Abstract
Total pancreatectomy (TP) is performed for diseases of the entire pancreas. However, reluctance remains regarding TP because of the fear of high morbidity and mortality. Our retrospective study aimed to evaluate the postoperative outcomes of TP performed at a high-volume single center and to identify the risk factors associated with major morbidities and mortality after TP. A total of 142 patients who underwent elective TP at Samsung Medical Center between 1995 and 2015 were included. TP was usually planned before surgery or decided during surgery [one-stage TP], and there were some completion TP cases that were performed to manage tumors that had formed in the remnant pancreas after a previous partial pancreatectomy [2-stage TP]. The differences between the 1-stage and 2-stage TP groups were analyzed. Chronological comparison was also conducted by dividing cases into 2 periods [the early and late period] based on the year TP was performed, which divided the total number of patients to almost half for each period. Among all TP patients, major morbidity occurred in 25 patients (17.6%), the rate of re-admission within 90-days was 20.4%, and there was no in-hospital and 30-days mortality. Between the 1-stage and 2-stage TP groups, most clinical, operative, and pathological characteristics, and postoperative outcomes did not differ significantly. Chronological comparison showed that, although the incidence of complications was higher, hospitalization was shorter due to advanced managements in the late period. The overall survival was improved in the late period compared to the early period, but it was not significant. A low preoperative protein level and N2 were identified as independent risk factors for major morbidity in multivariable analysis. The independent risk factors for poor overall survival were R1 resection, adenocarcinoma, and high estimated blood loss (EBL). TP is a safe and feasible procedure with satisfactory postoperative outcomes when performed at a high-volume center. More research and efforts are needed to significantly improve overall survival rate in the future.
Keywords: early period, late period, 1-stage TP, postoperative outcomes, risk factors, total pancreatectomy (TP), 2-stage TP
1. Introduction
Pancreatic cancer often exhibits aggressive tumor biology, so locoregional recurrence is frequent even after resection and the overall survival is poor.[1–3] Nevertheless, radical resection with lymphadenectomy remains the only curative treatment.[4–7] This is main reason why total pancreatectomy (TP) is performed to achieve radical clearance and improve oncologic outcomes.[4–9] When preoperative evaluation confirms that whole pancreas is involved, TP is planned and performed from the beginning. In operating room during partial pancreatectomy such as pancreaticoduodenectomy (PD) or distal pancreatectomy (DP), if tumor invasion of resection margin is confirmed several times through frozen biopsy, surgical decision can be converted to TP.[10–12] And for patients who have undergone previous partial pancreatectomy, completion TP is performed to remove recurrent malignancy in remnant pancreas.[12,13]
There are indications for benign tumors. TP is required when tumors with malignant potential such as intraductal papillary mucinous neoplasm (IPMN) or neuroendocrine tumor (NET) are present multifocally throughout pancreas.[10–12,14] There are also many cases of TP performed for unresolvable problems such as uncontrolled pain due to severe chronic pancreatitis.[14–17]
One of the important advantages of TP is that it can avoid specific complications after pancreatectomy, such as postoperative pancreatic fistula (POPF) and post-pancreatectomy hemorrhage (PPH).[18,19] This can be reason why TP is performed for cases when the pancreatic tissue texture is severely soft, so it is eventually decided to TP.
On the other hand, major disadvantage of TP is inevitable occurrence of severe metabolic sequelae due to absence of insulin and pancreatic digestive enzymes called endocrine and exocrine insufficiency, respectively. They typically cause diabetes mellitus (DM) and intestinal malabsorption that require life-long management. These can lead to many problems ranging from mildly decreased quality of life (QoL) to seriously increased mortality.[20–22] Fortunately, these metabolic insufficiencies after TP have been managed relatively well thanks to high advancement in insulin injection and pancreatic enzyme replacement.[22–24] Acceptable QoL and high functional performance have been achieved with adequate patient education, compliance, and medical support.
Consequently, TP has been performed steadily. Many studies have reported that postoperative outcomes of TP were favorable and postoperative management became sufficiently tolerable and acceptable.[11–13,15,16] There have also been studies reporting equivalent outcomes when compared to partial pancreatectomy such as PD.[8,17,25,26] After hypothesizing that TP would show favorable outcomes in our center, we aimed to describe experience and evaluate outcomes of TP performed at our high-volume single center by quantitatively identifying major morbidity and mortality. Another purpose was to identify risk factors associated with major morbidities and mortality after TP.
2. Materials and Methods
2.1. Patients and data collection
After obtaining approval from Institutional Review Board (IRB) (no. 2019-07-150), 142 consecutive patients who underwent elective TP at Samsung Medical Center from 1995 to 2015 were included in this retrospective study. TP in emergent setting were excluded.
TP was usually planned before surgery or decided during surgery. These cases accounted for the majority. For some cases, completion TP was performed because tumors had formed in remnant pancreas after previous partial pancreatectomy. These TP cases were referred to as 1-stage TP and 2-stage TP, respectively. All TP patients were divided into these 2 groups. There were 128 patients in 1-stage TP group and 14 patients in 2-stage TP group. Out of 14 patients who underwent 2-stage TP, the previously performed pancreatectomy was PD in 7 patients and DP in 7 patients. We investigated whether there were any differences in 2-stage TP performed to manage tumors that developed in remnant pancreas, compared with 1-stage TP.
Our study was conducted retrospectively over a long period (21 years). We planned to divide cases into 2 periods and evaluate whether there were any chronological differences between early period and late period. We tried to find a year when the overall survival rate was dramatically improved, however there was none. Thus, we divided cases into 2 periods based on the year when half subjects belonged to each period. Comparative analyses were conducted between 69 patients during the early period (from 1995 to 2007) and 73 patients during the late period (from 2008 to 2015).
General complications such as intra-abdominal fluid collection and wound problems were graded by Clavien-Dindo classification (CDC). CDC grade III or higher indicated major complication. Procedure-specific complications, such as delayed gastric emptying (DGE) and PPH were classified based on the criteria of the International Study Group of Pancreatic Surgery (ISGPS).[18,27] Along with major complications according to the CDC, grade B or higher of DGE and PPH were collectively referred to as major morbidities that required further management such as intervention, surgery, intensive care, and others.[28]
2.2. Statistical analyses
Statistical analyses were performed using IBM SPSS statistical software version 27 (Chicago, IL). Simple mean analysis and frequency analysis were used for continuous and categorical variables, respectively. Differences in categorical variables between 1-stage and 2-stage TP groups and between early and late period were compared using Chi-square test. Independent t-test was used to compare continuous variables between the 2 groups. Overall survival curves were plotted using the Kaplan–Meier method. To identify risk factors affecting major morbidity and overall survival, univariable and multivariable analyses were performed with SAS statistical software, version 9.4 (SAS Institute Inc, Cary, NC). Logistic regression method and Cox proportion hazard regression method were executed to find risk factors of major morbidity and overall survival, respectively. Differences with probability (P) -value ≤ 0.05 were considered statistically significant in all analyses.
3. Results
3.1. Clinical, operative, and pathological characteristics
Median age of patients who underwent TP was 61 years, and TP was performed more in men (62.0%) than in women (38.0%). 25 patients (17.6%) underwent vascular resection during TP, all of which were resection and anastomosis of invaded portal vein (PV) or superior mesenteric vein (SMV). Origin of indication for TP was mostly pancreas (92.3%), rate of malignancy was 82.4%, and rate of R0 resection was 90.1%. These results are presented in Tables 1 and 2.
Table 1.
Comparison of clinical, operative, pathological characteristics and short-term postoperative outcomes between the 1-stage and 2-stage TP (number (percent) and mean ± standard deviation).
| All patients (n = 142) | 1-stage TP (n = 128) | 2-stage TP (n = 14) | P-value | |
|---|---|---|---|---|
| [Clinical characteristics] | ||||
| Age (median, years) | 61 | 61 | 63 | .608 |
| Sex | .443 | |||
| Male | 88 (62.0) | 78 (60.9) | 10 (71.4) | |
| Female | 54 (38.0) | 50 (39.1) | 4 (28.6) | |
| BMI (kg/m2) | 22.6 ± 3.0 | 22.6 ± 3.0 | 22.2 ± 3.2 | .612 |
| Comorbidities | ||||
| Cardiovascular | 51 (35.9) | 47 (36.7) | 4 (28.6) | .546 |
| Cerebrovascular | 4 (2.8) | 4 (3.1) | 0 (0.0) | .502 |
| Pulmonary | 7 (4.9) | 6 (4.7) | 1 (7.1) | .687 |
| Etc. | 11 (7.7) | 10 (7.8) | 1 (7.1) | .929 |
| Preoperative DM | .091 | |||
| No | 71 (50.0) | 67 (52.3) | 4 (28.6) | |
| Yes | 71 (50.0) | 61 (47.7) | 10 (71.4) | |
| ASA score | .095 | |||
| 1 | 23 (16.2) | 23 (18.0) | 0 (0.0) | |
| 2 | 109 (76.8) | 95 (74.2) | 14 (100.0) | |
| 3 | 10 (7.0) | 10 (7.8) | 0 (0.0) | |
| Preoperative albumin (g/dL) | 4.0 ± 0.5 | 4.0 ± 0.5 | 4.0 ± 0.5 | .876 |
| Preoperative total protein (g/dL) | 6.8 ± 0.6 | 6.8 ± 0.6 | 6.7 ± 0.7 | .802 |
| [Operative characteristics] | ||||
| Combined vascular resection | .731 | |||
| No | 117 (82.4) | 105 (82.0) | 12 (85.7) | |
| Yes | 25 (17.6) | 23 (18.0) | 2 (14.3) | |
| Additional organ resection | .231 | |||
| No | 130 (91.5) | 116 (90.6) | 14 (100.0) | |
| Yes | 12 (8.5) | 12 (9.4) | 0 (0.0) | |
| Operation time (minutes) | 364.1 ± 90.6 | 372.1 ± 89.6 | 291.4 ± 66.0 | .001 |
| Estimated blood loss (mL) | 1062.6 ± 1363.9 | 1119.1 ± 1409.6 | 546.4 ± 667.8 | .136 |
| [Pathological characteristics] | ||||
| Origin of indication | .728 | |||
| Pancreas | 131 (92.3) | 117 (91.4) | 14 (100.0) | |
| Distal bile duct | 7 (4.9) | 7 (5.4) | 0 (0.0) | |
| Ampulla of Vater | 2 (1.4) | 2 (1.6) | 0 (0.0) | |
| Duodenum | 2 (1.4) | 2 (1.6) | 0 (0.0) | |
| Pathology | .464 | |||
| Malignancy | 117 (82.4) | 104 (81.3) | 13 (92.9) | |
| Benign | 25 (17.6) | 24 (18.7) | 1 (7.1) | |
| Histology | .562 | |||
| Adenocarcinoma | 89 (62.7) | 79 (61.7) | 10 (71.4) | |
| IPMN ± invasive carcinoma | 34 (23.9) | 31 (24.2) | 3 (21.4) | |
| Neuroendocrine carcinoma | 4 (2.8) | 4 (3.1) | 0 (0.0) | |
| Pancreatitis | 7 (4.9) | 7 (5.5) | 0 (0.0) | |
| Metastatic tumors | 2 (1.4) | 1 (0.8) | 1 (7.2) | |
| SCN | 1 (0.7) | 1 (0.8) | 0 (0.0) | |
| SPN | 2 (1.4) | 2 (1.6) | 0 (0.0) | |
| Acinar cell carcinoma | 1 (0.7) | 1 (0.8) | 0 (0.0) | |
| Anaplastic carcinoma | 2 (1.4) | 2 (1.6) | 0 (0.0) | |
| Margin status | .144 | |||
| R0 | 128 (90.1) | 117 (91.4) | 11 (78.6) | |
| R1 | 14 (9.9) | 11 (8.6) | 3 (21.4) | |
| Tumor differentiation | .756 | |||
| Well | 37 (32.5) | 34 (33.3) | 3 (25.0) | |
| Moderately | 48 (42.1) | 43 (42.2) | 5 (41.7) | |
| Poorly/undifferentiated | 29 (25.4) | 25 (24.5) | 4 (33.3) | |
| Unknown | 28 | 26 | 2 | |
| N stage | .704 | |||
| N0 | 87 (61.3) | 77 (60.2) | 10 (71.4) | |
| N1 | 39 (27.5) | 36 (28.1) | 3 (21.4) | |
| N2 | 16 (11.3) | 15 (11.7) | 1 (7.1) | |
| [Postoperative outcomes] | ||||
| All of complication | 54 (38.0) | 50 (39.1) | 4 (28.6) | .443 |
| Major morbidity | 25 (17.6) | 22 (17.2) | 3 (21.4) | .692 |
| Clavien-Dindo classification | .899 | |||
| No complication | 88 (62.0) | 78 (60.9) | 10 (71.4) | |
| I | 15 (10.6) | 14 (10.9) | 1 (7.1) | |
| II | 19 (13.4) | 18 (14.1) | 1 (7.1) | |
| IIIa | 14 (9.9) | 13 (10.2) | 1 (7.1) | |
| IIIb | 4 (2.8) | 3 (2.3) | 1 (7.1) | |
| IVa | 1 (0.7) | 1 (0.8) | 0 (0.0) | |
| IVb | 1 (0.7) | 1 (0.8) | 0 (0.0) | |
| V | 0 (0.0) | 0 (0.0) | 0 (0.0) | |
| Delayed gastric emptying | ||||
| All | 7 (4.9) | 6 (4.7) | 1 (7.1) | .687 |
| Grade B/C | 5 (3.5) | 4 (3.1) | 1 (7.1) | .669 |
| Post-pancreatectomy hemorrhage | ||||
| All | 4 (2.8) | 4 (3.1) | 0 (0.0) | .502 |
| Grade B/C | 4 (2.8) | 4 (3.1) | 0 (0.0) | .502 |
| Intra-abdominal fluid collection | ||||
| All | 12 (8.5) | 11 (8.6) | 1 (7.1) | .853 |
| Major | 5 (3.5) | 4 (3.1) | 1 (7.1) | .439 |
| Wound problem | ||||
| All | 8 (5.6) | 7 (5.5) | 1 (7.1) | .796 |
| Major | 8 (5.6) | 7 (5.5) | 1 (7.1) | .796 |
| Others | ||||
| All | 23 (16.2) | 22 (17.2) | 1 (7.1) | .333 |
| Major | 5 (3.5) | 5 (3.9) | 0 (0.0) | .452 |
| Postoperative hospitalization (days) | 20.8 ± 10.9 | 21.6 ± 10.9 | 13.7 ± 7.7 | .010 |
| Postoperative ICU stay (days) | 2.0 ± 1.7 | 2.1 ± 1.7 | 1.1 ± 1.4 | .044 |
| In-hospital mortality | 0 (0.0) | 0 (0.0) | 0 (0.0) | – |
| Re-admission within 90-days | 29 (20.4) | 24 (18.8) | 5 (35.7) | .135 |
| 30-days mortality | 0 (0.0) | 0 (0.0) | 0 (0.0) | – |
| 90-days mortality | 3 (2.1) | 3 (2.3) | 0 (0.0) | .563 |
ASA = American society of anesthesiologists, BMI = body mass index, DM = diabetes mellitus, ICU = intensive care unit, IPMN = intraductal papillary mucinous neoplasm, SCN = serous cystic neoplasm, SPN = solid pseudopapillary neoplasm, TP = total pancreatectomy.
Table 2.
Chronological comparison of clinical, operative, pathological characteristics and short-term postoperative outcomes (number (percent) and mean ± standard deviation).
| All patients (n = 142) | Early period 1995–2007 (n = 69) | Late period 2008–2015 (n = 73) | P-value | |
|---|---|---|---|---|
| [Clinicalcharacteristics] | ||||
| Age (median, years) | 61 | 58 | 64 | .016 |
| Sex | .389 | |||
| Male | 88 (62.0) | 40 (58.0) | 48 (65.8) | |
| Female | 54 (38.0) | 29 (42.0) | 25 (34.2) | |
| BMI (kg/m2) | 22.6 ± 3.0 | 22.5 ± 3.1 | 22.6 ± 2.9 | .826 |
| Comorbidities | ||||
| Cardiovascular | 51 (35.9) | 16 (23.2) | 35 (47.9) | .003 |
| Cerebrovascular | 4 (2.8) | 0 (0.0) | 4 (5.5) | .120 |
| Pulmonary | 7 (4.9) | 4 (5.8) | 3 (4.1) | .713 |
| Etc. | 11 (7.7) | 1 (1.4) | 10 (13.7) | .009 |
| Preoperative DM | .093 | |||
| No | 71 (50.0) | 40 (58.0) | 31 (42.5) | |
| Yes | 71 (50.0) | 29 (42.0) | 42 (57.5) | |
| ASA score | .544 | |||
| 1 | 23 (16.2) | 13 (18.8) | 10 (13.7) | |
| 2 | 109 (76.8) | 50 (72.5) | 59 (80.8) | |
| 3 | 10 (7.0) | 6 (8.7) | 4 (5.5) | |
| Preoperative albumin (g/dL) | 4.0 ± 0.5 | 3.9 ± 0.4 | 4.0 ± 0.5 | .074 |
| Preoperative total protein (g/dL) | 6.8 ± 0.6 | 6.9 ± 0.5 | 6.7 ± 0.6 | .015 |
| [Operative characteristics] | ||||
| Combined vascular resection | <.001 | |||
| No | 117 (82.4) | 65 (94.2) | 52 (71.2) | |
| Yes | 25 (17.6) | 4 (5.8) | 21 (28.8) | |
| Additional organ resection | 1.000 | |||
| No | 130 (91.5) | 63 (91.3) | 67 (91.8) | |
| Yes | 12 (8.5) | 6 (8.7) | 6 (8.2) | |
| Operation time (minutes) | 364.1 ± 90.6 | 373.6 ± 74.2 | 355.1 ± 103.5 | .222 |
| Estimated blood loss (mL) | 1062.6 ± 1363.9 | 1176.0 ± 1199.5 | 955.5 ± 1503.3 | .337 |
| [Pathological characteristics] | ||||
| Origin of indication | .160 | |||
| Pancreas | 131 (92.3) | 61 (88.4) | 70 (95.9) | |
| Distal bile duct | 7 (4.9) | 6 (8.7) | 1 (1.4) | |
| Ampulla of Vater | 2 (1.4) | 1 (1.4) | 1 (1.4) | |
| Duodenum | 2 (1.4) | 1 (1.4) | 1 (1.4) | |
| Pathology | .271 | |||
| Malignancy | 117 (82.4) | 54 (78.3) | 63 (86.3) | |
| Benign | 25 (17.6) | 15 (21.7) | 10 (13.7) | |
| Histology | .219 | |||
| Adenocarcinoma | 89 (62.7) | 41 (59.4) | 48 (65.8) | |
| IPMN ± invasive carcinoma | 34 (23.9) | 17 (24.6) | 17 (23.3) | |
| Neuroendocrine carcinoma | 4 (2.8) | 2 (2.9) | 2 (2.7) | |
| Pancreatitis | 7 (4.9) | 5 (7.2) | 2 (2.7) | |
| Metastatic tumors | 2 (1.4) | 0 (0.0) | 2 (2.7) | |
| SCN | 1 (0.7) | 0 (0.0) | 1 (1.4) | |
| SPN | 2 (1.4) | 2 (2.9) | 0 (0.0) | |
| Acinar cell carcinoma | 1 (0.7) | 0 (0.0) | 1 (1.4) | |
| Anaplastic carcinoma | 2 (1.4) | 2 (2.9) | 0 (0.0) | |
| Margin status | .402 | |||
| R0 | 128 (90.1) | 64 (92.8) | 64 (87.7) | |
| R1 | 14 (9.9) | 5 (7.2) | 9 (12.3) | |
| Tumor differentiation | .389 | |||
| Well | 37 (32.5) | 21 (36.8) | 16 (28.1) | |
| Moderately | 48 (42.1) | 23 (40.4) | 25 (43.9) | |
| Poorly/ undifferentiated | 29 (25.4) | 13 (22.8) | 16 (28.1) | |
| Unknown | 28 | 12 | 16 | |
| N stage | .145 | |||
| N0 | 87 (61.3) | 46 (66.7) | 41 (56.2) | |
| N1 | 39 (27.5) | 18 (26.1) | 21 (28.8) | |
| N2 | 16 (11.3) | 5 (7.2) | 11 (15.1) | |
| [Postoperative outcomes] | ||||
| All of complication | 54 (38.0) | 15 (21.7) | 39 (53.4) | <.001 |
| Major morbidity | 25 (17.6) | 1 (1.4) | 24 (32.9) | <.001 |
| Clavien-Dindo classification | .001 | |||
| No complication | 88 (62.0) | 54 (78.3) | 34 (46.6) | |
| I | 15 (10.6) | 8 (11.6) | 7 (9.6) | |
| II | 19 (13.4) | 6 (8.7) | 13 (17.8) | |
| IIIa | 14 (9.9) | 1 (1.4) | 13 (17.8) | |
| IIIb | 4 (2.8) | 0 (0.0) | 4 (5.5) | |
| IVa | 1 (0.7) | 0 (0.0) | 1 (1.4) | |
| IVb | 1 (0.7) | 0 (0.0) | 1 (1.4) | |
| V | 0 (0.0) | 0 (0.0) | 0 (0.0) | |
| Delayed gastric emptying | ||||
| All | 7 (4.9) | 1 (1.4) | 6 (8.2) | .117 |
| Grade B/C | 5 (3.5) | 0 (0.0) | 5 (6.8) | .059 |
| Post-pancreatectomy hemorrhage | ||||
| All | 4 (2.8) | 0 (0.0) | 4 (5.5) | .120 |
| Grade B/C | 4 (2.8) | 0 (0.0) | 4 (5.5) | .120 |
| Intra-abdominal fluid collection | ||||
| All | 12 (8.5) | 3 (4.3) | 9 (12.3) | .131 |
| Major | 5 (3.5) | 1 (1.4) | 4 (5.5) | .367 |
| Wound problem | ||||
| All | 8 (5.6) | 0 (0.0) | 8 (11.0) | .007 |
| Major | 8 (5.6) | 0 (0.0) | 8 (11.0) | .007 |
| Others | ||||
| All | 23 (16.2) | 11 (15.9) | 12 (16.4) | 1.000 |
| Major | 5 (3.5) | 0 (0.0) | 5 (6.8) | .059 |
| Postoperative hospitalization (days) | 20.8 ± 10.9 | 23.6 ± 11.0 | 18.1 ± 10.2 | .002 |
| Postoperative ICU stay (days) | 2.0 ± 1.7 | 2.1 ± 1.6 | 1.8 ± 1.8 | .194 |
| In-hospital mortality | 0 (0.0) | 0 (0.0) | 0 (0.0) | – |
| Re-admission within 90-days | 29 (20.4) | 7 (10.1) | 22 (30.1) | .004 |
| 30-days mortality | 0 (0.0) | 0 (0.0) | 0 (0.0) | – |
| 90-days mortality | 3 (2.1) | 2 (2.9) | 1 (1.4) | .612 |
ASA = American society of anesthesiologists, BMI = body mass index, DM = diabetes mellitus, ICU = intensive care unit, IPMN = intraductal papillary mucinous neoplasm, SCN = serous cystic neoplasm, SPN = solid pseudopapillary neoplasm, TP = total pancreatectomy.
Table 1 also shows results of comparison between 1-stage and 2-stage TP groups. Among clinical and operative characteristics, only operation time was significantly different. It was shorter in 2-stage TP group (291.4 min vs 372.1 min; P = .001). Other characteristics such as body mass index (BMI), DM, American society of anesthesiologists (ASA) score, and estimated blood loss (EBL) were not significantly different between 2 groups. None of pathological characteristics showed significant difference between 1-stage and 2-stage TP group. The pathological/histological distribution of the 14 patients who underwent 2-stage TP showed the majority (10 patients) with pancreatic adenocarcinoma, 1 with malignant IPMN, 2 with IPMN low grade, and the other 1 with metastatic tumor.
Results of chronological comparison are presented in Table 2. In late period, patients were older (64 years vs 58 years; P = .016), more likely to have cardiovascular disease (47.9% vs 23.2%; P = .003) and other underlying diseases (13.7% vs 1.4%; P = .009), and had lower preoperative total protein (6.7 g/dL vs 6.9 g/dL; P = .015). In operative characteristics, only the rate of combined vascular resection was significantly higher in late period (28.8% vs 5.8%; P < .001). There was no significant difference in operation time or EBL. No chronological differences in pathological characteristics were identified.
3.2. Postoperative outcomes
In all 142 patients who underwent TP, incidence of any complications was 38.0% and that of major morbidities was 17.6%. Results of comparison of short-term postoperative outcomes including the 2 rates between 1-stage and 2-stage TP groups are shown in Table 1. Rates of all complications and major complications did not differ significantly (39.1% vs 28.6%; P = .443 and 17.2% vs 21.4%; P = .692, respectively). However, there were significant differences in postoperative total hospitalization and postoperative intensive care unit (ICU) stay, both of which were shorter in 2-stage TP group (13.7 days vs 21.6 days; P = .010 and 1.1days vs 2.1 days; P = .044, respectively). As shown in Table 2, incidence of complications significantly differed between early and late periods. In early period, the rates of no complication and CDC grade I (any deviation from normal progression without any specific management) was higher compared to late period. On the other hand, in late period, overall complications were found to occur more commonly (53.4% vs 21.7%; P < .001), and major morbidity was also higher (32.9% vs 1.4%; P < .001). Rate of wound problem was exceptionally higher (11.0% vs 0.0%; P = .007), conversely, postoperative hospitalization was significantly shorter in late period (18.1days vs 23.6days; P = .002). The rate of re-admission within postoperative 90-days was higher in late period (30.1% vs 10.1%; P = .004).
There was no in-hospital mortality or no mortality within 30-days after TP. There were 3 mortalities within 90-days. Detailed information is presented in Table 3.
Table 3.
90-days mortality cases.
| Sex/Age | Comorbidity | OP date | Group | Cause of TP | Combined OP | OP Time | EBL | Site & Pathology | ICU stay | Postoperative hospitalization | CDC | Survival (days) | Cause | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | M/63 | DM | 1997-03-19 | one-stage TP | Hardpancreas, | STG | 435 | 1400 | Pancreas | 5 | 19 | 0 | 89 | Unknown |
| Severe | d/t | Anaplastic Ca | ||||||||||||
| pancreatitis | huge tumor | (sarcomatoid) | ||||||||||||
| T3 N0 | ||||||||||||||
| R0 | ||||||||||||||
| 2 | M/54 | DM, Tb, | 2005-09-05 | one-stage TP | Positive margin | – | 390 | 800 | Pancreas | 1 | 11 | 0 | 72 | Unknown |
| Lung fibrosis | (pancreatic duct atypical cell) | Adenocarcinoma | ||||||||||||
| T2 N0 | ||||||||||||||
| Poorly diff | ||||||||||||||
| R0 | ||||||||||||||
| 3 | M/67 | AS s/p AVR, | 2015-04-03 | one-stage TP | Entire | – | 511 | 800 | Pancreas | 2 | 38 | IVb | 39 | Septic |
| ESD | pancreas | IPMN | Septic shock | shock | ||||||||||
| d/t EGC | involved | Intermediate grade | d/t aspiration | |||||||||||
| (IPMN) | pneumonia |
AS = aortic stenosis, AVR = aortic valve replacement, CDC = Clavien-Dindo classification, DM = Diabetes Mellitus, EGC = early gastric cancer, EBL = estimated blood loss, ESD = endoscopic submucosal dissection, ICU = intensive care unit, IPMN = intraductal papillary mucinous neoplasm, OP = operation, STG = subtotal gastrectomy, Tb = tuberculosis, TP = total pancreatectomy.
Overall survival rate analysis was limited to malignancy patients, excluding those with metastatic or benign diseases. Figure 1 shows curves of overall survival rates in 115 malignant cases. 5-year survival rate after TP was 22.6% and there was no distinct difference between 1-stage and 2-stage TP groups (22.3% vs 25.0%; P = .773) as shown in Figure 2. Figure 3 is result showing that there was also no significant difference in 5-year survival rate after TP between 2 chronological periods (20.4% vs 24.6%; P = .140).
Figure 1.
Overall survival rates in all malignant cases.
Figure 2.
Overall survival rates in the 1-stage and 2-stage TP.
Figure 3.
Overall survival rates in the early period (1995–2007) and late period (2008–2015).
3.3. Risk factors analysis
We conducted analysis to identify risk factors affecting postoperative outcomes. Because the 1-stage TP and 2-stage TP may be different procedure in terms of postoperative complications, the analysis was conducted separately. Results of the analysis are presented in Table 4. In 1-stage TP group, multivariable analysis showed that a low preoperative protein level (OR = 3.324, 95%CI: 1.011–10.927, P = .048) and N2 (OR = 4.190, 95%CI: 1.193–14.717, P = .025) were independent risk factors for occurrence of major complications. Analysis was also conducted to find risk factors for major morbidity limited to 2-stage TP group, however did not show any significant result.
Table 4.
Risk factors analysis for major morbidity in the 1-stage TP group.
| Variables | Reference | Effect | Univariable analysis | Multivariable analysis | ||||
|---|---|---|---|---|---|---|---|---|
| OR | 95% CI | P-value | OR | 95% CI | P-value | |||
| Site | Pancreas | CBD + AoV + Duodenum | 1.934 | 0.470–7.962 | .361 | |||
| Age | 1.009 | 0.965–1.056 | .682 | |||||
| Sex | M | F | 0.528 | 0.192–1.458 | .218 | |||
| BMI (kg/m2) | 1.052 | 0.903–1.224 | .517 | |||||
| ASA score | 1 | 2 | 2.800 | 0.605–12.956 | .188 | |||
| Preoperative DM | No | Yes | 2.197 | 0.850–5.677 | .104 | |||
| Multiple comorbidities | No | Yes | 2.655 | 1.039–6.787 | .041 | 2.320 | 0.859–6.262 | .097 |
| Preoperative protein | >6 g/dL | ≤ 6 g/dL | 3.600 | 1.149–11.281 | .028 | 3.324 | 1.011–10.927 | .048 |
| Preoperative albumin | >3 g/dL | ≤ 3 g/dL | 5.421 | 1.017–28.897 | .048 | 3.735 | 0.543–25.679 | .180 |
| Additional organ resection | No | Yes | 1.702 | 0.421–6.874 | .455 | |||
| Combined vascular resection | No | Yes | 2.625 | 0.925–7.448 | .070 | |||
| Operation time (minutes) | 1.004 | 0.999–1.009 | .089 | |||||
| Estimated blood loss | ≤ 600 mL | > 600 mL | 1.000 | 1.000–1.000 | .126 | |||
| Tumor | Benign | Malignancy | 1.565 | 0.423–5.787 | .502 | |||
| Pathology | Adenocarcinoma | IPMN | 0.757 | 0.251–2.282 | .621 | |||
| NECa | 0.656 | 0.074–5.846 | .706 | |||||
| LN metastasis | N0 | N1 | 0.968 | 0.309–3.026 | .955 | 1.051 | 0.319–3.461 | .935 |
| N2 | 4.000 | 1.188–13.472 | .025 | 4.190 | 1.193–14.717 | .025 | ||
| Radicality | R0 | R1 | 0.457 | 0.055–3.767 | .467 | |||
OR = odds ratio, CI = confidence interval, CBD = common bile duct, AoV = ampulla of Vater, BMI = body mass index, ASA = American society of anesthesiologists, DM = Diabetes mellitus, IPMN = intraductal papillary mucinous neoplasm, NECa = neuroendocrine carcinoma, LN = lymph node.
Table 5 shows results of risk factor analyses for overall survival. Analysis to find risk factors for overall survival was performed only for malignant cases. After multivariable analysis, high EBL and R1 resection were independent risk factors for poor overall survival (HR = 1.639, 95%CI: 1.079–2.491; P = .021 and HR = 2.296, 95%CI: 1.249–4.222; P = .007, respectively). And it was confirmed that intraductal papillary mucinous carcinoma (IPMCa) and neuroendocrine carcinoma (NECa) were significantly favorable factors for overall survival compared to adenocarcinoma (HR = 0.282, 95%CI: 0.141–0.565, P < .001 and HR = 0.067, 95%CI: 0.008–0.598, P = .015, respectively).
Table 5.
Risk factors analysis for overall survival in malignant cases.
| Variables | Reference | Effect | Univariable analysis | Multivariable analysis | ||||
|---|---|---|---|---|---|---|---|---|
| OR | 95% CI | P-value | OR | 95% CI | P-value | |||
| Site | Pancreas | CBD + AoV + Duodenum | 0.801 | 0.416–1.541 | .506 | |||
| Age | 1.015 | 0.996–1.034 | .128 | |||||
| Sex | M | F | 0.950 | 0.630–1.433 | .806 | |||
| BMI (Kg/m2) | 1.012 | 0.945–1.085 | .728 | |||||
| ASA score | 1 | 2 | 1.327 | 0.770–2.289 | .308 | 1.463 | 0.799–2.678 | .218 |
| 3 | 2.896 | 1.168–7.181 | .022 | 1.800 | 0.623–5.198 | .277 | ||
| Preoperative DM | No | Yes | 1.118 | 0.752–1.661 | .582 | |||
| Multiple comorbidities | No | Yes | 1.044 | 0.666–1.636 | .852 | |||
| Preoperative protein | > 6 g/dL | ≤ 6 g/dL | 1.317 | 0.759–2.286 | .327 | |||
| Preoperative albumin | > 3 g/dL | ≤ 3 g/dL | 1.405 | 0.614–3.216 | .421 | |||
| Additional organ resection | No | Yes | 1.519 | 0.764–3.020 | .233 | |||
| Combined vascular resection | No | Yes | 1.330 | 0.827–2.138 | .239 | |||
| Operation time (minutes) | 1.003 | 1.001–1.005 | .004 | 1.001 | 0.998–1.004 | .639 | ||
| Estimated blood loss | ≤ 600 mL | > 600 mL | 1.847 | 1.232–2.769 | .003 | 1.639 | 1.079–2.491 | .021 |
| Pathology | Adenocarcinoma | IPMCa | 0.242 | 0.122–0.481 | <.001 | 0.282 | 0.141–0.565 | <.001 |
| NECa | 0.188 | 0.023–1.507 | .116 | 0.067 | 0.008–0.598 | .015 | ||
| LN metastasis | N0 | N1 | 2.256 | 1.450–3.510 | <.001 | 1.509 | 0.919–2.476 | .104 |
| N2 | 2.792 | 1.535–5.078 | .001 | 1.581 | 0.824–3.035 | .168 | ||
| Radicality | R0 | R1 | 1.801 | 1.014–3.201 | .045 | 2.296 | 1.249–4.222 | .007 |
| Adjuvant treatment | No | Yes | 1.464 | 0.892–2.402 | .132 | |||
HR = hazards ratio, CI = confidence interval, CBD = common bile duct, AoV = ampulla of Vater, BMI = body mass index, ASA = American society of anesthesiologists, DM = Diabetes mellitus, IPMCa = intraductal papillary mucinous carcinoma, NECa = neuroendocrine carcinoma, LN = lymph node.
4. Discussion
We set the inclusion period of this study as until 2015 for long-term survival analysis, and total number of TP included was 142. This number did not appear to be small compared to other studies presented in Table 6.[10–13,15–17,25,26,29] Centers participating in all the above studies appeared to be high-volume centers that performed more than 20 cases of PD per year.[30]
Table 6.
Literature review on TP.
| Authors (published year) | Country | Inclusion periods | Involved center | patients’ number | Morbidity (%) | 30-days mortality (%) | 90-days mortality (%) | |
|---|---|---|---|---|---|---|---|---|
| Overall | Major | |||||||
| Muller et al (2007) | Germany | 2001–2006 | Single | 147 | 44.2 | – | – | – |
| Reddy et al (2009) | USA | 1970–2007 | Single | 100 | 69.0 | 43.0 | 8.0 | – |
| Crippa et al (2010) | Italy | 1996–2008 | Single | 65 | 38.5 | – | – | – |
| Casadei et al (2010) | Italy | 2006–2009 | Single | 7 | 25.0 | – | – | – |
| Hartwig et al (2015) | Germany | 2001–2012 | Single | 434 | 37.6 | 37.3 | 3.7 | – |
| Casadei et al (2016) | Italy | 2011–2015 | Single | 257 | 73.5 | 29.4 | – | – |
| Pulvirenti et al (2019) | Italy | 2000–2014 | Multiple (2) | 329 | 59.3 | – | – | 3.3 |
| Scholten et al (2019) | Netherlands | 2006–2016 | Multiple (17) | 148 | – | 32.0 | – | 8.0 |
| Hayama et al (2020) | Japan | 2001–2016 | Single | 26 | 26.9 | – | – | – |
| Stoop et al (2020) | Sweden | 2008–2017 | Single | 145 | – | 34.5 | 2.8 | 5.5 |
| Present study (2021) | Korea | 1995-2015 | Single | 142 | 38.0 | 17.6 | 0.0 | 2.1 |
TP = total pancreatectomy.
In our study, short-term postoperative outcomes such as overall morbidity (38.0%), major morbidity (17.6%), 30-days mortality (0.0%), 90-days mortality (2.1%), and rate of re-admission within 90-days (20.4%) were relatively favorable and tolerable. These outcomes were comparable to those of other studies, as shown in Table 6. Regarding postoperative long-term outcomes, 5-years survival rate of malignant cases underwent TP in late period was 24.6%. This survival rate was similar and relatively favorable compared with the result of other previous studies.[10–13,15–17,25,26,29]
All patients were divided into 2 groups, the 1-stage TP group and the 2-stage TP group, to evaluate whether there were differences in perioperative characteristics and outcomes in cases that previously underwent partial pancreatectomy. Except for a few, most factors were not significantly different between 2 groups. Operation time was significantly shorter in 2-stage TP group, possibly because the amount of tissue or lymph nodes to be dissected was relatively smaller, although considerable time might be required to perform adhesiolysis. Lower EBL in 2-stage group was probably due to similar reasons, although this difference was not significant. The finding that postoperative hospitalization and ICU stay were significantly shorter in 2-stage TP group also suggests that 2-stage completion TP was less extensive and less aggressive procedure than 1-stage TP. Thus, it can be a favorable decision to plan completion TP when tumor develops in remnant pancreas after previous partial pancreatectomy.
Analyses of chronological change of TP were performed. The duration of 2 periods, in which total subjects were divided into almost half in each period, were early 13 years and late 8 years. Therefore, it was considered that TP was performed more recently. In late period than early period, patients were older, had more underlying diseases, underwent more aggressive surgeries such as vascular resection/anastomosis, and had more overall complications including wound problem. High rate of overall complication and major complication suggests that various managements have been applied significantly more in late period. High rate of no complication, high rate of CDC grade I, and long hospitalization in early period can indicate that appropriate management could have been taken. Although the rates of overall complications were significantly higher in late period, the distinctly shorter hospitalization and no in-hospital/30-days mortality mean that the complications were resolved through early detection and effective management. The managements that have been performed to resolve complications, whether in the past or recent, include medical management such as blood transfusion, antibiotics, and ICU, as well as radiological/endoscopic intervention, surgery, and others. The more recent compared to the past, they have made remarkable development, and have been actively provided to patients. High rate of re-admission in late period was mostly for glycemic control, which also suggests that active management for problem has been implemented. These lead to better overall survival rate in late period, although the difference in survival rate was found to be insignificant. More research and efforts are needed to distinctly improve the survival rate in the future.
Results of multivariable analysis for major morbidity conducted in 1-stage TP group showed that preoperative protein level reflecting overall nutritional status contributed to major morbidity. Protein is modifiable factor, therefore it is thought that supplementing protein during preoperative period could be helpful strategy. Numerous studies have shown that preoperative protein significantly affects short-term/long-term postoperative outcomes in various cancers.[31–33] Multivariable analysis revealed that N2 was also a strong factor associated with occurrence of major complication. When investigating patients who had major morbidity among the patients confirmed as N2, it was identified that all of their major complications were wound problem and were resolved by resuturing. Although high N stage is unchangeable factor, we can have suggestion that wound healing state should be closely monitored in patients with N2. And it is thought that reason why there was no significance in the risk factor analysis for major morbidity conducted limited to 2-stage TP group was because 14 patients in the group was too few and there were no or few patients who corresponded to the risk factors.
As results of multivariable analysis for overall survival in malignant cases, R1 resection, adenocarcinoma, and high EBL were identified as independent risk factors of reduced survival rates. All R1 cases were confirmed microscopically positive in the retropancreatic margin. Because these were reported from the postoperative final pathologic examination, such tumor extent cannot be modifiable factor. Likewise, adenocarcinoma is not modifiable. If it is possible to reduce EBL during surgery, it seems to be the only factor that surgeon can try to improve the survival rate.
Limitation of our study was that there were no detailed findings about endocrine or exocrine insufficiency among postoperative outcomes. We investigated only number of re-admissions for DM control among re-admission within 90-days after TP. Our study was entirely based on medical records, inevitably, data on DM control, nutritional status, and other aspects of endocrine and exocrine insufficiency were either too scarce or too heterogeneous to evaluate systematically. We plan to conduct research at the time when enough information is accurately collected in the future.
There might be patients who were lost to follow-up, therefore postoperative outcomes of such patients could not be obtained. These missing data might have negatively affected our estimation of postoperative outcomes. Due to these losses, 2 cases of 90-days mortality cases that occurred after discharge had unknown causes of death. Because medical records from our center have been thoroughly reviewed to ensure no documented information was missed, our data including documented complications, postoperative hospitalization, and re-admission are likely to be accurate. In particular, mortality data are accurate because Department of Medical Records of our center collects information on the facts and dates of patient deaths from government departments and saves it in electronic medical records.
Another strength of our study was that we organized and analyzed various characteristics and postoperative outcomes of 142 cases of TP performed at a high-volume single center. We had relatively larger dataset. In the future, it would be useful to study progression of specific complications that occur after TP, such as endocrine and exocrine insufficiency.
5. Conclusions
In our study, major morbidity after TP was 17.6%, and there was no in-hospital or 30-days mortality after TP. As a result, it can be said that TP is a safe and feasible procedure with satisfactory short-term postoperative outcomes when performed at a high-volume center. More research and efforts are needed to significantly improve long-term postoperative outcomes, including overall survival rate in the future.
Author contributions
Conceptualization: In Woong Han.
Data curation: Ji Hye Jung.
Formal analysis: Ji Hye Jung.
Investigation: Ji Hye Jung, Ok Joo Lee.
Methodology: Ji Hye Jung, Sang Hyun Shin.
Project administration: Jin Seok Heo, In Woong Han.
Resources: Ji Hye Jung, In Woong Han.
Software: Ji Hye Jung, So Jeong Yoon, Ok Joo Lee.
Supervision: Jin Seok Heo, In Woong Han.
Validation: Sang Hyun Shin, In Woong Han.
Visualization: Ji Hye Jung, So Jeong Yoon, Ok Joo Lee.
Writing – original draft: Ji Hye Jung.
Writing – review & editing: Ji Hye Jung.
Abbreviations:
- ASA =
- American society of anesthesiologists
- BMI =
- body mass index
- CDC =
- Clavien-Dindo classification
- DGE =
- delayed gastric emptying
- DM =
- diabetes mellitus
- DP =
- distal pancreatectomy
- EBL =
- estimated blood loss
- ICU =
- intensive care unit
- IPMCa =
- intraductal papillary mucinous carcinoma
- IPMN =
- intraductal papillary mucinous neoplasm
- IRB =
- Institutional Review Board
- ISGPS =
- International Study Group of Pancreatic Surgery
- NECa =
- neuroendocrine carcinoma
- NET =
- neuroendocrine tumor
- PD =
- pancreaticoduodenectomy
- POPF =
- postoperative pancreatic fistula
- PPH =
- post-pancreatectomy hemorrhage
- PV =
- portal vein
- QoL =
- quality of life
- SMV =
- superior mesenteric vein
- TP =
- total pancreatectomy
The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.
How to cite this article: Jung JH, Yoon SJ, Lee OJ, Shin SH, Heo JS, Han IW. Is it worthy to perform total pancreatectomy considering morbidity and mortality?: experience from a high-volume single center. Medicine 2022;101:36(e30390).
The authors have no funding and conflicts of interest to disclose.
Contributor Information
Ji Hye Jung, Email: sog-hei@daum.net.
So Jeong Yoon, Email: wooyabi@gmail.com.
Ok Joo Lee, Email: altanis7@gmail.com.
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