Indications for Sentinel Lymph Node Biopsy in Thin Melanoma: A Systematic ReviewAbstract Skin cancer is the most common cause of cancer. Within the field of dermatology, melanoma causes most skin cancer deaths. Furthermore, the incidence of people being diagnosed with melanoma has been rising over the past three decades. The current guidelines set forth by the American Joint Committee on Cancer (AJCC), include very specific parameters for indications for sentinel lymph node biopsy (SLNB) in melanoma patients.A search was made for peer reviewed articles that contained randomized trials and retrospective cohort studies involving different histological features of melanoma. This study reviewed the literature on SLNB for patients diagnosed with melanoma, to provide insight into the rationale for SLNB, specifically for patients diagnosed with thin melanomas of thickness measuring < 1 mm. Most articles analyzed in this review agreed that SLNB is one of the most important factors for staging the disease. A negative SLNB increases the likelihood of a disease-free survival. Breslow thickness, ulceration, and mitotic rate were found to be the strongest histological factors that can be used to predict the outcome of the SLNB. For patients diagnosed with thin melanoma, even though they have a low percentage of having a positive sentinel lymph node (SLN), the procedure should still be utilized in patients who are good surgical candidates. Further studies are indicated to find support for the current guidelines. Key words: sentinel lymph node biopsy (SLNB), Breslow thickness, prognostic factors, thin melanomaIntroduction In 2018 in the United States, it is estimated that around 91,270 patients will be diagnosed with invasive melanoma and approximately 9,300 persons are expected to die of the disease. Based on key statistics from the American Cancer Society, the rates of melanoma have been going up for the past 30 years, affecting men (60%) at a higher percentage rate than women (40%).1  For persons who have been diagnosed with melanoma, the disease status of regional lymph node is the most significant indicator for melanoma.2  Up until the 1990s, elective lymphadenectomy was the standard procedure for determining disease status, but, this procedure or staging tool, has since been replaced by sentinel lymph node biopsy (SLNB), a less invasive alternative for staging lymph nodes in melanoma and other cancers.2  More specifically, a sentinel lymph node (SLN) is the first node draining the cutaneous melanoma along the lymphatic system. Most metastatic melanomas travel via the lymphatic pathway, with malignant cells joining the cardiovascular system (CVS). Once connected with the CVS, malignant cells can use this route to travel to distant areas of the body depositing tumor cells in practically any organ of the body.2The Eighth Edition American Joint Committee on Cancer (AJCC,2018) staging system for melanoma, which took effect in January 2017, remains the gold standard reference for the medical community at large. The AJCC staging system is used across the globe to ensure that practitioners caring for cancer patients are fully versed in the language of cancer staging.3 Exhaustive research on cancer incidence, prognosis, and overall survival is added in addition to updates on clinically relevant prognostic markers.4  Not all stages of melanoma require pathological staging, but for melanomas that measure ? 1 mm (thin melanoma) great controversy remains. The indication for SLNB in accordance with the AJCC starts with the categorization of Breslow thickness after an excisional biopsy. The Breslow thickness is a measure of a tumor’s vertical depth of invasion stated in millimeters. One of the changes made by the AJCC involves the regrouping or definition of thin melanomas in the primary tumor (T) category; specifically, T1a and T1b. In addition, ulceration status (with or without) is considered as well when regrouping the T1 subgroups. In addition, tumor mitotic rate (MR) has been removed as a T1 staging criterion as of January 2017.3While statistically, five percent of persons diagnosed with thin melanoma (? 1.0 mm Breslow depth) end up with lymph node positivity, SLNB remains the most important procedure to stage the disease. SLNB is the most proactive way to prevent further spread by removing a diseased node as early in the disease process as possible. For those patients diagnosed with intermediate thickness melanoma, (1.0-2.0 mm) 15 % will test positive for nodal metastases.2SLNB is the most important prognostic and staging tool available, however, not every patient is a good candidate for the procedure. As with most surgical procedures, there can be postoperative complications, particularly in patients with comorbid conditions. The most common complications include seromas, nerve injury, and wound infection. A more severe but less common complication is the development of lymph edema.5  Not all stages of melanoma require pathological staging, but for melanomas that measure ? 1 mm (thin melanoma), the debate over the widespread use for SLNB is ongoing. MethodsOn September 6th, 2018, Medline in PubMed was searched for journal articles with the keywords: “melanoma” and “sentinel node biopsy” and “risk factors” and “morbidity” which resulted in 186 articles. Then, 160 articles were eliminated because full text and free text of the article was not available. Articles that were more than ten years old were also excluded in this screening process. Then 23 articles were excluded because they were either review articles, opinion pieces or not relevant to the topic. Then, four articles were handpicked references using the “snowballing” method, which resulted in a total of seven articles from this search.On September 29th, 2018, JAMA network under Jama Dermatology journals was searched for journal articles with the keywords: “melanoma” and “sentinel node biopsy” and “risk factors” and “morbidity” which resulted in 33 articles. Then, 21 articles were eliminated by applying the following filters: collection: melanoma, article type: research, topic: melanoma, content type: article, and filter: free. Then nine articles were excluded because they were irrelevant to the topic. Therefore, three studies were included in this systematic review. When adding the eight articles from the initial search in Medline and PubMed, together with the three articles from Jama network, at total of ten articles were included in this systematic review of Indications and rationale for sentinel node biopsy in patients diagnosed with thin melanoma.Topic: Indications for sentinel lymph node biopsy in thin melanoma.Figure 1. PRISMA Flow chart6ResultsRecords identified through database searching(n = 33)Records identified through database searching(n = 186)IdentificationRecords after duplicates removed(n = 186)Records after duplicates removed(n = 33)ScreeningRecords screened(n = 186)Records screened(n = 33)EligibilityFull text articles assessed for eligibility(n = 38)Full text articles excluded with reasons(n = 32)Additional records identified through references(n =4)Studies included in qualitative synthesis(n = 10)IncludedThe result of the systematic literature search is summarized in the PRISMA flow diagram (Fig 1). After screening 219 studies, ten were selected for this review including nine cohorts and one randomized controlled trial. The most common reason for excluding articles were irrelevance to the topic or the lack of clinical outcomes with specific measures. More than half of the studies were from Europe (six), with two carried out in Spain, two carried out in Italy, one carried out in Spain and France as a collaboration, and one carried out in Germany. There were no language limitations as all studies found on the two databases searched were written in English. The remaining four studies were carried out in the USA. Study designs in this review were mainly cohorts utilizing databases to collect retrospective data, using either univariate and/or multivariate regression analysis. The Morton et al. study was a randomized controlled Multicenter Selective Lymphadenectomy Trial (MSLT-I). Inclusion criteria for the ten studies required patients to have been diagnosed with primary cutaneous melanoma (CM). The smallest study included a population of 350 patients while the largest study contained 2001 patients. The ages ranged between 13-93 years of age. Most studies included histological prognostic factors such as tumor thickness (Breslow), ulceration, mitotic rate, Clark level, microsatellitosis, and regression to determine association and indications for sentinel lymph node biopsy. Two of the studies used non-histological prognostic factors such as age and time to investigate any association between these variables and SLN positivity.Indication for sentinel lymph node positivity based on thickness of lesion A study done by Bartlett et al. in 2014, focused specifically on predicting sentinel node positivity in patients diagnosed with thin melanoma. The study found that in the univariate analysis mitotic rate, Clark level (IV-V) and thickness of lesions were significantly associated with SLN positivity in patients with thin melanoma (?1mm). It concludes that the presence of mitosis was the most important factor for predicting SLN positivity, in patients diagnosed with stage T1 melanoma.7  The authors of this study state that patients with “high risk” histopathological factors such as a mitotic rate and ulceration should be considered on a discrete basis. For patients with cutaneous melanoma that range between 0.76-1.00 mm T1a lesions, a sentinel lymph node biopsy should be discussed and considered. Furthermore, for patients with 0.76-1.00 mm lesions with mitotic rate of ? 1/mm2 (T1b over 0.76 mm) and ulceration, practitioners should discuss and offer a SLNB.7  A positive node metastasis of 3.7 % was found in patient with thin melanoma. In addition, the study showed that in patients with non-mitogenic lesions, the SLN positivity rate was 0.7 % of the 781 patients in the cohort.7  The MSLT-1 trial divided their patients into intermediate-thickness melanoma (1.20-3.5 mm) from those with melanoma thicker than 3.5 mm. The MSLT-1 trial found that for patients with melanomas between 1.20-3.5 mm thickness and who had occult nodal metastasis when presenting in the office, early intervention decreased the risk of recurrence of melanoma in the nodes and reduced distant metastasis and death from melanoma.8  The 10 -year disease-free survival (DFS) and the 10-year rate of melanoma-specific survival (MSS) were seen in patients with intermediate thickness melanoma and in patients with thick melanoma (>3.5 mm).8In a retrospective cohort study done by Ribero et al., patients diagnosed with a primary tumor of T4 (>4 mm) using multivariate were analyzed and stratified into three main groups; SLN-negative, SLN-positive, and one group that was observed where SLNB was not performed.9 The results of this study concluded that the SLN-negative group compared to patients in the observational group confirmed a better prognosis in terms of disease-free interval (DFI) and disease-specific survival (DSS).The observational group showed no difference in clinical outcome when compared to the positive-SLN patients.9A cohort study, done by Bartlett et al. using multivariate and univariate regression analysis, focused on patients diagnosed with intermediate thickness melanoma (1.01-4.00 mm) found that 16.5 % of 952 study patients had a positive SLNB result.10Association between sentinel node-positivity, histological and non-histological prognostic factors other than thickness The study done by Testori et al. concluded that SLN status was the most important prognostic factor for overall survival. Furthermore, the study concluded that the probability of having SLN positivity increased with Clark level, tumor thickness, and the presence of ulceration.11  The Testori study did not find regression to be a good predictor of SLN positivity. In addition, the study noted that regression seemed to be a protective factor, at least in patients diagnosed with thin melanoma.11  A German study done by Elsae?er et al. investigated and concluded that prognostic factors associated with SLN positivity were as follows: tumor thickness, ulceration, histopathologic subtype, and body site. This study did not include mitotic rate due to the fact up until 2010, mitotic rate was not taken into consideration in primary melanoma.12A retrospective cohort conducted in Spain by Tejera-Vaquerizo et al. in 2012, looked at growth rate (GR) of cutaneous melanoma as a variable and a possible association with melanoma aggression. The authors of the study concluded that the GR may provide additional information together with more classical histological features such as Breslow thickness, miotic rate, and ulceration but more studies need to be done to investigate GR and association with SLN positivity.13The results of the Botella-Estrada study concluded that regression is not associated with SLN positivity. Variables that were found to have statistical significance and association with SLN positivity included; Breslow thickness, ulceration, mitosis, and histopathologic subtypes, superficial spreading melanoma, nodular melanoma and lentiginous melanoma.14One retrospective study that was split between two centers, one in France and one in Spain, investigated the effect of time between an excisional biopsy of a primary cutaneous melanoma and SLNB. The objective of this study was to determine if a certain delay between the two procedures would have any prognostic implications.15  More specifically, did the delay time have any effect on survival in patients? It was found that a delay time of more than 40 days was related with better 5-year disease-free survival and better 5-year melanoma-specific survival.15An additional cohort study done in 2017 by the Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, analyzed 8772 patients with melanoma thickness between 0.5-1.00 mm, including those who had undergone SLNB.16  This data was then evaluated against age to see if a strong relationship existed between age and lymph node positivity.Age was divided into three age groups including <40, 40-65, and ? 65 for this study. The results showed that patients <40 years of age showed a higher rate of SLN positivity (5.6%), versus patients 65 years and older showing a lower rate of SLN positivity (3.9 %).16Table 1: Key Characteristics of Included StudiesAuthor and YearTitleInclusion CriteriaHistological/ non-histological featuresStudy designResultsTestori A, De Salvo GL, Montesco MC, et al.11(2009)Clinical considerations on sentinel node biopsy in melanoma from an Italian multicentric study on 1,313 patients (SOLISM-IMI).Primary cutaneous melanomaBreslow thickness(? 1.00,1.01-2.00,2.01-4.00, >4mm)RegressionObservational prospective studyThis study concluded that SLN status is the most important prognostic factor for 5-year overall survival of patients with +SLNB. Regression may be a protective factor.Elsaeßer O, Leiter U, Buettner PG, et al.12(2012)Prognosis of sentinel node staged patients with primary cutaneous melanomaPrimary cutaneous melanomaBreslow thickness(? 1.00,1.01-2.00,2.01-4.00, >4 mm)cohortThis study demonstrates that tumor thickness, SLNB status, ulceration, histological subtype and body site were identified as independent significant prognostic factorsTejera-Vaquerizo A, Nagore E, Herrera-Acosta E, et al.13(2012)Prediction of sentinel lymph node positivity by growth rate of cutaneous melanomaPrimary cutaneous melanomaBreslow thickness(? 1.00, 1.01-2.00, 2.01-4.00, >4 mm)Growth RateRetrospective cohortThis study demonstrated that growth rate, Breslow thickness, and microscopic satellitosis are independently associated with SLN positivity.Bartlett EK, Gimotty PA, Sinnamon AJ, et al.7(2014)Clark level risk stratifies patients with mitogenic thin melanomas for sentinel lymph node biopsy.Primary cutaneous melanomaBreslow thickness? 1 mmcohortSLN positivity is low in patients with thin melanoma. Mitoses and elevated Clark level were significantly associated with SLN metastases and may help identify patients with an appreciable incidence of SLN positivity.Botella-Estrada R, Traves V, Requena C, Guillen-Barona C and Nagore E.14(2014)Correlation of histologic regression in primary melanoma with sentinel node statusPrimary cutaneous melanomaBreslow thickness(? 1.00, 1.01-2.00, >4 mm)RegressionRetrospective cohortResults of this study suggest that the presence of regression on the histology report, does not justify the performance of a sentinel node biopsy in patients diagnosed with primary melanoma.Morton DL, Thompson JF, Cochran AJ, et al.8(2014)Final trial report of sentinel-node biopsy versus nodal observation in MelanomaPrimary cutaneous melanomaBreslow thickness1.20-3.5 mmRandomized controlled trialThe results of this study showed no significant treatment-related difference in a 10-year melanoma-specific survival rate in the overall population.Ribero S, Osella-Abate S, Sanlorenzo M, et al.9(2015)Sentinel lymph Node Biopsy in thick-melanoma patients (N=350): What is the prognostic role?Primary cutaneous melanomaBreslow thickness>4.00 mmRetrospective cohortThick-melanoma patients are a heterogenous group with different prognosis. Routine SLNB recommended in melanoma >4mmTejera-Vaquerizo A, Nagore E, Puig S, et al.15(2015)Effects of time to sentinel node biopsy on the prognosis of cutaneous melanoma. Primary cutaneous melanomaBreslow thickness? 2.00 mmtimeRetrospective observational studyWorse melanoma specific survival was observed in patients who had early biopsies performed.Bartlett EK, Peters MG, Blair A, et al.10(2016)Identification of patients with intermediate thickness melanoma at low risk for sentinel lymph node positivityPrimary cutaneous melanomaBreslow thickness(1.01-4.00 mm)Retrospective cohortThe results of this study indicated that 75 % of patients with lesion thickness between 1.01-1.5mm could be classified into groups with a < 5 percent rate of SLN positivity. This being similar to that observed in patients with thin melanoma.Sinnamon AJ, Neuwirth MG, Yalamanchi P, et al.16(2017)Association between patient age and lymph node positivity in thin melanoma.Primary cutaneous melanomaBreslow thickness(0.5-0.75, ? 0.76)ageRetrospective cohortYounger age, female sex, deeper Breslow thickness, higher Clark level, presence of mitoses, ulceration, lymphovascular invasion, and regression were associated with nodal metastases.  DiscussionThree retrospective studies and the MSLT-1 trial analyzed patients with cutaneous melanoma of different tumor thickness, ranging from ?1mm to >4 mm and the association with sentinel node positivity.7,9,10,8 The study of thin melanoma (? 1 mm) concluded that the presence of mitosis was the most important factor for predicting SLN positivity, in patients diagnosed with stage T1 (? 1.0mm) melanoma.7  A study done by the same author two years later, concluded that mitosis was not the most important predictor of SLN positivity in patients with melanoma thickness ranging between 1.01-4.00 mm. Instead, this study from 2016 found that for patients with intermediate thickness melanoma of a thickness > 1.5 mm, lymphovascular invasion (LVI) played a more significant role than mitosis in predicting SLN positivity.10 Interestingly, no other studies discussed the significance of LVI as a prognostic factor for SLN positivity. A total of 16.5 % of these patients had a positive SLNB result. While this may seem high, the risk is not distributed evenly among the whole group with intermediate thickness melanoma. This study found that the SLN positivity rate for those with tumor thickness <1.5 mm, absent lymphovascular invasion (LVI), absent satellitosis, and age ? 60 dropped to 6.6 %.10Based on the results of the Bartlett studies, controversy remains in determining the importance of pathological staging in melanomas of a thickness ? 1mm. It would be prudent for a clinician to look at other variables such as mitotic rate when dealing with patients who have melanotic lesions that are ? 1 mm in thickness. In addition, for lesions measuring > 1.5 mm, lymphovascular invasion should be incorporated as a clinicopathological characteristic.One noteworthy observation is that tumor mitotic rate (MR) has been removed as a T1 staging criterion as of January 2017 by the AJCC, although the AJCC still recommends that the mitotic rate should still be collected. The 2017 AJCC T classification groups a T1 melanoma as ? 1mm with either unknown or unspecified ulceration status. A T1a is classified as <0.8 mm without ulceration and a T1b, <0.8 mm with ulceration or 0.8-1.00 mm with or without ulceration. These new standards differ from the 2010 AJCC T classification. In the previous edition, a T1 melanoma was classified as ? 1 mm, a T1a was a lesion without ulceration and < 1 mitosis/mm2, a T1b was ulceration or ? 1 mitosis/mm2.3  It is concluded that sentinel lymph node biopsy should be performed on most patients with melanomas with Breslow thickness of > 0.75 mm which was also stated in the findings from the 2016 Bartlett study. These guidelines are necessary for conducting studies and performing statistical analysis, however, the guidelines become somewhat less meaningful as practitioners work with individual patients to determine an appropriate treatment plan.The Morton et al. study and the study done by Ribero et al. looked at melanomas of intermediate thickness 1.20-3.5 mm, and thickness >4 mm respectively. These two studies agreed that biopsy-based management is a strong predictor of disease recurrence or death from melanoma in patients with both intermediate and thick primary melanomas. The overall SLN positivity rate found in the Morton et al. study for patients with intermediate thickness was 16 %, which was comparable to the 16.5 % positivity rate found in the Bartlett study.8,10  For patients with melanomas of intermediate and greater thickness, the consensus of these two studies was that SLNB should be performed on patients who are good surgical candidates. The benefits appear to outweigh the risks for these patients who have been diagnosed with intermediate and thick melanomas based on the high overall SLN positivity found in this population and low morbidity of the sentinel lymph node biopsy procedure.Two studies looked at regression and its role as a potential factor for SLN positivity. Both the Botella-Estrada and the Testori studies agreed that Breslow thickness, ulceration, and mitosis were good predictors of SLN positivity.11,14  They both found that regression was not a good predictor. After reviewing these two studies, regression should be included only as an optional histological feature in a pathological report. The Botella-Estrada study did not show any statistically significant correlation between regression and sentinel node status.14  In addition, the studies did not quantify regression which may contribute to the studies not having enough evidence to consider regression as a relevant prognostic indicator for SLNB.The Tejera-Vaquerizo et al. 2015 was a retrospective study that examined the effects of time on the overall 5-year disease-free survival and 5-year melanoma-specific survival. Patients were divided into two groups, those whose procedures (excisional biopsy and SLNB) were performed with less than 40 days of separation and those whose procedures (excisional biopsy and SLNB) were separated by more than 40 days.15  The study found that a delay time of 40 days or more between the excisional biopsy of the tumor and SLNB was related to better 5-year disease-free survival and better 5-year melanoma-specific survival.15  This finding was explained by the fact that the patients with the longer delay had the less severe diagnosis. The outcome of this study should not have come as a surprise. It seems obvious that patients that are diagnosed with a more severe melanoma would be handled in a more expedited manner.ConclusionIn conclusion, the disease status of regional lymph nodes is the most important prognostic indicator for patients diagnosed with cutaneous melanoma. It is important for practitioners to have a working knowledge of the current AJCC cancer staging system for melanoma to be able to interpret pathology and effectively communicate with other practitioners and members of the oncologic community.Most of the studies included in this review agreed that Breslow thickness, ulceration and mitotic rate were among the most important factors in identifying lymph node status. These studies showed little deviation in treating patients with intermediate or thick melanoma. They all recommended that SLNB should be pursued. However, in cases of patients diagnosed with thin melanoma, there are still some differences in opinion about when SLNB should be recommended. Most of the studies tried to create decision criteria concerning when to perform a SLNB, based on the results of their studies along with the AJCC staging criteria.Studies like the ones reviewed here together and with the AJCC guidelines are necessary for advancing our ability to diagnose and treat melanoma. We need to have a better understanding of the nature of melanoma, and when the lymphatic system is going to be invaded by the cancer cells to be used as a vehicle for spreading the disease. The fact that we do not yet possess this capability combined with the fact that we are dealing with patients who are faced with a life-threatening cancer, SLNB should be used whenever practical and the patient is a good surgical candidate.ReferencesAmerican Cancer Society. Melanoma Skin Cancer Overview. http://cancer.org/Cancer/SkinCancer-Melanoma/index.Accessed September 29, 2018.Phan GQ, Messina JL, Sondak VK, Zager JS. Sentinel lymph node biopsy for melanoma: Indications and rationale. 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