NET Guidelines for White Patients may not fit Asian patients

Abstract

Introduction

Pancreatic neuroendocrine tumors (pNETs) are slow growing, malignant tumors that show different survival outcomes by race. Current size-based guidelines were largely developed in White patients. Our aim was to investigate tumor size and incidence of lymph node metastasis (LNM) between White and Asian pNET patients to evaluate generalizability of established guidelines.

Methods

Using the National Cancer Database (NCDB), we conducted a multi-institutional analysis of patients with low grade, resected, nonfunctional, sporadic, non-metastatic pNETs. Chi-squared tests were implemented to determine correlation between PTS and LMN incidence as well as race and LMN incidence. A logistic regression model was utilized to determine correlation between LMN, tumor size, and race. Overall survival was assessed using the Kaplan-Meier method.

Results

A total of 4,977 pNET patients (205 Asian and 4,772 White) were included in our analysis. Asian patients presented with smaller tumors (3.0cm vs 3.9cm, p=0.029) but when grouped by size, there was no difference in the distribution (p=0.77). White patients demonstrated a higher incidence of lymph node metastasis at presentation compared to Asian patients (27% vs 19%, p=0.013), a higher likelihood of an R0 resection (95.3% vs. 89.3%, p<0.0001).

Within both populations, tumor size (<2cm, 2–3cm, and ≥3cm) positively correlated with incidence of LNM (11.5%, 24.6%, and 39.1%). No difference of LNM was seen between racial cohorts at PTS <3cm, however, Asian patients were less likely to exhibit LNM at PTS ≥3cm (28.2% and 39.5%, p=0.04) (Figure 3). Overall survival was not significantly different between racial groups (p=0.92) (Figure 4).

Conclusion

Size based surgical resection guidelines for pancreatic neuroendocrine tumors based on a predominantly White patient population may not be generalizable to the Asian population. Within this population, we found the risk of lymph node metastasis did not increase at similar rates with increasing primary tumor size.

Graphical Abstract

INTRODUCTION

Pancreatic neuroendocrine tumors (pNETs) are rare, neuroendocrine tumors accounting for 1–2% of all pancreatic neoplasms.^1–4 Compared to functional pNETS, nonfunctional pNETs are more challenging to diagnose and treat; often presenting with larger and more advanced lesions.³ The management of metastatic PNETs can vary^5–8 but for non-metastatic, non-functional tumors, the current guidelines advise surgical resection for tumors ≥2cm, and observation for tumors <2cm.^9–13

However, these guidelines were developed in predominantly White study populations, and their generalizability into other racial populations has recently been called into question.¹⁴ Racial disparities in cancer outcomes has been well documented; in our institutional analysis regarding pNETS, we saw that Black patients were more likely to present at larger tumor sizes, however, there were not predictive of disease recurrence compared to White patients.¹⁵ These associations have not been explored within the Asian population. Our aim was to explore if tumor size was predictive of lymph node metastasis and overall survival in Asian patients with well-differentiated, nonfunctional pNETs.

METHODS

Study Materials

The National Cancer Database (NCDB) is a resource of the American College of Surgeons and American Cancer Society that collects de-identified patient and hospital data across ~1,500 Commission on Cancer accredited hospitals within the United States.^16,17. We aimed to use a data collection period of at least 10 years to allow for sufficient patient numbers We conducted a multi-institutional analysis of patients with low-grade, well-differentiated, nonfunctional, sporadic pNETS who underwent surgical resection, using patients identified as White or Asian within the NCDB. Asian was defined as patient who were of genetic and cultural similarity and encompassed the following listed racial groups within the NCDB: Chinese, Japanese, Filipino, Hawaiian, Korean, Vietnamese, Laotian, Hmong, Kampuchean, Thai, Asian Indian or Pakistani, Asian Indian, Pakistani, Micronesian, Chamorran, Guamanian, Polynesia, Tahitian, Samoan, Tongan, Melanesian, Fiji Islander, New Guinean, American Indian, Aleutian, Eskimo (or Inuit), Pacific Islander, and other Asian. Tumor stage was defined according to the North American Neuroendocrine Tumor staging guidelines.⁹ The type of facility the patient underwent surgery at was pre-defined in the NCBD database.

Statistical Analysis

Chi-squared tests were implemented to identify associations between Tumor Size and incidence of Lymph node metastasis as well as patient racial group and incidence of Lymph node metastasis. A logistic regression model was utilized to determine correlation between Lymph node metastasis, tumor size, and patient racial group. Disease-free survival was assessed using the Kaplan-Meier method. All statistics were performed using SPSS Version 29 (IBM, Armonk, New York).

RESULTS

Using NCDB data from 2004–2017, we identified 4,977 patients (205 Asian patients and 4,772 White patients) that were included in our study. As compared to White patients, Asian patients were less likely to be male (45.9% vs 54.0% p=0.02). There was no difference in age (59.1 vs 56.2 years, p=0.63). Asian patients presented with smaller tumors (3.0cm vs 3.9cm, p=0.029) but when grouped by size, there was no difference in the distribution (p=0.77). White patients demonstrated a higher incidence of lymph node metastasis at presentation compared to Asian patients (27% vs 19%, p=0.013), a higher likelihood of an R0 resection (95.3% vs. 89.3%, p<0.0001). There was no significant difference in follow-up duration between the two racial groups (p=0.155) (Table 1). The majority of patients in both groups underwent surgery at Academic Program (59.3% and 54.1%), however Asian patient were more likely to undergo resection at a Community Cancer Program (5.9% vs 1.5%).

Table 1.

Patient Demographics

Variable	Overall (n=4977)	White (n=4772)	Asian (n=205)	p-value
Age, in years	59 (13)	59.1 (13)	56.2 (13.1)	0.63
Sex, Male	2669 (53.6%)	2575 (54.0%)	94 (45.9%)	0.023
Grade				0.323
1	3971 (79.8%)	3813 (79.9%)	158 (77.1%)
2	1006 (20.2%)	959 (20.1%)	47 (22.9%)
Tumor Size, cm	3.9 (7.6)	3.9 (7.8)	3.0 (2.2)	0.029
Lymph Node Metastasis Rate	1321 (26.5%)	1282 (26.9%)	39 (19.0%)	0.013
Regional Nodes Positive	1.1 (5.1)	1.1 (5.2)	0.7 (1.4)	0.01
Primary Tumor Size (cm)				0.766
<2cm	1669 (33.5%)	1596 (33.4%)	73 (35.6%)
2–3cm	1131 (22.7%)	1084 (22.7%)	47 (22.9%)
≥3cm	2177 (43.7%)	2092 (43.8%)	85 (41.5%)
R0 Resection				<0.0001
R0	4495 (95.0%)	4313 (95.3%)	183 (89.3%)
R1	235 (5.0%)	213 (4.7%)	22 (10.7%)
Type of Institution				<0.001
CCP	84 (1.7%)	72 (1.5%)	12 (5.9%)
CCCP	1042 (20.9%)	1003 (21.0%)	39 (19.0%)
AP	2943 (59.1%)	2832 (59.3%)	111 (54.1%)
INCP	509 (10.2%)	493 (10.3%)	16 (7.8%)
N/A	399 (8.0%)	372 (7.8%)	27 (13.2%)
Follow up Duration, months	58.2 (31.8)	58.3 (31.2)	56.3 (30.0)	0.155
Vital Status				0.04
Alive	4243 (85.3%)	4058 (85.0%)	185 (90.2%)
Dead	734 (14.7%)	714 (15.0%)	20 (9.8%)

(CCP: Community Cancer Program, CCCP: Comprehensive Community Cancer Program, AP: Academic Program, INCP: Integrated Network Cancer Program, NA: Not Available)

Within both populations, tumor size (<2cm, 2–3cm, and ≥3cm) positively correlated with incidence of LNM (11.5%, 24.6%, and 39.1%). No difference of LNM was seen between racial cohorts at PTS <3cm, however, Asian patients were less likely to exhibit LNM at PTS ≥3cm (28.2% and 39.5%, p=0.04) (Figure 1). Overall survival was not significantly different between racial groups (p=0.92) (Figure 2).

Figure 1.

Risk of Lymph Node Metastasis (LNM) based on Primary Tumor Size (PTS) in pNET Patients

Figure 2.

Kaplan-Meier of Overall Survival by Race

DISCUSSION

The need for tailored approaches in different populations has become more prominent over the past decade. Surgical resection guidelines are based upon a predominantly White patient population. This recommendation is based on the increased risk of lymph node metastasis with PTS ≥3cm. For Asian patients, risk of lymph node metastasis did not increase with increased tumor size ≥3cm. Our data suggests that Asian pNET patients may be undergoing surgical resections at increased rates without an increased risk of lymph node metastasis. Additionally, we noted that White patients had a higher rate of R0 resection when compared to their Asian counterparts. In the setting of smaller tumors at presentation, this was a very surprising finding. Whilst this analysis does not allow us to determine this reasons for this finding, we hypothesize they could be multifactorial; with differences including but not limited to: body habitus, access to care, type of institution, socioeconomic status.

Despite there being approximately 18 million Asian adults in the US, there is very little data on pNETS specifically within this population¹⁸. Disparity studies that have compared White to Black patients have shown results that may indicate a difference in tumor biology between races. Survival disparities in pNET outcomes have shown that at similar stage on presentation, Black pNET patients experienced lower rates of surgical management and worse disease-free survival.^14,19 Black patients are also more likely to present with larger tumors at an earlier age compared to White pNET patients.¹⁵ In addition, Black patients had a significantly higher incidence of LNM in tumors smaller than 2cm compared with White patients.²⁰

As the incidence and our understanding of pancreatic neuroendocrine tumors continues to increase, data specifically addressing Asian American patients with pancreatic neuroendocrine tumors remains largely insufficient globally.²¹ The largest series of resected non-functional pNETs (n=55) showed a lymph node positivity of 21.2% with a mean tumor size of 4.85cm.²² The Chinese guidelines for the management of non-functional pNETS refer to data from the US Neuroendocrine Tumor study group, which may not reflect their population as hypothesized in this study.²³

These results need to be interpreted within their limitations. Our study included a small Asian population subset and broad spectrum of “Asian” patients included in our study (which risks Type-1 error in our analysis). We understand that the Asian heritage is diverse, as is their biologic and genetic background. This grouping was based on genetic ancestry homology, so grouping these individuals based on cultural definitions does not explicitly describe this diverse population (ranging geographically from American Indian to Asian American Native Hawaiian Pacific Islander [AANHPI]). Further studies elucidating Asian patients by specific nationality is warranted; however, this may be limited by low incidence of “Asian” patients within national cancer databases.

Guidelines that exist do not account for variations in disease presentations amongst different races. Whilst this disparity has been demonstrated in other racial patient populations, it has not been investigated in Asian patients.^15,20 Surgical decision-making for pancreatic PNET should be personalized to each patient, and we propose that race may be an important component of that decision.^24,25 The current data that is at our disposal globally does not answer whether Asian pNET patients require a different treatment algorithm, but our data suggests that they may present with less lymph node positivity when compared to their counterparts. We suggest further investigation to better elucidate tumor progression and impact of surgical resection for Asian pNET patients.

CONCLUSIONS

Size based surgical resection guidelines for pancreatic neuroendocrine tumors based on a predominantly White patient population may not be generalizable to the Asian population. Within this population, we found the risk of lymph node metastasis did not increase at similar rates with increasing primary tumor size. We recommend further, race specific studies to better elucidate tumor progression and surgical implication on Asian pNET patient to better provide idealized care.

Highlights.

• Pancreatic neuroendocrine tumors (pNETs) are slow growing, malignant tumors that show different survival outcomes by race.

• We found that Asian patients were less likely to exhibit Lymph Node Metastasis at tumor sizes ≥3cm when compared to White patients.

• Therefore size based surgical resection guidelines for PNETs based on a predominantly White patient population may not be generalizable to the Asian population.