Body Composition Assessment in Patients with Periampullary Neoplasma Undergoing Pancreaticoduodenetomy and its Predictive Value for Postoperative Complications


 BackgroundTo observe body composition parameters variance in patient with periampullary neoplasmas with different clinical characteristics and assess its predictive value for postoperative complications after pancreaticoduodenectomy. MethodsIn this study, we retrospectively reviewed the clinical and image data of 144 patients with periampullary neoplasmas.The area of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and total abdominal muscle area (TAMA) were measured from preoperative CT images at the 3rd lumbar vertebra level, the TAMA was normalized to stature and termed as skeleton muscle index (SMI). The perioperative and pathological data were collected. ResultsOf the included 144 patients, 80(55.6%), 29(20.1%) and 24(16.7%) patients were classified as sarcopenia, visceral obesity and sarcopenic obesity. 84(58.3%) patients were jaundiced and 28 (19.4%)，50 (34.7%)，66(45.8%) patients were diagnosed with benign pancreatic tumors, pancreatic cancer and non-pancreatic cancer respectively. The incidence rate of clinical postoperative pancreatic fistula(POPF) and other major complications were 38.2% and 16%.In the univariate analysis, jaundiced patients experienced more weight loss and had higher nutrition risk score, the TAMA[103.1(61.1-176.7) vs 111.8(74.1-198.2),P=0.021] and SMI(39.2±7.0 vs 42.6±9.1,P=0.012)were lower compared with non-jaundiced group. However, no significant difference were founded between different pathological results and it was not associated with occurrence of POPF and major complications.ConclusionJaundiced patients may experience more weight loss and have lower TAMA and SMI. Body morphometric analysis of preoperative CT did not show predictive value for postoperative complications and further multicenter studies are needed.Trail registrationRegistration number：2021-437-01.


Introduction
Incidence of biliopancreatic tumors is increasing year by year and pancreatic carcinoma shall be the second malignancy leading to death until 2030 [1] . For the patients with periampullary neoplasmas such as pancreatic cancer, distal cholangiocarcinoma, duodenal tumors may rstly manifest as jaundice, abdominal pain and gradually the lumen of duodenal will be obstructed, patients more or less may experience dyspesia and weight loss for digestion and absorption of food being in uenced. Although great improvements have been achieved in oncological and endoscopic therapy, radical surgical resection is still the rst choice [2] . Pancreaticoduodenectomy is the standard procedure for the treatment of periampullary tumors, while the high incidence of postoperative complication about 30%-50% not only affecting patients' recovery thus extended hospitalization but also delaying the time received adjuvant therapies [3][4] .
Recently, reports have shown that preoperative body composition change can predict the surgical complication and survival of several malignant tumors, especially who are sarcopenic and visceral obesity [5][6][7] . Given the fact that patients with pancreatic cancer may experience exocrine insu ciency and sarcopenia is common [8][9][10] , so we suppose that body composition change may have some relationship with postoperative complication. In this article ,we are aimed to analyze the change of body composition in patients with periampullary tumors and assess its value in predicting postoperative complications.

Patients
This retrospective studies were approved by the Health Research Ethics Board of Drum-Tower Hospital A liated to Nanjing University Medical School.Every patient had signed the informed consent.
Patients had radiology-proven or pathology-diagnosed tumors in pancreatic head, distal biliary tract or duodenal wall and met the inclusion criteria below from December 2017 to January 2020 were included.
All patients were successfully performed pancreaticoduodenectomy. The inclusion criteria were as follows: (a) patients who were treated with pancreatoduodenectomy for periampullary neoplasmas (b) patients without other active cancer; (c) patients > 18 years of age; and (d) patients who underwent preoperative enhanced CT within 1 month before operation. The exclusion criteria were as follows: (a) whose preoperative CT cannot be obtained with 1 month before operation;(b) whose clinical data are incomplete.
Acquisition and analysis of CT image CT images were downloaded from the Picture Archiving and Communication System(PACS) of the Radiology Department including unenhanced-,artery-and portal venous phase of upper abdomen. Two radiologist(Shanshan Xu Yifan Zhang)analyzed the images and calculated the areas using 3D Slicer software (v. 4.10.2, www.slicer.org) and the other physician(Jian He) checked the results, both of them were blinded to the patients' information. Different tissue were distinguished by speci ed Houns eld Unit and area of SAT(HU:-190 to -30),VAT(HU:-150 to -50),TAMA(HU:-29 to +150)were measured at the 3 rd lumbar vertebra level(L3) [11] (Figure 1). The TAMA was normalized to stature by dividing the muscle area by the patient's height squared, and which is termed the skeletal muscle index (SMI= TAMA (cm 2 )/height (m 2 )).Sarcopenia was de ned using SMI cut-off value:42.2cm 2 /m 2 for men and 33.9cm 2 /m 2 for women [12] . Visceral obesity was de ned as VFA > 136 cm 2 in men and > 95 cm 2 in women [13] . The cut-off value for diagnosing sarcopenic obesity was 3.2(VAT/SMI) [14] .
Clinical data collection and de nition of complication Clinical data were collected including demographics(age, sex, pre-hospitalization weight loss, history of diabetes),preoperative nutrition risk score(NRS-2002,PG-SGA),preoperative laboratory data(hemoglobulin, transaminase, total bilirubin, albumin, prealbumin, C reactive protein),data of surgery(type of surgical procedure, length of operation volume of blood loss and transfusion),pathologic results. Postoperative complications included clinical pancreatic stula(Grade B/ C) and surgery-related complications classi ed by the Clavien-Dindo classi cation, with major complications de ned as grade ≥ [15][16] .

Statistics
Statistical analysis was performed using SPSS 23.0 software (SPSS Inc.). Measurement data with normal distribution were presented as mean and standard deviation, and comparison between groups was analyzed using independent t test. Measurement data with skewed distribution were described as median(range),and comparison between groups was analyzed using Mann-Whitney U test. Count data were expressed as absolute number and percentage, and comparison between groups was analyzed using c 2 test. Univariate analysis was conducted using the c 2 test. P<0.05 was considered as statistics signi cantly.

Comparison of body composition according to preoperative bilirubin level
The clinical characteristic between jaundiced and non-jaundiced patients were listed on Table 1 .Beside the variables re ects liver function were higher in jaundice group, more weight loss and higher nutrition risk score were founded compared with non-jaundiced group. The average TAMA and SMI were lower and VAT/TAMA ratio was higher in jaundiced group. Gender, BMI, SAT, VAT , rates of sarcopenia, visceral obesity and sarcopenic obesity showed no difference between the two groups. The 144 patients enrolled in this study were classi ed into three groups as benign tumor group, pancreatic cancer(PC)group, non-pancreatic cancer group(Non-PC)according to the pathological result of the specimen. When compared the clinical data of these groups together as shown in Table 2 , only gender, serum bilirubin level and pro-albumin concentration showed statistical difference, while age, BMI, nutrition risk score, body composition parameters(SAT,VAT,TAMA,SMI)did not show any signi cant difference.

Analysis of related variables of postoperative complications
In the univariate analysis, several related factors that may predict POPF and major complication are shown in Table 3 and Table 4. Between patients with and without POPF, only the diameter of MPD showed difference signi cantly. Between patients with and without major complications, only the preoperative WBC counts differed signi cantly. Contrary to our previous hypothesis, body composition parameters(SAT,VAT,TAMA,SMI)did not show any value in predicting POPF and major complications.

Discussion
In this retrospective study, it revealed that jaundiced patients with periampullary tumors is more prone to loss weight and have higher nutrition risk scores. when introduced CT images as an evaluation modality, it showed signi cant difference between jaundice and non-jaundice patients in TAMA and SMI. While morphometric parameters such as sarcopenia and visceral obesity were not predictive factors of POPF and other major complications after pancreaticoduodenectomy.
Recent years, the incidence of biliopancreatic carcinoma is increasing and surgical resection still remains the curative therapy. Nevertheless, the high incidence of morbidity and mortality about 40% and 5% respectively threaten patients' recovery. It had been thought that perioperative management and the TNMstage of tumor were vital factors affected the recovery and prognosis [17][18] , but it is gradually drawing attention that patient individual characteristic such as combined-disease, nutritional status may play an important role as well. BMI, nutrition risk score(NRS-2002,PG-SGA score) are the common nutrition appraisal tools, but BMI re ects the overall nutrition status and might cause some bias. For example, an obese patient may have excessive adipose accumulation while the muscle may atrophy or be in ltrated by fat [19][20] . Our institution also conducted body composition analysis by bioelectrical impedance(BIA), but the result maybe inconsistent [21][22] . Nowadays, CT acts as a new tool assessing the body composition is gaining its popularity for its accuracy and reliability [23] . Several study on hepatocellular carcinoma, gastric and colorectal carcinoma showed that preoperative sarcopenia and visceral obesity have signi cant impact on postoperative complication and overall survival rate [6,24] .
Jaundice is the common symptom of bilio-pancreatic disease for the outlet of the bile tract is obstructed, dyspepsia and weight loss were general complaints of these patients as well. Clugston et al's [25] study showed that jaundiced group were signi cantly malnourished and thus the surgery-related mortality and duration of stay after intervention were differed from non-jaundiced group, which was similar to our results in some extents. We further evaluated the nutrition status of the included patients according to the area of muscle and adipose tissue at the L3 vertebral body level. The TAMA and SMI were higher in nonjaundiced group and was consistent with its higher nutrition risk score. Several points may account for it. First of all, bile is an important substance to promote fat digestion, insu cient production of bile can lead to steatorrhea and vitamin de ciency [26] . Secondly, dysfunction of kupffer cell, proliferation and translocation of gut normal bacterium and accumulation of bacterium in bile make the body be in in ammatory state and prone to suffer from cholangitis, which leads to the increased consumption of protein [27][28] . Last but not least, impaired hepatocellular function results in insu cient protein synthesis, gluconeogenesis, and ketogenesis disorders [29] . Although there is no consensus on routine biliary drainage before operation, it is wise to adopt biliary drainage and reuse to maintain the normal enterohepatic circulation in malnourished patients and morphometric parameters from CT images could be a reference.
When the body composition parameters of three different pathologic types of periampullary tumors classi ed as benign tumors, pancreatic carcinoma and non-pancreatic carcinoma were compared, no signi cant difference were observed. Pancreas is the exocrine organ of great importance through secreting several enzymes assisting the digestion, and more than 50% of patients with pancreatic ductal carcinoma suffered from weight loss compared to the percentage about 10% in ampullary cancer group [30][31] . Causes of high incidence of weight loss in pancreatic carcinoma group can be attributed to tissue-brosis, exocrine and endocrine insu ciency, obstruction of duodenum and cancer induced cachexia [32][33] . Contrary to the original hypothesis, patients with resectable pancreatic carcinoma experienced less muscle loss compared with unresectable or borderline resectable group, which had been indenti ed in Sandini et al's study that loss of muscle tissue is associated with tumor resectability [34] .
In the univariate analysis ,diameter of MPD is the only factor associated with POPF which has been validated in previous study [35] . However, out of expectation, we did not nd sarcopenia, visceral obesity and sarcopenic obesity impact the morbidity. It was doubtful that whether sarcopenia relate to the POPF.
Kosei et al's [36] study showed that sarcopenia was the risk factor of postoperative infectious complications for the cancer impaired immune function, but more research insisted that sarcopenia alone may not predict the clinical outcome in that it only re ects the depleted mass not the quality of muscle [37][38] . A clinical prospective study conducted by Huang et al proposed sarcopenia should be de ned as low muscle mass, low strength and physical performance [39] .In their results, low muscle mass(OR 3.853, 95% CI 1.446-10.263, P = 0.007)(be regarded as sarcopenia in most study)and sarcopenia(OR 4.758, 95% CI 1.627-13.917, P = 0.004)were independent risk factors for the postoperative morbidity, while sarcopenia had better predictive power when the two functional tests were added.
It had been identi ed in a series of studies that excessive visceral not subcutaneous adipose tissue was the risk factor of postoperative morbidities. On the one hand, increased adipose mass may add extra di culties to the operation [41][42] , on the other hand, visceral adipose tissue is considered to be an active organ producing some cytokines and pro-in ammatory adipocytokines such as leptin, TNF-α, IL-1, and IL-6 leading to the delayed healing of wound especially the pancreaticoenteric anastomosis [43][44][45] .
Nevertheless, The results of this study were inconsistent with our expectations that visceral obesity or sarcopenic obesity did not impact the outcome. It can be attributed to the inde nite cutoff point of visceral obesity and sarcopenic obesity between different population or nations, so further studies need to be conducted [46] .
The present study has various limitations. First, it was a retrospective study based on available data, so we can not evaluate the function of muscle such as handgrip strength and 6-m usual gait speed, which was adopted in limited research and further prospective studies of functional tests ought to be conducted. Second, the study was a small study from a single center, to validated the value of body composition parameters on complications, multicenter researches are indispensable.
In conclusion, the results of our study showed that jaundiced patients may experience more weight loss

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and/or analysed during the current study are available from YD Qiu and J He on reasonable request.

Figure 1
Body composition measurement based on CT image, areas of green, yellow and red represent subcutaneous adipose tissue, visceral adipose tissue and skeleton muscle respectively.