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A systematic review and meta-analysis of predictors of recurrence in patients with Solid Pseudopapillary Tumors of the Pancreas
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https://doi.org/10.1016/j.hpb.2019.06.005
REVIEW ARTICLE
A systematic review and meta-analysis of predictors of recurrence in patients with Solid Pseudopapillary Tumors of the Pancreas Natesh Yepuri1, Rana Naous2, Andreas H. Meier1, Robert N. Cooney1, Dilip Kittur1, Chandrakanth Are3, Ajay Jain1 & Mashaal Dhir1 1
Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, 13210, USA, 2Department of Pathology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA, and 3Department of Surgery, Division of Surgical Oncology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
Abstract Background: The recurrence rates and predictors of recurrence in patients with Solid Pseudopapillary tumors (SPT) are unclear, which makes it challenging to determine the duration of follow-up. The aim of the current study was to perform a systematic review and meta-analysis to determine the recurrence rates and pathologic factors associated with recurrence in patients with SPT. Methods: A PubMed, Scopus, and Web of Science search was conducted to identify studies of SPT published during the last 15 years: (09/2002–09/2017). Studies reporting on patients with SPT and follow-up of >5 years were included. The search strategy was conducted per 2009 PRISMA guidelines. Results: A total of 103 studies reporting on 2599 non-metastatic SPT patients were identified. Sixtynine patients (2.6%) developed recurrence during follow-up. Pooled estimates from studies with a sample size >20 (N = 33) noted an overall recurrence rate of 2% (95% CI 1–2%). Male gender (OR 1.960), positive lymph nodes (OR 11.9), R1 margins (OR 11.1), and LVI (OR 5.5), were associated with a significantly (all p < 0.05) increased risk of recurrence. Conclusion: Current meta-analysis suggests that only 2% of patients with SPT experience recurrence after resection. These data will guide the treating physicians and patients regarding recurrence rates and help identify patients at increased risk of recurrence during follow-up. Received 10 November 2018; accepted 9 June 2019
Correspondence Mashaal Dhir, Division of Surgical Oncology, Department of Surgery, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210, USA. E-mail: [email protected]
Introduction Solid Pseudopapillary tumors (SPT) are rare pancreatic neoplasms that typically affect adolescent and young adults (AYA), especially women.1–3 The majority of patients are symptomatic at presentation due to the large size of these tumors.1,4 Thirty percent of SPTs are >10 cm at presentation and are most commonly located in the pancreatic body and tail.1,4 Surgery remains the mainstay of treatment.1,4 The histopathologic analysis of SPTs usually demonstrates characteristic solid areas of poorly cohesive cells forming pseudopapillae and cystic areas containing hemorrhage.5 Additionally, many of these tumors harbor somatic mutations in beta-catenin, leading to nuclear localization of beta-catenin, which can be easily detected by immunohistochemistry and aids in pathologic diagnosis.
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Although patients with SPTs have an excellent long-term prognosis, 10–15% of the patients experience recurrence during long term follow-up.2 Based on the current literature, histologic features cannot reliably predict the malignant/recurrence potential of these tumors. Therefore these tumors are classified as borderline to low grade malignant potential tumors, regardless of the microscopic features per 2010 WHO classification.6 Cancer diagnosis and the required long-term follow-up at a young age can have significant psychosocial and socioeconomic implications for these young patients as they are often going through significant life events such as transitioning to higher education, marriage, gaining financial independence or starting a family.7 Given the lack of established clinical or histologic criteria predicting
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Please cite this article as: Yepuri N et al., A systematic review and meta-analysis of predictors of recurrence in patients with Solid Pseudopapillary Tumors of the Pancreas, HPB, https://doi.org/10.1016/j.hpb.2019.06.005
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recurrence or biologic behavior, it is challenging to discuss prognosis and determine the duration of post-resection followup in these patients. Malignant behavior (e.g., the risk of recurrence) has been previously linked to the male gender, advanced age, large tumor size, high mitotic index, high Ki-67 and extensive necrosis.2,8 However, the majority of the data are from small and retrospective studies given the low incidence of SPT.2,8 This study aimed to perform a systematic review and meta-analysis to determine the recurrence rates and identify pathologic factors associated with recurrence to help stratify the subset of patients who will need long-term follow-up.
Methodology Search strategy: definitions, data extraction, inclusion, and exclusion criteria A literature search was performed using PubMed, Scopus, and Web of Science databases for the last 15 years (09/2002–09/2017) using the keywords “Solid Pseudopapillary tumor of Pancreas.” Only articles published in the English language were included. For data extraction, the first author (N.Y.) and senior author (M.D) selected the studies and assessed for eligibility. This tumor has been previously described by several other terms such as ‘solid cystic tumor’, ‘papillary cystic tumor’, ‘papillary epithelial neoplasia’, ‘solid and papillary epithelial neoplasia’, ‘papillary epithelial tumor’, ‘Frantz’s tumor’, ‘solid and papillary tumor’, ‘solid-cystic papillary epithelial neoplasm’, and ‘benign or malignant papillary tumor of the pancreas’. However, in 1996 World Health Organization (WHO) standardized the terminology with the name ‘Solid Pseudopapillary tumor’ of the pancreas. Although, the other accessory terms for this tumor were not included in the forward search, these were included in the backward search. An extensive backward was performed using cross-references from the bibliographies of relevant articles and review articles to ensure a comprehensive search. PRISMA 2009 guidelines for search and reporting were followed.9 The following articles were excluded from the analysis 1) review articles/letters, case reports, meeting abstracts 2) duplicate publications 3) articles including patients with Stage IV disease at presentation. As case reports can cause significant bias in the calculation of recurrence rates, these were excluded. In the event of duplicate publication, the largest series was included in the final analysis. Studies with only case series (i.e.,> 1 patient with SPT) with a follow-up of >5 years were included in the final qualitative and quantitative synthesis. Early recurrence was defined as recurrence within five years of follow-up and recurrence between 5 and ten years was characterized as late recurrence. Very late recurrence was defined as recurrence beyond ten years. Quality assessment of the studies was not performed given the limited number and retrospective nature of all studies. Whenever available, individual patient data were extracted for clinical and
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histopathologic features including the presence of lymphovascular invasion (LVI), capsular invasion, perineural invasion (PNI), resection margins, Ki-67 index (%), and time to recurrence of each patient. Statistical methods Summary statistics were reported as total and percentages for categorical variables. The continuous variables were reported as mean or median with corresponding standard deviation or ranges, respectively. Meta-analysis was performed using the STATA 14.2 statistical software (StataCorp, 4905 Lakeway Drive, College Station, Texas). A meta-analysis of proportions strategy using the command “metaprop” was utilized for calculation of pooled recurrence rates. Pooled estimates of proportions with corresponding 95% Confidence intervals were reported and calculated using Freeman–turkey double arcsine transformation.10 Random effects model was used due to the suspicion of heterogeneity among different studies. Heterogeneity was explored using the chi-squared test with a significance level of p = 0.05. I2 was calculated to quantify heterogeneity further. Publication bias was explored using funnel plots, and symmetry of the funnel plot was analyzed using visual inspection and Egger’s tests to rule out any bias from the studies with small patient samples.11,12 For the meta-analysis of individual pathologic features such as lymphovascular invasion, odds ratios, and 95% confidence intervals (CI) were computed using 2 × 2 tables. These tables were constructed using the number of patients with the presence and absence of risk factors vs. those who had recurrence vs. no recurrence. The ‘metan’ command in STATA was used for computing the odds ratios and 95% CI. A random-effects model was used. Heterogeneity, I2, and publication bias were assessed as above.
Results Study characteristic and recurrence rates A total of 877 articles, with some overlap between databases, were identified. After application of exclusion criteria, title, and abstract review was performed for the remaining 497 articles. Full texts were reviewed for the relevant 248 articles. Duplicate publications by authors on the same dataset (i.e., patients from the same institution), were excluded (n = 33). Fig. 1 depicts the search strategy in detail. A total of 103 articles (patient series) reporting on 2599 nonmetastatic patients with SPT were included in the final quantitative analysis (supplementary table 1). All studies were retrospective in nature. The number of patients in the included studies ranged from 2 to 128, with a median of 14 (interquartile range [IQR] 7–30). A total of 69 (2.6%) patients developed recurrence during the follow-up. To minimize small study bias, only studies with a sample size of >20 were included in the metaanalysis. Pooled estimates from studies with a sample size >20
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Please cite this article as: Yepuri N et al., A systematic review and meta-analysis of predictors of recurrence in patients with Solid Pseudopapillary Tumors of the Pancreas, HPB, https://doi.org/10.1016/j.hpb.2019.06.005
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Figure 1 PRISMA diagram demonstrates the detailed search strategy
(number of studies = 33, patients = 1897) noted an overall recurrence rate of 2% (44/1897) (95% CI 1–2%)13–50 [Fig. 2]. There was statistically significant heterogeneity within the studies (p = 0.020), and the contribution of heterogeneity to variation in the pooled estimates was 36.5%. Publication bias was explored using a funnel plot. The visual inspection of the funnel plot noted that it was symmetric, thus ruling out any significant bias from small study effects (supplementary figure 1). Additionally, Egger’s test noted a p-value of >0.05 (Coefficient −0.001, standard error 0.0187, t = −0.05, p-value 0.189), thus ruling out any significant publication bias.
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Time to recurrence The time to recurrence was available for 48 patients. The median time to recurrence was 41 months (IQR 22–72 months). Thirtyfour of the 48 patients (71%) recurred within the first five years, whereas twelve patients (12/48, 25%) developed recurrence at >5 but <10 years. Only two patients (4%) recurred at >10 years. The longest recurrence was reported at 168 months (14 years). Details of follow-up beyond 15 years were available in four patients and none of these patient with a follow-up beyond 15 years developed recurrence. Scatter plot (supplementary figure 2) depicts the times to recurrence for individual patients.
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Please cite this article as: Yepuri N et al., A systematic review and meta-analysis of predictors of recurrence in patients with Solid Pseudopapillary Tumors of the Pancreas, HPB, https://doi.org/10.1016/j.hpb.2019.06.005
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Figure 2 The forest plot demonstrates the pooled recurrence rates (%) for studies with >20 patients
Factors associated with recurrence Data were gathered on gender, resection margins, LVI, lymph node status, Ki-67, capsular invasion, and PNI for non-recurrent and recurrent patients, and odds ratios were computed as described above. Data on gender and recurrence rates was available for 24 studies with 660 patients. Male gender was associated with statistically significant odds for recurrence (OR 1.960, 95% confidence interval 1.010–3.805, p = 0.047, supplementary figure 3A). The heterogeneity within the studies was not statistically significant (Heterogeneity chi-squared 12.74, p = 0.957), and there was no significant publication bias (Egger test p = 0.064). Among pathologic factors, positive lymph nodes (OR 11.9), R1 resection margins (OR 11.1), and LVI (OR 5.5) were associated with a statistically significant odds ratio for recurrence
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(supplementary Fig. 3B-D). PNI, Capsular invasion, and Ki67 were associated with increased odds for recurrence, but these were not statistically significant. Table 1 summarizes the odds ratios with corresponding 95% confidence intervals, number of studies, and patients included in each meta-analysis along with factors evaluating heterogeneity and bias. There was no statistically significant heterogeneity or publication bias noted for lymph node status, resection margins, and LVI. Subcategorization of the factors associated with recurrence by the time to recurrence was done. Interestingly, positive resection margins, LVI, and capsular invasion were seen in both patients with early and late recurrences. Only LVI was seen in patients with very late recurrences (supplementary figure 4). Additionally, elevated Ki-67 was only reported in patients with early recurrences.
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Please cite this article as: Yepuri N et al., A systematic review and meta-analysis of predictors of recurrence in patients with Solid Pseudopapillary Tumors of the Pancreas, HPB, https://doi.org/10.1016/j.hpb.2019.06.005
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Table 1 Summary of pooled estimates for meta-analysis for various factors associated with recurrence in patients with solid pseudopapillary
tumors I2 (%)
Egger’s P value for bias
0.957
0
0.064
5.28
0.809
0
0.235
333
11.3
0.418
0.3
0.217
15
536
9.35
0.808
0
0.198
13
355
9.27
0.68
0
0.987
2.135 (0.550–8.277)
8
290
10.94
0.141
35.9
0.761
2.217 (0.177–27.694)
2
35
0.02
0.884
0
–
Factors
Odds Ratio (95% CI)
Number of studies
Total Patients
Heterogeneity Chi2
P value
Male gender
1.960 (1.010–3.805)
24
660
12.74
Positive lymph nodes
11.918 (3.798–37.393)
10
355
R1 margins
11.132 (4.342–28.541)
12
LVI
5.504 (2.461–12.311)
Perineural invasion
1.381 (0.580–3.292)
Capsular invasion Ki67 4%
Recurrence type and survival Data on the type of recurrence was available for 58 patients. Seventy-two percent (42/58) of the patients who had a recurrence experienced distant recurrence only. Nineteen percent (11/58) of the recurrent patients experienced local recurrence only whereas nine percent (5/58) experienced both local and distant recurrence. Additionally, in this analysis, 3.9% (45/ 1143) of patients had R1 margin, and 26.6% (12/45) patients with R1 margins developed recurrence. Among these recurrent patients with R1 margins, 16.6% (2/12) developed local recurrence, which is close to 19% (11/58) of overall local recurrence occurring in all recurrent patients. Data on all alive and deceased patients in the recurrent and non-recurrent categories were available for 18 studies with 731 patients. The presence of recurrence was associated with increased odds for mortality (OR 43.830, 17.944 –107.060, p < 0.001, Fig. 3). There was no significant heterogeneity among the studies (Heterogeneity chi-squared 11.69, p = 0.819, I2 0%). However, publication bias was noted (Egger p = 0.049). A funnel plot was used to identify the outlier study (Supplementary figure 5).20 A meta-analysis of the remaining 17 studies with 691 patients again note that recurrence was associated with increased odds for mortality (OR 63.219, 95% CI 24.867–160.717, p < 0.001). In this subset of 17 studies, no publication bias was noted (Egger, p = 0.563). During the follow-up period, (16/69) recurrent patients died, but the majority were alive (53/69). Among these 53 patients who underwent treatment, ten patients had local recurrence, 21 patients developed systemic recurrence, one patient with local recurrence developed distant recurrence, while details about recurrence were not available in 21 patients. Ten patients with local recurrence underwent a second resection and remained disease-free. One patient with local recurrence that developed distant recurrence during follow-up but underwent surgery and remained disease-free. There are 21 patients with distant metastasis (hepatic, peritoneal, omental metastasis) who underwent hepatectomy and received chemotherapy. Of these patients, 18/21 patients were alive and remained disease-free, 2/21 developed second recurrence and underwent additional surgeries
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but were disease-free during the last follow-up. Only one patient (1/21) died of disease recurrence.
Discussion The current data suggest that approximately 2% of patients with SPT experience recurrence after resection. This is an interesting finding as previous smaller studies have reported higher recurrence rates (5–15%).2 Law et al. conducted a systematic review of SPT patients to determine the changes in the number of patients with SPT and management over time. In their review of 2744 patients, recurrence data were available for 1866 patients, and recurrence was noted in 4.4% of the patients. Similarly, Papavramidis et al. reviewed 718 patients of SPT (1933–2003) in English literature and noted a recurrence rate of 6.63% [112]. Studies with >20 patients were included when computing the recurrence rates to minimize bias, and this may have resulted in lower recurrence rates observed in the current study. The median time to recurrence in the current study was 41 months (IQR 22–72 months). This is similar to the previous report by Law et al., who noted a mean time to recurrence of 50.5 months.51 In the current study, we further stratified the patients by the time to recurrence. Although the majority developed recurrence within five years, a fourth of the patients developed recurrence beyond five years. This further highlights the fact that long-term follow-up is essential to detect recurrences, especially for those who are at risk for recurrence. In four patients who were followed beyond 15 years, no recurrences have been reported. As many patients are young and otherwise healthy, a finite follow up of fifteen years can be considered until more data become available. The current study is the first study to perform a meta-analysis of pathologic factors associated with recurrence. The presence of lymph node-positive disease and LVI were associated with a statistically significant risk of recurrence. Additionally, from a technical standpoint, an R1 resection margin also increases the risk of recurrence. PNI, capsular invasion and elevated Ki-67 although associated with an increased odds of recurrence, the association was not found to be statistically significant. The
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Please cite this article as: Yepuri N et al., A systematic review and meta-analysis of predictors of recurrence in patients with Solid Pseudopapillary Tumors of the Pancreas, HPB, https://doi.org/10.1016/j.hpb.2019.06.005
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Figure 3 The forest plot demonstrates the pooled odds ratio for mortality in patients with SPT who developed recurrence
current results are supported by Kang et al., who reported that factors such as capsular invasion and perineural invasion were not statistically significant in predicting recurrence of resected SPT of the pancreas.6 However, the lack of statistical significance for these factors in the current study could also be a type 2 error due to smaller numbers. Since the rate of recurrence is overall low, some experts may question the need for long term follow up in those without any risk factors. Given the lack of individual patient data and missing data, a definitive assessment of the likelihood of recurrence in the absence of all risk factors could not be performed. The goal of the current study was to provide data regarding recurrence rates and determine association with pathologic factors which may be implicated in these patients. Conclusions regarding the deescalated follow up in those without any clinical or pathologic risk factors are beyond the scope of this article. However, those patients who develop recurrent disease have an increased risk of dying from the disease. The current study has several limitations. All studies included in the systematic review and meta-analysis were retrospective in nature. Although multiple databases were searched, and an extensive backward search was performed, there is a possibility that some studies were not included. Additionally, studies not published in the English language were not included in the
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current review and meta-analysis. Many of the studies did not report on the outcomes studied in the current meta-analysis. Factors such as advanced age and tumor size >5 cm have been previously reported by some to be associated with increased risk of malignancy but could not be analyzed in the current study. Due to limited numbers, one cannot definitively exclude PNI, capsular invasion and Ki-67 as risk factors for recurrenc as this could be a type 2 error. Additionally, individual patient data were not able to be extrapolated from the included studies. Many previous studies have followed arbitrary criteria to suggest malignancy. In the current study, only recurrence rates after resection in those who presented with non-metastatic disease were analyzed. Rates of recurrence may be higher in patients with metastatic disease and data from the current study cannot be extrapolated to such patients. Despite the limitations, this is the largest review and meta-analysis on the recurrence rates and pathologic factors associated with recurrence in patients with SPT. In conclusion, the current data suggests that only 2% of patients with SPT experience recurrence after resection. This is an interesting and somewhat new finding as previously reported recurrence rates in smaller studies were 5–15% and systematic reviews reported 4–6% recurrence rates. The majority of recurrences occur at 5 years. However, 23% experience
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recurrence between 5 and ten years, thus necessitating long-term follow-up. Male patients and patients with positive lymph nodes, R1 margins and LVI are associated with an increased risk for recurrence. A standard reporting template for the pathology reports of SPT should be followed, which may further allow a systematic study of the factors associated with recurrence, along with international registries to track the long-term outcomes of these patients The current data will help the treating physicians to counsel patients with SPT regarding recurrence rates and help underscore the need for long-term follow up.
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Acknowledgments None.
et al. (2010) Pancreatic tumors in children and adolescents: the Italian TREP project experience. Pediatr Blood Cancer 54:675–680. 17. Ellerkamp V, Warmann SW, Vorwerk P, Leuschner I, Fuchs J. (2012)
Funding None declared.
Exocrine pancreatic tumors in childhood in Germany. Pediatr Blood Cancer 58:366–371. 18. El-Bahrawy MA, Rowan A, Horncastle D, Tomlinson I, Theis BA,
Conflicts of interest None declared.
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824–833. 39. Serrano PE, Serra S, Al-Ali H, Gallinger S, Greig PD, McGilvray ID et al. (2014) Risk factors associated with recurrence in patients with solid
(2014) A systematic review of solid-pseudopapillary neoplasms: are these rare lesions? Pancreas 43:331–337.
pseudopapillary tumors of the pancreas. JOP: J Pancreas 15:561–568. 40. Speer AL, Barthel ER, Patel MM, Grikscheit TC. (2012) Solid pseudo-
Appendix A. Supplementary data
papillary tumor of the pancreas: a single-institution 20-year series of
Supplementary data to this article can be found online at https://doi.org/10.
pediatric patients. J Pediatr Surg 47:1217–1222.
1016/j.hpb.2019.06.005.
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https://doi.org/10.1016/j.hpb.2019.06.005
REVIEW ARTICLE
A systematic review and meta-analysis of predictors of recurrence in patients with Solid Pseudopapillary Tumors of the Pancreas Natesh Yepuri1, Rana Naous2, Andreas H. Meier1, Robert N. Cooney1, Dilip Kittur1, Chandrakanth Are3, Ajay Jain1 & Mashaal Dhir1 1
Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, 13210, USA, 2Department of Pathology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA, and 3Department of Surgery, Division of Surgical Oncology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
Abstract Background: The recurrence rates and predictors of recurrence in patients with Solid Pseudopapillary tumors (SPT) are unclear, which makes it challenging to determine the duration of follow-up. The aim of the current study was to perform a systematic review and meta-analysis to determine the recurrence rates and pathologic factors associated with recurrence in patients with SPT. Methods: A PubMed, Scopus, and Web of Science search was conducted to identify studies of SPT published during the last 15 years: (09/2002–09/2017). Studies reporting on patients with SPT and follow-up of >5 years were included. The search strategy was conducted per 2009 PRISMA guidelines. Results: A total of 103 studies reporting on 2599 non-metastatic SPT patients were identified. Sixtynine patients (2.6%) developed recurrence during follow-up. Pooled estimates from studies with a sample size >20 (N = 33) noted an overall recurrence rate of 2% (95% CI 1–2%). Male gender (OR 1.960), positive lymph nodes (OR 11.9), R1 margins (OR 11.1), and LVI (OR 5.5), were associated with a significantly (all p < 0.05) increased risk of recurrence. Conclusion: Current meta-analysis suggests that only 2% of patients with SPT experience recurrence after resection. These data will guide the treating physicians and patients regarding recurrence rates and help identify patients at increased risk of recurrence during follow-up. Received 10 November 2018; accepted 9 June 2019
Correspondence Mashaal Dhir, Division of Surgical Oncology, Department of Surgery, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210, USA. E-mail: [email protected]
Introduction Solid Pseudopapillary tumors (SPT) are rare pancreatic neoplasms that typically affect adolescent and young adults (AYA), especially women.1–3 The majority of patients are symptomatic at presentation due to the large size of these tumors.1,4 Thirty percent of SPTs are >10 cm at presentation and are most commonly located in the pancreatic body and tail.1,4 Surgery remains the mainstay of treatment.1,4 The histopathologic analysis of SPTs usually demonstrates characteristic solid areas of poorly cohesive cells forming pseudopapillae and cystic areas containing hemorrhage.5 Additionally, many of these tumors harbor somatic mutations in beta-catenin, leading to nuclear localization of beta-catenin, which can be easily detected by immunohistochemistry and aids in pathologic diagnosis.
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Although patients with SPTs have an excellent long-term prognosis, 10–15% of the patients experience recurrence during long term follow-up.2 Based on the current literature, histologic features cannot reliably predict the malignant/recurrence potential of these tumors. Therefore these tumors are classified as borderline to low grade malignant potential tumors, regardless of the microscopic features per 2010 WHO classification.6 Cancer diagnosis and the required long-term follow-up at a young age can have significant psychosocial and socioeconomic implications for these young patients as they are often going through significant life events such as transitioning to higher education, marriage, gaining financial independence or starting a family.7 Given the lack of established clinical or histologic criteria predicting
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recurrence or biologic behavior, it is challenging to discuss prognosis and determine the duration of post-resection followup in these patients. Malignant behavior (e.g., the risk of recurrence) has been previously linked to the male gender, advanced age, large tumor size, high mitotic index, high Ki-67 and extensive necrosis.2,8 However, the majority of the data are from small and retrospective studies given the low incidence of SPT.2,8 This study aimed to perform a systematic review and meta-analysis to determine the recurrence rates and identify pathologic factors associated with recurrence to help stratify the subset of patients who will need long-term follow-up.
Methodology Search strategy: definitions, data extraction, inclusion, and exclusion criteria A literature search was performed using PubMed, Scopus, and Web of Science databases for the last 15 years (09/2002–09/2017) using the keywords “Solid Pseudopapillary tumor of Pancreas.” Only articles published in the English language were included. For data extraction, the first author (N.Y.) and senior author (M.D) selected the studies and assessed for eligibility. This tumor has been previously described by several other terms such as ‘solid cystic tumor’, ‘papillary cystic tumor’, ‘papillary epithelial neoplasia’, ‘solid and papillary epithelial neoplasia’, ‘papillary epithelial tumor’, ‘Frantz’s tumor’, ‘solid and papillary tumor’, ‘solid-cystic papillary epithelial neoplasm’, and ‘benign or malignant papillary tumor of the pancreas’. However, in 1996 World Health Organization (WHO) standardized the terminology with the name ‘Solid Pseudopapillary tumor’ of the pancreas. Although, the other accessory terms for this tumor were not included in the forward search, these were included in the backward search. An extensive backward was performed using cross-references from the bibliographies of relevant articles and review articles to ensure a comprehensive search. PRISMA 2009 guidelines for search and reporting were followed.9 The following articles were excluded from the analysis 1) review articles/letters, case reports, meeting abstracts 2) duplicate publications 3) articles including patients with Stage IV disease at presentation. As case reports can cause significant bias in the calculation of recurrence rates, these were excluded. In the event of duplicate publication, the largest series was included in the final analysis. Studies with only case series (i.e.,> 1 patient with SPT) with a follow-up of >5 years were included in the final qualitative and quantitative synthesis. Early recurrence was defined as recurrence within five years of follow-up and recurrence between 5 and ten years was characterized as late recurrence. Very late recurrence was defined as recurrence beyond ten years. Quality assessment of the studies was not performed given the limited number and retrospective nature of all studies. Whenever available, individual patient data were extracted for clinical and
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histopathologic features including the presence of lymphovascular invasion (LVI), capsular invasion, perineural invasion (PNI), resection margins, Ki-67 index (%), and time to recurrence of each patient. Statistical methods Summary statistics were reported as total and percentages for categorical variables. The continuous variables were reported as mean or median with corresponding standard deviation or ranges, respectively. Meta-analysis was performed using the STATA 14.2 statistical software (StataCorp, 4905 Lakeway Drive, College Station, Texas). A meta-analysis of proportions strategy using the command “metaprop” was utilized for calculation of pooled recurrence rates. Pooled estimates of proportions with corresponding 95% Confidence intervals were reported and calculated using Freeman–turkey double arcsine transformation.10 Random effects model was used due to the suspicion of heterogeneity among different studies. Heterogeneity was explored using the chi-squared test with a significance level of p = 0.05. I2 was calculated to quantify heterogeneity further. Publication bias was explored using funnel plots, and symmetry of the funnel plot was analyzed using visual inspection and Egger’s tests to rule out any bias from the studies with small patient samples.11,12 For the meta-analysis of individual pathologic features such as lymphovascular invasion, odds ratios, and 95% confidence intervals (CI) were computed using 2 × 2 tables. These tables were constructed using the number of patients with the presence and absence of risk factors vs. those who had recurrence vs. no recurrence. The ‘metan’ command in STATA was used for computing the odds ratios and 95% CI. A random-effects model was used. Heterogeneity, I2, and publication bias were assessed as above.
Results Study characteristic and recurrence rates A total of 877 articles, with some overlap between databases, were identified. After application of exclusion criteria, title, and abstract review was performed for the remaining 497 articles. Full texts were reviewed for the relevant 248 articles. Duplicate publications by authors on the same dataset (i.e., patients from the same institution), were excluded (n = 33). Fig. 1 depicts the search strategy in detail. A total of 103 articles (patient series) reporting on 2599 nonmetastatic patients with SPT were included in the final quantitative analysis (supplementary table 1). All studies were retrospective in nature. The number of patients in the included studies ranged from 2 to 128, with a median of 14 (interquartile range [IQR] 7–30). A total of 69 (2.6%) patients developed recurrence during the follow-up. To minimize small study bias, only studies with a sample size of >20 were included in the metaanalysis. Pooled estimates from studies with a sample size >20
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Figure 1 PRISMA diagram demonstrates the detailed search strategy
(number of studies = 33, patients = 1897) noted an overall recurrence rate of 2% (44/1897) (95% CI 1–2%)13–50 [Fig. 2]. There was statistically significant heterogeneity within the studies (p = 0.020), and the contribution of heterogeneity to variation in the pooled estimates was 36.5%. Publication bias was explored using a funnel plot. The visual inspection of the funnel plot noted that it was symmetric, thus ruling out any significant bias from small study effects (supplementary figure 1). Additionally, Egger’s test noted a p-value of >0.05 (Coefficient −0.001, standard error 0.0187, t = −0.05, p-value 0.189), thus ruling out any significant publication bias.
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Time to recurrence The time to recurrence was available for 48 patients. The median time to recurrence was 41 months (IQR 22–72 months). Thirtyfour of the 48 patients (71%) recurred within the first five years, whereas twelve patients (12/48, 25%) developed recurrence at >5 but <10 years. Only two patients (4%) recurred at >10 years. The longest recurrence was reported at 168 months (14 years). Details of follow-up beyond 15 years were available in four patients and none of these patient with a follow-up beyond 15 years developed recurrence. Scatter plot (supplementary figure 2) depicts the times to recurrence for individual patients.
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Figure 2 The forest plot demonstrates the pooled recurrence rates (%) for studies with >20 patients
Factors associated with recurrence Data were gathered on gender, resection margins, LVI, lymph node status, Ki-67, capsular invasion, and PNI for non-recurrent and recurrent patients, and odds ratios were computed as described above. Data on gender and recurrence rates was available for 24 studies with 660 patients. Male gender was associated with statistically significant odds for recurrence (OR 1.960, 95% confidence interval 1.010–3.805, p = 0.047, supplementary figure 3A). The heterogeneity within the studies was not statistically significant (Heterogeneity chi-squared 12.74, p = 0.957), and there was no significant publication bias (Egger test p = 0.064). Among pathologic factors, positive lymph nodes (OR 11.9), R1 resection margins (OR 11.1), and LVI (OR 5.5) were associated with a statistically significant odds ratio for recurrence
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(supplementary Fig. 3B-D). PNI, Capsular invasion, and Ki67 were associated with increased odds for recurrence, but these were not statistically significant. Table 1 summarizes the odds ratios with corresponding 95% confidence intervals, number of studies, and patients included in each meta-analysis along with factors evaluating heterogeneity and bias. There was no statistically significant heterogeneity or publication bias noted for lymph node status, resection margins, and LVI. Subcategorization of the factors associated with recurrence by the time to recurrence was done. Interestingly, positive resection margins, LVI, and capsular invasion were seen in both patients with early and late recurrences. Only LVI was seen in patients with very late recurrences (supplementary figure 4). Additionally, elevated Ki-67 was only reported in patients with early recurrences.
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Table 1 Summary of pooled estimates for meta-analysis for various factors associated with recurrence in patients with solid pseudopapillary
tumors I2 (%)
Egger’s P value for bias
0.957
0
0.064
5.28
0.809
0
0.235
333
11.3
0.418
0.3
0.217
15
536
9.35
0.808
0
0.198
13
355
9.27
0.68
0
0.987
2.135 (0.550–8.277)
8
290
10.94
0.141
35.9
0.761
2.217 (0.177–27.694)
2
35
0.02
0.884
0
–
Factors
Odds Ratio (95% CI)
Number of studies
Total Patients
Heterogeneity Chi2
P value
Male gender
1.960 (1.010–3.805)
24
660
12.74
Positive lymph nodes
11.918 (3.798–37.393)
10
355
R1 margins
11.132 (4.342–28.541)
12
LVI
5.504 (2.461–12.311)
Perineural invasion
1.381 (0.580–3.292)
Capsular invasion Ki67 4%
Recurrence type and survival Data on the type of recurrence was available for 58 patients. Seventy-two percent (42/58) of the patients who had a recurrence experienced distant recurrence only. Nineteen percent (11/58) of the recurrent patients experienced local recurrence only whereas nine percent (5/58) experienced both local and distant recurrence. Additionally, in this analysis, 3.9% (45/ 1143) of patients had R1 margin, and 26.6% (12/45) patients with R1 margins developed recurrence. Among these recurrent patients with R1 margins, 16.6% (2/12) developed local recurrence, which is close to 19% (11/58) of overall local recurrence occurring in all recurrent patients. Data on all alive and deceased patients in the recurrent and non-recurrent categories were available for 18 studies with 731 patients. The presence of recurrence was associated with increased odds for mortality (OR 43.830, 17.944 –107.060, p < 0.001, Fig. 3). There was no significant heterogeneity among the studies (Heterogeneity chi-squared 11.69, p = 0.819, I2 0%). However, publication bias was noted (Egger p = 0.049). A funnel plot was used to identify the outlier study (Supplementary figure 5).20 A meta-analysis of the remaining 17 studies with 691 patients again note that recurrence was associated with increased odds for mortality (OR 63.219, 95% CI 24.867–160.717, p < 0.001). In this subset of 17 studies, no publication bias was noted (Egger, p = 0.563). During the follow-up period, (16/69) recurrent patients died, but the majority were alive (53/69). Among these 53 patients who underwent treatment, ten patients had local recurrence, 21 patients developed systemic recurrence, one patient with local recurrence developed distant recurrence, while details about recurrence were not available in 21 patients. Ten patients with local recurrence underwent a second resection and remained disease-free. One patient with local recurrence that developed distant recurrence during follow-up but underwent surgery and remained disease-free. There are 21 patients with distant metastasis (hepatic, peritoneal, omental metastasis) who underwent hepatectomy and received chemotherapy. Of these patients, 18/21 patients were alive and remained disease-free, 2/21 developed second recurrence and underwent additional surgeries
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but were disease-free during the last follow-up. Only one patient (1/21) died of disease recurrence.
Discussion The current data suggest that approximately 2% of patients with SPT experience recurrence after resection. This is an interesting finding as previous smaller studies have reported higher recurrence rates (5–15%).2 Law et al. conducted a systematic review of SPT patients to determine the changes in the number of patients with SPT and management over time. In their review of 2744 patients, recurrence data were available for 1866 patients, and recurrence was noted in 4.4% of the patients. Similarly, Papavramidis et al. reviewed 718 patients of SPT (1933–2003) in English literature and noted a recurrence rate of 6.63% [112]. Studies with >20 patients were included when computing the recurrence rates to minimize bias, and this may have resulted in lower recurrence rates observed in the current study. The median time to recurrence in the current study was 41 months (IQR 22–72 months). This is similar to the previous report by Law et al., who noted a mean time to recurrence of 50.5 months.51 In the current study, we further stratified the patients by the time to recurrence. Although the majority developed recurrence within five years, a fourth of the patients developed recurrence beyond five years. This further highlights the fact that long-term follow-up is essential to detect recurrences, especially for those who are at risk for recurrence. In four patients who were followed beyond 15 years, no recurrences have been reported. As many patients are young and otherwise healthy, a finite follow up of fifteen years can be considered until more data become available. The current study is the first study to perform a meta-analysis of pathologic factors associated with recurrence. The presence of lymph node-positive disease and LVI were associated with a statistically significant risk of recurrence. Additionally, from a technical standpoint, an R1 resection margin also increases the risk of recurrence. PNI, capsular invasion and elevated Ki-67 although associated with an increased odds of recurrence, the association was not found to be statistically significant. The
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Figure 3 The forest plot demonstrates the pooled odds ratio for mortality in patients with SPT who developed recurrence
current results are supported by Kang et al., who reported that factors such as capsular invasion and perineural invasion were not statistically significant in predicting recurrence of resected SPT of the pancreas.6 However, the lack of statistical significance for these factors in the current study could also be a type 2 error due to smaller numbers. Since the rate of recurrence is overall low, some experts may question the need for long term follow up in those without any risk factors. Given the lack of individual patient data and missing data, a definitive assessment of the likelihood of recurrence in the absence of all risk factors could not be performed. The goal of the current study was to provide data regarding recurrence rates and determine association with pathologic factors which may be implicated in these patients. Conclusions regarding the deescalated follow up in those without any clinical or pathologic risk factors are beyond the scope of this article. However, those patients who develop recurrent disease have an increased risk of dying from the disease. The current study has several limitations. All studies included in the systematic review and meta-analysis were retrospective in nature. Although multiple databases were searched, and an extensive backward search was performed, there is a possibility that some studies were not included. Additionally, studies not published in the English language were not included in the
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current review and meta-analysis. Many of the studies did not report on the outcomes studied in the current meta-analysis. Factors such as advanced age and tumor size >5 cm have been previously reported by some to be associated with increased risk of malignancy but could not be analyzed in the current study. Due to limited numbers, one cannot definitively exclude PNI, capsular invasion and Ki-67 as risk factors for recurrenc as this could be a type 2 error. Additionally, individual patient data were not able to be extrapolated from the included studies. Many previous studies have followed arbitrary criteria to suggest malignancy. In the current study, only recurrence rates after resection in those who presented with non-metastatic disease were analyzed. Rates of recurrence may be higher in patients with metastatic disease and data from the current study cannot be extrapolated to such patients. Despite the limitations, this is the largest review and meta-analysis on the recurrence rates and pathologic factors associated with recurrence in patients with SPT. In conclusion, the current data suggests that only 2% of patients with SPT experience recurrence after resection. This is an interesting and somewhat new finding as previously reported recurrence rates in smaller studies were 5–15% and systematic reviews reported 4–6% recurrence rates. The majority of recurrences occur at 5 years. However, 23% experience
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recurrence between 5 and ten years, thus necessitating long-term follow-up. Male patients and patients with positive lymph nodes, R1 margins and LVI are associated with an increased risk for recurrence. A standard reporting template for the pathology reports of SPT should be followed, which may further allow a systematic study of the factors associated with recurrence, along with international registries to track the long-term outcomes of these patients The current data will help the treating physicians to counsel patients with SPT regarding recurrence rates and help underscore the need for long-term follow up.
13. Butte JM, Brennan MF, Gonen M, Tang LH, D’Angelica MI, Fong Y et al. (2011) Solid pseudopapillary tumors of the pancreas. Clinical features, surgical outcomes, and long-term survival in 45 consecutive patients from a single center. J Gastrointest Surg: Off J Soc Surg Aliment Tract 15:350–357. 14. Cai Y-Q, Xie S-M, Ran X, Wang X, Mai G, Liu X-B. (2014) Solid pseudopapillary tumor of the pancreas in male patients: report of 16 cases. World J Gastroenterol: WJG 20:6939–6945. 15. Carlotto JRM, Torrez FRA, Gonzalez AM, Linhares MM, TriviÑO T, Herani-Filho B et al. (2016) Solid Pseudopapillary neoplasm of the pancreas. Arquivos Brasileiros de Cirurgia Digestiva: ABCD 29:93–96. 16. Dall’igna P, Cecchetto G, Bisogno G, Conte M, Chiesa PL, D’Angelo P
Acknowledgments None.
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Funding None declared.
Exocrine pancreatic tumors in childhood in Germany. Pediatr Blood Cancer 58:366–371. 18. El-Bahrawy MA, Rowan A, Horncastle D, Tomlinson I, Theis BA,
Conflicts of interest None declared.
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Appendix A. Supplementary data
papillary tumor of the pancreas: a single-institution 20-year series of
Supplementary data to this article can be found online at https://doi.org/10.
pediatric patients. J Pediatr Surg 47:1217–1222.
1016/j.hpb.2019.06.005.
HPB xxxx, xxx, xxx
© 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Yepuri N et al., A systematic review and meta-analysis of predictors of recurrence in patients with Solid Pseudopapillary Tumors of the Pancreas, HPB, https://doi.org/10.1016/j.hpb.2019.06.005