Prognostic Factor In Primary Melanoma Research Articles

The relationship between obesity and immunotherapy: It's complicated.

9562 Background: Obesity is a poor prognostic factor in primary melanoma, and preclinical data has linked it to an immunosuppressive phenotype. Paradoxically, recent reports suggest that obesity may confer a survival benefit in patients with metastatic melanoma (MM) who received immune checkpoint inhibition (ICI). Herein we tested the hypothesis that the relationship between body mass index (BMI) and response to ICI depends on type of ICI and tumor type. Methods: We examined 2 cohorts (MM patients [n = 423] and metastatic bladder cancer [MBC] patients [n = 42]). We tested the associations between BMI and PFS, stratified by first vs. second or greater-line of treatment and treatment type (anti-CTLA4, anti-PD1, combination therapy), adjusting for age, gender, stage, LDH level, ECOG status, number of metastatic sites, and BMI classification changes in the MM cohort. Results: We observed a moderate but insignificant association between being overweight (BMI 25.0-29.9 kg/m2) or obese (BMI > 30kg/m2) and better PFS in patients who received first line ICI therapy (aHR 0·77 [95% CI 0·50-1·20]), and an association with worse PFS in patients who received non-first line ICI therapy (aHR 1.31 [0·74-2.33], P interaction = 0.11). Overweight and obese patients receiving combination ICI had a statistically significant survival benefit (aHR 0.27 [0·10-0.70]), p = 0.007), whereas patients receiving the other treatment types showed heterogeneous trends (P interaction = .005). In the MBC cohort, being overweight conferred the greatest PFS benefit, followed by normal BMI, with obesity being associated with the worst PFS (p = 0.035). Conclusions: Stratifying by clinical features including treatment type, treatment line, and tumor type demonstrated vastly different results and reversal of trends, which underpins the complexity of the relationship between BMI and response to ICI. The lack of consistency amongst our data and published reports highlights the need for a thorough investigation, on a significantly larger scale, to truly elucidate obesity's impact on clinical outcomes in cancer. The scientific community must consider this complexity as well as the known detrimental health effects of obesity when counseling patients.

Differences in Tumor Thickness Between Hematoxylin and Eosin and Melan-A Immunohistochemically Stained Primary Cutaneous Melanomas

Tumor thickness (Breslow thickness) represents the main prognostic factor in primary melanoma. Potential differences in melanoma tumor thickness measurements between conventional hematoxylin and eosin (H&E) and Melan-A immunohistochemical staining were evaluated. Ninety-nine excisional biopsies were included in the study. From each sample, 2 consecutive histological sections were stained with H&E and Melan-A, respectively. Tumor thickness was measured from both sections by 2 independent observers. In 59 biopsy specimens (59.6%), higher tumor thickness measurements were recorded in Melan-A-stained than in H&E-stained sections. In 42.4% of such cases (25 biopsies), the observed differences were ≥0.2 mm. After Melan-A evaluation, 33% of in situ melanoma cases were reclassified as invasive melanoma, with thickness measurements ranging from 0.15 to 0.35 mm. In 23 biopsies, identical values were recorded with both techniques, whereas in 17 cases, measurements obtained with H&E staining were slightly higher (from 0.01 to 0.18 mm) than those obtained with Melan-A staining. A high rate of interobserver agreement was noted, and significant intertechnique measurement differences were detected. Significant discrepancies (≥0.2 mm) in thickness measurements between the 2 techniques were mainly attributed to the presence of individual or small clusters of melanocytic cells in the papillary dermis. These melanocytic cells could be easily overlooked in H&E-stained sections, especially in sections showing dense lymphohistiocytic inflammatory infiltrates, numerous melanin-containing histiocytic cells in the upper dermis, or extensive fibrotic changes or regression phenomena. This study confirms the practical interest of immunohistochemical staining with Melan-A in evaluating primary melanoma and, specifically, in situ melanoma cases.

The role of VEGF-C staining in predicting regional metastasis in melanoma

Sentinel lymph node status is the most important prognostic factor in primary melanoma. The number of melanoma-associated lymphatic vessels has been associated with sentinel lymph node status and survival. Vascular endothelial growth factor-C (VEGF-C) is found to promote tumour-associated lymphatic vessel growth. In many human neoplasms, VEGF-C expression in neoplastic cells or tumour-associated macrophages (TAMs) has been linked to lymphatic dissemination of tumour cells. Recent studies have suggested a correlation between VEGF-C expression in primary melanoma and the presence of lymph node metastasis. We performed VEGF-C immunohistochemical staining on melanoma tissues of 113 patients with known sentinel lymph node status. We showed that both high VEGF-C expression in melanoma cells and TAMs are positively associated with the presence of a positive sentinel lymph node. No correlation with Breslow thickness, Clark invasion level or ulceration could be detected. VEGF-C expression in melanoma cells was predictive of a shorter overall and disease-free survival, without being an independent predictor of survival. Our results confirm that VEGF-C expression in primary cutaneous melanoma plays a role in the lymphatic spread of the tumour.

Ki-67, Bcl-2 and p53 expression in primary and metastatic melanoma

The aim of this study was to clarify the roles of the tumour proliferation marker Ki-67, the anti-apoptotic protein Bcl-2 and the cell cycle regulator p53 in primary cutaneous and metastatic melanoma. One hundred and seventeen primary melanomas and 18 metastatic tissue samples were analysed for immunohistochemical expression of Ki-67, Bcl-2 and p53. The staining results were correlated with disease progression and clinical outcome. The patient population comprised patients diagnosed with melanoma between 1988 and 1991. The clinical follow-up period for disease recurrence was 4.6 years (median; range, 0.2-7.5 years) and the follow-up period for overall survival was 10.0 years (median; range, 8.6-15.6 years). Ki-67 expression was not a prognostic factor in primary melanoma. High Bcl-2 expression was associated with such adverse prognostic factors as male gender, old age of the patient and tumour ulceration. High Bcl-2 expression was also associated with an adverse prognosis in intermediate-thickness (1.01-4.0 mm) melanomas (n=52) for disease-free (P=0.09) and overall (P=0.08) survival. In multivariate analysis, tumour thickness was the strongest prognostic factor for disease-free survival (P<0.01). High p53 expression indicated a poorer prognosis (P=0.05). In metastatic melanoma, the expression levels of Bcl-2 and p53 were lower than those in their primary counterparts (P=0.08 for each). Ki-67 expression showed no remarkable changes. It can be concluded that high p53 expression in tumour cells is associated with a poorer prognosis in primary melanoma, and high Bcl-2 expression in tumour cells is an adverse prognostic marker in intermediate-thickness primary melanoma.

Erfahrungen mit der neuen American Joint Committee on Cancer (AJCC)‐Klassifikation des kutanen malignen Melanoms

ZusammenfassungIm Jahr 2001 wurde eine neue AJCC/UICC‐Klassifikation und Stadieneinteilung des malignen Melanoms publiziert, die seitdem für die Eingruppierung des malignen Melanoms gültig ist. Im Vergleich zu der vorherigen für einen Zeitraum von etwa 15 Jahren gültigen Klassifikation wurden erhebliche Änderungen eingeführt. Die Klassifikation des Primärtumors stützt sich jetzt auf neue Klassenbildungen für die Tumordicke nach Breslow (0 – 1,0 mm; 1,01 – 2,0 mm, 2,01 – 4,0 mm; &gt; 4,0 mm). Zusätzlich wird eine histopathologisch diagnostizierte Ulzeration mit zur Einteilung herangezogen, die zur Eingruppierung in die nächsthöhere T‐Kategorie führt. Der Invasionslevel nach Clark hat nur noch für Tumoren mit einer Tumordicke bis 1 mm Bedeutung, hier führt Level IV und V zur Einordnung in die nächsthöhere T‐Kategorie. Die Einteilung der regionären Lymphknotenmetastasierung basiert auf der Unterscheidung zwischen nur mikroskopisch erkennbarer Metastasierung in der Wächterlymphknotenbiopsie oder makroskopisch‐klinisch erkennbarer Metastasierung, weiterhin gehen in die Einteilung die Zahl der befallenen Lymphknoten und das Auftreten von Satelliten‐ und In‐transit‐Metastasen mit ein. Bei Fernmetastasierung spielt die Art des Organbefalls (nur Haut und Lymphknoten vs. Lunge vs. andere Organe) sowie der LDH‐Wert eine Rolle, bei dessen Erhöhung eine Eingruppierung in die ungünstigste Kategorie erfolgt. Kritisch bleibt anzumerken, dass die starke Rolle, die der Ulzeration des Primärtumors zukommt, anhand der Daten des deutschen Zentralregisters malignes Melanom nicht bestätigt werden konnte. Weiter ist es ungünstig, dass das Stadium IIC eine signifikant ungünstigere Prognose aufweist als das Stadium IIIA, hier ist die Klassifikation inkonsistent. Die neue Stadieneinteilung sollte dennoch, insbesondere in klinischen Studien, um eine internationale Vergleichbarkeit der Daten zu ermöglichen, verwendet werden.

The impact of surgery on the course of melanoma.

Skin melanoma, unlike other cancers, occurs on the body surface: it can be detected and treated before it reaches the stage where it can metastasise; the impact of surgery is unrivalled, but only while it is at this early stage. In melanomas more than 0.75-1.00 mm thick, an increasing proportion acquire metastatic properties. There is today evidence showing that wide excision does not help, and that the effect of surgery is limited to local control of the disease. According to randomised trials, the territory of early spread--without concomitant distant micrometastases--that can be eradicated by surgery is shrinking. It has been demonstrated that resection margins of 3-4 cm are no better in terms of recurrence and survival than margins of 1 or 2 cm. Most melanomas can now be adequately resected without skin grafting. Regional elective lymph node dissection for high-risk melanoma (1.5 mm thick or more) does not improve survival over that obtained with delayed lymph node dissection performed when clinical metastases appear. By analogy, prophylactic isolated limb perfusion with melphalan reduces the rate of in-transit metastases but does not improve survival. Sentinel node biopsy allows early detection of regional lymph node metastases with minimally invasive surgery. On-going randomised studies will show whether it can have any impact on survival. Considering the experience with elective lymph node dissection, it seems unlikely that selective--as opposed to elective--lymph node dissection, of positive sentinel nodes, will influence survival. The already extensive experience with sentinel node biopsy provides a death risk hierarchy: one N2 node (with clinical metastasis), one N1 node--or sentinel node--with micrometastasis and one N0 node with no histologically detectable micrometastasis but PCR positive give, respectively, 50%, 60% and 70% 5-year survival rates. In other words, the earlier the detection of metastasis, the longer the survival. In terms of growth kinetics, the earlier the detection of metastasis, the longer the time to death, with no evidence that surgery would have an impact. There is just one, as yet unpredictable, subset of pa- tients with lymph node-confined disease in whom surgery might have an impact. It is hoped that, in the future, gene expression profiles of primary melanoma will help to pick out these patients. Multivariate analysis has shown that the sentinel node status is the most powerful prognostic factor in primary melanoma. Sentinel node biopsy is a valuable tool for selecting patients for adjuvant treatments within the frame of clinical trials, in which micrometastatic and clinically involved lymph nodes are entered separately. In-transit metastases can be eradicated in 50% of cases by isolated limb perfusion with melphalan under mild hyperthermia. When in-transit metastases are recurrent, deep seated, or bulky, the combination of tumour necrosis factor (TNF) with melphalan and interferon gamma yields a complete response rate of around 80%. This is the first antiangiogenic treatment of cancer that is effective in clinical practice, but it has no effect on survival. Current better knowledge of melanoma biology indicates that local, limited surgery has an impact on local or regional spread only.

Problems in defining cutoff points of continuous prognostic factors: Example of tumor thickness in primary cutaneous melanoma

Continuous prognostic factors are often categorized by defining optimized cutoff points. One component of criticism of this approach is the problem of multiple testing that leads to an overestimation of the true prognostic impact of the variable. The present study focuses on another crucial point by investigating the dependence of optimized cutoff points on the observed distribution of the continuous variable. The continuous variable investigated was the vertical tumor thickness according to Breslow, which is known to be the most important prognostic factor in primary melanoma. Based on the data of 5093 patients, stratified random samples were drawn out of six artificially created distributions of tumor thickness. For each of these samples, Cox models were calculated to explore optimized cutoff points for tumor thickness together with other prognostic variables. The optimized cutoff points for tumour thickness varied considerably with the underlying distribution. Even in samples from the same distribution, the range of cutoff points was amazingly broad and, for some of the distributions, covered the whole region of possible values. The results of the present study demonstrate that optimized cutoff points are extremely data dependent and vary notably even if prerequisites are constant. Therefore, if the classification of a continuous prognostic factor is necessary, it should not be based on the results of one single study, but on consensus discussions including the findings of several investigations.