Significance of skeletal muscle index-to-body mass index ratio as a predictor of post-surgical bleeding after mastectomy in patients with breast cancer

Post-surgical bleeding is a major complication of mastectomy in patients with breast cancer. However, the risk factors for post-surgical bleeding have not been well studied. Although obesity or reduced skeletal muscle mass is an indicator of cancer surgery complications, its impact on post-surgical bleeding after mastectomy remains unknown. In total, 563 patients with breast cancer who underwent mastectomy were included in this study. We evaluated the preoperative body mass index (BMI), skeletal muscle index (SMI), and SMI-to-BMI ratio and analyzed the association between these values and the incidence of post-surgical bleeding. Post-surgical bleeding occurred in 33 (5.6%) patients. Mean BMI was significantly higher in the bleeding group (26.3 ± 4.7) than in the no-bleeding group (23.0 ± 4.1) (p < 0.001), whereas mean SMI was lower in the former group (45.0 ± 8.5) than in the latter group (48.0 ± 8.5) (p = 0.08). The bleeding group had significantly lower SMI-to-BMI ratio (1.71 ± 0.16) than the no-bleeding group (2.10 ± 0.23) (p < 0.001). Among these three parameters, SMI-to-BMI ratio had the highest area under the curve value in their receiver operating characteristic curves (0.73 for BMI, 0.59 for SMI, 0.92 for SMI-to-BMI ratio). Furthermore, on multivariate analysis, SMI-to-BMI ratio was an independent risk factor for post-surgical bleeding (hazard ratio, 38.4; 95% confidence interval, 13.9–136.2; p < 0.001). SMI-to-BMI ratio is a superior predictive factor of post-surgical bleeding after mastectomy to either BMI or SMI alone.


Background
Breast cancer is the most frequent solid malignancy in women and one of the leading causes of cancer-related death worldwide [1].Despite recent progress in pharmacotherapy and radiation therapy, surgery remains the cornerstone of early breast cancer treatment.Although breast-conserving surgery followed by whole-breast irradiation is a widely accepted treatment for women with relatively small breast cancers [2], mastectomy has been the main choice of surgical procedure, particularly for patients with widespread breast cancers or those who cannot receive radiation therapy [3].
Major complications of mastectomy include post-surgical bleeding, surgical site infection, seroma formation, and skin flap necrosis [4][5][6].Among them, post-surgical bleeding is one of the significant complications because it can require blood transfusion or reoperation to control bleeding, although it may rarely be fatal.Even if this is not the case, this complication can delay drain removal and consequently prolong hospital stay.Hence, it is imperative for breast surgeons to avoid post-surgical bleeding by elucidating the predictive factors for this complication.
Obesity has been indicated as a risk factor for postoperative complications following breast surgeries [5][6][7][8][9][10].Garland et al. demonstrated that high body mass index (BMI) was associated with bleeding risk after mastectomy [8].On the other hand, increasing evidence suggests that sarcopenia, which is characterized by skeletal muscle loss and decreased physical activity [11], is correlated with the incidence of complications associated with surgery for various solid malignancies, including lung, colorectal, and hepatobiliary cancers [12][13][14].Accordingly, the skeletal muscle index (SMI), which is standardized by calculating the ratio of skeletal muscle area (SMA) at the third lumbar vertebral (L3) level divided by the square of the height, is an indicator of complications after surgery for lung and gastrointestinal cancers [15,16].However, no study has investigated the association between SMI and frequency of complications after breast surgery.Hence, whether SMI correlates with the incidence of post-surgical bleeding after mastectomy remains unknown.
This study aimed to explore the risk factors for post-surgical bleeding after mastectomy in patients with breast cancer.To this end, we evaluated the preoperative BMI, SMI, and SMI-to-BMI ratio in patients undergoing mastectomy and investigated the association between these values and the incidence of post-surgical bleeding.

Patients and study design
We retrospectively assessed patients with breast cancer who underwent surgery at Shinshu University Hospital between December 2015 and January 2022.The inclusion criteria were as follows: (1) patients who had pathologically confirmed breast cancer by core needle biopsy or vacuumassisted biopsy, (2) those who underwent computed tomography (CT) before surgery, and (3) those who underwent mastectomy.Type of surgical procedure for the axillary lymph nodes [none, sentinel lymph node biopsy (SLNB), or axillary dissection (Ax)] was not mattered to be included in this study.Patients who underwent one-stage reconstruction and male patients were excluded from this study.In total, 563 patients were included in this study.As 21 patients had synchronous bilateral breast cancer and underwent bilateral mastectomy, 584 breasts were analyzed.Patients with nodepositive breast cancer received neoadjuvant chemotherapy (NAC) consisting of fluorouracil-epirubicin-cyclophosphamide (FEC) [triweekly administered FEC (500 mg/m 2 fluorouracil, 100 mg/m 2 epirubicin, and 500 mg/m 2 cyclophosphamide)] followed by taxane regimens (triweekly administered docetaxel 75 mg/m 2 or weekly administered paclitaxel 80 mg/m 2 ).Four cycles of the taxane regimen were administered after four cycles of FEC.A subset of patients with human epidermal growth factor receptor type 2 (HER2)-positive or triple-negative (TN) breast cancer were also treated with NAC even if lymph node involvement was not preoperatively confirmed.In HER2-positive patients, 6 mg/kg (triweekly) or 2 mg/kg (weekly) trastuzumab with or without 420 mg (triweekly) pertuzumab was simultaneously administered with a taxane regimen.All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.This study was approved by the local ethics committee on the clinical investigation of Shinshu University (no.5323).Our institution uses a form on its website to enable patients to opt out of the use of their clinical data for study purposes, and the requirement for written informed consent was waived.All patient data were anonymized.

Data collection
Clinical information, including age, comorbidities (hypertension, dyslipidemia, and diabetes), affected side of the breast, height, body weight, presence of NAC, surgical procedure, type of surgeon, operation time, blood loss during the operation (ml), histological type, pathological tumor size, lymph node metastasis, estrogen receptor (ER) status, progesterone receptor (PgR) status, HER2 status, length of drainage, and hospital stay, was collected from the patients' medical records.The surgeons were stratified into two groups: resident and faculty.A faculty was defined as a board-certified surgeon at the Japan Breast Cancer Society.Breast cancer subtypes were defined as follows: luminal (ER-or PgR-positive and HER2-negative), luminal HER2 (ER-or PR-positive and HER2-positive), HER2-enriched (ER-and PR-negative, HER2-positive), and TN (ER-, PR-, and HER2-negative).For patients who underwent mastectomy with SLNB or simple mastectomy, a 15Fr J-VAC® (Johnson & Johnson, NJ) drain was placed at the subcutaneous space of the breast.For patients undergoing mastectomy with Ax, another 15Fr J-VAC® drain was placed at the axilla, in addition to a subcutaneous drain.Drainage duration was defined as duration (days) from the surgery to the day when all the J-VAC® drains were removed.

Definition of post-surgical bleeding
We routinely compressed the wound with a bust band to prevent post-surgical bleeding.If we suspected post-surgical bleeding with swelling of the wound or the continuous bloody discharge from the J-VAC® drain, we attempted hemostasis by placing a layer of gauze over the wound and manually compressing the bleeding point.In this study, post-surgical bleeding was defined as a hemorrhage requiring postoperative manual compression or bloody drainage of > 100 ml until the morning of the day after surgery.In patients undergoing mastectomy with Ax, a bloody discharge of > 100 ml from either of the two J-VAC® drains was considered post-surgical bleeding.The J-VAC® drain was removed when the drainage volume was < 25 ml per day.

Measurement of skeletal muscle index (SMI)-to-body mass index (BMI) ratio
Preoperative CT was performed within 1 month prior to the surgery.For patients receiving NAC, CT was performed > 3 weeks after the completion of NAC.SMA was measured using preoperative CT images, irrespective of the administration of NAC.SMA was measured as the crosssectional area of the surrounding muscles (i.e., psoas, paraspinals, transversus abdominis, rectus abdominis, and internal and external obliques) by semiautomatic tracing using images at L3 level visualized within a range of − 29 to 150 Hounsfield units using the EV Insite R (PSP Corporation, Tokyo, Japan) system and expressed in cm 2 .SMI was calculated as the ratio of SMA divided by height squared (m 2 ), whereas BMI was calculated as body weight (kg) divided by height squared (m 2 ).Body weight within 1 month prior to the surgery was used to calculate BMI.The preoperative SMI-to-BMI ratio was calculated by dividing SMI by BMI.The receiver operating characteristic (ROC) curve was analyzed to determine the best BMI, SMI, and SMI-to-BMI ratio cutoff values for post-surgical bleeding.

Statistical analyses
Categorical variables were analyzed using the chi-squared test, whereas continuous variables were analyzed using twosided t-tests.Univariate and multivariate analyses using a logistic regression model were performed to determine the significant factors for post-surgical bleeding.Multivariate analysis was performed for parameters with p < 0.3 in the univariate analysis.All statistical analyses were performed using GraphPad Prism 9.3.1 (GraphPad Software, CA, USA), and p < 0.05 was considered statistically significant.

Comparison of clinicopathological characteristics according to the presence of post-surgical bleeding
Overall, post-surgical bleeding was observed in 33 (5.6%) cases.We divided the patients into two groups according to the presence of post-surgical bleeding (no-bleeding group, n = 551; bleeding group, n = 33) and compared the clinicopathological characteristics of these two groups (Table 1).There were no differences in the clinicopathological features, including age, comorbidities, laterality of the primary tumor, type of surgeon, blood loss during the operation, histological type, tumor size, lymph node metastases, pathological stage, and subtype, between the no-bleeding and bleeding groups.The operation time was significantly longer in the no-bleeding group than in the bleeding group (p = 0.01).The frequency of patients who received NAC, underwent mastectomy plus Ax, and had pathologically node-positive breast cancer was significantly lower in the bleeding group than in the no-bleeding group (p < 0.001 for NAC, p < 0.001 for surgical procedure, and p < 0.01 for lymph node metastases).As for SMI, the bleeding group (45.0 ± 8.5) showed lower SMI than the no-bleeding group (48.0 ± 7.5), although the difference did not reach statistical significance (p = 0.08).On the other hand, BMI was significantly higher in the bleeding group (6.3 ± 4.7) than in the no-bleeding group (23.0 ± 4.1) (p < 0.001) (Table 1).

Comparison of postoperative course according to the presence of post-surgical bleeding
We compared the drainage volume until the morning of the day after surgery, drainage duration, and postoperative hospital stay between the no-bleeding and bleeding groups (Table 2).Patients undergoing mastectomy with SLNB or simple mastectomy held one drain in the subcutaneous space of the breast, whereas those undergoing mastectomy plus Ax held an additional drain at the axilla, as described in the Methods section.Hence, in this analysis, we stratified the patients into two groups according to the presence of Ax (none or SLNB: n = 334, Ax group: n = 250).In the Ax group, the amount of drainage from both the subcutaneous and axillary drains was significantly greater in the bleeding group than in the no-bleeding group (subcutaneous drain: 23.2 ± 16.4 in the no-bleeding group vs. 159.0± 111.8 in the bleeding group, p < 0.001; axillary drain: 38.8 ± 22.6 in the no-bleeding group vs. 220.8± 238.6 in the bleeding group, p < 0.001).Similarly, in the none or SLNB group, the bleeding group had significantly higher drainage volume from the subcutaneous drain compared with the no-bleeding group (33.8 ± 21.9 in the no-bleeding group vs. 178.7 ± 128.3 in the bleeding group, p < 0.001).Among the 33 cases with post-surgical bleeding, one required reoperation to stop postsurgical bleeding.In this case, within the first 3 h after mastectomy with SLNB, the output of bloody discharge from the subcutaneous drain reached 156 ml, despite manual compression efforts.Consequently, we deemed it necessary to perform a reoperation to control the persistent bleeding.
As for drainage duration and postoperative hospital stay, in the Ax group, there was a tendency that drainage duration (5.4 ± 1.7 in the no-bleeding group vs. 6.5 ± 0.5 in the bleeding group, p = 0.06) and postoperative hospital stay (8.0 ± 2.8 in the no-bleeding group vs. 10.0 ± 2.1 in the bleeding group, p = 0.08) were longer in the bleeding group than in the no-bleeding group.In the none or SLNB group, both drainage duration (3.5 ± 1.2 in the no-bleeding group vs. 5.8 ± 1.2 in the bleeding group, p < 0.001) and postoperative hospital stay (7.0 ± 2.2 in the no-bleeding group vs. 8.0 ± 2.2 in the bleeding group, p = 0.01) were significantly longer in the bleeding group than in the no-bleeding group.
These results indicate that post-surgical bleeding might delay drain removal and prolong the hospital stay.

Correlation between preoperative SMI and BMI
BMI is positively correlated with SMI in patients with cancer [17].In the patient cohort in this study, BMI and SMI showed a significant positive correlation (p < 0.001, R = 0.54) in our breast cancer cohort (Fig. 1a).Subsequently, we examined whether there were any differences in the correlation between SMI and BMI in the no-bleeding and bleeding groups, and the scatterplot in which each patient in the bleeding and no-bleeding groups was individually indicated suggested that patients in the bleeding group were susceptible to having a low SMI for BMI (Fig. 1b).Based on this observation, we hypothesized that low SMI for BMI may be a predictive factor for post-surgical bleeding and that low SMI was significantly associated with the incidence of post-surgical bleeding in patients with similar BMI.To test this hypothesis, we stratified the patients into two groups according to a BMI of 25 kg/m 2 and compared the SMI in each group.Subsequently, patients in the bleeding group had significantly lower SMI than those in the nobleeding group in both the BMI ≥ 25 kg/m 2 (55.3 ± 7.5 in the no-bleeding group vs. 50.6± 7.5 in the bleeding group, p = 0.02) and the BMI < 25 kg/m 2 group (44.9 ± 5.8 in the no-bleeding group vs. 39.0 ± 5.1 in the bleeding group, p < 0.001) (Fig. 2).

Impact of SMI-to-BMI ratio as a risk factor for post-surgical bleeding
Given that low SMI was associated with the incidence of post-surgical bleeding in patients with similar BMI, we next hypothesized that standardization of SMI by BMI provided a more accurate risk factor for post-surgical bleeding than the single use of BMI or SMI.To address this, we calculated the SMI-to-BMI ratio and compared its values between the no-bleeding and bleeding groups.The SMI-to-BMI ratio in the bleeding group was significantly lower (1.71 ± 0.16) than that in the no-bleeding group (2.10 ± 0.23) (p < 0.001) (Fig. 3).

Impact of sarcopenic obesity as a risk factor for post-surgical bleeding
Patients with low SMI-to-BMI ratio is associated with a condition having high BMI and low SMI.This condition is in accordance with the concept of sarcopenic obesity, which has recently gained considerable attention as a superior marker to sarcopenia for predicting the prognosis and postoperative complications in patients with cancer [17][18][19][20].To evaluate the impact of sarcopenic obesity, we stratified the patients into four groups (high-SMI/low-BMI, high-SMI/high-BMI, low-SMI/low-BMI, and low-SMI/ high-BMI).The optimal cutoff values for BMI and SMI determined by the ROC analysis were 23.6 (AUC = 0.73, sensitivity/specificity = 0.66) and 45.2 (AUC = 0.59, sensitivity/specificity = 0.60), respectively.The incidence rate of Fig. 3 Box-and whisker plot for SMI-to-BMI ratio in the bleeding and the no-bleeding group (p < 0.001).SMI: skeletal muscle index, BMI: body mass index post-surgical bleeding was highest in the low-SMI/high-BMI group (27.5%) and gradually decreased toward the low-SMI/ low-BMI (20.4%), high-SMI/high-BMI (1.4%), and high-SMI/low-BMI groups (0.4%), with statistical significance (p < 0.001) (Supplementary Table 1).

Discussion
This study demonstrated that the SMI-to-BMI ratio was a superior indicator of post-surgical bleeding compared with BMI or SMI alone.To the best of our knowledge, this is the first study to show that a low SMI-to-BMI ratio is a risk factor for post-surgical bleeding in patients with breast cancer who undergo mastectomy.Post-surgical bleeding is the second most frequent complication following surgical site infection [21].Previous reports have shown that obesity was associated with a higher incidence of post-surgical bleeding [6][7][8].This is consistent with the results of our study, which showed that patients with post-surgical bleeding had a significantly higher BMI than those without this complication.The main cause of post-surgical bleeding after mastectomy may be insufficient sealing or ligation of the vessels in front of the pectoralis major and serratus anterior muscles or in the subcutaneous fat.Abundant subcutaneous fat may make it difficult to detect small subcutaneous vessels and, consequently, may result in inadequate ligation of these vessels.Furthermore, patients with a high BMI are likely to have a high breast volume, which is associated with an increase in the subcutaneous peeling area.Hence, obese patients with abundant subcutaneous fat have a higher risk of post-surgical bleeding than patients without obesity.
Sarcopenia is correlated with physical frailty in patients with cancer.Regarding postoperative complications, sarcopenia is a risk factor for higher intraoperative blood loss or blood transfusion in surgery for gastrointestinal cancers [22,23], indicating that sarcopenia may be associated with vulnerability of blood vessels.Hence, it can be hypothesized that low skeletal muscle mass can also be a predictive factor of bleeding after breast surgery.The results of this study showed that SMI was not significantly associated with the frequency of post-surgical bleeding.However, when patients were stratified according to the BMI of 25 kg/m 2 , there were significant differences in SMI between the bleeding and the no-bleeding groups both in the BMI ≥ 25 and < 25 kg/m 2  groups.This indicates that SMI has an impact on the incidence of post-surgical bleeding if patients with comparable physiques are compared; namely, a low SMI for BMI can be a predictor of post-surgical bleeding after mastectomy.The skeletal muscle mass can vary among individuals with the same BMI.To date, no study has investigated the effects of identical SMI values in patients with different BMIs on the incidence of postoperative complications.In this regard, standardization of skeletal muscle mass by body weight may be worth investigating as a more accurate parameter to estimate the body composition and a risk factor for postoperative complications.We hypothesized that the SMI-to-BMI ratio may have the potential to predict the incidence of post-surgical bleeding more accurately than either BMI or SMI alone.The results of this study showed that the AUC of the SMI-to-BMI ratio in the ROC analysis was higher than that of BMI or SMI, which provides a novel insight that the SMI-to-BMI ratio may be superior to BMI or SMI as an indicator of post-surgical bleeding.
From another point of view regarding the association between SMI and BMI, sarcopenic obesity has gained significant attention in the field of cancer treatment [17][18][19][20].Since Prado et al. had first profiled sarcopenic obesity in relation to the mortality risk in solid malignancies [24], numerous reports have demonstrated that sarcopenic obesity has a negative effect on the outcomes of patients with cancer [17][18][19][20].Moreover, currently, obese patients with reduced skeletal muscle mass are at a special risk for adverse outcomes [17].In line with this, the present study showed that patients with low SMI and high BMI had the highest risk of post-surgical bleeding.These findings support the notion that a combination of SMI and BMI can provide a more accurate marker for predicting the risk of post-surgical bleeding than either SMI or BMI alone.
Multivariate analysis revealed that the axillary procedure was associated with the risk of post-surgical bleeding (Table 3).In general, the dissected area is larger in mastectomy plus Ax than in mastectomy plus SLNB, suggesting a higher risk of post-surgical bleeding in the former than in the latter.Nonetheless, this study showed that mastectomy plus Ax was associated with a lower risk of post-surgical bleeding.This paradoxical result suggests that surgeons tend to confirm hemostasis more thoroughly when performing mastectomy plus Ax than mastectomy plus SLNB.Another possible explanation is that the bleeding point after mastectomy is more likely to be on the surface of the pectoralis major muscle rather than in the axillary area.Several reports have demonstrated that the pectoralis major muscle area (PMA) and SMA at the L3 level are equally useful for defining sarcopenia [25,26].Consequently, PMA is currently used to characterize sarcopenia, even in patients with breast cancer [27,28].Hence, patients with low SMI in our patient cohort may have an atrophic pectoralis major muscle, which might be related to the increased vulnerability of the blood vessels in the pectoralis major muscle and an increased risk of postsurgical bleeding.Further studies exploring the association between SMA and PMA and the correlation between PMA and the risk of post-surgical bleeding are warranted.
To minimize the incidence of postoperative bleeding in patients with a low SMI-to-BMI ratio, it is imperative to ensure thorough hemostasis during the surgery in these patients.In addition, a vessel sealing device (VSD) may decrease the incidence of post-surgical bleeding.A randomized controlled study comparing the benefits of using a VSD (Liga Sure Small Jaw, Covidien, Energy-Based Devices, Boulder, Colorado) with the conventional technique in breast cancer surgery with Ax reported that the frequency of post-surgical bleeding was higher in the conventional technique group (3.3%) than in the vessel sealing system group (0%), although the difference was not significant [29].This result indicates that using VSD may minimize the incidence of post-surgical bleeding.
This study has some limitations.First, this was a retrospective analysis with a relatively small patient cohort from a single institution in an Asian country.Second, the cutoff values of BMI, SMI, and SMI-to-BMI ratio were determined using data from the patient cohort in this study, in which all patients were Japanese.Although our results indicated the utility of the SMI-to-BMI ratio as an indicator of postsurgical bleeding after mastectomy, we could not conclude that the effect of the SMI-to-BMI ratio was equally applicable to other races with different body compositions.Furthermore, although we previously demonstrated that NAC could induce a decrease in SMI [30], none of the patients receiving NAC experienced post-surgical bleeding in this study.Although this is at least partly due to the fact that 91.9% of patients who were treated with NAC (125 out of 136 patients) underwent mastectomy plus Ax, which is associated with a low risk of post-surgical bleeding, the association between NAC and the risk of post-surgical bleeding should be further explored.Large-scale studies with different patient cohorts are warranted to overcome these limitations and validate our results.

Conclusions
The findings of this study indicate that SMI-to-BMI ratio is a superior predictor of post-surgical bleeding to either BMI or SMI alone.Our results underscore the importance of skeletal muscle mass for body weight as a marker of outcomes in patients with cancer.

pFig. 1 a
Fig. 1 a Scatter plot of SMI against BMI.Correlation is shown using Pearson correlation coefficients (R) (R = 0.54), and significance was determined using the Spearman correlation (p < 0.001).b patients in

Fig. 2
Fig. 2 Box-and whisker plot for SMI in the bleeding group and the no-bleeding group.The left panel shows the result of BMI ≥ 25 cohort (p = 0.02), while the right panel of BMI < 25 cohort (p < 0.001).SMI: skeletal muscle index, BMI: body mass index

Fig. 4
Fig. 4 ROC curves of BMI (left), SMI (center), and SMI-to-BMI ratio (right) against post-surgical bleeding.AUC is indicated in each panel.ROC: receiver operating characteristic, SMI: skeletal muscle index, BMI: body mass index, AUC: area under curve SLNB sentinel lymph node biopsy, Ax axillary dissection, DCIS ductal carcinoma in situ, pCR pathological complete response, HER2 human epidermal growth factor receptor type 2, BMI body mass index, SMI skeletal muscle index

Table 2
Comparison of postoperative course between the no bleeding group and the bleeding group SLNB sentinel lymph node biopsy, Ax axillary dissection

Table 3
Univariate and multivariate Logistic regression analysis for post-surgical bleedingAx axillary dissection, SLNB sentinel lymph node biopsy, SMI skeletal muscle index, BMI body mass index