Introduction

Pancreatic neuroendocrine neoplasms (PanNENs) are a heterogeneous group of neoplasms that show variable behavior, from indolent to aggressive. The clinical behavior is mainly related to the grade of the disease. In recent years, the incidence of such neoplasms has increased markedly, in part due to incidental findings of small low-grade lesions (either G1 or G2), both of which are often treated conservatively.

Aims & Methods

Aim of the study was to explore the biological and clinical heterogeneity of grade 2 (G2) PanNENs to better define clinical features, prognosis, and therapeutic options.
​This is an observational, retrospective, single-center study examining patients with confirmed G2 PanNENs from January 2005 to December 2022. Demographic, clinical, biochemical, histopathological, imaging, and therapeutic data were collected for each included patient. Overall survival (OS) and progression-free survival (PFS) from diagnosis were also evaluated and compared with the G1 PanNENs group.

Results

A total of 51 PanNENs were collected: 29 were G1, 20 were G2, and 2 were G3. Among the G2 PanNENs, 12 patients (60%) were female and the median age at diagnosis was 56.5 years [IQR, interquartile range from 50.25 to 70.5]. Five patients were at stage I at diagnosis, 3 at stage II, 2 at stage III, and 10 at stage IV; 5 patients (25%) had a functioning PanNEN. The median Ki67% at diagnosis was 5% [IQR 4-12]; the median size of the primary tumor was 30 mm [IQR 16-43]. Fifteen patients (75%) underwent surgery, 13 as 1st-line therapy, and 2 as 2nd-line. Pancreaticoduodenectomy and distal splenopancreatectomy were equally the most frequently performed types of surgery (both 30.7%). Of the 15 surgical patients, an R0 outcome was achieved in 9 (60%) and 8 (53.3%) other patients underwent further therapies: 7 patients received somatostatin analogs (SSAs), 3 peptide receptor radionuclide therapy (PRRT), 2 targeted therapy, and 1 chemotherapy. Of the other nonsurgical patients, one received first-line systemic treatment (4 SSAs and 1 PRRT). The median PFS of G2 PanNENs after 1st-line treatment was significantly different from that of G1 PanNENs (25.5 months vs undefined, p <0.0001). The median OS of G2 PanNENs was shorter compared to G1 PanNENs, but did not reach statistical significance (83 vs 87 months, p=n.s.). When comparing demographic, clinical, biochemical, histopathological, and therapeutic data between G2 and G1 PanNENs, no variables other than disease stage at diagnosis (p=0003) were significantly different.

Conclusion

This study found that surgery was a common treatment option for G2 PanNENs. However, while the majority of surgical patients achieved R0 results, a significant proportion had to undergo further therapies due to disease progression. The prognosis of G2 PanNENs was significantly worse than that of G1 in terms of both PFS and OS, although the median OS was not statistically different. The disease stage was more advanced in G2 PanNENs than in G1 PanNENs. Overall, these findings suggest that G2 PanNENs deserve a different personalized treatment approach than G1 PanNENs and that further research is needed to better understand the factors affecting their prognosis.

Clinical Case Summary

About 1-2% of pancreatic tumors are neuroendocrine pancreatic tumors (NETs). They are often solid masses; rarely they appear as cystic lesions.
The authors report the clinical case of a 66-year-old woman with unspecific abdominal pain, who was referred to the Pancreato-biliary clinic for pancreatic cystic lesions. Magnetic resonance cholangiopancreatography and abdominal CT showed multiple cystic lesions in the distal body and a lesion of 26 mm in the anterior region of the body with diffusion restriction; the duct of Wirsung was dilated (8 mm). Endoscopy ultrasound showed: several hyperechoic foci in the pancreatic parenchyma; a nodular hyperechoic lesion measuring 9 mm in the pancreatic body; a cystic lesion measuring 6 mm in the body; and two cystic lesions measuring 38 and 25 mm in the tail. Fine needle biopsy of the nodular lesion and fine needle aspiration of the larger cystic lesions was performed; the aspiration punction showed amylase 33207 U/L and carcinoembryonic antigen 0.9 ng/mL; however, the cytology of both lesions was inconclusive. Somatostatin receptor scintigraphy showed uptake in the pancreatic body's anterior region and high somatostatin receptor expression, suggesting a neuroendocrine pancreatic tumor diagnosis. In the multidisciplinary team discussion, the decision was to perform total duodenopancreatectomy with splenectomy, which occurred without complications. Histological examination revealed several well-differentiated NETs, the largest of which measured 4 cm, with < 2 mitoses per 2 mm², a proliferation index of 3-20% and regional ganglionic metastasis (pT3(m)N1). At 2 years of follow-up, the patient remains clinically stable without evidence of recurrence of the disease.
This case report, while displaying remarkable images, intends to highlight the challenge of the differential diagnosis between cystic lesions and neuroendocrine tumors of the pancreas; both entities can coexist synchronously and they may share imagiological features.

References

Images list:

1. Multiple cystic pancreatic lesions and a pancreatic lesion in the anterior region of the body with diffusion restriction (Magnetic Resonance Cholangiopancreatography).
2. Multiple cystic lesions in the distal body and a pancreatic lesion in the anterior region of the body (Abdominal Computed Tomography).
3. Several hiperecoic foci in the pancreatic parenchyma; a nodular hiperecoic lesion measuring 9 mm in the pancreatic body; a cystic lesion measuring 6 mm in the body; and two cystic lesions measuring 38 and 25 mm in the tail (Endoscopy ultrasound).
4. Uptake in the pancreatic body's anterior region and high somatostatin receptor expression (Somatostatin receptor scintigraphy)

Introduction

Pancreatic neuroendocrine tumors (NETs) are rare neoplasms that are classified as functional (F-NET) or nonfunctional (NF-NET) depending on the presence or absence of excess hormone production. Endoscopic Ultrasound guided fine needle aspiration (EU-FNA) is often used to diagnose NETs but there are limited data on its sensitivity for this purpose.

Aims & Methods

To determine the sensitivity of EUS-FNA for the diagnosis of a NET.
A prospective randomized trial study, from May 2013 to Abril 2025 was performed in a referred Gastrointestinal hospital in Brazil. A total of 184 patients underwent EUS for suspected NETS and collected materials from fine needle aspiration and sent to histopathology analyzes. The diagnosis of a NET was confirmed by: 1) EUS-FNA with or without confirmatory immune chemistry (ICC) with synaptophysin and chromogranin form pancreatic mass or metastatic site; or 2) an alternative biopsy method and/or surgical resection of the pancreas or other metastatic site

Results

184 patients (112 male; median age: 54 yrs, range: 21-78 yrs) with 68 (37%) F-NETs and 116 (63%) NF-NETs were identified. By EUS, the tumors were located in the pancreas head, body, tail or were multifocal in 76 (41%), 54 (29%), 38 (21%) and 16 (18%), respectively. Of these 184, 152 (83%) underwent EUS-FNA of a pancreatic mass, 72 (47%) of whom also had a EUS-FNA of an alternative (nonpancreatic) site including liver (n=30; 16%), another lesion in the pancreas (n=14; 8%), or lymph node (n=18; 10% peripancreatic in 10, celiac in 6 and mediastinal in 2). Immunohistochemistry was performed in 102/152 (67%) EUS-FNA specimens and the result were: ICC-positive (n=88), ICC-negative (n=10), not interpretable (n=2) or inadequate for interpretation (n=2), Surgery was performed in 82 (54%): distal pancreatectomy (n=32), Whipple procedure (n=20), enucleation (n=20) and subtotal (n=4) and total pancreatectomy (n=2). The remaining four who underwent surgery had an exploration laparotomy only. 132 patients had a confirmed diagnosis of NET and the sensitivity of EUS-FNA was respectively: all patients 84%, F-NET 78%, NF-NET (89%) and lesions less than or equal to 13 mm (62%). The results of the false-negative EUS-FNA biopsies of pancreas (n=24) were interpreted as: normal in 4; suspicious in 4, nondiagnostic in 10, adenocarcinoma in 4, and a solid pseudopapillary tumor in 2.

Conclusion

EUS-FNA is a sensitive method for the diagnosis of pancreatic NETS but yield is lower in tumor smaller than 13mm in diameter.