**3. Results**

#### *3.1. Patients Features*

Among 53 patients included, there was a prevalence of male patients (74%); the average age was 72.7 years old. Most patients had advanced tumor stage disease, with stage IV in 45 patients. B-symptoms were present in 10 patients, while bulky disease in 6 cases. LDL and β2 microglobulin were higher than normal range values in 19 and 18 patients, respectively. Table 1 summarizes the clinical characteristics of the population. Pathological increased 18F-FDG-uptake was present in all patients, showing the presence of at least one nodal or extranodal hypermetabolic lesion. The average SUVbw was 9.6 (range 3.3–27), average SUVlbm was 7.4 (range 2.4–22.3), average SUVbsa was 2.4 (range 0.9–7.3), average L-L SUV R 46.27 (1.7–54), average L-BP SUV R 5.3 (1–44), average tMTV was 358 cm3 (3–1800 cm3) and average TLG was 2023 (10–20088). The average SMI was 49.9 cm2/m2 (range 36.3–67) and was significantly higher in men, with a mean of 53.1 cm2/m2 (range 39–67), than women, with a mean value of 42 cm2/m2 (range 36.3–46.3) (Table 1). Based on Lugano classification metabolic response [18], 30 (57%) patients had a complete metabolic response at eotPET/CT. Fifteen (28%) patients had partial metabolic response and five (9%) patients had progression of disease. Three patients died before the execution of eotPET/CT.


**Table 1.** Main features of our sample (53 patients).

BMI: body mass index; LDH: lactate dehydrogenase; MIPI: Mantle international prognostic index; SUV: standardized uptake value; bw:body weight; lbm: lean body mass; bsa: body surface area; BP: blood pool; MTV: metabolic tumor volume; TLG: total lesion glycolysis; SMI: skeletal muscle index; SD: standard deviation.

#### *3.2. Sarcopenic Analysis*

For the definition of sarcopenia, in the absence of specific shared thresholds based on the MCL population, we derived our thresholds by applying ROC curve analysis. A separate analysis for male and female was performed (Supplemental Table S1). The genderspecific cut-offs were 53 cm2/m2 for male and 45.6 cm2/m2 for female. With these cut-offs, 32 (60%) of our patients were considered sarcopenic. There was a significantly higher prevalence of sarcopenia in females than males (93% vs. 47%, *p* = 0.001), with no significant differences found considering age, BMI, tumor stage, B symptoms, bulky disease, blood samples (LDH, β 2 microglobulin), MIPI score and complete metabolic response at eot PET (Table 2). Instead, the presence of the blastoid variant was significantly higher in patients with sarcopenia. Focusing on the relationship between semiquantitative PET/CT variables

and sarcopenia, no significant differences among SUVbw, SUVlbm, SUVbsa, lesion to BP SUVmax ratio and lesion to liver SUVmax ratio were registered, comparing sarcopenic and not sarcopenic cases. Further, tMTV and tTLG were significantly higher in patients with low SMI.



BMI: body mass index; LDH: lactate dehydrogenase; MIPI: mantle international prognostic index; SUV: standardized uptake value; bw: body weight; lbm: lean body mass; bsa: body surface area; BP: blood pool; MTV: metabolic tumor volume; TLG: total lesion glycolysis; SD: standard deviation.

#### *3.3. Survival Analysis*

At a median follow-up of 50 months, a progression of disease or relapse was registered in 37 patients (70%), with an average time of 17.2 months (range: 2–62 months), while death occurred in 26 patients (49%), with a mean time of 33.6 months (range: 2–120). Overall, the 3-year and 5-year PFS rates were 29% and 23%, while the 3-year and 5-year OS rates were 43% and 33%. In univariate analysis, blastoid variant, Deauville Score 4–5, tMTV, tTLG and SMI were significantly correlated with PFS (*p =* 0.015, *p =* 0.032, *p =* 0.001, *p* < 0.001, *p* < 0.001), while the other clinical and metabolic features were not (Figure 2, Table 3). In multivariate analysis, the Deauville Score 4–5, tMTV, tTLG and SMI were confirmed to be independent prognostic factors. Considering OS, only tMTV and tTLG were shown to be significantly related to outcome at univariate analysis, but not at multivariate analysis. SMI demonstrated no prognostic impact (Figure 3, Table 3). Combining tMTV and SMI thresholds, patients without sarcopenia and with low metabolic volume disease (<90 cm3) had the best PFS, without any case of progression/relapse during the follow-up. The worst PFS was specific of patients with sarcopenia independent from the tMTV value (Figure 4).

**Figure 2.** Progression free survival according to Deauville score (**a**), tMTV (**b**), tTLG (**c**) and SMI (**d**).

**Figure 3.** Overall survival according to Deauville score (**a**), tMTV (**b**), tTLG (**c**) and SMI (**d**).


**Table 3.** Univariate and multivariate analyses for PFS and OS.

PFS: progression free survival; OS: overall survival; HR: hazard ratio; CI: confidence interval; N◦: number; SUV: standard uptake value; bw: body wheight; lbm: lean body mass; bsa: body surface area; L-L R: lesion to liver ratio; L-BP R: lesion to blood pool ratio; MTV: total metabolic tumor volume; TLG: total lesion glycolysis. \* Variables dichotomized using cutoff values after ROC analysis reported in Supplemental Table S1.

**Figure 4.** Kaplan–Meier curve considering the combination of tMTV and SMI.

#### **4. Discussion**

The clinical meaning of the sarcopenia has already been investigated and it is emerging as a promising tool for predicting the survival and treatment response [20–23]. However, in lymphoma patients, its usefulness is not yet clear because controversial evidence is available and the studies present are based specifically on HL and DLBCL [12,24], while for the other lymphoma histotyopes, specific studies are lacking. For this reason, we aimed to analyze patients affected by MCL, which is a lymphoma typical in advanced age. Just in this setting, the evaluation of the role of sarcopenia may be fundamental. For the measurements of sarcopenia, several techniques and imaging examinations have been proposed, such as hand-held dynamometer, CT and MRI [25,26]. These tools are very different for availability, cost, ease of execution and accuracy. CT seems to have the best compromise and it is often applied for the evaluation of the muscular area, due to its ability to distinguish adipose and muscular tissue from other soft tissues of the body. A recent paper demonstrated a good agreement and reproducibility between low-dose CT of PET and high-dose CT in the measurements of the adipose and muscular area [27]. These results underlined the possibility to use 2-[18F]-FDG PET/CT, both for the measurements of "classical" PET/CT parameters (like SUV, MTV, TLG) and sarcopenia.

To the best of our knowledge, no studies about the rate and the role of sarcopenia in MCL are available, particularly in advanced age patients. We decided to select elderly MCL patients, because they are, by definition, frail patients with a high risk of toxicities and poor prognosis.

Due to the lack of consensus for optimal cut-off levels to define sarcopenia in lymphoma patients, and especially in MCL, we derived specific values for our population using ROC curve analysis. Many different thresholds have been proposed [12], specific for gender, BMI, ethnicity and geographic regions. Thus, it is hazardous to consider a unique threshold validated in other lymphoma variants. The cut-off values obtained in our analysis were 53 cm2/m2 for males and 45.6 cm2/m2 for females. Further studies with larger samples are essential to confirm or change these results, especially for women, where our cases are relatively low (n 14). However, these values may be considered a starting point to investigate. With these cut-offs, we found a prevalence of sarcopenia in 60% of our sample and it was more diffused in women than men. Besides gender, only the blastoid variant is significantly related to sarcopenia status, assuming a more aggressive disease in blastoid CML [28].

The second goal of our study was to analyze the prognostic role of several variables, including 2-[18F]-FDG PET/CT features and sarcopenia, in terms of PFS and OS.

Besides quantitative parameters, visual analysis, applying the Deauville score, remains a valid prognostic variable for PFS in MCL, as demonstrated by several papers and confirmed in our analysis [9,29].

Among 2-[18F]-FDG PET/CT parameters, MTV and TLG were shown to be superior than SUV-related factors, but also in this case, the significant correlation from the multivariate analysis was confirmed only for PFS. The same evidence was revealed considering sarcopenia. However, the combination of tMTV and sarcopenia better predicts the PFS. The absence of prognostic factors to predict OS may be explained by the advanced age of patients, which probably significantly influenced the outcome; moreover, it could be other variables not evaluated in this study with a prognostic impact. The open question, not yet resolute, is the choice of the cut-off values to apply to define sarcopenia with CT.

Several limitations affect the quality of this work, such as the retrospective study design, the heterogeneous management received by patients (for example primary treatment) and the relatively low number of patients included due to the inclusion criteria chosen. This is the first attempt to investigate the prognostic role of sarcopenia, detected by CT in combination with PET/CT features, in elderly MCL. Prospective studies are warranted to better define, in real-life settings, whether these easy and patient-level approaches retain their significance and utility and could be used to improve treatment tailoring in the setting of elderly MCL.

#### **5. Conclusions**

Baseline evaluation CT of PET may help to define sarcopenia, with a specific cutoff for gender in elderly MCL. Sarcopenia, together with Deauville score, tMTV and tTLG, may help to predict PFS. Instead, they had no role in predicting OS.

**Supplementary Materials:** The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/jcm11051210/s1, Supplemental Table S1: Receiver operating characteristic (ROC) curve analysis of metabolic and sarcopenic PET/CT parameters.

**Author Contributions:** Conceptualization, D.A., F.B., R.G.; methodology, N.P., F.D., A.T.; formal analysis, N.P., D.A., R.G.; investigation, A.T.; F.B., F.D.; writing—original draft preparation, D.A., N.P.; writing—review and editing, D.A., R.G., F.B., F.D., N.P.; supervision, R.G. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Ethical review and approval were waived for this study due to the retrospective design of the study, according to local laws.

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** Data are not public, but are present in our institution.

**Conflicts of Interest:** The authors declare no conflict of interest.
