Lymph Nodes and Survival in Pancreatic Neuroendocrine Tumors (pNET)

Abstract

Background

The significance of lymph node metastases on survival of patients with pNET is controversial.

Hypothesis

Lymph node metastases decrease survival in patients with pNET.

Design

Prospective databases of the National Institutes of Health (NIH) and Stanford University Hospital (SUH) were queried.

Main Outcome Measures

Overall survival, disease-related survival, and time to development of liver metastases

Results

326 underwent surgical exploration for pNET at the NIH (n=216) and SUH (n=110). 40 (13%) and 305 (94%) underwent enucleation and resection, respectively. Of the patients who underwent resection, 117 (42%) had partial pancreatectomy and 30 (11%) had a Whipple procedure. 41 also had liver resections, 21 wedge resections and 20 lobectomies. Average follow-up was 8 years (range 0.3–28.6 years). The 10-year overall survival for patients with no metastases or lymph node metastases only was similar at 80%. As expected, patients with liver metastases had a significantly decreased 10-year survival of 30% (p<0.001). The time to development of liver metastases was significantly reduced for patients with lymph node metastases alone compared to those with none (p<0.001). For the NIH cohort with longer follow-up, disease-related survival was significantly different for those patients with no metastases, lymph node metastases alone, and liver metastases (p<0.0001). Extent of lymph node involvement in this subgroup showed that disease-related survival decreased as a function of number of lymph nodes involved (p=0.004).

Conclusion

As expected, liver metastases decrease survival of patients with pNET. Patients with lymph node metastases alone have a shorter time to development of liver metastases that is dependent on the number of lymph nodes involved. With sufficient long-term follow-up, lymph node metastases decrease disease-related survival. Careful evaluation of number and extent of lymph node involvement is warranted in all surgical procedures for pNET.

Introduction

Pancreatic neuroendocrine tumors (pNET) are clinically rare and comprise a heterogeneous group of neoplasms.^{1, 2} pNET can be classified as hormonally functional or nonfunctional.³ Despite recent advances in medical therapies for pNET,^4–6 surgical resection remains the only curative therapy.^{3, 6, 7} pNET are more indolent than exocrine pancreatic cancer; however, most patients with metastatic tumor ultimately die of their disease.^8–11

Except for insulinoma, pNETs are malignant in 50–90% of cases.³ While the significance of hepatic metastases on patient survival is well established,^{8, 11–22} the importance of lymph node metastases on survival is unclear. This is in marked contrast to results with a number of non-endocrine gastrointestinal tumors (pancreatic, esophageal, gastric, colon)^23–26 and other endocrine tumors (follicular or medullary thyroid)^{27, 28} where the presence and number of lymph node metastases have important prognostic significance and influence the surgical approach.

Prior studies have reported that the presence of lymph node metastases is not a significant determinant of survival,^{19, 20, 29–43} not associated with recurrence post resection,^{44, 45} or not related to disease progression.⁴⁶ In contrast, others report that lymph node involvement adversely affects survival and is associated with recurrence post-resection or progressive disease.^47–51 As such, the true effect of lymph node involvement in pNET on patient survival remains poorly understood and controversial. This has clinical implications because the presence of lymph node metastases could affect the surgical approach as well as the follow-up if they were found to have prognostic significance. Consequently, we sought to further define the significance of lymph node metastases on survival of patients with pNET by analyzing results from a large number of patients with long-term follow-up.

Methods

Two prospective databases of patients with functional or nonfunctional pNETs who underwent surgical exploration for cure as previously described⁵² were reviewed. In one, surgery was done at Stanford University Hospital (SUH) since 1996, and in the other, at the National Institutes of Health (NIH) since 1981. In total, 326 patients underwent operations for pNET. Two hundred sixteen operations were performed at NIH and 110 at SUH. The main outcome measures were overall survival, disease-related survival, and time to development of liver metastases.

The diagnosis of hormonally functional and nonfunctional tumors has been previously described in detail.^{3, 53, 54} After confirming the diagnosis, patients underwent detailed localization imaging studies as previously described. Patients were invited to undergo surgery to remove the tumor if they had no co-morbid medical condition markedly limiting life expectancy, had apparently operable tumor, and if MEN1 was present, had tumor ≥2.5 cm in diameter.^{11, 22, 55} Patients with potentially completely resectable liver metastases were also included as previously described.⁸ MEN1 was established by assessing plasma hormone levels (PTH [intact, mid-molecule], prolactin, insulin, proinsulin, glucagon), serum calcium (ionized, total), and glucose as well as from personal and family history.^{56, 57}

The operative techniques have been previously described.^{11, 15, 22, 55, 58} Briefly, pNET in the head of the pancreas were enucleated unless they were either large tumor (>3cm) or had bulky lymph node metastases in that case a Whipple proximal pancreaticoduodenectomy was performed, duodenal tumors were excised with a full thickness duodenal excision, tumors in the body and tail were excised with a distal pancreatectomy plus splenectomy. For duodenal tumors or tumors in the head that were enucleated, a systematic adjacent lymph node sampling was performed. Postoperatively, patients underwent evaluation for disease-free status immediately after surgery (i.e., 2 weeks post-resection), within 3 to 6 months post-resection, and then yearly^{11, 15, 22, 55, 58} A recurrence post-resection was defined as previously reported.⁵⁵

All continuous variables were reported as mean ± standard error of the mean. Survival analysis was done using the Kaplan–Meier method and two-group comparisons using log-rank tests. Proportions are compared statistically by Fisher’s exact test. Statistical analysis was performed by means of the SAS statistical software package and significance was defined as two-tailed P value less than 0.05.

Results

Three hundred twenty-six patients were analyzed and the complete demographics are listed (Table 1). The primary tumor was localized preoperatively in 210 (64%) patients (Table 2). Primary tumors and distant metastases were seen in 106 (33%) patients, while lymph node metastases were localized in 85 (26%) patients. There were 52 (16%) patients with limited liver metastases. Computed tomography (CT) was positive in 52% of cases, abdominal ultrasound 30%, whereas magnetic resonance imaging (MRI) 35%. Somatostatin-receptor scintigraphy (SRS) accurately identified primary tumors 75% of the time, whereas hormonal gradient studies revealed positive results in 80% of cases in which it was used.

Table 1.

Patient Demographics

Characteristic	Number (%)
Patient number	326 (100%)
Male	178 (55%)
Race
Caucasian	171 (79%)(a)
Black	34 (16%)(a)
Hispanic	8 (4%)(a)
Asian	3 (1%)(a)
Age Diagnosis (years)
Mean ± SEM	45.7 ± 0.8(a)
[range]	[14–69](a)
Age Surgery (years)
Mean ± SEM	49.9 ± 9.9
[range]	[14–94]
Type of pNET
Nonfunctional pNET	115 (35%)(b)
Functional pNET	250 (77%)
Gastrinoma	218 (67%)
Insulinoma	26 (8%)
VIPoma	3 (1%)
Somatostatinoma	1 (0.3%)
Glucagonoma	3 (1%)
Other(c)	8 (3%)
Presenting symptom(s)
Pain	165 (76%)(a)
Other functional pNET symptom(s)(d)	78 (36%)(a)
MEN1 present	64 (20%)
Duration of functional pNET symptoms at diagnosis (years)
Mean ± SEM	5.8 ± 0.5(a)
[range]	[0.01–34.6](a)
Hormone elevation (fold increase)
Median	6.4(a)(e)
[range]	[1.1–5500](a)

^(a)Data available only for NIH cohort, Stanford data not available

^(b)39 patients with MEN1 with functional pNETs also had NF-pNETs identified

^(c)Other functional syndromes include ectopic Cushing’s syndrome (n=5), carcinoid syndrome (n=2), PTHRPoma (n=1).

^(d)Other functional PET symptoms include for ZES (GERD, diarrhea), insulinoma hypoglycemic symptoms, symptoms carcinoid or ectopic Cushings syndrome

^(e)Fasting hormone level elevation over normal preoperatively in patients with functional PETs

Table 2.

Preoperative Tumor Features Assessed by Localization Studies

Characteristic	Number (%)
Tumor extent
Primary localized	210 (64%)
Primary and metastases	106 (33%)
Possible lymph node metastases	85 (26%)
Liver metastases (limited)(a)	52 (16%)
Liver mets -one lobe	4 (1.8%)(a) (e)
Liver mets ->1 lobe	7 (3.2%)(a) (e)
Primary tumor
Mean ± SEM	3.1 ± 2.4
[range]	[0.3–15]
Preoperative primary location(b)
Pancreatic head/duodenum(c)	199 (61%)
Pancreatic body	32 (10%)
Pancreatic tail	59 (18%)
Other(d)	7 (3%)
Preoperative study positive(e)
CT scan	110/212 (52%)
Ultrasound	55/203 (30%)
MRI	91/160 (35%)
Any conventional imaging study	140/216 (65%)
Selective angiogram	111/201 (55%)
SRS	116/154 (75%)
Hormonal gradient positive(f)	128/161 (80%)

^(a)Limited liver metastases refers to patients without diffuse liver metastases and liver metastatic disease thought completely resectable.

^(b)Nine patients with MEN1 had multiple pNETs identified preoperatively.

^(c)Imaging studies could not frequently clearly differentiate whether in pancreatic head or duodenum.

^(d)Other tumor locations include PET primary localized in heart, lung, liver, ovary, common bile duct, and mesentery.

^(e)Data available only for NIH cohort, Stanford data not available.

^(f)Refers to positive hormonal gradient with either portal venous sampling or intra-arterial secretin injection (gastrinoma) or calcium (insulinomas) with hepatic venous sampling.

Surgical findings are summarized in Table 3 Primary tumors were located in the pancreas (112, 34%), duodenum (178, 55%), and other locations (34, 10%). Fifty-eight (18%) patients had multiple primary tumors. The mean primary tumor size was 2.6 cm (range 0.3–15 cm). For the Stanford cohort, the mean size of the primary tumor for patients without metastases was 2.5 cm, with lymph node metastasis 4.6 cm, liver metastasis 4.5 cm, and both lymph node and liver metastases 6.6 cm. At initial surgery, 181 (55%) patients had metastatic disease of whom 171 (52%) had lymph node involvement and 41 (13%) had liver metastases. Patients had an average of 4.4 lymph nodes positive for tumor (range 0–58). There were 155 (48%) patients without positive lymph nodes, 68 (21%) with one lymph node positive, 45 (14%) with 2 lymph nodes positive, 40 (12%) with 3–5 lymph nodes positive, 11 (3%) with 6–10 lymph nodes positive, 4 (1%) with 11–20 lymph nodes positive, and 3 (1%) with greater than 20 lymph nodes positive. Within the Stanford cohort, there were 30 patients (27%) with a lymph node ratio greater than 0.20 and 59 (54%) with a ratio equal to or less than 0.20. The extent of tumor at initial surgery was also analyzed. At the time of surgery, 145 (44%) had only a primary tumor, 154 (47%) had a primary tumor with lymph node involvement, and 41 (13%) had synchronous liver metastasis with or without lymph node involvement, and 17 (5%) had only lymph node metastases.

Table 3.

Surgical Findings

Characteristic	Number (%)
Patient number	326 (100%)(a)
Primary pNET location/size at surgery
Location
Pancreas	112 (34%)
Duodenum	178 (55%)
Other	34 (10%)(b)
>1 primary tumor	58 (18%)(c)
Primary tumor size (cm)
Mean ± SEM	2.6 ± 2.4
[range]	[0.3–15]
Mean for primary only	2.5(d)
Mean forprimary plus lymph node metastasis	4.6(d)
Mean for primary plus liver metastasis	4.5(d)
Mean for primary plus both LN and liver metastases	6.6(d)
Metastases found at surgery
Any metastases found	181(55%)
Lymph node involvement	171(52%)
Liver metastases (initial surgery)	41 (13%)
Lymph node metastases
Number positive/patient
Mean ± SEM	4.4 ± 3.6
[range]	[0–58]
Number positive lymph nodes per patient
0	155(48%)
1	68(21%)
2	45(14%)
3–5	40(12%)
6–10	11(3%)
11–20	4 (1%)
>20	3 (1%)
Lymph node ratio
>0.20	30 (27%)(d)
0–0.20	59 (54%)(d)
Tumor extent at surgery
Primary only	145 (44%)
Primary plus lymph node involvement	154(47%)
With liver involvement ± lymph node involvement	41 (13%)
Lymph node metastases only(e)	17 (5%)

^(a)The number of patients undergoing surgery was used as 100% in this table.

^(b)Other refers to primary pNETs located in the ovary, liver, mesentery, heart, lymph node, and lung.

^(c)>1 primary pNETs primarily occurred primarily in MEN1 patients (n=45) patients or with multiple functional pNETs (n=9).

^(d)Data available only for Stanford cohort, NIH data not available.

^(e)Patients from the NIH cohort with gastrinomainvolving lymph nodes and no identifiable primary as previously described.⁶⁹

Surgical procedure and results, follow-up, and complications are summarized in Table 4. There were 78 (24%) Stage I, 68 (21%) Stage II, 139 (43%) Stage III, and 41 (13%) stage IV tumors. Of the 326 patients who underwent surgical exploration, 318 (98%) had tumors enucleated or resected. Eight patients had either unresectable disease or a negative laparotomy. 40 (12%) patients had enucleation alone. 178 (54%) had tumor excised from the duodenum. Of the 305 patients who underwent resection, 117 (36%) had distal pancreatectomy and 30 (9%) had a Whipple pancreaticoduodenectomy. Forty-two patients also had liver resections, of which 21 were wedge resections and 20 were hepatic lobectomies. There was 1 surgical death and 78 (24%) had postoperative complications. At last follow-up, 253 (78%) of patients were alive, and there were 73 (22%) deaths of which 40 (12%) were disease-related. The mean duration from surgery to disease-related death was 6.2 years (range 0.5–28.6 years). The time from diagnosis to last follow-up averaged 13 years (range 0.9–44.4 years) and from surgery to last follow-up averaged 8.1 years (range 0.1–28.6 years). During the follow-up period, 68 (21%) patients developed liver metastases. The mean time to developing liver metastases was 4 years (range 0.2–18 years). One hundred fourteen (35%) patients developed new lesions during follow-up. In the NIH cohort, 32 (15%) patients underwent other anti-tumor treatments during the follow-up period, including 21 (10%) chemotherapy, 20 (9%) somatostatin analogues, and 16 (7%) with either alpha-interferon or peptide receptor radionuclide therapy.^{55, 59}

Table 4.

Type and Result of Surgery, Follow-Up and Complications

Result	Number (%)
ENETs tumor stage
Stage I	78 (24%)
Stage II	68 (21%)
Stage III	139 (43%)
Stage IV	41(13%)
Tumor resected/enucleated	318 (98%)(a)
Primary only	145 (44%)(b)
With lymph node metastases	171(52%)
With liver metastases	41 (13%)
Type of primary surgery
Enucleation	40 (12%)(c)
Resection	305 (94%)
Duodenal tumor excision	178 (54%)
Partial pancreatectomy	117 (36%)
Whipple pancreaticoduodenectomy	30 (9%)
Liver Resection
Wedge resection	21 (6%)
Lobectomy	20 (6%)(d)
Surgical complications
Surgical death	1(0.003%)
Complications	78(24%)(e)
Status at last follow-up
Alive	249(76%)
Dead	77(24%)
Disease-related death	51(16%)
Years from surgery to disease-related death
Mean ± SEM	6.2 ± 3.4
[range]	[0.5–28.6]
Duration of follow-up (yrs)
Time from surgery to last follow-up (yrs)
Mean ± SEM	8.1 ± 4.5
[range]	[0.1–28.6]
Time from diagnosis to last follow-up (yrs)
Mean ± SEM	13.0 ± 0.5(g)
[range]	[0.9–44.4](g)
Liver metastases during follow-up
No. developing liver metastases	68(21%)
Time to development (yrs)
Mean ± SEM	4.1 ± 2.1
[range]	[0.2–18]
No. developing new lesions during follow-up	114(35%)
Other anti-tumor treatment, post initial surgery
Chemotherapy	21 (10%)(g)
Somatostatin analogues	20 (9%)(g)
Other(f)	16 (7%)(g)

^(a)Percentage based on 326 patients who underwent surgical exploration. Eight patients had either unresectable disease or negative laparotomy (with gastrinomas).

^(b)31 patients with liver metastases also had lymph node metastases.

^(c)29 patients had both enucleation of pancreatic tumors and resections of other PETs.

^(d)Include a trisegmentectomy (n=2), l hepatic lobe resection (n=19), and segmentectomy (n=6).

^(e)There was 1 postoperative death secondary to a pulmonary embolus. Complications include postoperative pancreatitis (n=9), abscess (n=5),bleeding (n=2),wound infection (n=12), bile duct injury (n=1), pulmonary embolus/deep venous thrombosis (n=7), leak at pancreaticojejunostomy (n=8) and ischemic bowel (n=2), pancreatic fistula (n=12), bile leak (n=3), prolonged ileus (n=4) and pseudomembranous colitis (n=1).

^(f)Patients treated withalpha interferon (n=14), PRRT (n=2)

^(g)Data available only for NIH cohort, Stanford data not available.

Comparison of results in surgical patients with primary pNET only, primary plus lymph nodes only, or with liver metastases is summarized in Table 5. There were 145 patients with primary only lesions, 123 with primary and lymph node involvement, and 41 with primary and liver metastases. The mean post-operative follow-up was 7.5 years (range 0.3–26.5 years) for patients with primary only lesions, 10.1 years (range 0.3–28.6 years) for patients with primary and lymph node involvement, and 5 years (range 0.6–12.2 years) for patients with liver metastases. At last follow-up for the primary only group, there were 130 (90%) patients alive, 20 (14%) dead from other causes, and no disease-related deaths. The primary and lymph node group had 107 (87%) patients alive at last follow-up, 30 (24%) dead from other causes, and 24 (20%) disease-related deaths. Disease related deaths were significantly greater in the primary plus lymph node group (20%) compared to the primary only group (0%, p<0.01). The primary and liver metastasis group had 12 (29%) patients alive at last follow-up and 27 (68%) dead, all disease-related. This was significantly greater than both the primary only group and the primary plus lymph node group (p<0.01). All 41 patients in the primary and liver metastases group developed disease recurrence, and 28 (68%) patients developed new liver lesions following initial resection. This contrasted with the primary only group, in which 12 (8%) patients developed new lesions and 3 (2%) developed metachronous liver metastases. The primary and lymph node group had intermediate results with 61 (50%) patients developing new lesions and 37 (30%) developing metachronous liver metastases. Each group was significantly different from the other groups (p<0.01) At 10 years, the probability of developing liver metastases was 100% for the primary and liver metastases group, 30% for the primary and lymph node group, and 1% for the primary only group. Each of the three groups was significantly different from each other (p<0.01).

Table 5.

Comparison of results in surgical patients with primary pNET only, primary plus lymph nodes only, or with liver metastases

Characteristic	Number (%)
	Primary only	Primary and lymph node	Primary and liver metastases
Patient number	145	123	41
Time follow-up postop (yrs)
Mean ± SEM	7.5 ± 4.9	10.1 ± 4.4	5.0 ± 2.9
[range]	[0.3–26.5]	[0.3–28.6]	[0.6–12.2]
Current status
Alive, last follow-up	130 (90%)	107 (87%)	12 (29%)
Dead any cause	20(14%)	30(24%)	27(68%)
Disease-related death	0 (0%)*	24(20%)*	27(68%)*
Developed new lesions
Developed any new lesions	12 (8%)*	61 (50%)*	41 (100%)*
Developed new liver metastases	3 (2%)*	37 (30%)*	28 (68%)*
Probability of developing liver mets at 10 years	1%*	30%*	100%*
1–2 lymph nodes involved		25%*
>2 lymph nodes involved		35%*
Probability of overall survival at 10 years	80%	80%	30%*
Age at surgery (yrs)
Mean ± SEM	51.9 ± 9.9	47.5 ± 9.8	48.3 ± 6.3
Male gender	85 (59%)	68 (55%)	26 (63%)
Time from diagnosis to surgery (yrs)(a)
Mean ± SEM	12.6 ± 0.7	13.8 ± 0.7	8.6 ± 1.3
Primary pNET characteristics
Size (cm)	2.0 ± 0.2	2.1 ± 1.5	3.2 ± 1.2
Preoperative characteristics(a)
Hormonal marker increased > x fold	17 (12%)	50 (41%)	5 (12%)
[Functional PET]
MEN1 present	18 (12%)	41 (33%)	5 (12%)
PET characteristic
Nonfunctional	48 (33%)	42 (34%)	9 (22%)
Largest PET in pancreatic tail(a)	9/25 (36%)	21/45 (47%)	6/11 (54%)

^(a)Data available only for NIH cohort, Stanford data not available.

^*Statistically significant difference from other two groups by Fisher’s exact test (p< 0.01).

For the combined cohort, the overall survival was not significantly different between patients with lymph node involvement and those without lymph node metastases (Figure 1A). Further, we analyzed the data based on functional status of pNET (functional vs. nonfunctional). There was no difference in either overall survival or liver-metastases free survival between patients with functional tumors and those with nonfunctional tumors. We compared the behavior of the duodenal and pancreatic gastrinomas. The duodenal and pancreatic gastrinomas had a similar percentage with lymph node metastases (71 vs. 76%, p=0.26); however, they differed markedly in the percentage that had liver metastases at any time (initially or during follow-up) (17 vs. 45%, p=0.0001); the percentage that had liver metastases initially (1.8 vs. 17%, p=0.0004), the percentage that developed liver metastases during follow-up (16 vs. 28%, p=0. 012). Furthermore, they differed in the percentage of patients with a duodenal or pancreatic gastrinoma who had a disease related death (9.2 vs. 27%, p=0.0040)

Figure 1.

Kaplan-Meier plot of overall survival (Part A), time to development of liver metastasis (Parts B and C), and disease-related survival (Parts D and E). For NIH and SUH patients (n=326), overall survival was not significantly different between patients with lymph node involvement and those without metastases (Part A). As a result, we analyzed the time to development of liver metastases and found a significant difference (p<0.001) between the two groups (Part B). This difference in time to development of liver metastases was related to the number of lymph nodes involved (p<0.001) (Part C). Due to the longer follow up time for the NIH cohort (n=216), we performed an analysis of disease-related survival on this subgroup (Part D) and found significant differences among patients with no metastases, lymph node metastases only, and liver metastases (p<0.0001). We then looked at the extent of lymph node involvement in the subgroup analysis (Part E) and found that disease-related survival decreases as a function of the number of lymph nodes involved with tumor (p=0.004).

We analyzed the time to development of liver metastases for all patients with pNET with and without lymph node metastases and found a significant difference (p<0.001) between these two groups (Figure 1B). This difference in time to development of liver metastases was related to the number of lymph nodes involved (p<0.001) (Figure 1C). Due to the longer mean follow-up time for the NIH cohort (11 years compared to 2.7 for the Stanford cohort), we performed an analysis of disease-related survival for the NIH subgroup (Figure 1D) and found significant differences among patients with no metastases, lymph node metastases only, and liver metastases (p<0.0001). We then looked at the extent of lymph node involvement in the subgroup analysis (Figure 1E) and found that disease-related survival decreases as a function of the number of lymph nodes involved with tumor (p=0.004).

The 10-year overall survival probabilities for patients with only primary tumors or positive lymph nodes were indistinguishable at 80%. However, patients with liver metastases had a 10-year survival probability of 30% (p<0.0010). While few patients free of lymph node involvement developed liver metastases postoperatively, the 10-year probability of developing liver metastases for the lymph node positive group was approximately 30%. The 10-year probability of developing liver metastases for patients with 1–2 positive lymph nodes was about 25% while that for patients with greater than 2 positive lymph nodes was approximately 35%.

Comment

Yu et al. conducted the first large, prospective study describing the long-term natural history of gastrinomas and concluded that the 10-year survival rate for patients without liver metastases was 96%, single lobe metastases 78%, bilobar metastases 80%, and diffuse metastases is 16%.²⁰ In various studies, 50% to 80% of patients with advanced disease from malignant pNETs have died within 5 years of tumor progression.^{3, 60, 61} A number of ensuing studies of patients with pNET established that survival was primarily determined by the presence and/or development of liver metastases.^12–20 As a result, subsequent studies demonstrated that early resection of potentially malignant pNETs decreased the development of liver metastases and increased survival.^{22, 62} In addition, studies have shown that aggressive surgical resection in the setting of advanced disease improved survival.^{15, 18, 30} The current study also demonstrates that localized surgically resectable liver metastases decrease survival. Surgical resection of liver metastases from pNETs has been advocated; however, with long follow-up disease recurs and survival is adversely affected. Furthermore, in this group all deaths were disease-related.

In contrast to the well-established effect of liver metastases on survival in patients with pNETs, the effect of lymph node metastases on patient survival is controversial and unclear. A single institution prospective study by Weber et al. demonstrated that lymph node metastases alone had no significant impact on survival.¹⁹ Similarly, a multicenter study by Cadiot et al. concluded that the presence of lymph node metastases was not associated with increased risk of metachronous liver metastases or survival.⁶³. In a recent analysis of the SEER database from 1980–2004 in 2350 patients with pNETs, the presence of lymph node involvement without liver metastases did not affect survival.⁴² A number of other studies also concluded that lymph node metastases do not significantly decrease survival in patients with pNETs.^{19, 20, 29–41, 43} Furthermore, a recent study suggests that lymph node metastases in patients with pNETs does not increase recurrence rates after surgical resection.⁴⁵

Conversely, some studies have reported that lymph node involvement can be an important prognostic factor in pNETs; however, in some of these studies it is not apparent whether the analysis included only lymph node metastases or rather lymph node and liver metastases. In 2005, Tomasetti et al. reported that lymph node metastases decreased survival, and in 2008, Bettini et al. reported that nodal metastases were significantly associated with mortality with a prognostic significance similar to liver metastasis and Ki-67 expression.^{47, 48} In 2011, Boninsegna et al. found that a lymph node ratio 0 to 0.2 did not have a significant prognostic effect on recurrence, however a higher lymph node ratio (i.e. greater than 0.2) was a significant predictor of recurrence, whereas the simple data of lymph node involvement and number of positive nodes were not significant in predicting recurrence.⁴⁹ Because of these disparate results from different studies in the literature and the potential importance to pNET patients of clarifying this issue to their surgical management and to their subsequent follow-up and prognosis, we undertook the present study.

In the current study, when results from both surgical series were combined, the overall survival was not significantly different between patients with and those without lymph node metastases. However, the patients with lymph node metastases had a shorter time to development of metachronous liver metastases than those without metastases (p<0.001) and this difference was related to the number of lymph nodes involved (p<0.001). This has important potential implications for overall survival, because either the development or presence of liver metastases has been shown in numerous studies to be the most important predictor of survival.^{3, 19, 20, 60, 61, 63} However, this may not be apparent on short term follow-up, but becomes manifested later with longer follow-up.^{22, 62} To examine this possibility we did a subset analysis on the NIH patients because they had a follow-up 4 times longer than the Stanford group (i.e. 11 yrs vs 2.7 yrs). This subgroup analysis demonstrated that with this longer follow-up there were significant differences in disease-related survival among patients with no metastases, lymph node metastases only, and liver metastases (p<0.0001). Furthermore, the decrease in disease-related survival was related to the number of lymph nodes involved with tumor (p=0.004).

In terms of surgical management, our results support the conclusion that all patients with potential malignant pNETs at surgical exploration should have a routine removal of lymph nodes in the peritumoral area and that each should be carefully examined histologically for metastatic disease. Our study does not define the exact number of nodes that should be removed routinely, although we found the number of positive lymph nodes had addition prognostic significance. This suggests that this may be an important area of future study to attempt to define the optimum lymph node number that should be excised. In contrast to the surgical approach now widely used in many other malignancies, the inclusion of routine lymph node removal with pNETs would be a marked change from the standard surgical approach that is used in patients without gastrinoma. In patients with Zollinger-Ellison syndrome, lymph node primary gastrinomas have also been described, although their existence is controversial.⁵⁸ This has led to the suggestion that lymph nodes be routinely removed in patients with gastrinoma.⁵⁸ However, in the other pNETs, which are potentially malignant (i.e. non-insulinoma), the tumor is frequently enucleated or removed by a limited resection without lymph node harvest, and therefore our study would suggest important prognostic information is lost.

Our study has important implications for the follow-up of patients with pNETs after surgery. At present the tumor markers commonly used have not been clearly established (serum chromogranin A, serum pancreatic polypeptide), and repeat imaging studies are expensive. Our results provide an additional prognostic marker that allows better stratification of patients for follow-up. Further, chemotherapy and new biological treatments may be applicable to patients with advanced nodal disease after radical resection.^64–66 These results, as well as those from previous studies, suggest that lymph node metastases from pNETs place patients at high risk for the development of recurrence with subsequent metachronous liver metastases, and consequently decreased disease-related survival. These patients may benefit from more aggressive treatment..