Redesigning Sentinel Lymph Node Biopsy Guidelines in Melanoma Cases

According to the American Cancer Society, an estimated 100,000 new cases of melanoma will be diagnosed in 2022, making it one of the top 5 most common cancers in the United States.¹ Melanoma originates in melanocytes and spreads via the lymphatic and circulatory system. When staging melanomas, providers first assess tumor thickness (Breslow measurement) and ulceration. However, another key component when assessing melanomas is performing a sentinel lymph node biopsy (SLNB). SLNBs are frequently executed in the outpatient setting but may require a short stay in the hospital. To perform an SLNB, a surgeon injects radioactive substance or dye near the tumor site and uses a device to detect which lymph nodes contain the dye or substance.² Once identified, the surgeon then makes an incision in the overlying skin and removes the lymph node.² The lymph node is sent for pathologic evaluation where it is examined for the presence of cancer cells.² If the pathologist detects cancer cells, the surgeon may choose to remove additional lymph nodes.² Furthermore, the results of the SLNB contribute to staging, prognostication, and treatment of the melanoma.

A positive SLNB impacts management far greater than a negative SLNB. Currently, the overall incidence of positive sentinel lymph nodes in patients undergoing SLNB ranges from 15% to 20%, with T4 tumors (>4.0 mm Breslow depth) demonstrating SNLB positivity rates of 35% to 40% and T1 tumors (≤1.0 mm Breslow depth) demonstrating SNLB positivity rates of 5% to 7.8%.³ As with any procedure, there exists risks associated with SNLB, including bleeding, pain, infection, anatomical injury, allergic reaction to the dye, and lymphedema.² In a systemic review of SNLB in melanoma that included 21 articles and 9047 patients, the overall complication rate was found to be 11.3% (95% confidence interval [CI], 8.1%-15.0%).⁴ The most common complications included a 2.9% (95% CI, 1.5%-4.6%) incidence of infection, 5.1% (95% CI, 2.5%-8.6%) incidence of seroma, 0.5% (95% CI, 0.3%-0.9%) incidence of hematoma, 1.3% (95% CI, 0.5%-2.6%) incidence of lymphedema, and 0.3% (95% CI, 0.1%-0.6%) incidence of nerve injury.⁴ Comparing the complication rates with SLNB positivity rates in shallower tumors (≤1.0 mm Breslow depth), providers are actually more likely to cause a complication than to identify a positive lymph node (5%-7.8% SLNB positivity vs 11.3% complication rate). Recognizing this as an opportunity to improve quality patient care, the authors investigated how to best yield high SLNB positivity rates and decrease the number of unnecessary SLNBs.

Current guidelines recommend SLNB in melanomas <0.8 mm with ulceration or >0.8 mm without ulceration.⁵ They also suggest consideration for SLNB in melanomas <0.8 mm without ulceration when additional high-risk factors for lymph node involvement are present, such as young age, high mitotic rate, lymphovascular invasion, and positive margins on biopsy.⁵ Closely examining studies that support these guidelines revealed that although melanomas >0.8 mm produce positive sentinel lymph nodes, the highest rates of positivity occur in melanomas ranging from 2 mm to 5 mm in depth.^6-8 Chang et al reported a 12% SLNB positivity rate for melanomas 1.01 to 1.99 mm in depth. For melanomas 2.0 to 2.99 mm in depth they reported a 22% SLNB positivity rate, and for melanomas 3.0 to 4.0 mm in depth they reported a 26% SLNB positivity rate (P < .00012).⁷ Paek et al reported similar rates: 19%, 32%, and 45% positivity for melanomas 1.01 to 2.0 mm, 2.01 to 3.99 mm, and ≥4.0 mm in depth, respectively (P < .0001).⁸ Mraz-Gernard et al further delineated these correlations, reporting 17%, 16%, 50%, 41%, and 17% positivity for melanomas 1.0 to 1.9 mm, 2.0 to 2.9 mm, 3.0 to 3.9 mm, 4.0 to 4.9 mm, and 5.0 to 17.0 mm in depth, respectively (P <.001).⁶

These studies also categorize node positivity as melanomas >0.8 mm and melanomas <0.8 mm, or by stratifying melanomas into groups of <0.8 mm, 0.8 mm to 1.0 mm, 1 mm to 4 mm, and >4.0 mm.^6-8,9 Consequently, the American Joint Committee on Cancer (AJCC) stratified their guidelines in a similar manner.^6-8 However, in melanomas >1.0 mm, prognostication value and positivity rates of SLNB change with every millimeter, whereas positivity rates are surprisingly similar in melanomas measuring <1.0 mm (<0.25 mm, 8% positive; 0.25-0.50 mm, 4% positive; 0.51-0.75 mm, 4% positive; and 0.76-1.0 mm, 6% positive).^6-8,10,11 Therefore, restratification of SLNB guidelines appears necessary as melanomas <1.0 mm are overly stratified and melanomas >1.0 mm are insufficiently stratified.

When differences do appear with sentinel lymph node positivity in thin melanomas, additional factors are often present. For example, mitotic rate predicts sentinel lymph node positivity in melanomas 0.75 mm to 1.0 mm (P = .0007).⁹ In fact, a mitotic rate >1 mm² was previously an AJCC criterion in determining SLNB candidates but was removed in the eighth edition due to insignificant data and because ulceration and Breslow depth were found to be stronger predictors.¹² However, more recent data show mitotic rate deserves reevaluation as a criterion for SLNB because a mitotic rate >4 mm² is statistically significant for SLNB positivity. Furthermore, a mitotic rate >3.5 mm²  is statistically significant for a worse prognosis with shorter survival times (P = .002).^13,14

In addition to examining supporting studies, the authors also identified that the modifiers of young age, ulceration, lymphovascular invasion, and positive margins were limiting when solely applied to melanomas <0.8 mm. Younger patients (aged <50 years) continued to yield increased SLNB positivity rates in melanomas >1.0 mm compared with older patients (aged >50 years) who had thicker and more ulcerated tumors (P < .0001).⁸ Ulceration was also associated significantly with positive SLNB in melanomas >1.0 mm (P = .005).⁸ Lymphovascular invasion remained a significant predictor of SLNB positivity in melanomas >1.0 mm as well (P < .0001).⁸ Furthermore, the positive margin criterion could be expanded to include satellite lesions because satellitosis in melanomas >1.0 mm was significantly associated with positive SLNB.⁸

Considering all of the discussed data, it becomes evident that if one uses Breslow depth alone for SLNB candidacy, 0.8 mm is likely too low of a threshold. However, regardless of whether or not this threshold is changed, the current modifiers of mitotic rate, age, ulceration, lymphovascular invasion, and satellitosis deserve to be expanded to include all melanomas, not only those <0.8 mm. Doing so will likely lead to higher SLNB positivity rates and reduce the number of unnecessary SLNBs performed.

After identifying areas of improvement with the current SLNB indications, the authors also examined factors outside the standardized guidelines. Reviewing studies that assessed the 4 main subtypes of melanoma revealed that superficial spreading and lentigo maligna did not affect the rate of positivity in SLNB. However, in comparison, nodular melanoma and acral lentiginous melanoma were strongly associated with SLNB positivity and were significant predictors of metastatic involvement of sentinel lymph nodes (P < .05).^15,16 Thus, nodular and acral lentiginous subtypes of melanomas may be prone to developing more aggressive features, important factors to evaluate when deciding candidacy for a SLNB.

In addition to subtype of melanoma, evidence was found in the literature to confirm that anatomical location plays a role in SLNB positivity. Melanomas on the trunk were predictive of increased positivity rates of SLNB (P = .0099), as were melanomas found on the lower extremities (P = .0411).⁸ Meanwhile, melanomas on the upper extremities (P = .0242) and head and neck (P = .0027) were associated with a lower likelihood of a positive SLNB status.⁸ A multivariable model demonstrated that the significance of these anatomical locations as predictors of positive SLNB status were independent of age and histological subtype.⁸

An explanation as to why certain anatomical locations elicit greater rates of SLNB positivity is not well documented. Conversely, more is known about why head and neck melanomas produce lower rates of SLNB positivity. The complex lymphatic network of the head and neck creates difficulty determining which node to biopsy, often resulting in several negative SLNBs.^14,17 To combat this phenomenon, physicians began extensively mapping the head and neck lymphatic network with lymphoscintigraphy before SLNB rather than performing a biopsy on the first lymph node detected.^14,17 O’Brien et al demonstrated that 34% of patients would have had sentinel lymph nodes left behind if clinical predicted sites were used without lymphoscintigraphy.¹⁸ Therefore, applying extensive lymphatic mapping to other anatomical sites, in addition to the head and neck, may assist in producing increased SLNB positivity rates.

Another variable investigated was that of immunocompromised status as a factor of SLNB positivity rates. Unfortunately, this topic was sparsely represented in the literature. Therefore, the authors can only speculate that immunocompromised status increases SLNB positivity rates, similar to how immunocompromised status frequently worsens disease containment and prognosis. Further exploration into this topic will guide how SLNB criteria changes for immunocompromised patients.

After reviewing and assessing current AJCC criteria as well as additional, outside variables, an opportunity to improve and redesign the guidelines for melanoma SLNB becomes evident. Redesigning should incorporate the variables of Breslow depth, ulceration, age, mitotic rate, lymphovascular invasion, satellitosis, melanoma subtype, anatomical location, and immunocompromised status to achieve the goal of reducing unnecessary SLNB and increasing SLNB positivity rates and prognostication (Figure 1). A future study performing integrative statistical analysis of all of these variables is warranted and will ideally result in the creation of an algorithm or formula that produces a patient-specific recommendation on whether or not to pursue sentinel lymph node biopsy. Creating this patient-specific model that evaluates multiple data points in melanoma cases will exemplify a facet of precision therapy and contribute to the progression and future of medicine.

Affiliations: ¹Department of Medicine, UCLA-Oliveview Medical Center, Sylmar, CA; ²Jobst Vascular Institute, Promedica Health Network, Toledo, OH; ³Department of Surgery, Division of Plastic and Reconstructive Surgery, University of Toledo, Toledo, OH

Correspondence: Samuel Stetkevich, MD; Sstetkevich@dhs.lacounty.gov

Disclosures: The authors disclose no conflicts of interest.

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