Risk of second primary malignancies in patients with cutaneous melanoma

BACKGROUND: In several studies an increased risk for development of breast cancer, malignant lymphoma and neoplasms of the kidney as second primary cancers in patients with cutaneous melanomas was discussed. OBJECTIVES: To determine the risk for development of second primary neoplasms in patients with cutaneous melanomas. METHODS: A prospective study was performed between 1977 and 1992 to evaluate the occurrence of second primary malignancies in 4597 patients (2083 men, 2514 women) with invasive cutaneous melanomas, diagnosed and treated at the Department of Dermatology and Allergology, Ludwig-Maximilians-University, Munich, Germany. RESULTS: During a median follow-up of 7.2 years, 296 of 4597 patients (6.4%) developed one or more neoplasms at the time of or subsequent to the diagnosis of the first cutaneous melanoma. More than half of these patients developed one or more further melanomas (152, 3.3%). Cancers of the breast, prostate, colon, rectum and kidney occurred less frequently. Statistical calculations revealed a 33.8-fold increased risk for the development of a second melanoma in the entire group [relative risk 38.5 for men (95% CI, 30.4-48.1), 29.0 for women (95% CI, 22.0-37.5)]. Moreover, a significantly increased risk for the development of kidney carcinoma in men was found [relative risk 3.5 (95%, CI, 1.4-7.2)]. CONCLUSIONS: Thorough follow-up and skin examination in patients with cutaneous melanomas is recommended for early detection of other primary melanomas. Furthermore, ultrasound examinations routinely performed in melanoma patients for the detection of melanoma metastases may also be of value for early detection of kidney carcinomas in male patients.     

Descriptive analysis of cutaneous recurrence patterns in patients with melanoma

Background and objectivesFew studies have addressed cutaneous recurrence of melanoma. The aim of this retrospective study was to analyze the characteristics and prognostic significance of the different patterns of cutaneous recurrence.Material and methodsPatients diagnosed with melanoma between 1988 and 2008 at Hospital de Bellvitge, Barcelona, Spain and for whom data were available for at least 2 years of follow-up were included in the study. Local recurrence was defined as melanoma invasion of the skin adjacent to the scar left by excision of the primary tumor, regional metastasis or recurrence as metastasis restricted to the area drained by a regional lymph node station, and distant cutaneous metastasis as metastasis occurring outside this area. The relationship between cutaneous recurrence pattern and age, sex, primary tumor site, tumor subtype, Breslow depth, and ulceration was assessed.ResultsEighty-five out of 1,080 patients (7.87%) had cutaneous recurrence. In 71 of those patients (83.53%; 27 men and 44 women; mean age, 60.68 years), this was the first indication of melanoma recurrence. Thirty-two patients had local recurrence, 32 regional metastasis, and 7 distant metastasis. Significant differences were observed in survival time from diagnosis of the primary tumor (P = .044) and from diagnosis of cutaneous recurrence (P < .001) according to the type of recurrence.ConclusionsOur results suggest that the pattern of cutaneous recurrence is prognostically significant and related to the site of the primary tumor given that the majority of local and regional recurrences occurred in primary tumors located on the lower limbs and head.     

Perilesional injection of r-GM-CSF in patients with cutaneous melanoma metastases

Based on evidence that granulocyte-macrophage colony stimulating factor (GM-CSF) induces a potent systemic antitumor immunity, we tested recombinant GM-CSF in advanced melanoma. Seven patients with histologically confirmed cutaneous melanoma metastases were treated with perilesional intracutaneous injections of recombinant GM-CSF and observed for a follow-up time of 5 y. All but two patients had a decrease in the total number of metastases. At the end of the 5 y follow-up three of the seven patients are still alive with only one patient receiving other than surgical therapy, and one patient died tumor free at the age of 93. The remaining three patients died from progressive melanoma. Perilesional intradermal GM-CSF therapy resulted in a mean survival time of 33 mo. The treatment was well tolerated and no side-effects other than local erythema at the injection sites and mild drowsiness were seen. Immunohistochemical analysis with staining for CD14 and GM-CSF receptor demonstrated an increased infiltration of monocytes into both injected and noninjected cutaneous melanoma metastases compared with lesions excised prior to the initiation of therapy. The same was true for CD4- and CD8-positive lymphocytes. This phenomenon, together with GM-CSF-induced leukocyte counts of more than 20,000 during therapy, support the possible impact of a systemic over a locally induced reaction by GM-CSF. To our knowledge this is the first report that intracutaneously injected GM-CSF results in long-lasting reduction of melanoma metastases.     

Risk factors for in-transit metastasis in patients with cutaneous melanoma

BackgroundIn-transit metastases have been associated with the presence of various negative prognostic factors in patients with cutaneous melanoma. It has recently been suggested that sentinel lymph node biopsy (SLNB) may lead to an increase in the incidence of this particular type of metastasis. In this study, we analyzed risk factors for the appearance of in-transit metastasis and its potential association with the use of SLNB.Material and methodsA prospective study was undertaken in a cohort of 404 patients with cutaneous melanoma seen in the melanoma unit of Hospital San Cecilio in Granada, Spain. Statistical analysis was performed with SPSS 15.0 and Epidat 3.1 using the χ² and Fisher exact tests.ResultsOut of 93 (23%) patients with recurrence at any time, 28 (6.9%) had in-transit metastases. The occurrence of in-transit metastasis was associated with age greater than 50 years, greater Breslow depth and Clark level, the presence of ulceration, positive SLNB, and the presence of other types of recurrence (local recurrence, lymph node metastasis, or distant metastasis). There was no relationship between surgical treatment or performing SLNB and the presence of in-transit metastasis.ConclusionsThe risk factors for in-transit metastasis are the same as those for any type of recurrence and coincide with factors linked to poor prognosis. Given that in-transit metastases are much more common in patients with positive SLNB, while the technique itself is not linked to their occurrence, these findings suggest that the appearance of in-transit metastasis is linked to biological characteristics of the tumor cells rather than an influence of the surgical technique.     

High prevalence of hypothyroidism in male patients with cutaneous melanoma

A recent study reported a higher than expected prevalence of hypothyroidism among patients with cutaneous melanoma. To further characterize and validate those findings, we conducted a retrospective review of the prevalence of hypothyroidism among all consecutive patients diagnosed with cutaneous melanoma in the dermatology clinic at the Michael E. DeBakey VA Medical Center (VAMC) in Houston, Texas. To accomplish this task, the electronic medical records of all patients diagnosed with cutaneous melanoma at the VAMC from January 2001 through October 2004 were examined for signs of hypothyroidism. Data regarding the site of melanoma and age at diagnosis were obtained for these hypothyroid cases and for age- and gender-matched euthyroid controls from the same melanoma cohort. Among 156 cutaneous melanoma patients (151 male and 5 female), 8 (5.1 %) showed a history of hypothyroidism [7 of 151 male (4.6 %) and 1 of 5 female (20 %)]. The prevalence of hypothyroidism among the male melanoma patients was significantly higher than that reported for the general population. The prevalence data concerning hypothyroidism among our female patients was not considered evaluable due to the primarily male distribution of our study population. We conclude that hypothyroidism (excluding iatrogenic etiologies) is frequent among male patients with cutaneous melanoma. Our results further suggest that a subset of melanoma tumors may respond to hormones of the hypothalamus-pituitary-thyroid axis, raising many questions that could influence the diagnosis, care, and treatment of a subset of melanoma patients.     

Innate immunity in cutaneous melanoma

The skin immune system is composed of a vast network of immune cells, including lymphocytes, macrophages, neutrophils, dendritic cells and Langerhans cells, which not only are involved in inflammatory responses but also contribute to homeostatic function and may participate in the various steps of carcinogenesis. Many studies support the notion that innate immunity has a key role in the development, growth and prognosis of cutaneous malignant melanoma (MM), through the release of pro‐ and/or anti‐inflammatory cytokines and tumour growth factors. The tumour environment in a major subset of cutaneous MM shows evidence of a T cell‐infiltrated phenotype, but there is less known about the presence and the phenotype of other immune system cells. Response to immunotherapy is largely correlated with the presence of T cells in the tumour microenvironment, while the regulation exerted by stromal components such as macrophages and mast cells has been less investigated. In the current report, we review the recent literature, focusing our attention on the role of macrophages, dendritic cells, mast cells and natural killer cells in orchestrating MM progression, to better understand tumour immunobiology. The identification of new therapeutic targets and the application of approaches aimed at modulating crosstalk between immune and tumour cells, could have a crucial impact on immunotherapy and result in better clinical outcome. We hope this review will be helpful in cutaneous MM research.     

泛素连接酶在皮肤黑素瘤的研究进展

皮肤黑素瘤是一种起源于皮肤黑素细胞的恶性肿瘤,具有高度增殖性和侵袭性,并常发生转移.尽管近年来皮肤恶性黑素瘤的治疗取得很大进展,但晚期黑素瘤患者预后依然很差.泛素蛋白酶体系统可通过调节细胞内蛋白对各种生理过程进行调控,泛素连接酶是泛素化过程中识别底物特异性的酶,可作为癌基因或抑癌基因参与黑素瘤发病机制,能够调节各种不同的信号通路和多种在黑素瘤发展中起重要作用的蛋白.因此,针对泛素连接酶的分子靶向治疗是目前研究黑素瘤的热点之一.     

Ethical issues in cutaneous melanoma

Early diagnosis of cutaneous melanoma (CM) is associated with the finding of superficial tumors resulting in high cure rates with surgery, whereas those with deeply invasive tumors are at higher risk of recurrence and melanoma-specific mortality. Unfortunately, once metastatic to the visceral organs, CM is usually refractory to the presently available treatment modalities, resulting in uniformly poor outcomes in patients. Educating susceptible populations about the risk of developing CM has played an important role in preventive strategies despite the fact that benefits of primary skin screening are controversial. Although a number of reliable prognostic factors are recognized, clinical unpredictability is reflected by a small but significant proportion of patients who experience adverse outcomes from CM, even though lacking the known poor prognostic markers. Because CM is an immunogenic tumor, most of the new treatments have engaged in harnessing antimelanoma immunity, and recent advances in genomics have led to promising targeted therapies. A number of ethical issues have confronted health care providers when taking care of CM patients in different stages of the disease, which have included areas of primary prevention, early diagnosis, strategies to reduce recurrence of the tumor, and managing patients with advanced tumors. With the increasing incidence of CM in fair-skinned people, as well as the increasing recognition of CM in nonwhites, addressing the discussed ethical issues will be even more challenging and important as we provide comprehensive management of this disease.     

Autophagy in cutaneous malignant melanoma

We show that malignant melanoma cells display high levels of autophagy, a cytoplasmic process of protein and organelle digestion that provides an energy source in times of nutrient deprivation. In a panel of 12 cases of cutaneous malignant melanoma of the superficial spreading type, cells in florid melanoma in situ (MIS) and invasive cells in the dermis appeared to be undergoing autophagy. Autophagosomes were detected through immunohistochemistry using the marker LC3B (microtubule‐associated light chain 3B), and by electron microscopy. Some autophagosomes contained melanized melanosomes, accounting for the phenomenon of ‘coarse melanin’ in malignant melanoma. Autophagosomes also contained the Golgi 58k protein, a structural component of the Golgi apparatus, and β1, 6‐branched oligosaccharides, indicating that at least some of the autophagosomal proteins were glycosylated with these structures. The findings suggest that autophagy could be a constitutive metabolic state for invasive and metastatic melanoma cells. Interestingly, a similar phenotype was also expressed by tumor‐associated melanophages. The findings are consistent with previous reports that endoplasmic reticulum (ER) stress drives melanoma progression, since ER stress is known to trigger autophagy. The results suggest that therapies inhibiting autophagy may be effective for the treatment of malignant melanoma by depriving cells of an important energy source. Lazova R, Klump V, Pawelek J. Autophagy in cutaneous malignant melanoma.     

Genetic predisposition in cutaneous melanoma

The incidence of cutaneous melanoma has increased worldwide in the last 20 years. Research on potential risk factors, both environmental and genetic, has led us to some new and interesting conclusions. Ultraviolet radiation is clearly the main environmental risk factor for melanoma, but its relationship is complex and controversial. With regard to genetic factors, the discovery of two types of genes was a great advance in further understanding the biology of the melanocyte. CDKN2A (p16) is the prototype of the high-penetrance, low-prevalence gene related to melanoma. This gene has been studied in some families in which several members have been diagnosed with melanoma. In the general population with non-familial melanoma, low-penetrance, high-prevalence genes such as MC1R seem to be more interesting. Studies on the MC1R gene have not only shown its importance in skin and hair pigmentation, but also in the development of melanoma. Functional studies on CDKN2A and MC1R have led us to new and important conclusions. The analysis of data from studies on families, twins and control cases, with the collaboration of several countries, will lead us to new discoveries. For the primary and secondary prevention of this tumor, we must promote public health campaigns on the dangers of sun exposure and the identification of individuals at high risk.     

Epidemiology of cutaneous melanoma

Although intermittent intense solar exposure and genetic traits such as fair skin continue to be associated with the risk of developing cutaneous melanoma, these factors fail to account for much of the incidence. Suggestive evidence has increased speculation that viral agents, radiation, hormones, chemicals in the workplace, and dietary factors play some etiologic role.     

Multiple cutaneous melanoma metastases

An 84-year-old white woman presented with diagnosed vascular failure in the left leg. The patient had had diabetes mellitus for over 50 years. Five years earlier, her right leg was amputated because of an obliterating arteriopathy. At the time of hospitalization, she showed dry gangrene in all the toes on her left foot. A laser Doppler test performed on the left leg showed severe peripheral arteriopathy affecting the anterior and posterior tibial arteries, with a Windsor index of 20% in her ankle. On physical examination, the patient showed several nodular lesions on the anterior and anterior-medial surface of her left leg. These lesions were infiltrated, of a hard elastic consistency, and occasionally confluent, with a diameter ranging from 0.5 to 4 cm (Fig. 1) and the color varying from ochre-yellow to brownish-red to slate-brown. The patient reported that these lesions had erupted approximately 2 years earlier and had been accompanied by itching and mild burning. She had shown them to her family doctor who had diagnosed seborrhoeic keratosis. A series of biopsies performed on the nodules revealed the presence of atypical melanocytes arranged in alveolar formations that reached the epidermis. The epidermis appeared thin, compressed, and atrophic; no signs of junctional activity could be seen (Fig. 2). The tumor cells were round, with a clear cytoplasm and atypical, hyperchromatic, oval nuclei containing nucleoli (Fig. 3). Some atypical melanocytes contained small amounts of melanic pigment that was concentrated in the cytoplasm of macrophages which were mixed with the elements of the tumor. There had been no melanoma in the clinical history of the patient. The patient had a chest roentgenogram with tomography and a computer tomography (CT) scan of the liver, spleen, mediastinum, and brain, all with negative results. The case is worth reporting because of the peculiar cutaneous lesions that could suggest several diagnostic hypotheses. The clinical picture could have been interpreted as being Kaposi's sarcoma, seborrhoeic keratosis, angiosarcoma, or multiple Spitz nevi. A Spitz nevus is a benign variant of a compound nevus that is characterized histopathologically by atypical, large melanocytes with abundant eosinophilic cytoplasm and large vesicular nuclei with prominent nucleoli. Histologic examination removed any doubt, suggesting a metastatic origin for the proliferating nodules. Marked expression of S-100 protein and of HMP45 was found by immunohistochemistry; HMP45 was also intensely positive in the deep layers of the dermis. It was not possible to define the site of the primary lesion from the patient's history or from physical examination;^1,2 however, one cannot exclude that the primary lesion was at the same site as where the metastases had diffused, either by growing spontaneously from healthy tissue or through a transformation of anevus.^3,4     

Primary cutaneous malignant melanoma

The prognosis of localized malignant melanoma is related to several histologic features of the primary lesion. Growth pattern, level of invasion, and tumor thickness are currently most widely used in clinical practice, but other features, including ulceration, mitotic rate, density of the inflammatory response, evidence of partial regression, angioinvasion, cell type, cross-sectional profile, and amelanosis have been accorded prognostic significance in single factor analyses. Although stringently controlled prospective studies have yet to demonstrate the validity of these factors for the determination of optimal surgical treatment in individual cases, newer statistical methods of multivariate analysis have made possible assessment of the relative importance of each of these histologic characteristics. The most important and reproducible factor for predicting survival is maximum tumor thickness. Consensus also supports ulceration as another important, independent prognostic indicator, whereas growth pattern and level of invasion derive most of their prognostic value from a secondary correlation with tumor thickness. Mitotic rate may influence survival in the subgroup of patients with high-risk, thick melanomas.     

Gender and cutaneous melanoma

Current evidence suggesting that a patient's sex is relevant to the progression of cutaneous melanoma is largely epidemiological. Although databases of patients with melanomas have for many years shown a survival advantage for female patients with primary melanoma, it has been difficult to evaluate the contribution of other known prognostic variables such as thickness and site of the primary tumour, factors which also tend to be related to sex. In addition, there are data from a limited number of experimental studies and clinical trials which support the concept of female survival superiority in melanoma. This paper attempts to summarize the evidence for gender being an important factor in melanoma survival.     

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.