Non-functioning pancreatic NETs

Classification of Non-functioning Pancreatic NETs
Non-functioning or “non-syndromic” pancreatic NETs are not associated with a distinct hormonal syndrome but may still have elevated hormone levels in the blood, such as chromogranine A, pancreatic polypeptide (PP, revealed in 50-70%), calcitonin, somatostatin, but occasionally also insulin/proinsulin or glucagone. Non-functioning pancreatic NETs often become clinically apparent due to their large size or invasion of adjacent organs or the occurrence of metastases. They may be discovered as unusually large tumours without the typical malignant cachexia of pancreatic carcinoma. As many as 10-35% are found incidentally at abdominal imaging for other reasons.

Epidemiology of non-functional pancreatic NETs
The proportion of non-functioning pancreatic NETs is increasing due to increased awareness and improved diagnostic procedures, and constitute about 50% of all pancreatic NETs. They account for 3-5% of pancreatic tumours overall, but are important to recognize because of more favourable survival than patients with adenocarcinoma. The non-functioning endocrine pancreatic tumours are often diagnosed at 50-60 years of age, but occur also in younger individuals.

Diagnosis of non-functional pancreatic NETs
Diagnosis of non-functioning pancreatic NETs is made by demonstrating hypervascularization on contrast enhanced CT and positive octreoscan (Fig.4), raised serum levels of chromogranine A or serum PP, or by ultrasound-guided fine or semi-fine needle biopsy stained with chromogranine A (Fig.5) or synaptophysin.

Neck lymph node metastasis from endocrine pancreatic tumourpositive on octreoscan. Ultrasound guided fine needle biopsy from EPT positive for chromogranin A.
Fig. 4. Neck lymph node metastasis from endocrine pancreatic tumourpositive on octreoscan. Fig. 5. Ultrasound guided fine needle biopsy from EPT positive for chromogranin A.

 

The non-functioning pancreatic NETs often (~60%) occupy the pancreatic head, but may occur in the entire pancreas. They may cause jaundice, or discomfort due to local extension, or pain due to pancreatitis. Growth is typically slow, but the progress is variable, some are indolent, with only a growing primary lesion, other progress rapidly with lymph node and liver metastases. High Ki67 proliferation index (~10-20%) has been associated with more rapid progression and aggressive tumors. Extra-abdominal spread from non-functioning pancreatic NETs generally occurs late. The non-functioning tumors may grow into surrounding structures, the ventricle, the duodenum, or the transverse colon, and can be associated with obstruction or bleeding. The mesenteric vein can become invaded and occluded, causing portal hypertension and tendency to gastrointestinal bleeding. Also the celiac, the hepatic, and the mesenteric artery may be involved.

Treatment of non-functioning pancreatic NETs
Non-functioning pancreatic NETs should be considered for surgical therapy, but also for chemotherapy, depending on the Ki67 index and the WHO classification.
Surgery is indicated for removal of the primary tumor to reduce risk for gastric outlet obstruction and mesenteric vein involvement, and to facilitate chemotherapy. Operation may be undertaken also in presence of low volume liver metastases. Even if the portal vein is occluded also large pancreatic NETs can often be removed by extended pancreatico-duodenectomy or subtotal pancreatectomy, with use of vein graft to restore patency of the porto-mesenteric vein (Figs 6 and 7).

Figures 6 and 7. Surgery may be indicated for large tumours, despite presence of low volume liver metastases to reduce risk of overgrowth on surrounding organs, favourable survival may be expected with medical treatment. Figures 6 and 7. Surgery may be indicated for large tumours, despite presence of low volume liver metastases to reduce risk of overgrowth on surrounding organs, favourable survival may be expected with medical treatment.
Figures 6 and 7. Surgery may be indicated for large tumours, despite presence of low volume liver metastases to reduce risk of overgrowth on surrounding organs, favourable survival may be expected with medical treatment.

 

Results of Surgery in the Uppsala series of 191 patients with non-fuctioning pancreatic NETs, in relation to WHO group of differentiation.

WHO I: well differentiated tumours, no spread, median survival 16 years
WHO II: well differentiated carcinoma, local invasion or metastases, median survival 8 years
WHO III: poorly differentiated endocrine carcinoma, median survival 2 years (12% of non-functioning tumours)

 

WHO II: well differentiated carcinoma, local invasion or metastases, median survival 8 years
 
Markedly improved survival in operated patients.

 

The rate of metastases in non-functioning pancreatic NETs varies from 62-92%. Results of surgery for large non-functioning tumours with vascular invasion have reported 5-year survival of 65%, and 10-year survival of 49%. Survival benefit has been evident in absence of liver metastases or when such metastases have been resected.