Edited by: Simona Gurzu, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology of Târgu Mureş, Romania
Reviewed by: Marcial García-Rojo, Hospital Universitario Puerta del Mar, Spain; Ming Cui, Peking Union Medical College Hospital (CAMS), China
*Correspondence: Jianming Zheng,
This article was submitted to Gastrointestinal Cancers, a section of the journal Frontiers in Oncology
†These authors have contributed equally to this work
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
To explore the impact of distant metastases on cancer-specific survival in patients with intraductal papillary mucinous neoplasm (IPMN) with associated invasive carcinoma and identify the risk factor of distant metastases in IPMN with associated invasive carcinoma.
Patients with IPMN with associated invasive carcinoma between 2010 and 2015 were retrospectively selected from the Surveillance, Epidemiology, and End Results (SEER) database. The survival analyses were assessed by Kaplan-Meier analyses and log-rank test. The impact of distant metastases was evaluated by Cox regression model and the risk factors of distant metastases were identified by logistic regression analyses, respectively.
The median cancer-specific survival time of patients with no metastases, isolated liver, isolated lung, and multiple site metastases were 19 months, 4 months, 7 months, and 3 months, respectively. In patients with isolated liver metastases, multivariate analysis after adjustment indicated that chemotherapy (Hazard Ratio [HR]=0.351, 95% confidence interval [CI]=0.256-0.481, P<0.001) was a protective prognostic factor for cancer-specific survival (CSS) in patients with isolated liver metastases. In isolated lung metastases subgroup, old age (HR=1.715, 95% CI=1.037-2.838, P=0.036) and chemotherapy (HR=0.242, 95% CI=0.134-0.435, P<0.001) were related to CSS in multivariable Cox regression analysis(P<0.05). Tumor located in the pancreatic body/tail (HR=2.239, 95% CI=1.140-4.400, P=0.019) and chemotherapy (HR=0.191, 95% CI=0.108-0.340, P<0.001) were independent prognostic factors for CSS in patients with multiple metastases. Finally, a nomogram was constructed for cancer-specific survival and the predicted C-index was 0.780 (95% CI=0.762-0.798).
The liver is the most common site of distant metastases in IPMN with associated invasive carcinoma. Tumor located in the pancreatic body/tail and chemotherapy are independent prognostic factors for CSS in patients with multiple metastases. Further, tumor located in body/tail is identified as a risk factor of distant metastases.
Intraductal papillary mucinous neoplasms (IPMN) is defined as a tumor arising from the ductal epithelium, characterized by mucin production, cystic dilation of the pancreatic duct, and intraductal papillary growth (
Distant metastasis is a characteristic of malignant tumors. According to previous studies, lymph node metastases occurred in 5–54% of patients with IPMN with associated invasive carcinoma (
A retrospective cohort study was performed by extracting the data from the SEER database. The SEER database is free, and informed consent was waived because the SEER data are anonymous, and the study complied with the cancer is a reportable disease in every state of the USA. The incidence-SEER 18 Regs Custom Data (with additional treatment fields), Nov 2018 Sub (1975-2016 varying) was employed as the data source. The 5-year relative survival rate was extracted from SEER 18 Regs Custom Data (with additional treatment fields) from 2000 to 2016. Because the SEER database is reasonable for the classification of invasive carcinomas, only patients who had a histologic diagnosis as IPMN with associated invasive carcinoma of the pancreas were included. We selected cases through the “SEER Site Recode” using the term “pancreas” and identified along with the label “malignant” using the variable “Histologic Type ICD-O-3” with the following codes: 8050, 8260, 8450, 8453, 8471, 8480, 8481 and 8503 (
The flow chart of eligible patients’ selection in this study.
Statistical analyses were performed using SPSS (version 22.0 IBM Corporation, Armonk, NY). Categorical variables were reported as counts. Independent predictors for cancer-specific survival were identified by univariate and multivariable Cox proportional hazard models. Kaplan-Meier analysis and log-rank test were used to compare survival duration between different subgroups. Distant metastasis-associated factors were identified by logistic regression models. A two-sided P value <0.05 was considered statistically significant in all analyses. The validated variables were incorporated into the nomogram to predict the probability of 1‐, 3‐, and 5‐year CSS rates for patients with IPMN with associated invasive carcinoma using the rms package in R software (
A total of 1178 patients with IPMN with associated invasive carcinoma that met our criteria were included in the analysis. Among them, 10 patients (0.85%) with isolated bone metastases, 245 (20.80%) with isolated liver metastases, 94 (8.0%) with isolated lung metastases, and 107 (9.1%) with multiple metastases. The distant metastases rate was 38.7% in patients with IPMN with associated invasive carcinoma. Patients were diagnosed at the age of more than 65 (55.8%), male (50.4%), white (78.8%), and married (55.3%). Regarding the primary site, 547 (46.4%) patients with tumor located in the pancreatic head, and 34.5% in the pancreatic body/tail. As for therapeutic options, most patients did not undergo surgery (68.7%) or radiotherapy (83.4%), while 686 (58.2%) received chemotherapy. The demographic and clinicopathological characteristics of patients with IPMN with associated invasive carcinoma are summarized in
Clinical characteristics of patients with IPMN with associated invasive carcinoma.
Variables | Total | No metastasis | Metastatic site | |||
---|---|---|---|---|---|---|
Bone | Liver | Lung | Multiple site | |||
Age | 1178 | 722 | 10 | 245 | 94 | 107 |
≤65 | 521 (44.2%) | 328 (45.4%) | 3 (30%) | 114 (46.5%) | 37 (39.4%) | 40 (37.4%) |
>65 | 657 (55.8%) | 394 (54.6%) | 7 (70%) | 131 (53.5%) | 58 (61.7%) | 67 (62.6%) |
Gender | ||||||
Male | 594 (50.4%) | 370 (51.2%) | 5 (50%) | 128 (52.2%) | 43 (45.7%) | 48 (44.9%) |
Female | 584 (49.6%) | 352 (48.8%) | 5 (50%) | 117 (47.8%) | 51 (54.3%) | 59 (55.1%) |
Race | ||||||
White | 928 (78.8%) | 555 (76.9%) | 10 (100%) | 198 (80.8%) | 79 (84.0%) | 86 (80.4%) |
Black | 121 (10.3%) | 79 (10.9%) | 0 | 23 (9.39%) | 8 (8.5%) | 11 (10.3%) |
Other | 129 (10.9%) | 88 (12.2%) | 0 | 24 (9.8%) | 7 (7.4%) | 10 (9.3%) |
Site | ||||||
Head | 547 (46.4%) | 415 (57.5%) | 5 (50%) | 72 (29.4%) | 34 (36.2%) | 21 (19.6%) |
Body/tail | 406 (34.5%) | 185 (25.6%) | 1 (10%) | 118 (48.2%) | 45 (47.9%) | 57 (53.3%) |
Other | 225 (19.1%) | 122 (16.9%) | 4 (40%) | 55 (22.4%) | 15 (16.0%) | 29 (27.1%) |
Grade | ||||||
I | 139 (11.8%) | 119 (16.5%) | 1 (10%) | 7 (2.9%) | 6 (6.4%) | 6 (5.6%) |
II | 231 (19.6%) | 184 (25.5%) | 2 (20%) | 28 (11.4%) | 8 (8.5%) | 9 (8.4%) |
III | 124 (10.5%) | 90 (12.5%) | 0 | 20 (8.2%) | 5 (5.3%) | 9 (8.4%) |
IV | 6 (0.5%) | 5 (6.9%) | 0 | 1 (0.4%) | 0 | 0 |
Unknown | 678 (57.5%) | 324 (44.9%) | 7 (70%) | 189 (77.1%) | 75 (79.8%) | 83 (77.6%) |
Histologic type | ||||||
Mucinous adenocarcinoma | 786 (66.7%) | 482 (66.8%) | 9 (90%) | 156 (63.7%) | 69 (73.4%) | 70 (65.4%) |
Mucin-producing adenocarcinoma | 220 (18.7%) | 81 (11.2%) | 1 (10%) | 83 (33.9%) | 20 (21.3%) | 35 (32.7%) |
Intraductal papillary-mucinous carcinoma | 126 (10.7%) | 123 (17.0%) | 0 | 2 (0.8%) | 1 (1.1%) | 0 |
Others* | 46 (3.9%) | 36 (5.0%) | 0 | 4 (1.6%) | 4 (4.3%) | 2 (1.9%) |
Surgery | ||||||
Yes | 369 (31.3%) | 360 (49.9%) | 1 (10%) | 239 (97.6%) | 1 (1.1%) | 1 (0.9%) |
No | 809 (68.7%) | 362 (50.1%) | 9 (90%) | 6 (2.4%) | 93 (98.9%) | 106 (99.1%) |
Radiotherapy | ||||||
Yes | 195 (16.6%) | 155 (21.5%) | 5 (50%) | 236 (96.3%) | 8 (8.5%) | 18 (14.0%) |
No | 983 (83.4%) | 567 (78.5%) | 5 (50%) | 9 (3.7%) | 86 (91.5%) | 89 (83.2%) |
Chemotherapy | ||||||
Yes | 686 (58.2%) | 426 (59.0%) | 5 (50%) | 104 (42.4%) | 61 (64.9%) | 53 (49.5%) |
No | 492 (41.8%) | 296 (41.0%) | 5 (50%) | 141 (57.6%) | 33 (35.1%) | 54 (50.5%) |
Marital status | ||||||
Married | 652 (55.3%) | 420 (58.2%) | 5 (50%) | 117 (47.8%) | 53 (56.4%) | 57 (53.3%) |
Unmarried | 468 (39.7%) | 277 (38.4%) | 5 (50%) | 110 (44.9%) | 30 (31.9%) | 46 (43.0%) |
Unknown | 58 (4.9%) | 25 (3.4%) | 0 | 18 (7.3%) | 11 (11.7%) | 4 (3.7%) |
*Including papillary carcinoma, papillary adenocarcinoma, papillocystic adenocarcinoma, papillary mucinous cystadenocarcinoma, and noninfiltrating intraductal papillary adenocarcinoma.
The CSS of patients with single or multiple distant metastases involvements were compared according to the distant site. In patients with no distant metastases, liver, lung, and multiple metastases, the median CSS was 19 months, 4 months, 7 months, and 3 months, respectively. And the median OS in patients with no distant metastases, liver, lung, and multiple metastases was 17 months, 4 months, 4 months, and 2 months, respectively. The Kaplan-Meier curves were shown in
Kaplan-Meier curves of patients with IPMN with associated invasive carcinoma: Stratified by distant metastases
Univariable Cox regression analysis of cancer-specific survival in patient with IPMN with associated invasive carcinoma.
Variables | No metastasis | liver | lung | Multiple metastases | ||||
---|---|---|---|---|---|---|---|---|
HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | |
Age | ||||||||
≤65 | 1 | 1 | 1 | 1 | ||||
>65 | 1.245 (1.038-1.494) | 0.018 | 1.084 (0.834-1.409) | 0.545 | 1.892 (1.180-3.033) | 0.008 | 1.526 (1.008-2.308) | 0.046 |
Gender | ||||||||
Male | 1 | 1 | 1 | 1 | ||||
Female | 1.315 (1.096-1.577) | 0.003 | 1.063 (0.818-1.382) | 0.646 | 0.839 (0.544-1.294) | 0.426 | 1.221 (0.820-1.817) | 0.326 |
Race | ||||||||
White | 1 | 1 | 1 | 1 | ||||
Black | 1.014 (0.758-1.355) | 0.928 | 0.882 (0.561-1.386) | 0.586 | 0.588 (0.236-1.466) | 0.254 | 0.698 (0.348-1.399) | 0.310 |
Other | 0.658 (0.481-0.899) | 0.009 | 0.659 (0.415-1.047) | 0.078 | 0.774 (0.335-1.790) | 0.550 | 1.136 (0.586-2.204) | 0.706 |
Primary site | ||||||||
Head | 1 | 1 | 1 | 1 | ||||
Body/tail | 1.515 (1.229-1.867) | <0.001 | 1.009 (0.743-1.371) | 0.953 | 1.034 (0.641-1.668) | 0.890 | 1.725 (0.989-3.007) | 0.055 |
Other | 1.119 (0.866-1.445) | 0.389 | 1.179 (0.819-1.698) | 0.375 | 1.528 (0.804-2.903) | 0.196 | 1.962 (1.068-3.602) | 0.030 |
Histologic grade | ||||||||
I | 1 | 1 | 1 | 1 | ||||
II | 1.676 (1.207-2.327) | 0.002 | 1.118 (0.457-2.735) | 0.808 | 0.511 (0.161-1.626) | 0.256 | 0.960 (0.313-2.944) | 0.943 |
III | 1.903 (1.304-2.778) | 0.001 | 1.169 (0.460-2.968) | 0.743 | 2.108 (0.635-6.996) | 0.223 | 1.029 (0.343-3.082) | 0.960 |
IV | 1.071 (0.334-3.431) | 0.908 | 1.593 (0.191-13.307) | 0.667 | – | – | ||
Unknown | 2.513 (1.856-3.402) | <0.001 | 1.584 (0.699-3.588) | 0.270 | 0.767 (0.328-1.793) | 0.540 | 0.940 (0.379-2.333) | 0.894 |
Histological subtype | ||||||||
Mucinous adenocarcinoma | 1 | 1 | 1 | 1 | ||||
Mucin-producing adenocarcinoma | 0.554 (0.428-0.718) | <0.001 | 0.988 (0.751-1.300) | 0.933 | 0.822 (0.488-1.385) | 0.461 | 0.645 (0.424-0.981) | 0.041 |
Intraductal papillary-mucinous carcinoma | 0.174 (0.116-0.261) | <0.001 | 0.836 (0.205-3.408) | 0.803 | 2.185 (0.288-16.606) | 0.450 | – | |
-Others | 0.294 (0.176-0.489) | <0.001 | 0.643 (0.203-2.036) | 0.452 | 1.572 (0.532-4.646) | 0.413 | 1.285 (0.306-5.398) | 0.732 |
Tumor size | ||||||||
≤3 cm | 1 | 1 | 1 | 1 | ||||
>3 cm |
1.778 (1.464-2.160) | <0.001 | 0.741 (0.546-1.004) | 0.053 | 1.398 (0.890-2.198) | 0.146 | 1.334 (0.861-2.067) | 0.198 |
Surgery | ||||||||
No | 1 | 1 | 1 | 1 | ||||
Yes | 0.209 (0.171-0.256) | <0.001 | 0.394 (0.162-0.958) | 0.040 | 0.038 (0.000-6.488) | 0.212 | 0.587 (0.081-4.231) | 0.587 |
Radiotherapy | ||||||||
No | 1 | 1 | 1 | 1 | ||||
Yes | 0.731 (0.584-0.914) | 0.006 | 1.236 (0.633-2.414) | 0.534 | 0.705 (0.324-1.534) | 0.378 | 0.950 (0.555-1.627) | 0.853 |
Chemotherapy | ||||||||
No | 1 | 1 | 1 | 1 | ||||
Yes | 0.993 (0.823-1.199) | 0.945 | 0.383 (0.292-0.503) | <0.001 | 0.290 (0.180-0.469) | <0.001 | 0.223 (0.140-0.357) | <0.001 |
Marital status | ||||||||
Unmarried | 1 | 1 | 1 | 1 | ||||
Married | 0.822 (0.682-0.991) | 0.040 | 0.796 (0.606-1.045) | 0.796 | 0.831 (0.512-1.348) | 0.454 | 0.663 (0.440-0.997) | 0.048 |
Unknown | 0.623 (0.368-1.054) | 0.078 | 0.688 (0.399-1.184) | 0.177 | 1.172 (0.563-2.441) | 0.672 | 1.206 (0.431-3.375) | 0.721 |
Multivariable Cox regression analysis of cancer-specific survival in patient with IPMN with associated invasive carcinoma.
Variables | No metastasis | liver | lung | Multiple metastases | ||||
---|---|---|---|---|---|---|---|---|
HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | |
Age | ||||||||
≤65 | 1 | 1 | 1 | 1 | ||||
>65 | 1.072 (0.885-1.298) | 0.476 | 0.981 (0.728-1.322) | 0.901 | 1.715 (1.037-2.838) | 0.036 | 1.161 (0.688-1.5959) | 0.576 |
Gender | ||||||||
Male | 1 | 1 | 1 | 1 | ||||
Female | 0.977 (0.817-1.187) | 0.817 | 0.962 (0.714-1.296) | 0.796 | 1.315 (0.799-2.163) | 0.281 | 1.485 (0.905-2.438) | 0.118 |
Race | ||||||||
White | 1 | 1 | 1 | 1 | ||||
Black | 0.859 (0.635-1.161) | 0.322 | 0.851 (0.511-1.418) | 0.535 | 1.126 (0.437-2.898) | 0.806 | 1.594 (0.704-3.605) | 0.263 |
Other | 0.639 (0.462-0.884) | 0.007 | 0.585 (0.357-0.959) | 0.034 | 0.819 (0.219-3.060) | 0.767 | 1.254 (0.398-3.949) | 0.699 |
Primary site | ||||||||
Head | 1 | 1 | 1 | 1 | ||||
Body/tail | 1.337 (1.077-1.659) | 0.008 | 1.160 (0.831-1.618) | 0.383 | 1.180 (0.675-2.063) | 0.562 | 2.239 (1.140-4.400) | 0.019 |
Other | 1.042 (0.799-1.360) | 0.760 | 1.197 (0.817-1.755) | 0.857 | 1.131 (0.558-2.291) | 0.733 | 1.638 (0.821-3.269) | 0.161 |
Histologic grade | ||||||||
I | 1 | 1 | 1 | 1 | ||||
II | 1.547 (1.101-2.173) | 0.012 | 0.752 (0.286-1.979) | 0.564 | 0.402 (0.101-1.595) | 0.195 | 0.756 (0.210-2.729) | 0.670 |
III | 1.718 (1.159-2.546) | 0.007 | 0.668 (0.232-1.923) | 0.454 | 1.632 (0.423-6.292) | 0.477 | 0.886 (0.244-3.220) | 0.854 |
IV | 0.782 (0.239-2.554) | 0.684 | 3.110 (0.324-29.817) | 0.325 | – | – | ||
Unknown | 1.114 (0.802-1.548) | 0.520 | 1.055 (0.422-2.634) | 0.909 | 0.339 (0.115-1.001) | 0.050 | 0.933 (0.339-2.566) | 0.893 |
Histological subtype | ||||||||
Mucin-producing adenocarcinoma | 1 | 1 | 1 | 1 | ||||
Mucinous adenocarcinoma | 0.698 (0.534-0.913) | 0.009 | 1.042 (0.775-1.402) | 0.784 | 0.897 (0.485-1.662) | 0.730 | 0.870 (0.549-1.381) | 0.555 |
Intraductal papillary-mucinous carcinoma | 0.350 (0.228-0.538) | <0.001 | 0.963 (0.216-4.295) | 0.961 | 1.412 (0.052-38.318) | 0.838 | 0.535 (0.112-2.564) | 0.434 |
Others | 0.556 (0.326-0.947) | 0.031 | 0.723 (0.223-2.345) | 0.590 | 1.839 (0.467-7.240) | 0.383 | – | |
Tumor size | ||||||||
≤3 cm | 1 | 1 | 1 | 1 | ||||
>3 cm |
1.380 (1.126-1.692) | 0.002 | 0.803 (0.565-1.140) | 0.220 | 1.050 (0.629-1.752) | 0.853 | 1.593 (0.970-2.614) | 0.066 |
Surgery | ||||||||
No | 1 | 1 | 1 | 1 | ||||
Yes | 0.218 (0.171-0.278) | <0.001 | 0.467 (0.172-1.268) | 0.135 | – | 1.717 (0.148-19.978) | 0.666 | |
Radiotherapy | ||||||||
No | 1 | 1 | 1 | 1 | ||||
Yes | 0.663 (0.523-0.841) | 0.001 | 1.320 (0.640-2.725) | 0.452 | 0.767 (0.309-1.904) | 0.567 | 1.176 (0.653-2.119) | 0.589 |
Chemotherapy | ||||||||
No | 1 | 1 | 1 | 1 | ||||
Yes | 0.770 (0.620-0.956) | 0.018 | 0.351 (0.256-0.481) | <0.001 | 0.242 (0.134-0.435) | <0.001 | 0.191 (0.108-0.340) | <0.001 |
Marital status | ||||||||
Unmarried | 1 | 1 | 1 | 1 | ||||
Married | 0.885 (0.725-1.080) | 0.228 | 1.122 (0.814-1.545) | 0.482 | 1.098 (0.620-1.944) | 0.748 | 0.799 (0.495-1.289) | 0.358 |
Unknown | 1.077 (0.637-1.822) | 0.782 | 0.998 (0.539-1.849) | 0.995 | 0.997 (0.439-2.267) | 0.995 | 2.751 (0.846-8.950) | 0.093 |
To identify the risk factors associated with distant metastases in patients with IPMN with associated invasive carcinoma, the univariable and multivariable regression analyses were performed. In the univariable regression model, tumor primary site, histologic grade, surgery, lymph node surgery, chemotherapy, and marital status were associated with distant metastases. However, in multivariable logistic regression model after adjustment revealed that tumor located in body/tail was the independent risk factor related to distant metastases. The results were summarized in
Univariate and multivariate logistic regression analyses of baseline factors associated with distant metastases in patients with IPMN with associated invasive carcinoma.
Variables | Univariate analyses | Multivariate analyses | |||||
---|---|---|---|---|---|---|---|
OR | 95% CI | P | OR | 95% CI | P | ||
Age | >65 vs.≤65 | 1.134 | 0.895-1.437 | 0.296 | 0.910 | 0.676-1.226 | 0.537 |
Gender | Male vs. Female | 1.089 | 0.861-1.376 | 0.478 | 0.849 | 0.632-1.141 | 0.277 |
Race | Black vs. White | 0.791 | 0.532-1.176 | 0.247 | 0.662 | 0.411-1.066 | 0.089 |
Other vs. White | 0.693 | 0.468-1.027 | 0.068 | 0.783 | 0.485-1.264 | 0.317 | |
Site | Body/tail vs. Head | 3.756 | 2.848-4.952 | <0.001 | 2.740 | 1.971-3.811 | <0.001 |
Other vs. Head | 2.654 | 1.913-3.682 | <0.001 | 1.748 | 1.194-2.557 | 0.004 | |
Grade | II vs. I | 1.520 | 0.858-2.692 | 0.151 | 1.175 | 0.583-2.367 | 0.653 |
III vs. I | 2.248 | 1.213-4.164 | 0.010 | 1.614 | 0.742-3.508 | 0.227 | |
IV vs. I | 1.190 | 0.132-10.725 | 0.877 | 1.016 | 0.061-16.930 | 0.991 | |
Unknown vs. I | 6.501 | 3.955-10.687 | <0.001 | 1.750 | 0.959-3.192 | 0.068 | |
Surgery | Yes vs. No | 0.020 | 0.010-0.040 | <0.001 | 0.055 | 0.021-0.142 | <0.001 |
Lymph node surgery* | Yes vs. No | 0.037 | 0.022-0.061 | <0.001 | 0.445 | 0.204-0.971 | 0.042 |
Radiotherapy | Yes vs. No/Unknown | 0.352 | 0.243-0.509 | <0.001 | 0.466 | 0.301-0.721 | 0.001 |
Chemotherapy | Yes vs. No/Unknown | 0.922 | 0.727-1.169 | 0.501 | 1.036 | 0.763-1.406 | 0.823 |
Marital status | Unmarried vs. married | 0.801 | 0.627-1.023 | 0.075 | 0.789 | 0.578-1.077 | 0.136 |
Unknown vs. married | 1.914 | 1.103-3.323 | 0.021 | 2.335 | 1.095-4.981 | 0.028 |
*Regional lymph nodes have been removed by surgery.
We divided the whole cohort into two groups: training cohort and validation cohort. The training cohort was used to construct the nomogram for CSS and the validation cohort was used for external validation. Based on the risk factors in the multivariable Cox regression, a nomogram was constructed to predict probabilities of CSS (
Prognostic nomogram predicting 1-, 3-, and 5-year cancer-specific survival probability for patients with IPMN with associated invasive carcinoma, IPMC, Intraductal papillary-mucinous carcinoma; MA, mucinous adenocarcinoma; MPA,mucin-producing adenocarcinoma.
Calibration plots for 1-, 3-, and 5-year CSS in the
IPMN with associated invasive carcinoma has a distinct poor prognosis compared with other pancreatic cyst lesions. IPMNs have been increasingly detected due to recent increased awareness and improved diagnostic modalities. To our knowledge, the current study was the first article focusing on the effect of distant metastases on the survival of patients with IPMN with associated invasive carcinoma. From our data, we concluded that around 38% of all the patients suffered distant metastases during the progression of the disease. The most common distant metastatic organ was the liver, following by multiple sites, lung, and bone. Compared with no distant metastatic subgroup, the survival time was much shorter in patients with distant metastases. Meanwhile, different prognostic factors were identified in patients with various metastatic patterns. Furthermore, tumor located in body/tail was the independent risk factor related to distant metastases.
It is widely believed that metastases were closely associated with poor outcomes in advanced malignancies. Cancer metastases include lymph node metastases and distant organ metastases. The 5-year relative survival rate of IPMN with associated invasive carcinoma was 9.7%, while that was 10% in pancreatic cancer, according to SEER Cancer Stat Facts. The 5-year relative survival rate of IPMN with associated invasive carcinoma with distant metastases was 1.7%, and the 5-year relative survival rate of pancreatic cancer was 2.9% (
Previous studies reported that lymph node metastasis is a negative factor affecting the prognosis of IPMN with associated invasive carcinoma. Schnelldorfer et al. retrospective reviewed a cohort with IPMN with associated invasive carcinoma and found that patients with lymph node metastases have a shorter median survival time of 16 months, compared with that of patients without lymph node metastases was 41 months (
IPMNs of the pancreas are widely considered precursors of invasive pancreatic cancer. Based on our result and previous studies, it should be noted that the liver and lung are the most metastatic sites of IPMN with associated invasive carcinoma, which is consistent with distant metastasis of pancreatic cancer. The tendency of tumors to metastasize to specific organ sites may reflect the interaction between the underlying biology of tumor cells and the host organ microenvironment. IPMN with associated invasive carcinoma has been defined as a subtype of invasive ductal adenocarcinoma (
The therapeutic option is an essential factor influencing the prognosis of IPMN with associated invasive carcinoma. In our study, the multivariate Cox regression analysis indicated that chemotherapy could improve the survival of IPMN with associated invasive carcinoma with metastatic disease. Although surgical resection is considered the standard treatment for IPMN with associated invasive carcinoma, patients with IPMN with associated invasive carcinoma will benefit from chemotherapy. Coponi et al. retrospectively analyzed outcomes of 64 patients who received gemcitabine-based chemotherapy, concluding that patients with resected IPMN with associated invasive carcinoma might benefit from adjuvant treatment (
The results of our study should be interpreted in the context of its potential limitations. First, the SEER data only provide information about bone, brain, liver, and lung; thus, we were unable to evaluate the effect of other organ metastases on the survival of patients with IPMN with associated invasive carcinoma. Therefore, there may be some patients with metastatic disease that cannot be captured in our analyses. Second, selection bias must be noted in our retrospective study, which usually occurs when the selection criteria are associated with the risk factors under investigation (
Our study first reports the information about the effect of distant metastases on patients with IPMN with associated invasive carcinoma. The liver is the most common site of distant metastases in IPMN with associated invasive carcinoma. Cox regression analyses show that tumor located in the pancreatic body/tail and chemotherapy are independent prognostic factors for CSS in patients with multiple metastases. Further, tumor located in body/tail is identified as a risk factor of distant metastases. It provides insight into the similar distant metastatic pattern between IPMN with associated invasive carcinoma and pancreatic cancer. Due to the limitations mentioned above, further trials are needed to investigate the metastatic pattern in IPMN with associated invasive carcinoma.
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
XH wrote the manuscript. XH and SY participated in data collection, manuscript drafting, table/figure creation, and manuscript revision. GD, XL and JW assisted with performing the experiments. YG helped to analyze the data. JZ designed the study and supervised the work. XH and SY contributed with essential ideas and discussion. All authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.