Generally there are two categories of pancreatic neuroendocrine tumors: functional, releasing in the peripheral blood active hormones responsible for a specific clinic syndrome and non-functional, secreting either a functionally inert hormone or in very small amounts, therefore not producing any clinical symptoms[7, 8].
The proportion of non-functional tumors varies largely in published series. A review by Ito et al. found 48% of pancreatic neuroendocrine tumors as non-functional[9]. Kazanjian et al., in a series of 70 consecutive resected neuroendocrine tumors of pancreas found 71% of them non-functional[10].
The peak incidence for these tumors is between 30 and 60 years of age[11]. Early clinical diagnosis of non-functional pancreatic tumors is very rare because usually they become symptomatic only when they grow larger or metastasize. Otherwise they are discovered incidentally on the occasion of imagistic tests performed for other medical reasons. In our case, there is a very rare situation of intraoperative discovery.
Abdominal ultrasound was performed before surgery but, on regular examination, PNETs present a hypoechoic aspect that cannot be differentiated from other types of tumor, and could escape detection because of operator's inexperience, flatulence, obesity, deep situations and locations in the tail[12]. In the case we describe the old and organizing blood clots around the spleen surely contributed to hide the tumor.
Intraoperative discovery poses problems of diagnostic and therapeutic decision. Association with a grossly aspect of chronic pancreatitis raises the suspicion of pancreatic cancer. Pancreatic neuroendocrine tumors represents less than 3% from pancreatic tumors[13, 14]. It is far more rare than pancreatic adenocarcinoma, with a ratio of 1:25[6] being substantially rarer than adenocarcinomas and carrying a better prognosis[8]. Most neuroendocrine tumors of pancreas are located in the pancreatic head[15]. In our case the tumor was located near the splenic hilum.
In front of an accidentally discovered pancreatic tumor we had to decide whether to perform or not a frozen biopsy. Due to the fact that the tumor was well confined to the pancreas and relatively easy amenable to resection, there were no enlarged lymphnodes in the vicinity and the pancreas presented a firm consistency, well suitable for suture with low-risk for pancreatic fistula, a resection with safe margins was decided.
We think that in such cases a frozen section could not have brought any elements to change our decision. In neuroendocrine tumors of pancreas the only reason to perform a frozen section is when an enucleation is planned but even in such situations there could be problems of differential diagnosis with papillary tumors[16].
The mainstay of treatment for neuroendocrine tumors of pancreas is surgical resection. However, particularly for non-functional tumors, it remains controversial as to whether resection alters their natural history. Tumor enucleation can be performed in cases in which the pancreatic endocrine tumor is single, capsulated, of limited size (less than 2 to 3 cm) and peripheral, situated at a distance from the main duct[13, 14]. The safe margin of resection is not clearly indicated in the litterature. If the tumor is macroscopically well delimited the margin can be very narrow, from few millimeters to 1 cm[16].
Immunohistochemistry is of outmost importance for the study of neuroendocrine tumors of pancreas. Several antibodies are available against neuroendocrine markers such as NSE, CD56, synaptophysin, CgA, and other hormones. It is important to discriminate well-differentiated forms from poorly differentiated carcinomas using malignancy markers[17]. The malignant or metastatic potential of neuroendocrine pancreatic tumors can be estimated using the tumor size, mitotic index, expression of KI-67 protein, vascular invasion, and perineural invasion[18]. The proliferation marker MIB-1 (directed against the Ki-67 antigen) helps to determine tumor grade and prognosis[3].
Association with pancreatitis (acute or chronic) was already reported in the literature. Mostly, there are reports of acute pancreatitis generated by obstruction of the main duct by the tumor[5, 19, 20]. In some of the cases the acute pancreatitis became chronic. In other, there was no evident relationship between chronic pancreatitis and the neuroendocrine tumor[5]. In 71% of the cases the tumor was malignant[19].
In our case the association between chronic pancreatitis and PNET seemed purely incidental because the pancreatitis involved grossly the entire pancreatic gland and the tumor was located in the proximity of the splenic hilum. In addition, the patient was a chronic alcohol consumer, a well-known etiological factor for chronic pancreatitis.
There are very few studies in the literature searching a common genetic pathway for chronic pancreatitis and pancreatic neuroendocrine tumors. In an interesting comparative study in search for specific molecular markers, Bloomstone et al.[21] compared them with different other pancreatic diseases as chronic pancreatitis and pancreatic adenocarcinomas. They found that ELOVL4 (a gene codifing the protein for the elongation of very-long-chain fatty acids 4-like, responsible for the biosynthesis of fatty acids) and CALCR (gene responsible for calcitonine receptor) were increased both in neuroendocrine tumors and chronic pancreatitis.
Overall prognosis after resection is much better than of other pancreatic tumors. In a review of 3851 cases, survival was 59.3% at 5 years and 37.7% at 10-years. Age, grade, distant metastases, tumor functionality, and type of resection were independent predictors of survival, meanwhile gender, race, socioeconomic status, tumor size, nodal status, margins, adjuvant chemotherapy, and hospital volume had no influence[22].
Beside association with chronic pancreatitis, there are reports of a unique association between carcinoid tumors and renal cell carcinoma in a mature cystic teratoma of a horseshoe kidney. In this case the tumor presented also a low grade of malignancy and differentiation as adenocarcinoma as in our case[23]. Primary renal carcinoid tumors are morphologically and histologically similar to those in other sited. The surgical resection is curative and prognosis is good in the absence of metastasis but long term follow-up is recommended because distant recurrence may occur up to seven years postoperatively[23].
Immunohistochemical markers may be related also with prognosis beside their diagnostic role. Expression of NSE and CD 56 was studied in renal cell carcinoma and was correlated with prognosis. First of all, NSE marker was exhibited by 48% of the renal cell carcinoma in a series of 152 cases. In the same series there was an 18% of CD56 positive stain. Renal cell carcinomas that exhibited NSE and/or CD56 had a poorer prognosis.[24].
