Clinicopathological factors associated with recurrence in patients undergoing resection of pancreatic solid pseudopapillary neoplasm

Purpose Solid pseudopapillary neoplasm (SPN) is an uncommon pathology with a low-grade malignancy. Surgery is the milestone treatment. Nevertheless, despite appropriate management, some patients present recurrence. Risk factors associated with recurrence are unclear. The objective was to identify the clinicopathological factors associated with recurrence in patients with SPN treated with pancreatic resection. Methods Medical records of patients treated with pancreatic resection during 2006–2020 were evaluated. Patients with histological diagnosis of SPN were included. Survival analysis was performed to identify the clinicopathological factors related to recurrence. Results Seventy-four patients were diagnosed with SPN; 70 (94.6%) patients were female, and the median age was 20 years old. The median tumor diameter was 7.9 cm. Multivisceral resection was performed in 9 (12.2%) patients. Four (5.4%) patients presented lymph node metastasis.R0 resection was achieved in all cases. Six (8%) patients presented recurrence and the liver was the most frequent recurrence site (n = 5).After a median follow-up of 40.2 months, 9 (12%) patients died. Five (6.8%) patients died of disease progression. The 1–3- and 5-year overall survival (OS) was 97.1%, 90.2% and 79.9%, respectively. The 1–3-and-5-year recurrence-free survival (RFS) was 98.4%, 89.9% and 87%, respectively. In the univariate Cox-regression analysis, age ≥ 28 years(HR = 8.61, 95% CI 1.1–73.8),tumor diameter ≥ 10 cm(HR = 9.3, 95% CI 1.12–79.6),invasion of adjacent organs (HR = 7.45, 95% CI 1.5–36.9), lymph node metastasis (pN +) (HR = 16.8, 95% CI 2.96–94.9) and, AJCC Stage III (HR = 10.1, 95% CI 1.2–90.9) were identified as predictors for recurrence. Conclusions SPN is more frequently diagnosed in young women with a good overall prognosis after an R0 surgical resection even with disease recurrence. Age ≥ 28 years, larger tumors ≥ 10 cm, invasion of adjacent organs, lymph node metastasis(pN +) and, AJCC Stage III were predictors factors of recurrence in resected SPN. Supplementary Information The online version contains supplementary material available at 10.1007/s12672-021-00451-4.

level in fluid from the abdominal drainage tube > 3 times the upper limit of normal serum amylase level from the third postoperative day. According to the 2016 update of the ISGPF, pancreatic fistula grade A was redefined as a biochemical leak because of the absence of clinical relevance [25]. Postpancreatectomy hemorrhage (PPH) was defined according to the International Study Group of Pancreatic Surgery [26]. Postoperative morbidity and mortality were defined as complications and mortality which occurred within 90 days after surgery.

Follow-up
In our institution, patients treated with pancreatic resection were followed up after 2 weeks, 1 month, and later every 3 months for 1 year. In the second year, patients were followed up every 6 months and later annually from the third to fifth year. After the fifth year, patients continue their clinical evaluations in their locality and annually in our institution. In case of suspected disease recurrence, patients were sent to our center immediately. Each medical evaluation included: clinical examination, tumor markers (CEA, CA , chest X-ray, and abdominopelvic ultrasound. Pelvic computed tomography (CT) or Magnetic resonance image (MRI) was performed every year for 5 years.

Statistical analysis
Categorical variables were expressed as numbers and percentages and compared using Fisher's exact test or χ 2 test as appropriate. Continuous variables were expressed as median values with interquartile range (IQR) and compared using the non-parametric Mann-Whitney test. An analysis of the receiver operating characteristic curve (ROC curve) was used to obtain the optimal cut-off values for age and tumor diameter. Optimal cut-off values were used for the dichotomization of the variables in the univariate analysis. The optimal cut-off point for age was ≥ 28 years and for tumor diameter was ≥ 10 cm. Each AJCC stage and its relationship with the recurrence were evaluated separately; AJCC Stage III showed a statistically significant relationship with recurrence and was used for the variable dichotomization. Survival curves including overall survival (OS), and recurrence-free survival (RFS) were estimated using the Kaplan-Meier method. Deaths without recurrence were censored for the RFS analysis. A Cox proportional hazards model analysis was performed to identify factors associated with recurrence. The statistical analysis was performed with IBM SPSS version 22.0. Statistical significance was defined as p ≤ 0.05.

Ethics approval
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the National Institute of Neoplastic Diseases INEN, Lima, Peru. The authors declare that this article does not contain personal information that allows identifying patients enrolled.

Discussion
SPN is a relatively rare disease and is generally regarded as a low malignant potential [27]. In recent years, the number of publications on this topic has been increasing but the risk factors associated with recurrence remain unclear. This may be related to the small number of cases reported worldwide and the difficulty of having a large single-center series [6]. Our study presented the clinicopathological characteristics of SPN patients in Peru and contributed to clarifying the risk factor for recurrence after surgical resection. In the present study, it was shown that age ≥ 28 years old, tumor diameter ≥ 10 cm, invasion of adjacent organs, lymph node metastasis, and AJCC stage III were associated with recurrence in SPN patients.   Several studies reported that age at diagnosis was related to the prognosis of patients with resected SPN [28,29]. Waters et al. [28] reported in a retrospective study based on the United States National Cancer Database that pediatric patients (≤ 21 years) were significantly associated with better overall survival than adult patients (≥ 22 years). In contrast, in a retrospective study conducted in France, it was reported that patients under 13.5 years old were significantly associated with worse disease-free survival compared to patients ≥ 13.5 years old [29]. According to our results, younger patients (< 28 years old) presented a better prognosis compared to older patients (≥ 28 years old). These results are in line with previous studies reporting similar results and lead to a new hypothesis about biological differences between these groups of patients and their future significance in predicting the possibility of disease recurrence.
A larger tumor diameter has been reported as a risk factor for recurrence in SPN patients in previous studies [15,19]. Gao et al. [19], in a systematic review, reported that SPN patients with a tumor diameter > 5 cm presented a higher risk of recurrence compared to patients with a tumor diameter ≤ 5 cm (OR = 4.74, 95% CI 1.12-20.05). Likewise, a retrospective multicenter study conducted in Korea showed in a multivariate analysis, that a tumor diameter > 8 cm was significantly associated with recurrence in resected SPN patients [15]. In the present study, SPN patients with a tumor diameter ≥ 10 cm presented a higher risk of recurrence in the Cox proportional hazard model analysis (HR = 9.3, 95% CI 1.12-79.6). This result could be attributable to the relatively larger tumor diameter in our study compared to the tumor diameter in previous studies [4,14,15,30]. Also, our study enhances a new cut-off value (tumor diameter ≥ 10 cm) to predict the possibility of recurrence in resected SPN patients and introduce a new line of research regarding the association between the tumor diameter and recurrence in SPN.
Nine (12.2%) patients presented invasion of adjacent organs and required a multivisceral resection to ensure free surgical margins (R0), of these, three patients presented recurrence. In the Cox proportional hazard model analysis, the presence of invasion of adjacent organs was significantly related to recurrence in resected SPN patients (HR = 7.45, 95% CI 1.5-36.9). Likewise, several studies also reported that the invasion of the peripancreatic fat tissue and adjacent organs was related to a worse prognosis in SPN patients [31,32]. These results support the importance of a complete oncological surgical resection (R0) in patients with the diagnosis of SPN because of his malignant potential. In addition, we suggest that if an adjacent organ is compromised by the primary tumor, it must be resected en-bloc to ensure a better prognosis.
The role of performing a routine lymphadenectomy in SPN patients is currently debatable [33]. Lymphatic involvement in patients with the diagnosis of SPN has been reported in several studies with a percentage up to 8% [4,29,34]. Gao et al. [19], reported that the presence of positive lymph nodes metastasis was significantly related to postoperative relapse in patients with resected SPN (OR: 6.58, 95 CI 1.92-22.57). In the present study, four (5.4%) patients presented lymph node ). According to our results, we proposed that surgical resection of the primary tumor should be complemented with a lymphadenectomy to ensure better staging in SPN patients. In the present study, patients were categorized according to the AJCC (TNM) Prognostic Group classification. Patients who were categorized as Stage III presented a higher risk of recurrence compared to the patients categorized as Stage I and II. In a retrospective study conducted at the MD Anderson Cancer Center, similar results were reported, in this study, the AJCC staging group classification was significantly associated with recurrence (p ≤ 0.01) [4]. According to these results, the AJCC classification should be used systematically to categorize patients with resected SPN, to perform it, we should also have several resected lymph nodes to assess the lymph node involvement and subsequently evaluate the long-term prognosis. In previous studies, the recurrence rates in resected SPN are relatively low, ranging from 1.5 to 13.7% and the liver was the most frequent recurrence site. In the current study, 6 (8%) patients developed recurrence including liver metastases and peritoneal carcinomatosis. In our institution, SPN patients are treated with complete oncological resection of the primary tumor and multivisceral resection in case of involvement of adjacent organs. Likewise, lymphadenectomy is performed in all cases for treatment and staging. Our results are comparable with other studies worldwide and even with a lower recurrence rate.
In our series, 12.6% of all pancreatic resections were histologically diagnosed as SPN. In Peru, the National Institute of Neoplastic Diseases is the national reference center for oncological pancreatic surgeries especially in this pathology, this could explain the high percentage of SPN in our institution. However, more studies are required to analyze whether there is a higher incidence of SPN in the Latin American population.
In the present study, most patients were female (94.6%) and only four patients were male. This is in line with previous studies which showed that SPN was predominant in females suggesting a hormonal factor [35,36]. Also, studies reported that male patients with SPN present an incidence at a higher age and a compromised survival after surgery [14,37]. In our series, the oldest patient was a 68-year-old male; nonetheless, no recurrence was found in male patients. SPN is generally found with symptoms [29,38,39]. In our series, 70 (94.6%) patients had symptoms with the most frequent symptom, abdominal pain. Currently, there is no evidence of a prognostic role of tumor markers in patients with SPN [3,40,41]. In our study, Ca 19-9 levels were higher in patients with recurrence compared to patients without recurrence, but no significant difference was observed (p = 0.21). The pancreas tail is the most common location of SPN [34,38,42,43]. However, our study showed that the pancreas head was the most frequent location of SPN (n = 32; 43.2%) followed by the pancreas tail (26; 35.2%). This is similar to a report in the Chinese population, which showed that 39.8% of SPN were located at the pancreas head in 553 patients [44].
Our study should be understood in the context of limitations. First, our study is conducted under the retrospective study design with a relatively small number of patients. Nonetheless, the diagnosis of SPN is rare, and case series are scarce worldwide. Our study is the largest series in Latin America. The functional change after pancreatectomy was not followed because most patients live in remote areas far from our institution.

Conclusions
In conclusion, SPN is frequently diagnosed in young females. The prognosis is good after R0 resection. However, recurrence may develop in some patients. Our study found that age ≥ 28 years, tumors ≥ 10 cm, invasion to adjacent organs, lymph node metastasis and, AJCC Stage III were risk factors of recurrence in patients undergoing SPN resection.