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  Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 3  |  Page : 343-349
 

Epidemiology, diagnosis, surgical treatment and prognosis of the pancreatic neuroendocrine tumors: Report of 125 patients from one single center


Department of Hepato-Bilio-Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan Province, The People's Republic of China

Date of Web Publication18-Feb-2016

Correspondence Address:
B Tian
Department of Hepato-Bilio-Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan Province
The People's Republic of China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.176746

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 » Abstract 

Objective: The objective of the following study is to summarize the epidemiology of pancreatic neuroendocrine tumors (p-NETs) in our single institution, analyze the diagnostic characteristics, share the experience of surgical treatments and discuss the prognostic factors. Methods: A retrospective collection and analysis of clinical data of 125 patients with p-NETs which were pathologically confirmed in our hospital from January 2002 to December 2012. Results: A total of 125 patients of which 52 were males and 73 were females. Totally 92 patients had functional p-NETs, while non-functional p-NETs were diagnosed in 33 patients. The most common operative procedures performed were local resection of pancreatic tumor (47.2%), followed by distal pancreatectomy (29.6%). Thirty patients (28%) had post-operative complications, the most common of which was pancreatic fistula (22.4%). The overall survival rate at 5 years was 68.4%. The 5-year survival rate for patients with functional tumors was 75.1%, compared with 50.0% for those with non-functional tumors (P = 0.021). The survival time of patients with R0 resection was statistically longer than that of patients with Not R0 resection (P < 0.005). In univariate analysis, the most powerful predictors of poor outcome were gender, age, tumor size, functional status, surgical margins, lymph node invasion and distant metastasis. However only surgical margin and distant metastasis were significant predictors in multivariate analysis (P = 0.001, 0.047, respectively). Conclusion: p-NETs are an uncommon and heterogeneous group of tumors, with a rising incidence. Surgery is the most effective treatment. Surgical margin and distant metastasis were the most significant prognostic factors. Radical resection should be taken more into considerations.


Keywords: Diagnosis, epidemiology, pancreatic neuroendocrine tumors, prognosis, surgical treatment


How to cite this article:
Yang M, Tian B, Zhang Y, Su A, Yue P, Xu S, Wang L. Epidemiology, diagnosis, surgical treatment and prognosis of the pancreatic neuroendocrine tumors: Report of 125 patients from one single center. Indian J Cancer 2015;52:343-9

How to cite this URL:
Yang M, Tian B, Zhang Y, Su A, Yue P, Xu S, Wang L. Epidemiology, diagnosis, surgical treatment and prognosis of the pancreatic neuroendocrine tumors: Report of 125 patients from one single center. Indian J Cancer [serial online] 2015 [cited 2019 Jun 17];52:343-9. Available from: http://www.indianjcancer.com/text.asp?2015/52/3/343/176746



 » Introduction Top


Pancreatic neuroendocrine tumors (p-NETs) are a group of heterogeneous tumors. They can derive not only from mature pancreatic endocrine cells, but also from pluripotent stem cells of the pancreas.[1] p-NETs are considered to belong to amine precursor uptake and decarboxylation neoplasms and may carry the potentials to secrete some endocrine hormones, such as insulin, gastrin, glucagon, etc.[2] These tumors also express the typical neuroendocrine markers, such as chromogranin A (CgA), synaptophysin (SYN) and neuronspecific enolase, which were of great value in the pathological diagnosis of p-NETs.[3] The first article of p-NETs was published in 1902 by Nicholls.[4] A study published in 1929 by Howland et al.[5] have reported the first surgical cure of an insulinoma through enucleation from the body of the pancreas.

In order to evaluate the benign and malignant characteristic of p-NETs, the World Health Organization (WHO) in 2000 classified p-NETs into three categories.[6] In 2006, The European Neuroendocrine Tumor Society (ENETS) proposed the Tumor-Node-Metastasis (TNM) classification and grading system for the treatment and prognostic stratification of gastroentero-p-NET.[7] In 2010, WHO updated its classification system into neuroendocrine tumor G1, neuroendocrine tumor G2, neuroendocrine carcinoma G3, mixed adeno and neuroendocrine carcinoma.[8] Both classifications are widely used clinically. Several studies have evaluated the prognostic value of the WHO criteria and ENETS grading system.[9],[10]

There is no universal agreement on the definition of p-NETs. It is a common practice to label p-NETs as functional if the patients have symptoms of hormone overproduction and non-functional if patients are asymptomatic.[3] Functional p-NETs consist of insulinoma, gastrinoma, vasoactive intestinal polypeptidoma (VIPoma), adrenocorticotropic hormone adenoma (ACTHoma), pancreatic polypeptidoma (PPoma), glucagonoma, pheochromocytoma and so on. Patients with Functional p-NETs are usually admitted into hospital due to specific clinical symptoms, such as typical Whipple triad, refractory peptic ulcer, migratory erythema, intractable diarrhea, hypokalemia, Cushing syndrome, etc. Symptoms of non-functional p-NETs are often non-specific, including nausea and vomiting, abdominal pain and distension, abdominal mass, jaundice, etc.

Surgery is the only way to cure these p-NETs, which has become the gold standard for the treatment of p-NETs. Patients after surgery usually have a longer survival time and better quality of life compared with those who didn't.[11] Even if radical resection is not suitable, palliative surgery may alleviate patients' symptoms.[12] Some related articles about p-NETs have been reported before, but most of them were with either too small quantity or too long-time spanning. Based on the data of 125 patients in our single center for the past 10 years, we summarize and analyze the clinical characteristics of p-NETs, with an emphasis on sharing the experience of surgical treatment and discussing their prognosis.


 » Materials and Methods Top


Patient selection and follow-up

We reviewed the medical records of 125 patients who were surgically treated and pathologically diagnosed as p-NETs in our hospital from January 2002 to December 2012. The data included patients demographics (gender and age), auxiliary examination, surgical information (type of resection, duration of surgery, intraoperative findings), pathological diagnosis, post-operative morbidity and mortality rates, etc. Follow-up was done by telephone, office visit or out-patient clinic during July and August, 2013.

Tumor characteristics

Tumors of patients with particular symptoms, signs and laboratory evidence of hormonal excess were classified into functional p-NETs: Insulinoma (Whipple triad, hyperinsulinemia), gastrinoma (refractory peptic ulcer, diarrhea and esophagitis), VIPoma (intractable diarrhea, hypokalemia), ACTHoma (Cushing syndrome), glucagonoma (migratory erythema, hyperglycemia) and so on. The contrary was defined as Non-functional p-NETs, regardless of immunohistochemistry of the tumor specimen. Features of the tumors (quantity, size, position, lymph node invasion and distant metastasis, surgical margin, etc.) were based on intra-operative findings and pathological diagnosis. The WHO classifications in 2010 and the ENETS TNM staging and grading system were both used to assess tumors benign and malignant characteristics.

Post-operative complications

Post-operative mortality was defined as death occurring in the 1st 30 post-operative days or prior to discharge from the hospital. For morbidity analysis, a pancreatic fistula was classified according to the International Study Group on Pancreatic Fistula definition and defined as drainage of any measurable volume of amylase-rich fluid, at least 3 times the upper normal limit of serum amylase concentration on or after the 3rd post-operative day. Intra-abdominal infection (signs of peritonitis, fever, obvious elevation of the white blood cell, positive of intra-abdominal fluid culture); Wound infection (positive of the wound necrotic tissue culture, purulent drainage requiring open packing or re-operation); Delayed gastric emptying (intolerance to oral intake and need for nasogastric decompression after the 7th post-operative day). Other complications were using standard accepted criteria.

Statistical analyses

Data are presented as mean ± standard error of mean unless otherwise indicated. Differences in the continuous variables of demographics, operative data and length of hospitalization were analyzed using analysis of variance and t tests. Survival estimates were generated using the Kaplan-Meier method, survival curves were compared using the log-rank test. Univariate and multivariate analyses were used to explore the effects of several prognostic factors by COX Regression. Differences with P < 0.05 were considered to be statistically significant. Statistical analyses were performed using SPSS 17.0 statistical software of IBM Company.


 » Results Top


Patient demographics

From January 2002 to December 2012, there were 125 patients who underwent surgery and were pathologically confirmed into p-NETs in our center, the incidence of which each year can be seen in [Figure 1]. This entirety was comprised of 52 males and 73 females, whose ages ranged from 14 to 77 years, with a mean of 46.16 ± 13.68 years and a median of 46 years old. The majority of p-NETs were solitary, including 50 cases in the head, 34 in the body and 36 in the tail. Multiple tumors can be seen in five patients, which may simultaneously appear in any part of the pancreas. Tumors diameter ranged from 0.3 centimeter (cm) to 12 cm, with an average of 2.95 ± 2.57 cm [Table 1].
Figure 1: An increasing tendency was seen in the graph above. The incidence of pancreatic neuroendocrine tumors had increased approximately 5 times in the past 10 years

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Table 1: The clinical characteristics of the p-NETs in our hospital

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Clinical manifestations

Of all the 125 patients, there were 92 Functional p-NETs (73.6%), including 83 insulinoma, 4 gastrinoma, 1 VIPoma, 1 ACTHoma, 1 PPoma, 1 glucagonoma and 1 pheochromocytoma; whereas Non-functional p-NETs were found in 33 patients (26.4%) [Figure 2]. Typical Whipple triad occurred in 75 patients of insulinoma; gastrinoma had refractory peptic ulcer in 1 patient, abdominal pain and distention, nausea and vomiting in 3; glucagonoma manifested as diabetes and migratory erythema (1/1); VIPoma got intractable diarrhea and hypokalemia (1/1), ACTHoma showed Cushing syndrome (1/1); pheochromocytoma displayed that, blood pressure was usually normal, but when touching the mass in operation, the ventricular rate soared to 170 beats/min, blood pressure rose to 254/138 mmHg rapidly (1/1). Non-functional p-NETs manifested as abdominal pain and distension (21/33), abdominal mass (25/33), gastrointestinal bleeding (2/33), jaundice (3/33) or unintentional findings by physical examination (10/33).
Figure 2: The proportion of each kind of pancreatic neuroendocrine tumors (p-NETs) was shown in this chart. Insulinama was most seen in p-NETs, followed by Non-functional p-NETs and Gastrinoma. Other kinds of p-NETs were all very rare

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The age and diameter at onset of patients with Functional p-NETs were usually less than those of patients with non-functional tumors (P = 0.03, 0.00, respectively). Functional p-NETs were mostly located in the body and tail of pancreas (56/92, 60.8%), whereas the distribution of Non-functional p-NETs was basically and statistically equal between the head and the body and tail of pancreas (14/28, 50%). In addition, the major operative procedure of Functional p-NETs was local resection of pancreatic tumor; while that of non-functional p-NETs was distal pancreatectomy and pancreaticoduodenectomy. Compared with non-functional p-NETs, the operation duration and the total duration of hospitalization of functional p-NETs were statistically shorter (P = 0.01, 0.01, respectively). However, the post-operative duration of functional p-NETs and non-functional p-NETs was not statistically significant (P = 0.33) [Table 2].
Table 2: The clinical features of the p-NETs with different function

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Pathology and imaging examinations

Diagnoses were based on pathological paraffin sections and immunohistochemical examination, which were achieved in all patients. Positive findings of CgA and SYN were 109 cases (87.2%) and 119 cases (95.2%), respectively; while 125 patients were found in their combinations (100%). Differentiation and staging of the p-NETs had enumerated in [Table 1]. A total of 125 patients got one or more imaging examinations below: Abdominal ultrasound (AUS) had 45 positive findings in 78 patients, whereas intraoperative US (IUS) got 30 in 30, computed tomography (CT) 45 in 55, magnetic resonance imaging (MRI) 44 in 49, artery angiography 2 in 3 and positron emission tomography-CT (PET-CT) 1 in 2 [Figure 3].
Figure 3: Percentage of pancreatic neuroendocrine tumors successfully localized using the following examinations: Abdominal ultrasound, intra-operative US, computed tomography (CT), magnetic resonance imaging, positron emission tomography-CT (PET-CT) and artery angiography

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Operations and complications

All patients were surgically treated, which can be detailedly found in [Table 3]. The most common operative procedures performed were local resection of pancreatic tumor in 59 patients (47.2%), followed by distal pancreatectomy (29.6%) and pancreaticoduodenectomy (11.2%). Among the operations, the liver and pelvic metastases were found intra-operatively in 12 patients, on which the local resection of related tumor (9.6%) was carried out. Radical resection (R0 resection) was performed in 119 patients (95.2%), while only six patients (4.8%) underwent Not R0 resection. Post-operative complications occurred in 30 patients with an acceptable incidence of 24%, the most common of which was pancreatic fistula, which happened in 28 patients with an incidence of 22.4%. However, all of the pancreatic fistula were either Type A or B, patients recovered well through medical treatments and unobstructed drainage. Four patients underwent re-operation due to the post-operative complications: One removal of the necrotic tissues for the acute pancreatitis; one drainage of abscess for intra-abdominal abscess; one s-phase suture of wound for wound infection; one exploratory laparotomy for intra-abdominal hemorrhage. There were two in-hospital deaths totally with a mortality of 1.6%, who both died of intra-abdominal hemorrhage [Table 3].
Table 3: The operational characteristics of the p-NETs in our center

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Survival and outcome

Follow-up ranged from 5.93 to 135.93 months, with a mean of 48.93 ± 32.62 months. 81 patients (72.9%) were still alive, whereas 30 patients (27.1%) died (including the two in-hospital deaths), who were both secondary to tumor progressions. Fourteen patients were lost to follow-up and were excluded the analysis of survival time. The survival time of all patients ranged from 0 to 120.80 months, with a mean of 39.97 ± 27.67 months. Nine patients alive had tumor progress at follow-up (recurrence and/or metastases to liver or pelvic), time to progression ranged from 1.31 to 68.73 months, with a median of 12.97 months.

The overall survival rate at 5 years was 65.7% [Figure 4], with a median overall survival time of 88.34 months (95% confidence interval, 68.48-108.20 months). The 5-year survival rate for patients with functional p-NETs was 73.8%, which was significantly better than that of patients with non-functional p-NETs (49.3%, P = 0.021) [Figure 5]. The survival time of patients with R0 resection was statistically longer than that of patients with Not R0 resection, with a median survival time of 88.34 and 6.32 months, respectively (P = 0.000) [Figure 6]. It had be shown detailedly in [Table 4] that, in univariate analysis, gender, age, tumor size, functional status, surgical margin, lymph node invasion and distant metastasis were all statistically significant predictors of poor outcome for patients undergoing operation. But only surgical margin and distant metastasis were significant in multivariate analysis (P = 0.001, 0.047, respectively).
Figure 4: The overall 1-and 5-year survival rates of pancreatic neuroendocrine tumors were 94.6% and 68.4%, respectively, with a median overall survival time of 88.34 months (95% confidence interval, 68.48-108.20 months)

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Figure 5: Comparison of survival after curative resection in patients with functional and non-.functional pancreatic neuroendocrine tumors (P = 0.021)

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Figure 6: Comparison of survival in patients with pancreatic neuroendocrine tumors of different surgical margin (P < 0.005). (“Not R0 resection” includes surgeries of R1 and R2 resection, implantation of radioactive iodine particles and hepatic artery chemoembolization in our data)

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Table 4: Uni-and multivariate analysis of factors impacting on survival of patients with the p-NETs undergoing operation in our hospital

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 » Discussion Top


p-NETs, with an incidence of <5/1,000,000 each year, are uncommon, accounting for only 1-2% of pancreatic tumors.[11],[13],[14] However, p-NETs have an increasing tendency in recent decades. The American Surveillance, Epidemiology and End Result database shows that the incidence of p-NETs had increased approximately 5 times in the past 30 years, which was similar to that of our hospital in recent 10 years. This may be related with the improvement of diagnostic techniques and the enhancement of clinicians' awareness about this disease.[15] The p-NETs gave a priority to sporadic and single tumors; women slightly outnumbered men, with a median age of 46 years old, which were similar to the data published by the WHO.[16]

The diagnosis of p-NETs is primarily based on pathology and immunohistochemistry. Different kinds of p-NETs may be dyed by different hormone, but this does not mean it is the tumor which presents clinical manifestations. Immunohistochemistry showed that more than 50% of functioning tumors produced more than one hormone, but only one of these hormones was usually biologically active and released in sufficient quantities, resulting in clinical symptoms. Among the tumor markers of p-NETs, CgA is a water-soluble acidic glycoprotein stored in the secretory granules of neuroendocrine cells; its detection in plasma may be used as a general tumor marker for p-NETs.[17] Moreover, CgA concentration likely correlates with the extent of tumor differentiation, liver metastasis, disease progression and treatment efficiency.[18]

Imaging examinations are of great help to locate p-NETs. AUS is usually the first choice, which has been widely used in physical examination. However, due to easily being influenced by the patients' body fat and factors such as the gas inside the gastrointestinal tract after operation, the sensitivity of AUS is not more than 60%.[19] (Ours was about 55%). On the other hand, for the p-NETs are mostly small (especially the insulinoma) and uniformly distributed throughout the entire pancreas, IUS is essential for intra-operative localization and excision of tumors.[20] In our hospital, the use of IUS resulted in a surgical cure rate of 100%. CT are the most common techniques for the diagnosis of p-NETs, which have sensitivity and specificity >90%,[21] while MRI may be more suitable to detect the small metastatic nodule in liver. Moreover, CT/MRI can also be used for pre-operative staging, follow-up and evaluation of treatment efficacy. PET-CT may be suitable for the detection of poorly differentiated tumors.[22] Artery Angiography is used clinically on the decrease.

Surgery is of specific benefit, which is effective in relieving patients' symptoms and is the only potentially curative treatment of p-NETs if R0 resection of the primary tumor and metastasis is achieved.[11] The operative procedure differs from tumor location, size and the relationship with the surrounding tissues. The local resection of pancreatic tumor is the most common, especially for benign and small (usually <2.0 cm) insulinoma which accounts for the vast majority of p-NETs. Besides, the distal pancreatectomy and pancreaticoduodenectomy have also been performed clinically on the rise.[23] In contrast, for those tumors which cannot be resected radically, palliative resection should be considered to relief patients symptoms and improve his/her life quality.[12] In our cohort, 22 patients were pathologically confirmed to have lymph invasion and/or distant metastasis. 119 patients got a radical resection, including the local R0 resection of the metastasis, while six patients had palliative treatments (R1 or R2 resection, implantation of radioactive iodine particles, hepatic artery chemoembolization). The median survival time of patients who got R0 resection was 88.34 months, compared 6.32 months of patients with palliative treatments (P < 0.005).

The overall 5-year survival rate of our material was 68.4%, with a median survival time of 88.34 months, which was basically in agreement with some studies who concluded a survival rate of approximately 66%.[9],[24] However, it is higher than the data with a reported survival rate of 30-40%,[25],[26] but is lower than that of a data reaching up to about 75%.[27],[28] This discrepancy is probably due not only to the different features of the populations studied, but also to the different design of each study: Our clinical materials spanned 10 years, but most cases (including the benign and malignant) concentrated in past three and 4 years and some patients in early years were lost to follow-up.

The prognosis of p-NETs may relate to many factors. Resection margin may have a significant prognostic effect on p-NETs.[29] Whit's more, liver metastasis was concluded to be a bad predictor of p-NETs.[30],[31] Then, it had been demonstrated in 2008 that, age, tumor grade, metastasis and hormonal function had a bad influence on the prognosis of p-NETs.[32] It was also reported that, advanced stage, higher grade and age were the strongest predictors of worse survival; patients with functional tumors had better outcomes than patients with non-functional tumors both in univariate and multivariate analysis.[11] In the current study, we analyzed the data of the cohort and concluded that, gender, age, tumor size, functional status, surgical margin, lymph node invasion and distant metastasis were all statistically significant predictors of poor outcome for patients with p-NETs in univariate analysis. But only surgical margin and distant metastasis were significant in multivariate analysis, which meant radical resection should be the first choice of surgical treatment for p-NETs.


 » Conclusion Top


In summary, p-NETs are a group of uncommon tumors with different characteristics and a rising incidence. The diagnosis of p-NETs is mainly based on pathology and immunohistochemistry, while the imaging examinations are playing a more and more important role in locating these tumors. The data of 125 patients confirmed again that surgical treatment is the effective and curative strategy for p-NETs; we also demonstrated that both surgical margin and distant metastasis were the strongest predictors of worse survival for patients with p-NETs. Therefore, radical resection should be firstly taken into considerations.

 
 » References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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