Detection of False Negative Sentinel Lymph Node in Cutaneous Oncology: A General Reappraisal

This article refers to:

Does Wide Excisional Biopsy in Skin Cancer Prevent Finding The Real Sentinel Lymph Node?

Regional lymph nodes (LNs) are the most common site of initial metastasis in patients with cutaneous melanoma (CM) [1]. Recently, the American Academy of Dermatology published the new guidelines for the management of CM and the role of sentinel lymph node biopsy (SLNB) for staging, regional nodal control, and survival [1]. The staging accuracy of SLNB is not controversial, though its impact on survival remains less well defined [1]. Specifically SLNB represents the criterion standard for nodal staging in appropriate patients with CM, as well as it is also a key determinant for consideration of systemic adjuvant therapy and clinical trial enrollment [1]. Beside, sentinel lymph node (SLN) status is widely regarded as the most important prognostic factor for recurrence and the most powerful predictor of survival in patients with CM [1].

At the same time, despite the high accuracy and minimal invasiveness of the technique, the use of SLNB continues to show limitations, also for the significant rates of false negatives [2]. Specifically, a meta-analysis of 71 studies and 25.240 participants estimated an overall ≤ 5% risk of regional nodal recurrence following a negative SLNB, while a more recent study detected that the false negativity rate varies between 2.3% and 25%, according to the surgeon who performs the surgery [3–5]. In detail, the cause of a false-negative SLN may be due to several factors such as lymphatic mapping and radioactive labeling, surgical methods, pathological examination, and altered lymphatic drainage [3]. However, while the former factors have been widely debated in literature, little is known about the SLN status localization in those patients whose lymphatic drainage is altered.

Aberrant lymphatic drainage caused by a disruption of the lymphatic channels secondary to surgical excision is a recognized phenomenon. Specifically, a theory of postoperative “collateralization” of lymphatics has been proposed [6]. In the paper entitled “Does Wide Excisional Biopsy in Skin Cancer Prevent Detection of Finding the Real Sentinel Lymph Node?”, the authors hypothesized that excisional biopsy in patients with large lesions may change the lymphatic pathway and therefore cause the detection of a false negative SLN [3]. Indeed they found that the false SLN detection rate was significantly higher in larger lesions than in the smaller ones [3]. These results were similar to a previous study performed by Giudice et al. that found a 10% rate of false SLN when the excisional biopsy size of the primary tumor was 1.5 cm, and a 40% rate of false SLN when the excisional biopsy size was 2 cm [7]. In both studies, it is highlighted that, in large lesions, after an incisional biopsy is performed, the wide excision should be always combined with SLNB [3, 5]. Indeed, a reason for failure to visualize the SLN to excise and the risk to have a false negative SLNB is related to the fibrosis that follows the surgery of large lesions, since the fibrosis blocks the lymphatics, preventing and/or altering the spread of the tumor cells to the regional LNs [8].

Another important problem, not always taken into consideration in studies, is the involved body area by a cutaneous malignancy. Indeed, contrariwise to other malignancies, skin tumors can arise in several different anatomical locations, causing further problems for the radiological research of the SLN, as well as to its surgical excision and subsequent histological analysis. Indeed, head and neck region (one of the most affected area by CM and nonmelanoma skin cancers) is characterized by a complex lymphatic drainage, which can lead to a low accuracy of SLN. Indeed, in a recent report, among 87 patients that performed a SNLB, a positivity was found only in 5 cases (5.7%) [9]. Beside, specifically for the scalp, there is a high percentage of “skip metastases,” involving directly internal organs, rather than regional nodal chains [9]. According to the literature, this is related to the high number of blood vessel on the scalp, which is more elevated than the lymphatic ones, promoting vascular invasion, rather than lymphatic invasion, leading to early metastases [9]. Finally, CM and nonmelanoma skin cancers are also highly related to local milieu. Indeed recently, Schulman et al. found that the head and neck region is characterized by a higher predisposition to metastases, related to higher presence of T-regulatory (T-reg) cells and lower proportion of CD8+ cells [10]. Specifically, T-reg cells are preferentially localized in the hair follicles, and the scalp being an area of increased hair follicle density is more permissive to tumor growth because of increased T-reg density [10].

In conclusion, when a SLNB is expected, the wide excision of the primary cutaneous tumor should be always combined with SLNB. The risk to detect a false negative SLN is mainly related to lymphatic mapping, radioactive labeling, surgical methods, pathological examination, altered lymphatic drainage, and anatomic area where the malignancy is arisen. In this regard, the need for a standardization of the SLNB procedure, according to all the factors reported above, and the relative outcome measures remains a pivotal point.

Declaration of Interest

No conflict of interest has been declared by the author.