Comment on "Revealing the presence of lymphatic vessels within intervertebral discs: Novel insights into disc degeneration"

We read and enjoyed the study by Fei Zou's team titled “Revealing the presence of lymphatic vessels within intervertebral discs: Novel insights into disc degeneration,” which provided groundbreaking insights into the previously overlooked intervertebral disc (IVD) lymphatic system.1 Vascular alterations during IVD degeneration (IVDD) have been well studied over the past 30 years, in contrast to lymphatic studies that remain enigmatic, leading to a critical knowledge gap in the pathophysiology of IVD. The authors of this study pioneered the discovery of lymphatic vessels in the annulus fibrosus (AF) of healthy IVDs, whereas the number of lymphatic vessels was reduced in the AF of degenerating IVDs. Particularly striking, this study is the first to definitively suggest that de novo lymphatic vessels may improve the inflammatory microenvironment of IVD tissues by enhancing the clearance of inflammatory cells, a finding that has far-reaching implications for the treatment of IVDD. Despite the landmark significance of these findings in the field of IVDD, we would like to raise a number of questions and insights to facilitate in-depth discussions to better interpret the results and guide future research.

First, the study very cleverly used IVDs from patients with Hirayama disease as a control group, an innovative design that nicely circumvents the dilemma of the difficult collection of healthy IVDs. However, the age distribution of the cohort may be subject to selection bias, which could result in underrepresentation of the results. Despite the prevailing view that lymphatic vessels are not present in healthy IVDs, a small number of researchers have detected the presence of lymphatic vessels by immunohistochemistry in the AF from individuals under 20 years of age. Given that the distribution of lymphatic vessels may show an age correlation, we suggest using age-stratified non-degenerate samples as a control group to enhance the persuasiveness of the experimental results. For example, based on the existing data, IVD specimens were collected in age groups of 4–20, 21–25, and 26–30 years of age from patients who underwent surgery for traumatic spinal fracture, scoliosis/posterior kyphosis orthopedics, and intradural tumors, respectively. Moreover, all enrolled specimens were subjected to a rigorous systematic evaluation, including preoperative imaging screening (to meet a Pfirrmann grade ≤ II and no Modic changes in the endplates), intraoperative quality inspection (to confirm that the nucleus pulposus [NP] was gelatinous and the AF was intact and not ruptured), and postoperative pathological analyses (to exclude infectious lesions, granulation tissue, and infiltration of neoplastic tissue). It should be noted in particular that there are still certain difficulties and limitations in the implementation of this strategy, which should be adjusted appropriately in the light of the actual situation.

Second, studies have shown a relative decrease in the number of lymphatic vessels in degenerating IVDs, which requires more precise histopathologic grading as a supporting condition. Unfortunately, the degeneration grade of the specimens from patients with cervical spondylosis was not explicitly stated in the study, which may limit the extrapolation of the conclusions to some extent. In the existing studies, some scholars claimed that lymphatic vessels do not appear in IVDs without significant degeneration and that only a small number of lymphatic vessels appear even after significant degeneration, while others believed that the number of lymphatic vessels increases during the degeneration process. This variability may be closely related to the degeneration grade of the IVD. We suggest that the authors use IVDD grading criteria (e.g., the Pfirrmann and Thompson grading system) to clearly label IVDD grades and provide representative images of the corresponding stages of degeneration, as well as to include degenerated thoracic and lumbar IVDs, so that such an analysis can help to explore the deeper connections between IVD and lymphatic vessels and enhance the generalizability of the results.