Beyond conventional pathology: Towards preoperative and intraoperative lymph node staging

Abstract

Accurate detection of lymph node metastases is critical for many solid tumours to guide treatment strategies and determine prognostic outcomes. The gold standard for detection of metastasis is by histological analysis of formalin-fixed paraffinembedded (FFPE) sections of removed lymph nodes; this analysis method has remained largely unchanged for decades. Recent studies have highlighted limitations in the sensitivity of this approach, at least in its current clinical use, to detect very small metastatic deposits. Importantly, the poor prognostic outcomes associated with the presence of such small tumour deposits are now well established in a number of cancers. In addition, histological analysis of FFPE sections cannot be used practically for intraoperative node assessment. Novel lymph node staging technologies are therefore actively being developed. This review critically presents the main advances in this field and discusses why these technologies have not been able to provide a better alternative to the current gold standard diagnostic technique.Localized spread of cancer cells to lymph nodes has been established as one of the most significant prognostic indicators, and consequently its identification is of the highest importance in clinical oncology and a key element of solid tumour staging. The gold standard for the detection of lymphatic involvement is the postoperative examination of formalin-fixed paraffin-embedded (FFPE) sections of the resected lymph nodes. However, recent studies have shown limitations of this technique's sensitivity to detect occult tumour deposits in lymph nodes.

Cytomorphological Characterization of Individual Metastatic Tumor Cells from Gastrointestinal Cancer Patient Lymph Nodes with Imaging Flow Cytometry

“…Detection of cancer cells in lymph node tissues, especially micrometastasis and ITC, is highly dependent on the tissue processing and analysis technique [11]. In principle, dissociation and analysis of whole lymph nodes is more likely to eliminate sampling error and, therefore, accurately determine the total tumor load within resected tissue.…”

“…In principle, dissociation and analysis of whole lymph nodes is more likely to eliminate sampling error and, therefore, accurately determine the total tumor load within resected tissue. In comparison, the gold standard histological examination of FFPE lymph node tissue, even combined with IHC, may result in a false negative result as small tumor deposits or ITCs may not be included in the examined sections [11]. A previous study by Ito and colleagues demonstrated the feasibility of intraoperative detection of tumor cells in lymph node tissue with flow cytometry in patients with non-small cell lung cancer that could be carried out within 40 min [29].…”

“…Currently, lymph node involvement by tumor is assessed using histological methods which may be complemented by immunohistochemical (IHC) analysis of formalin fixed paraffin embedded (FFPE) tissue postoperatively or frozen sections intra-operatively [11]. Increasing the number of sections examined of the resected node analyzed, accompanied with the use of targeted molecular methods increases small deposit detection [1]; however, these methods are not routinely used in the pathological practice as their reliability to detect small deposits is questioned [12].…”

A comprehensive methylation signature identifies lymph node metastasis in esophageal squamous cell carcinoma

“…LNM is a major determinant of recurrence and prognosis in ESCC patients; hence identification of the LNM status is critical for deciding the course of treatment as well as extent of invasive surgery in this malignancy. However, in 20–40% of ESCC cases, LNM is misdiagnosed due to the limitations of current diagnostic methodologies . This accentuates the need for molecular biomarkers that can detect these patients with increased accuracy.…”

“…However, in 20-40% of ESCC cases, LNM is misdiagnosed due to the limitations of current diagnostic methodologies. 9,12,13,29 This accentuates the need for molecular biomarkers that can detect these patients with increased accuracy. In this study we developed a methylation signature (lymph node metastasis associated signature or LNAS) that can identify lymph node metastasized cases of ESCC more accurately using an unbiased genome-wide discovery, followed by clinical validation with quantitative pyrosequencing in two independent clinical cohorts.…”