In our study, adiposity measures (VAT and VATD) were noted to play an important role in the outcomes of patients with hematological malignancies who receive autologous HSCT. First, the amount of visceral adipose tissue (VAT) impacted disease recurrence; patients with higher VAT had better RFS than those with normal adiposity. When looking at the density of the adipose tissues, patients with high visceral adiposity density (VATD) had worse survival (OS) and shorter time to death without relapse/recurrence (NRM) than those with normal amount of visceral adiposity density. Measures of muscle (sarcopenia [low SMI] and myosteatosis [low SMD]) and obesity (BMI > 30kg/m2) were not associated with outcomes in the multivariate model.
Our findings support the current literature suggesting that in hematological malignancies, high VAT is protective 10 and that muscle measures such as sarcopenia and myosteatosis had an unclear impact on overall survival, with some studies suggesting that sarcopenia did not impact hematological malignancies 8 while another retrospective trial showed that patients with sarcopenia had worse OS after allogeneic stem cell transplant17. The protective role of high VAT was also confirmed in older patients with diffuse large B cell lymphoma treated with R-CHOP or mini-RCHOP chemotherapy18 and in older patients with acute myelogenous leukemia19,20. The mechanism proposed relates to differences in the pharmacokinetics of chemotherapy and drug distribution through tissues 21,22. Cancer cachexia and concurrent adipopenia may result in the loss of some protective mechanisms by decreasing the maturation of regulatory T cells, as those cells are selectively dependent on lipid oxidation23.
Even though the most recent meta-analysis showed that low VAT was predictive of worse outcomes in hematological malignancies, the results were not homogeneous10. For example, some studies suggested that higher adiposity was associated with worse outcomes in multiple myeloma24 and DLBCL25. Because of these differences, researchers started evaluating different adipose tissue types by adiposity radiodensity13, similar to the analysis done in muscle deemed myosteatosis26.
In our study VATD was associated with outcomes that were not associated with the amount of visceral adiposity (VAT) and the correlation between the two variables was moderate, which suggests that VATD may be a better marker for outcomes in patients who will receive autologous HSCT. Differences in visceral adipose tissue radiodensity (VATD) pertain mainly to the amount of lipids inside the adipocytes (Fig. 1). Adipose tissue with high lipid content has a low radiodensity (in some studies, this is suggestive of white adipose tissue 27); Those adipocytes store food calories, create a layer of thermal insulation, and provide mechanical protection essential for resisting infection and mechanical injury28. On the other hand, increased VATD means that the composition of the tissue is relatively low in lipid, and it has high vascularity and high extravascular matrix29; in some studies, these are the characteristics of brown adipose tissue27. In addition, adipose tissue with high and low radiodensity participate in immunomodulation with different profiles of the complement system30. Adiposity with low radiodensity increases proinflammatory cytokines that activate and recruit macrophages as well as dendritic cells31. In contrast, adipose tissue with high density was found to express high levels of programmed death ligand 1, reducing T cell activation32. All these mechanisms may be the reason for our cohort's high association of VATD and survival.
Our study supports most of the literature available regarding the impact of VATD in oncology9. Increased VATD has been associated with worse survival in colorectal 33, gastric 34, pancreatic cancer 35, hepatocellular 36, and Multiple myeloma13. Cancer cells usually use adipose tissue as their fuel to grow37. Some studies have shown that the changes from high to low adiposity density in patients with cancer are associated with cachexia and wasting 38,39. Altogether our findings suggest that high VATD is a phenotype that may reflect the energy depletion caused by recurrent NHL.
Some cancer-associated adipopenia and cachexia treatments have been proposed, including exercise therapy, nutrition interventions, and supplementation with vitamins and medications 40–42. Further trials may help clarify the best method to address abnormal body composition in cancer: therapies focusing on cachexia and adipopenia with physical therapy and nutritional therapy43 can have a powerful impact; however, it may take a long time to achieve results. Currently, there are no approved medications to target sarcopenia and adipopenia, which may change with future technologies 44. Adjusting cancer therapy dosage based on body composition may also be an option with new prospective randomized trials using body composition parameters for chemotherapy dosage instead of commonly used body surface area.
The limitations of our study come from the retrospective nature, which precludes an evaluation of cause and effect. Also, the homogeneous population with mostly white patients younger than 70 years old may impact the external validity of the results. Our study also did not have measures of frailty, as it would be interesting to evaluate the associations of frailty and adiposity. Another study limitation could be the lack of a standardized method for assessing body composition parameters from the CT scans. Variability in image acquisition protocols, slice thickness, and image resolution can influence the measurements of muscle and adipose tissue, potentially affecting the accuracy and consistency of the results. Despite the imaging limitations, we still found strong correlations between visceral adipose composition and outcomes and expect dedicated imaging protocols to strengthen the results.
In patients with NHL treated with autologous HSCT, higher VAT is associated with more prolonged relapse-free survival, and higher VATD is associated with worse overall Survival and Non-relapse mortality. Our findings warrant the need for future investigations into the impact of adiposity quantity and quality in NHL autologous HSCT recipients.