Molecular detection of circulating tumor cells is an independent prognostic factor in patients with high-risk cutaneous melanoma

Detection of circulating tumor cells (CTCs) might improve current staging procedures by identifying a subgroup of patients with minimal residual disease and thus a higher risk of disease recurrence. Forty patients with > or =2-mm-thick cutaneous melanoma with or without lymph node metastasis were enrolled. After standard radical surgery and adjuvant therapy in case of lymph node metastasis, patients were followed up with routine physical and radiologic assessments as well as serial PCR-based analysis of CTCs using 2 melanoma markers (tyrosinase and Melan-A/Mart-1). After a median follow-up of 30 months, 18 patients had disease recurrence and 28 were PCR-positive before the disease became clinically evident. The sensitivity of the molecular test was 83%. Median time to PCR positivity and median PCR-to-relapse time were 12 and 8 months, respectively. At multivariate analysis, PCR positivity was an independent predictor of disease recurrence (hazard ratio=2.06, 95% CI 1.07-3.35; p=0.03). Among high-risk melanoma patients, serial PCR-based analysis of CTCs can identify a subgroup at higher risk of disease recurrence, with clinically significant advance. Therefore, CTC detection might be employed for the selection of patients for adjuvant treatment and during follow-up for early indication of therapeutic failure.     

Survival and prognostic factors of patients with skin melanoma. A regression-model analysis based on nationwide cancer registry data

Survival and prognostic factors of skin melanoma patients were studied using a regression analysis of relative survival rates based on nationwide cancer registry data. The material consisted of 4980 cases of melanoma of the skin diagnosed in Finland in 1953 to 1981 and reported to the Finnish Cancer Registry. In the last diagnostic period, 1974 to 1982, the 5-year relative survival rate for male patients was 61.1% and that for female patients 76.6%. The analysis included variables sex, age, stage, year of diagnosis, follow-up year, and site of the tumor. All of them were needed to explain the differences in survival. The patients had the greatest relative risk of dying from skin melanoma during the second year from diagnosis. However, the difference in death risk due to melanoma by stage was most remarkable during the first follow-up year: the risk of patients with nonlocalized disease was over 12 times that of others. The male-female ratio in the risk of dying from skin melanoma was (to a marked extent) attributable to differences in the distributions of stage and site of the tumor. In all site groups males did worse than females but risk ratio varied from 1.15 (trunk) to 1.89 (limbs). The effect of some important prognostic factors on survival could be quantified with ample material and with a method taking into account the competing causes of death. The results suggest a difference either in biological behavior of skin melanoma or in a patient's delay between males and females.     

Late recurrence of stage I malignant melanoma

Although the introduction of well-established risk factors has made the clinical course and prognosis of malignant melanoma disease much more predictable, in a considerable number of patients the disease's course is still not as expected. One group to which this applies are stage I melanoma patients who develop metastatic disease after 10 years or more of a disease-free interval. In our series of 94 such patients, 6 developed late relapse of their disease. The subsequent survival of these patients did not relate to any of the primary tumors' characteristics, but to the pattern of the late recurrence. Four patients with visceral metastases were dead within 1 to 5 years following relapse, one patient with lymph node involvement is alive with metastases, and another patient with skin metastases has no signs of disease following surgery and immunotherapy. Our conclusion is that malignant melanoma patients should be placed under close follow-up for the rest of their lives.     

Central Nervous System Metastases of Cutaneous Malignant Melanoma: A Population-based Study

The objectives of this population-based study were to assess putative prognostic factors for central nervous system (CNS) metastases among patients with cutaneous malignant melanoma, to assess the cumulative risk of CNS metastases in different subsets of patients with recurrent disease, and to describe patient outcome. At a median follow-up of 11 years, 201/2516 patients with melanoma had developed CNS metastases, corresponding to a cumulative risk at 5 years of 7%. In 41 of these 201 patients the CNS metastases were recorded as the first site of recurrence. In a Cox's multivariate model, primary tumor thickness and ulceration in stage I patients were independent risk factors. The cumulative rates of incidence of CNS metastases 5 years after local or regional recurrence as first event were 5 and 42%, respectively. These results may help to form an individually based risk assessment, which might be of value for melanoma patients in certain occupations.     

Soluble interleukin-2 receptor, intercellular adhesion molecule-1 and interleukin-10 serum levels in patients with melanoma

Serum soluble interleukin-2 receptor (sIL-2R), intercellular adhesion molecule-1 (sICAM-1) and interleukin-10 (IL-10) have each been reported as useful markers for melanoma progression. To evaluate the clinical relevance of these three markers, we simultaneously analysed their serum levels in patients with melanoma. A longitudinal study with a 3-year follow-up was performed and different stages of the disease were considered. Mean values of sIL-2R were significantly higher than in normal controls in all stages and correlated with the disease progression. The prognosis of patients with levels > 529 U/ml of sIL-2R was significantly poorer than in patients with sIL-2R levels < 529 U/ml. Levels of sICAM-1 were also elevated in melanoma patients, specially at the time of the metastatic disease. Serum IL-10 levels were more frequently detectable in the patients that developed metastasis during follow-up, and the prognosis of patients with detectable IL-10 levels was significantly poorer than in those patients with IL-10 undetected levels. Statistical analysis based on Logistic and Cox regression models showed that only sex, stage and sIL-2R value are factors significantly associated with metastatic progression. Moreover, high levels of sIL-2R could be a risk factor for malignant progression in melanoma.     

The annual risk of melanoma progression. Implications for the concept of cure.

BACKGROUND. Melanoma may remain clinically dormant for years, and patients may have distant metastatic disease decades after the initial diagnosis is made. Because of this potential for late recurrence, the concept of "cure" for melanoma is not particularly meaningful. METHODS. To understand better the risks of future disease as a function of time elapsed after diagnosis, the clinical course of melanoma was reviewed in 5838 patients. Using conditional probability methods, the risk of recurrent disease and the risk of death were determined for 1-year and 5-year intervals during the first 15 years of follow-up. RESULTS. The estimated 5-year risk of recurrence declined from 44% at the time of diagnosis to 21% after 6 years. The 5-year risk of mortality decreased from 26% after 1 year to 16% after 9 years. Among patients with recurrent or metastatic disease, the annual risk of mortality was approximately 20% per year for 3 years; thereafter, the risk declined markedly. Among patients with thick primary lesions, the greatest risk was during the first few years after diagnosis, but in patients with thin lesions, the risk was distributed evenly over 15 years and did not decrease with time. CONCLUSIONS. Conditional probability methods permit estimation of future risks to address questions frequently asked by patients with cancer who want to know when they can be considered cured of cancer or when the risk of recurrent disease has decreased. These data on the future risk of recurrent disease and mortality can give a patient meaningful information on which to base life decisions.     

Comparison of two prognostic markers for malignant melanoma: MIA and S100 beta.

It has recently been shown that the serum level of melanoma-inhibitory protein (MIA) provides useful information for the therapy and follow-up of patients with malignant melanoma. Previously, S100 beta has been described as a useful tumor marker for malignant melanoma. In this study, we compare the significance of the two markers in follow-up, therapy outcome and prognosis by measuring MIA and S100 beta serum levels in 50 melanoma patients. Serum levels were measured in patients with malignant melanomas of stages I-IV with at least 3 time points of measurement. Serial MIA and S100 beta measurements were obtained from 32 patients with stage IV disease in parallel to chemotherapy and from 18 patients with a history of stage I and stage II disease during follow-up. The response to chemotherapy in stage IV disease and relapse of melanoma during follow-up correlated with changes in MIA and S100 beta serum levels. In comparison, MIA revealed slightly higher specificity and sensitivity. In conclusion, both markers are useful for detection of progression from localized to metastatic disease during follow-up and for monitoring therapy of advanced melanomas.     

Clinical significance of CXCR3 and CXCR4 expression in primary melanoma

Tumor cell migration involved in metastases is a tightly regulated, nonrandom process. Chemokines have been identified as critical molecules guiding cell migration. We performed a prospective study to analyze a possible association between the expression of chemokine receptors CXCR3 and CXCR4 by primary melanoma and clinical outcome. Forty primary melanomas were available for analysis; 57% of the tumors expressed CXCR3 and 35% expressed CXCR4 by melanoma cells. At initial diagnosis, 5 patients had subclinical lymph node involvement and after a median follow-up time of 32 months, 2 additional patients developed regional lymph node metastases and 5 patients developed distant metastases. The expression of CXCR4, but not CXCR3, by melanoma cells in primary lesions was significantly associated with the presence of ulceration, increased tumor thickness, a greater risk of developing regional and distant metastases and a higher mortality rate. Our study underscores the value of CXCR4 expression as a useful marker for predicting outcome in patients with localized melanoma. In addition, our findings support that, among chemokine receptors, CXCR4 might be an appropriate therapeutic target for adjuvant therapy in patients at risk for metastatic disease.     

No increase of melanoma after kidney transplantation in the northern part of The Netherlands

One medical problem of renal transplant patients who receive immunosuppression therapy is the development of a malignancy during the long-term follow-up. Existing studies, however, are not in agreement over whether patients who undergo renal transplantation have an increased risk of melanoma. The aim of this study was to determine the risk of melanoma in renal transplantation patients in the northern part of The Netherlands. We linked a cohort of 1,125 patients who received a renal transplantation in the University Medical Centre Groningen between 1989 and 2003 with the Cancer Registry of the Comprehensive Cancer Centre North-Netherlands, to identify all the melanoma patients in this cohort. The risk for melanoma after renal transplantation was calculated using the Standardized Incidence Ratio and the absolute excess risk. With a mean follow-up of 7.26 +/- 4.48 years, one patient developed a melanoma after the renal transplantation; the number of melanoma patients was among the lowest compared with other studies. The absolute excess risk for melanoma after renal transplantation was 0.5/10,000 person-years. Although several epidemiologic studies have shown that the risk of melanoma is increased in renal transplantation patients who receive immunosuppression therapy to prevent allograft rejection, this significant increase was not found in this study. The low net immunosuppressive agents given might be responsible for this low number of melanomas.     

Early stage (I,II, III) melanoma

Opinion statement Metastatic melanoma beyond the regional nodes (American Joint Committee on Cancer stage IV) is a highly lethal disease. Few affected individuals survive beyond 5 years despite aggressive treatment. Clearly, effective adjuvant therapies to prevent the development of stage IV disease in at-risk patients are worthwhile and acceptable to patients, even if they are associated with significant toxicities. Improvements in our understanding of the prognosis and staging of melanoma have allowed us to better categorize patients based on their risk of developing metastatic disease, permitting the development of logical strategies using adjuvant therapies with toxicity profiles that are appropriate based on the level of risk for recurrence. Adherence to the standards of care for the surgical management of melanoma patients with high-risk primary disease or regional disease will help optimize the benefit that can be derived from adjuvant therapy. Clinical trials remain critically important as we seek to improve the outcome for melanoma patients, but for high-risk melanoma patients outside the context of clinical trials, adjuvant therapy with high-dose interferon-alfa2b should be considered a standard treatment option.     

Radiotherapy as a risk factor for malignant melanoma after childhood skin hemangioma

The aim of this study was to determine therapy-related risk factors for the development of melanoma after hemangioma. A cohort study was conducted among 4620 patients treated before 16 years of age for skin hemangioma in France. A nested case-control study was also conducted on 13 patients who developed a melanoma (cases) matched with five controls in cohort according to sex, age at the hemangioma diagnostic, the calendar year of occurrence of the hemangioma, and follow-up. The radiation dose received at the site of the melanoma and at the same site in controls was estimated, and named 'local dose'. A total of 13 melanomas were registered during an average follow-up of overall 35 years, the risk of developing melanoma after a hemangioma treatment was 2.5-fold higher [95% confidence interval (CI): 1.4-4.1] compared with that of the general population, this ratio being only 0.8 (95% CI: 0.05-3.6) in 896 patients who did not receive radiotherapy, but 3.0 (95% CI: 1.6-5.1) after radiotherapy. When adjusting on sex, age, and year of the treatment and follow-up duration, melanoma risk was 11.9 (95% CI: 1.4-123) times higher in patients treated with ytrium 90 than in the ones who did not received radiotherapy. In the case-control study, the risk of melanoma was not linked to the local radiation dose. Indeed, the increase in melanoma risk was observed even for very low local doses. Compared with the corresponding skin areas in patients who did not receive radiotherapy, the ones having received less than 0.001 Gy had a melanoma risk of 3.9 (95% CI: 0.5-32) and those who received more than 0.01 Gy had a risk of 6.9 (0.5-99). This study suggests that radiation therapy of skin hemangioma increases the risk of further melanoma, but we were not able to evidence a relation with the local dose. Nevertheless, childhood treated for hemangioma should be considered at risk for developing melanoma and suspicious pigmented lesions should be carefully evaluated even far from treated areas.     

Childhood melanoma survival

BACKGROUND. Melanoma in childhood is uncommon. Some believe that melanoma among children is associated with a better prognosis than among adults. METHODS. The authors reviewed their institutional experience with melanoma in 40 patients younger than 18 years treated between 1950 and 1984. All slides were reviewed by a single dermatopathologist who was blinded to clinical outcomes. Long term follow-up was available for all but three patients. RESULTS. There were 26 girls and 14 boys. The median age at diagnosis was 15 years (range, 3-17 years). Eleven patients (28%) were younger than 12 years. Fifteen patients (38%) had melanoma arise in a congenital nevus (2 had bathing trunk nevi. The most common site was the extremity (n = 23), followed by the trunk (n = 10) and the head and neck (n = 7). Seventeen patients (43%) initially were considered to have benign lesions, and 23 patients (57%) were diagnosed correctly with melanoma at initial presentation. Only 21 of 37 evaluable patients (57%) were alive at last follow-up with a median follow-up of 18 years (range, 2-48 years). Fifteen patients (41%) died of their disease, with a median survival of 12 months (range, 6-60 months). One patient died of breast carcinoma 14 years after treatment for melanoma. Disease free survival was 57% at 5 and 10 years. Of the 15 patients who died of disease, 12 were female (P = 0.09) and 10 had melanoma arising in a congenital nevus (P < 0.05). Five-year overall survival was 78% for patients who presented with localized disease (n = 23) and 30% for patients who presented with regional metastasis (n = 16, P < 0.001). There were no survivors among those who presented with systemic disease (n = 1). CONCLUSIONS. Children with melanoma are at significant risk of dying of their disease. Survival is similar to that seen among adults and depends on stage at presentation. The survival advantage observed for adult females is not seen among children.     

Significance of serum protein S100 levels in screening for melanoma metastasis: does protein S100 enable early detection of melanoma recurrence?

A number of recent reports suggest serum protein S100 as a prognostic parameter in patients with metastatic melanoma. In the present study, serum protein S100 was investigated as a tumour marker for screening for melanoma metastasis in patients attending regular follow-up examinations. During the period from September 1997 to December 1998, serum protein S100 levels were measured by an immunoluminometric assay in 411 consecutive high risk melanoma patients (666 samples) and in 120 control subjects. Melanoma patients with resected primary tumours with a tumour thickness of 1.5 mm or more with resected metastasis were included in the study. Overall, 41 of the 411 patients developed metastasis during the period of observation. According to the distribution of protein S100 levels, the following different cut-off values were examined: 0.08 microg/l (95 percentile of the control group) and 0.13 microg/l (95 percentile of the group of melanoma patients without metastasis). The test efficiency for protein S100 as a diagnostic test for the detection of metastasis was highest for the cut-off value of 0.13 microg/l. In eight of the 41 patients (19.5%), elevation of protein S100 was the first sign of recurrence. Of the 41 patients with metastatic disease, 13 had elevated protein S100, giving a sensitivity of 0.32. The specificity for the detection of metastasis was 0.96. In eight of the 14 patients (57%) who developed distant metastasis, elevated S100 values were the first sign of tumour progression. In conclusion, determination of serum protein S100 levels enables earlier detection of distant metastasis in patients at high risk for metastasis. The impact on survival time needs to be investigated in follow-up studies.     

Fine-needle-aspiration cytodiagnosis of recurrent malignant melanoma

Sixty-four patients with melanoma (28 with clinical stage I disease and 36 with clinical stages II through IV disease) were fine-needle biopsied on suspicion of recurrent melanoma. Eighty-four biopsies were aspirated percutaneously and three at exploratory laparotomy. A tumor mass was present at 81 biopsies. The remaining biopsies were taken with theguidance of liver scan or fluoroscopy. In the patients with the diagnosis of recurrent malignant melanoma the cytodiagnosis was correct in 45 patients out of 47. One patient was diagnosed as breast cancer and one as malignant mesenchymal tumor. Of 40 biopsies considered normal, three were revised to be melanoma. No false-positive diagnosis was found. The frequency of false-negative diagnosis was 6%. Fine-needle-aspiration cytology is a suitable method t o establish a correct diagnosis when there is a suspicion of recurrent disease during the follow-up of melanoma patients. The high diagnostic accuracy in patients with enlarged lymph nodes is excellent and makes the method preferable to diagnostic surgical excision biopsies.     

Sentinel node biopsy for clear cell sarcoma.

Clear cell sarcoma (CCS), also known as clear cell sarcoma of tendons and aponeuroses or malignant melanoma of soft tissue, is a rare malignant tumor and is histogenitically related to melanoma. The aim of this study was to describe our experience with the sentinel node (SN) procedure for CCS patients and to discuss the potential value of this technique for CCS patients. Five patients with a subcutaneous CCS, who underwent an SN procedure, are described. Two patients had positive SNs, with additional tumor positive nodes in both lymph node dissection specimens. Only the patients with tumor positive SNs developed recurrent disease during an average follow-up of 33 months. None of the negative SN patients developed recurrent disease and all were alive after an average follow-up of 39 months. SN status seems to predict additional nodal involvement and recurrent disease as well as survival. The SN procedure might be a useful and accurate staging procedure in CCS patients, comparable to the situation in melanoma.     

Melanoma, Parkinson's disease and levodopa: causal or spurious link? A review of the literature

Since the early 1970s, a number of case reports have suggested that levodopa therapy for Parkinson's disease increases the risk of cutaneous malignant melanoma. As yet, no formal epidemiological study has been conducted to verify this hypothesis. To elucidate the relationship between levodopa and the risk of cutaneous malignant melanoma, a systematic literature search using computerized bibliographic databases was done. This review presents the case history evidence for and against the hypothesis of a causal association, and explores possible epidemiological, genetic, social, biochemical and toxicological factors that may increase the risk of melanoma in Parkinson's disease patients. All the case reports in the literature were considered. We concluded that (1) there is no epidemiological or experimental evidence of a causal role of levodopa in increasing the risk of melanoma incidence or progression; (2) there is good evidence of an excess risk of melanoma in patients with Parkinson's disease; (3) there is good evidence of a protective effect of tobacco smoking on the risk for Parkinson's disease; (4) there is good evidence of positive correlation between social class and melanoma risk; (5) the relationship between the risk of Parkinson's disease and the risk of melanoma may be due to a common genetic profile or it can be attributed to a confounding role of social class, associated with both melanoma and Parkinson's disease possibly through an inverse relationship with tobacco smoking.     

Utility of 3-year torso computed tomography and head imaging in asymptomatic patients with high-risk melanoma

There is no general consensus regarding the optimal follow-up strategy for patients with melanoma. We sought to determine the utility and cost effectiveness of radiological restaging of patients with stage IIB-IIIC melanoma at the 3-year follow-up time point. A retrospective review of 210 patients diagnosed with stage IIB-IIIC melanoma seen in the Cutaneous Oncology Program at Beth Israel Deaconess Medical Center between January, 2001 and July, 2006 was conducted. Fifty-two patients were asymptomatic and continuously disease free and underwent restaging head computed tomography (CT) or MRI and torso CT scans 3 years after completion of local-regional therapy or initiation of adjuvant treatment. True positive, false positive and normal scans were identified and the cost per diagnosis calculated. Fifty-five percent of patients developed melanoma recurrences: 88% before 3 years (median time to recurrence 12 months, 95% confidence interval: 10-16 months). The majority of patients (69%) recurred with disease symptoms. Twenty-five head CT scans, 27 head MRIs, and 52 torso CTs were performed. One false-positive head CT and five abnormal torso CT scans (three false positive, two true positive) were identified. The total cost per diagnosis was $312,990. Extensive 3-year restaging imaging seems to be of limited value for symptomatic and continuously disease-free patients with stage IIB-IIIC melanoma. Furthermore, given the low risk of recurrence beyond 3 years, it is likely that subsequent routine imaging would have similarly low utility.