Thin Melanoma Patients Research Articles

Prognosis in Thin Melanoma Patients: Is Slightly Less Than Excellent Still Okay?

Prognosis in Thin Melanoma Patients: Is Slightly Less Than Excellent Still Okay?

Risk factors and patterns of recurrence after sentinel lymph node biopsy for thin melanoma.

While having a thin melanoma (defined as AJCC 8 T1 stage tumor ≤ 1.0mm) with negative sentinel lymph node biopsy (SLNB) provides an excellent prognosis, some patients still develop recurrence and die. To determine risk factors for any recurrence (local/in-transit, nodal, distant) in thin melanoma patients with negative SLNB and assess survival outcomes. Retrospective review of thin melanomas with negative SLNB from 1999 to 2018 was performed. Two hundred and nine patients were identified. Clinicopathologic characteristics of the primary melanoma were collected. Patterns of recurrence for local/in-transit, nodal or distant recurrence and survival outcomes were analyzed. Eighteen patients (8.6%) developed recurrence: 3 (1.9%) local/in-transit, 4 (2.9%) regional/nodal, and 11 (5.3%) distant recurrence during a median follow-up time of 62months. A multivariate Cox regression model showed that head and neck site (HR 3.52), ulceration (HR 10.8), and mitotic rate (HR 1.39) were significant risk factors for recurrence. Median time to first recurrence was 49months. Patients with recurrence had a significantly worse 5year overall survival than those without recurrence (82.2 vs 99.2%). A retrospective single center study and limited sample size. Did not factor in possible false negative SLNBs when calculating hazard ratios. For thin melanoma patients with negative SLNB, heightened surveillance is warranted for those with ulceration, primary tumor location on the head or neck, and elevated mitotic rate.

Peritumoral Immune Infiltrate as a Prognostic Biomarker in Thin Melanoma.

Thin melanomas are tumors less than 1 mm thick according to Breslow classification. Their prognosis is in most cases excellent. However, a small subset of these tumors relapses. These clinical findings emphasize the need of novel prognostic biomarkers to identify this subset of tumors. Characterization of tumor immune microenvironment (TIME) is currently investigated as a prognostic and predictive biomarker for cancer immunotherapy in several solid tumors including melanoma. Here, taking into account the limited availability of tumor tissues, by characterizing some of the characteristics of TIME such as number of infiltrating lymphocytes, HLA class I antigen and PD-L1 expression, we show that number of infiltrating CD8+ and FOXP3+ T cells as well as CD8+/FOXP3+ T cell ratio can represent a useful prognostic biomarker in thin melanoma. Although further investigations in a larger patient cohort are needed, these findings have potential clinical significance since they can be used to define subgroups of thin melanoma patients who have a worse prognosis and might need different treatment modalities.

Metastases risk in thin cutaneous melanoma: prognostic value of clinical-pathologic characteristics and mutation profile.

BackgroundA high percentage of patients with thin melanoma (TM), defined as lesions with Breslow thickness ≤1 mm, presents excellent long-term survival, however, some patients develop metastases. Existing prognostic factors cannot reliably differentiate TM patients at risk for metastases.ObjectiveWe aimed at characterizing the clinical-pathologic and mutation profile of metastatic and not-metastatic TM in order to distinguish lesions at risk of metastases.MethodsClinical-pathologic characteristics were recorded for the TM cases analyzed. We used a Next Generation Sequencing (NGS) multi-gene panel to characterize TM for multiple somatic mutations.ResultsA statistically significant association emerged between the presence of metastases and Breslow thickness ≥0.6 mm (p=0.003). None of TM with lymph-node involvement had Breslow thickness <0.6 mm. Somatic mutations were identified in 19 of 21 TM analyzed (90.5%). No mutations were observed in two not-metastatic cases with the lowest Breslow thickness (≤0.4 mm), whereas mutations in more than one gene were detected in one metastatic case with the highest Breslow thickness (1.00 mm).ConclusionOur study indicates Breslow thickness ≥0.6 mm as a valid prognostic factor to distinguish TM at risk for metastases.

Tumor Mitotic Rate and Association with Recurrence in Sentinel Lymph Node Negative Stage II Melanoma Patients

Tumor mitotic rate (TMR) is a known prognostic variable in thin melanoma patients. Its significance in stage II melanoma patients is yet to be demonstrated. Retrospective analysis of a prospective melanoma database from 9/1997 to 7/2015 was performed. All stage II melanoma, with documented TMR, and six months of follow-up were included. We evaluated the association of clinicopathologic variables, TMR, as a continuous and categorical variable with recurrence-free survival (RFS) and overall survival (OS) using Cox proportional hazards modeling. We used a statistical model, X-tile, to develop optimal categorizations of TMR. A total of 265 patient characteristics are included in this study. Recurrences occurred in 82 (30.9%) patients, including 5 local, 41 regional, and 36 distant patients. In multivariate model, ulceration, Breslow, and continuous TMR were associated with worse RFS\OS. Continuous TMR demonstrated worse RFS (hazards ratio [HR] 1.02 (1.00-1.05)) and OS (HR 1.02 (1.00-1.04)), whereas dichotomized TMR (≥1 vs <1) was not significant. TMR >10.4 mitoses/mm2 has a 5-year RFS\OS of 27.2 and 44.3 per cent, respectively, compared with 57.4 and 71.4 per cent, respectively, for TMR <3.2 mitoses/mm2. Continuous TMR predicts incidence of recurrence in stage II melanoma. We propose a new categorization method developed by statistical modeling for optimal stratification that may guide surveillance for this disparate patient population.

Implementation of the 7th edition AJCC staging system: Effects on staging and survival for pT1 melanoma. A Dutch population based study

In the 7th edition of the AJCC staging system, the mitotic rate criterion replaced Clark level to increase correct classification of high-risk thin melanoma patients (pT1B). Additionally, sentinel node biopsy (SNB) was recommended for nodal staging of pT1B melanomas. The aim of this article was to evaluate the effects on pT1 substaging and clinical implications in the national pT1 melanoma population. All pT1 melanomas diagnosed in the Netherlands between 2003 and 2014 were selected from the Netherlands Cancer Registry (IKNL). Patients were stratified by cohort according to AJCC edition: (1) 2003-2009 (6th ) and (2) 2010-2014 (7th ). Relative survival was calculated to estimate melanoma-specific survival. A total of 29.546 pT1 melanoma patients were included. The pT1b proportion increased from 10.1% in Cohort 1 to 21.5% in Cohort 2. The proportion of performed SNBs per cohort increased: for pT1b melanomas alone from 4.5% to 13.0%. SNB positivity rate decreased from 10.5% to 8.8% for the entire pT1 population, and for pT1b melanomas from 11.3% to 8.6%. At 5 years, the relative survival rate was similar for pT1a and pT1b in both cohorts, namely, pT1a 100% vs pT1b 97% (Cohort 1), and pT1a 100% vs pT1b 98% (Cohort 2). The 7th edition of the AJCC staging system has caused an increased number of patients to undergo SNB, without an increase in SNB positivity rate. Survival between pT1 subgroups remains similar. The mitotic rate criterion for pT1b classification and the recommendation to perform SNB for pT1b melanomas should be reconsidered.

Regression in thin melanoma is associated with nodal recurrence after a negative sentinel node biopsy.

Prognostic markers for nodal metastasis in thin melanoma patients are debated. We present a single institution study looking at factors predictive of nodal disease in thin melanoma patients. Retrospective review from 1997 to 2012 identified 252 patients with thin melanoma (≤1 mm) who underwent a sentinel lymph node biopsy (SLNB). Node‐positive patients included positive SLNB patients and negative SLNB patients who developed a nodal recurrence (false‐negative SLNB). Clinicopathologic characteristics were correlated with nodal status and outcome. Median follow‐up was 45.5 months. Twelve of 252 patients (4.8%) were node‐positive including six positive SLNB (2.4%) and six false‐negative SLNB (2.4%) patients. No clinicopathologic factors were significantly correlated with nodal disease. For the six false‐negative SLNB patients, median time to nodal recurrence was 37.5 months. Regression was seen in only 16% of cases, but the rate increased to 60% for false‐negative SLNB cases. Both age (odds ratio [OR]: 1.09, 95% CI: 1.01–1.17; P = 0.02) and regression (OR: 8.33, 95% CI: 1.34–52.63; P = 0.02) were significantly associated with nodal recurrence after a negative SLNB on univariable analysis. Nodal disease in thin melanoma patients was seen in 4.8% of cases. Although regression was not correlated with nodal metastasis, it was correlated with a false‐negative SLNB. Patients with thin melanoma and regression may need more intensive surveillance after a negative SLNB. Further study is needed to determine if the same immune mechanisms that result in regression in primary tumors also lead to regression in lymph nodes, which may decrease detection of melanoma nodal metastases.

How staging of thin melanoma is changed after the introduction of TNM 7th edition: a population-based analysis.

In 2009, the American Joint Committee on Cancer (AJCC) incorporated the tumor mitotic rate in the melanoma pathological TNM staging system. To investigate the effect of this change on the pT1 substaging of primary cutaneous melanomas, we reclassified the cases collected by a cancer registry according to the 6th and the 7th editions of AJCC melanoma staging. Patients with pathological T1 melanoma diagnosed in the period 2000-2008 were selected from Tuscan Cancer Registry. The histological reports were reviewed and pT1 melanomas classified according to both the 6th and the 7th editions of the AJCC staging system. The shift of melanomas between pT1 substages was analyzed. Among the 242 pT1 melanomas collected in the study period and with mitotic index available, there were 202 (83 % of all pT1) and 175 (72 %) pT1a, according to the 6th and the 7th editions of the AJCC melanoma staging, respectively. When the 7th edition was used, 20 % of all pT1a melanomas shifted to pT1b, and 32 % of all pT1b melanomas shifted to pT1a. A poor level agreement between the two TNM staging systems, measured by the Cohen's kappa coefficient, was found (K = 0.37). The addition of mitotic activity to the pathological staging resulted in an increase in pT1b proportion and in a change in the classification of some cases. This modification could influence the clinical approach, with a different use of the sentinel lymph node biopsy, and underlines the role of mitosis evaluation in the management of thin melanoma patients.

Is sentinel lymph node biopsy (SLNB) routinely needed for breast cancers ≤5mm?

RESULTS: Of 120,272 NCDB thin melanoma patients, 98,083 patients met criteria. 35,043 (35.73%) had nodes examined and 2,283 (6.52%) had nodal metastasis. Nodal disease was seen within all depth ranges: (0.00-0.50mm: 7.9%, 0.51-0.75mm: 4.6%, 0.761.00mm: 6.26%). Ulceration significantly increased risk of nodal disease (15% vs 5%). Multivariate analysis using stepwise logistic regression demonstrated that age <40, male gender, nodular histology, ulceration, and higherClark’s level predicted nodalmetastasis (p<0.05). In a smaller subgroup, lymphovascular invasion statistically increased riskofnodal positivity (35% vs 4%), as did higher mitotic rate (8.4% vs 4.72%). Nodal positivity was a strong predictor of worse overall survival in this patient population with p <0.0001. Worse overall survival was predicted using multivariate analysis in patientswithmale gender, nodular histology, presence of ulceration, and higher Clark’s level (p<0.0001).

Sentinel lymph node biopsy in patients with thin melanoma: occurrence of nodal metastases and its prognostic value

We identified the proportion of positive sentinel lymph node biopsies (SNBs) in patients treated for thin melanoma (Breslow thickness <or= 1.0 mm). Breslow thickness is compared to the American Joint Committee of Cancer (AJCC) stage as a predictor for sentinel node involvement, and the prognostic value of the SNB in thin melanoma is analysed.Our prospective database of 248 patients, treated for melanoma between January 1994 and August 2007, was reviewed and completed. In 78 patients, SNB was performed for a thin melanoma. Overall, 23.8% of the SNBs were positive; in thin melanoma 6.4% were positive. All those nodal metastases were found in the group with a Breslow thickness of 0.76-1.0 mm, resulting in 12.8% of positive SNBs in this subgroup (X(2) p = 0.02). In AJCC stage 1a, 4.3% had a positive SNB, in AJCC stage 1b the SNB positive proportion was 9.4% (X(2) p = 0.38). Disease free survival in the node positive group was 100%. Breslow thickness only appears to be a practical tool in predicting lymph node involvement. SNB can be omitted in melanoma patients with a Breslow thickness <or= 0.75 mm. The prognostic value of SNB might be different in thin melanoma patients. Further research is warranted to asses the value of SNB in this subgroup of patients.

Meta-analysis of sentinel lymph node positivity in thin melanoma (

Despite the lack of an established survival benefit of sentinel lymph node (SLN) biopsy, this technique has been increasingly applied in the staging of thin (<or=1 mm) melanoma patients, without clear evidence to support this recommendation. The authors performed a meta-analysis to estimate the risk, potential predictors, and outcome of SLN positivity in this group of patients. MEDLINE, EMBASE, and Cochrane databases were searched for rates of SLN positivity in patients with thin melanoma. The methodologic quality of included studies was assessed using the Methodological Index for Non-Randomized Studies criteria. Heterogeneity was assessed using the Cochran Q statistic, and publication bias was examined through funnel plot and the Begg and Mazumdar method. Overall SLN positivity in thin melanoma patients was estimated using the DerSimonial-Laird random effect method. Thirty-four studies comprising 3651 patients met inclusion criteria. The pooled SLN positivity rate was 5.6%. Significant heterogeneity among studies was detected (P = .005). There was no statistical evidence of publication bias (P = .21). Eighteen studies reported select clinical and histopathologic data limited to SLN-positive patients (n = 113). Among the tumors from these patients, 6.1% were ulcerated, 31.5% demonstrated regression, and 47.5% were Clark level IV/V. Only 4 melanoma-related deaths were reported. Relatively few patients with thin melanoma have a positive SLN. To the authors' knowledge, there are no clinical or histopathologic criteria that can reliably identify thin melanoma patients who might benefit from this intervention. Given the increasing diagnosis of thin melanoma, in addition to the cost and potential morbidity of this procedure, alternative strategies to identify patients at risk for lymph node disease are needed.

Sentinel lymph node biopsy in thin melanoma patients

We sought to determine the incidence of positive sentinel lymph nodes in thin melanoma (<or=1.0 mm) patients and if subgroups could be identified with a higher risk of occult nodal disease. Patients with <or=1.0 mm lesions treated between 1997 and 2003 were reviewed. Sentinel nodes underwent microscopic analysis including step sectioning and immunohistochemical examination. Some nodes underwent reverse transcriptase-polymerase chain reaction (RT-PCR) evaluation for melanoma markers. Sixty-four of 107 thin melanoma patients underwent sentinel node biopsy (SNB). Mapped patients were more likely to have Clark >or= III and thicker lesions (mean 0.77 mm vs. 0.47 mm), but were not different in regards to age, sex, or lesion location. Eight percent and 58% of sentinel nodes were positive by routine histology and RT-PCR, respectively. Among mapped patients, younger age was the only significant prognostic factor for node positivity. With a median follow-up of 18 months among all patients, one regional recurrence (at 2 years) has been identified. Given the low morbidity of sentinel lymph node biopsy, this procedure should be discussed with selected thin melanoma patients to detect microscopic disease, however PCR positivity by our methods is too commonly seen to be clinically significant in thin melanoma patients and requires additional study.

Mitotic Rate as a Predictor of Sentinel Lymph NodePositivity in Patients With Thin Melanomas

Lymphatic mapping and sentinel lymphadenectomy (LM/SL) provide important prognostic information for patients with early-stage melanoma. Although the use of this technique in patients with thin melanomas (< or =1.00 mm) is not routine, risk factors that may predict sentinel lymph node (SLN) positivity in this patient population are under investigation. We sought to determine whether mitotic rate (MR) is associated with SLN positivity in thin-melanoma patients and, therefore, whether it may be used to risk-stratify and select patients for LM/SL. Clinical and histopathologic variables were reviewed for 181 patients with thin melanomas who underwent LM/SL from January 1996 through January 2004. Univariate and multivariate logistic regression analyses were performed to identify factors associated with SLN positivity. Risk groups were defined on the basis of the development of a classification tree. The overall SLN positivity rate was 5%. All patients with positive SLNs had an MR of >0. By univariate analysis, MR and thickness were significant predictors of SLN positivity. The association between MR and SLN positivity remained significant controlling for each of the other variables evaluated. On the basis of a classification tree, patients with an MR >0 and tumor thickness > or =.76 mm were identified as a higher-risk group, with an SLN positivity rate of 12.3%. In patients with thin melanomas, MR >0 seems to be a significant predictor of SLN positivity that may be used to risk-stratify and select patients for LM/SL. To confirm these results, the predictive value of MR for SLN positivity needs to be validated in other populations of thin-melanoma patients.