 cases were Spitz nevi. COX‐2 immunohistochemical staining was performed, and intensities were assessed quantitatively. Results The MM group and the benign melanocytic nevi group showed a highly statistically significant difference in the intensity of COX‐2 expression (P < 0.0001). Staining intensity in the dermal component of MM cases also showed a tendency to increase with increasing tumor depth. By contrast, the intensity of the dermal component in the melanocytic nevi group decreased with increasing depth as the nevus cells matured from type A to type C cells. No statistical difference was noted between the MM and Spitz nevi cases (P = 0.20). Conclusions Malignant melanoma shows stronger immunohistochemical expression of COX‐2 than benign melanocytic nevi. Although COX‐2 cannot be used alone to differentiate MM from melanocytic nevi, it may serve as an aid in the differential diagnosis of melanocytic skin lesions.     

Oestrogen and progesterone receptors in melanoma and nevi: an immunohistochemical study

Background

The effect of hormonal stimulation and fertility treatments, on the development of malignant melanoma (MM) remains to be determined.

Objectives

The aim of this study was to investigate the presence of oestrogen receptor alpha (ERα) and progesterone receptor (PR) inMM and nevi after hormonal stimulation.

Materials & Methods

Immunohistochemical analyses were performed utilizing antibodies specifically directed against ERα and PR in MM and atypical nevi specimens from patients: (1) diagnosed during pregnancy, (2) diagnosed in the six months following delivery, or (3) who had undergone repetitive cycles of hormonal stimulation for in vitro fertilization (IVF) in the year that preceded MM diagnosis. Controls were atypical nevi and MM specimens of female patients of the same age group who had received no hormonal therapies and reported no pregnancies in the five years before diagnosis.

Results

Twenty-eight female patients at childbearing age were selected for this study. Strong cytoplasmic positivity of ERα and PRwas detected in atypical melanocytes of two MM specimens of patients who had undergone repetitive cycles of hormonal stimulation during IVF procedures. All other specimens showed no expression ofERαor PR.

Conclusion

Since our results represent preliminary findings, conclusions regarding a possible correlation between IVF therapy and melanoma occurrence cannot be ascertained. Larger laboratory studies should be performed to investigate reproductive hormone receptor expression in MM in women following IVF, pregnancy, prolonged contraceptive use, or hormone replacement therapy.

     

Oestrogen receptor-beta expression in melanocytic lesions

Melanomas rarely occur before puberty, have a higher death rate for males, and tend to be more invasive during pregnancy. Prior to the discovery of a second oestrogen receptor (ERbeta), studies with the initial oestrogen receptor, ERalpha, showed no obvious role for oestrogen in the pathophysiology of benign or malignant melanocytic lesions. To investigate the specific immunostaining patterns of ERalpha and ERbeta, benign nevocytic nevi, dysplastic nevi with mild, moderate and severe cytological atypia, lentigo malignas and melanomas of varying depth (Clark) and thickness (Breslow) were studied. ERbeta but not ERalpha was the predominant oestrogen receptor we found in all types of benign and malignant melanocytic lesions. The most intense ERbeta immunostaining was seen in melanocytes in dysplastic nevi with severe cytological atypia and in lentigo malignas. ERbeta expression levels also correlated with the malignant tumor microenvironment; i.e., melanocytes in proximity with keratinocytes>deeper dermal melanocytes in contact with stroma>minimally invasive melanomas>Clark Level III/IV or thick melanomas (Breslow). Discovery that ERbeta expression varies in relation to the tumor microenvironment and increasing depth of invasion suggests its possible usefulness as a surrogate marker for neoplasia and prognosis in malignant melanoma.     

生存素在恶性黑素瘤中的表达及与VEGF和PCNA的关系

目的 探讨人恶性黑素瘤组织中凋亡抑制蛋白生存素的表达,及其与恶性黑素瘤临床特征、血管内皮生长因子(VEGF)和增殖细胞核抗原(PCNA)表达的关系.方法 免疫组化方法检测36例人恶性黑素瘤和30例色素痣组织中生存素、VEGF和PCNA蛋白表达.结果 ①生存素在恶性黑素瘤和色素痣中均有表达,但在恶性黑素瘤中表达明显高于色素痣(P<0.01).②在恶性黑素瘤组织中有30例表达VEGF(阳性率83.3%),36例表达PCNA(阳性率100%),而色素痣组织不表达VEGF和PCNA.③生存素的阳性表达与恶性黑素瘤患者的发病年龄、性别、淋巴结转移均无相关性(P>0.05),但其表达与VEGF和PCNA的表达密切相关(P<0.01).结论 生存素可能参与恶性黑素瘤的增殖和与VEGF相关的肿瘤血管生成.     

恶性黑素瘤和普通痣细胞痣细胞外信号调节激酶途径相关蛋白的研究

目的 探讨恶性黑素瘤(MM)和普通痣细胞痣细胞外信号调节激酶(ERK)途径相关蛋白ERK1和ERK2以及细胞周期素D1(Cyclin D1)蛋白的表达情况,分析这3种蛋白与MM的临床病理关系。方法 采用免疫组化SP法对30例MM和13例普通痣细胞痣中ERK1、ERK2和Cyclin D1蛋白的表达进行检测,并进行临床病理相关性分析。结果 ERK1、ERK2和Cyclin D1在MM组织中表达较普通痣细胞痣组织明显升高(P<0.01),ERK1、ERK2和Cyclin D1与MM的Clark分级和Breslow厚度无明显相关性,ERK1和ERK2与Cyclin D1在MM组织中表达显著相关。结论 MM中ERK途径得到了过度激活,并可能促使Cyclin D1表达增加,因此它们在MM的发病机制中可能起到一定作用,而它们在普通痣细胞中仅在A型痣细胞表达增加。     

N-ras基因产物p21蛋白在皮肤、软组织肿瘤中的表达

应用N-ras癌基因产物p21蛋白单克隆抗体,以ABC法检测150例皮肤、软组织肿瘤。结果显示:48例恶性黑素瘤阳性率54.17%,13例先天性巨痣、13例先天性小痣及15例后天性痣阳性率分别为30.77%、15.38%和0%。肿瘤浸润深、异型性较大、核丝分裂指数高的恶性黑素瘤N-ras p21蛋白表达强于相应的组别。其它皮肤、软组织肿瘤的p21蛋白表达率均低。提示恶性黑素瘤的发生及预后与N-ras p21蛋白的过量表达可能有一定关系,其它皮肤、软组织肿瘤与ras基因的激活可能无明显联系。     

Pilot study on the correlation between dermoscopic patterns and fluorescence in situ hybridization findings using whole‐slide digital imaging for acral volar melanocytic lesions

Dermoscopic evaluation of acral volar skin is helpful in differentiating malignant melanomas (MM) from benign melanocytic nevi. However, histological diagnosis remains difficult because sufficient evidence of histopathological changes to establish a diagnosis of MM are not easily obtained. The aim of the present study was to evaluate the effective use of fluorescence in situ hybridization (FISH) in the diagnosis of acral volar melanocytic lesions, and to determine whether acral volar melanocytic lesions show characteristic molecular biological features of malignant melanoma via FISH. We classified acral volar melanocytic lesions showing junctional findings into three groups: (A) parallel ridge pattern (PRP) on dermoscopic examination with melanoma in situ; (B) PRP with insufficient melanocyte proliferation and atypia to diagnose malignant melanoma using hematoxylin–eosin staining; and (C) junctional nevi. We performed FISH analysis using the same tissue section that was used for hematoxylin–eosin staining. FISH positivity was seen in 80% (4/5) of the group A sections, and in 80% (4/5) of the group B sections. One case in group C was only 0.3% over the established criteria line (63.3% > 63% in RREB1). Our results suggest that FISH using whole‐slide digital imaging may be useful in the diagnosis of early in situ MM when a typical PRP is observed in an acral volar skin lesion with non‐diagnostic histopathology.     

Genital lentigines and melanocytic nevi with superimposed lichen sclerosus: a diagnostic challenge

BACKGROUND: Benign pigmented lesions of the genitalia, such as genital lentigines and melanocytic nevi, often show clinical and histopathologic features highly suggestive of malignant melanoma (MM). Superimposed changes of lichen sclerosus (LS) may cause real concern and lead to an erroneous diagnosis of MM. OBJECTIVE: This study was performed to assess clinicopathologic characteristics of genital lentigines and melanocytic nevi with associated LS. METHODS: We performed a retrospective review of 5 cases. RESULTS: Histopathologic sections of the 2 cases of genital lentigines with concurrent changes of LS showed a lichenoid lymphocytic infiltrate and pigment incontinence with melanophages in a fibrosed papillary dermis, features reminiscent of completely regressed MM. The 3 cases of genital melanocytic nevi and superimposed LS were sharply circumscribed, relatively symmetric, but revealed confluent nests varying in size and shape and pagetoid upward spread of melanocytic nests and single melanocytes. Changes of LS extended beyond the melanocytic proliferation. CONCLUSION: Genital lentigines and melanocytic nevi with associated LS may show features that mimic MM.     

Dermatoscopy of "dysplastic nevi": a beacon in diagnostic darkness

The sequential progression model for melanocytic tumours from common nevus to malignant melanoma was proposed by Clark almost 30 years ago. The "dysplastic nevus" has frequently been considered a logical offspring of this concept and as a direct precursor of melanoma, analogous to the epithelial dysplasia-carcinoma sequence. Despite the use of modern molecular methods, there is no consensus as to if the dysplastic nevus represents a true precursor lesion of melanoma, a separate distinct type of nevus, or a diagnostic dilemma. Currently, the concept of melanocytic dysplasia remains subject to confusing definitions at all levels of the diagnostic process, i.e. clinical appearance, dermatohistopathology, and molecular biology. In this review, we collect evidence that nevi fulfilling Clark and Elder's classic histological criteria mostly represent "endpoints" of nevocytic evolution, whereas a minority of "dysplastic nevi" represent true melanoma precursors. The unsolved dilemma is that neither clinical, histopathological nor molecular criteria exist to make a distinction between dysplastic nevi and early melanomas. Our analysis of the current knowledge on dysplastic nevi shows that dermatoscopy remains the only quantifiable, easily applicable and reproducible diagnostic tool to approach the problem. Due to a "quantum leap" in optical resolution, objective scores can be established, e.g. the total dermatoscopy score (TDS) according to the ABCD rule, and documentation of changes over time are possible by digital image storage devices. Although dermatoscopy does not solve the dilemma of discriminating early, basically feature-less melanomas from dysplastic nevi, and it does not prove that dysplastic nevus is a distinct entity, it helps make melanocytic tumours with unclear malignant potential a manageable disease.     

Pregnancy and sex steroid hormone effects on nevi of patients with the dysplastic nevus syndrome

Female patients with the dysplastic nevus syndrome who were pregnant or taking sex steroid hormones were prospectively studied to evaluate the effectiveness of photography and close clinical follow-up in detecting nevus change or melanoma development. Seventeen patients, who served as their own controls, were studied during 22 pregnancies. Twenty-four patients who used oral contraceptives and seven who took hormone supplements were similarly studied. This clinical management method provided timely biopsy of changing nevi with a small number of biopsies required per patient. One melanoma occurred during pregnancy, but neither patients who were taking sex steroid hormones nor those in the control groups had melanomas. The rate of nevus change observed clinically was 3.9 times higher when patients with dysplastic nevus syndrome were pregnant than when they were not, whereas no differences were observed whether or not women took oral contraceptives or hormone supplements. The rate of histologically proven dysplastic nevi that changed was 2.0-fold higher when women were pregnant; 1.4-fold higher with the use of hormone supplements and 1.1-fold higher with the use of oral contraceptives. These preliminary data suggest pregnancy and hormone supplements may be temporally associated with an increased rate of dysplastic nevus change.     

microRNA在人皮肤黑素瘤与色素痣中共同差异表达的研究

目的 筛选人皮肤黑素瘤组织中表达的已知hsa-microRNA。方法 采用SBC microRNA芯片技术,将6例人皮肤黑素瘤组织总RNA分别与9例健康人色素痣总RNA混合物对比,筛选已知的468条hsa-microRNA表达情况。用qPCR分别检测这6例人皮肤黑素瘤组织中各候选hsa-microRNA的表达。将芯片和qPCR两种方法检测结果一致的候选hsa-microRNA确定为有意义的共同差异表达hsa-microRNA。结果 2倍以上差异表达miRNA占所检测miRNA的12.18% ～ 86.33%,5倍以上差异表达miRNA占1.28% ～ 19.02%,10倍以上差异表达miRNA占0.43% ～ 5.34%。 此6例人皮肤黑素瘤中miRNA-21 明显上调表达,miRNA-320和miRNA-494明显下调表达。结论 人皮肤黑素瘤组织中miRNA-21明显上调表达,miRNA-320和miRNA-494明显下调表达。