Background
Since first report in 1957 [
1], gangliocytic paragangliomas (GPs) have been found to occur mostly in the periampullary portion of the duodenum [
2], although some have been observed in the jejunum [
3], pylorus [
4], esophagus [
5], nasopharynx [
6], ovary [
7], and lung [
8]. The pancreas is also an extremely rare site of GP; only three cases have been reported to date, making the clinical characteristics of pancreatic GP unclear [
9‐
11]. GPs are typically associated with an extremely good prognosis, but patients harboring lymph node metastases have occasionally been reported [
12]. Radical surgery with lymph node dissection is therefore the mainstay of curative treatment [
13]. GPs consist of three characteristic tumor components: epithelioid, spindle, and ganglion-like cells [
14]. Histopathologically, it can be challenging to distinguish pancreatic GPs from other pancreatic neoplasms with neuroendocrine differentiation, such as paragangliomas and neuroendocrine tumors, because of their low incidence, rare location, and similar morphological and immunohistochemical characteristics [
15,
16]. Their clinical presentation and treatment strategy, however, appear to differ [
11,
17,
18], making precise differentiation crucial for pathological diagnosis.
This report describes a patient with pancreatic GP harboring lymph node metastasis. The patient was also found to have a pancreatic neuroendocrine tumor (NET) G1 (grade 1, WHO 2010) and an adrenocortical adenoma. Herein, the clinical characteristics of pancreatic GP are reviewed, as well as the differential diagnosis of these tumors from other endocrine tumors.
Discussion
Table
2 summarizes the clinical features of the four patients with pancreatic GP, including our patient, identified to date [
9‐
11]. The average age of these four patients was 63 years, and three (75%) were women. Interestingly, the tumors in all four patients were located in the head of the pancreas, but our patient was the only patient without abdominal symptoms, such as abdominal pain and jaundice. Although duodenal GP is characterized by a favorable clinical course and a low incidence of lymph node metastasis (6.9% of 173 patients [
13]), with none showing distant metastasis, three (75%) of the four patients with pancreatic GPs had metastases, including two with lymph node metastases and one with distant metastasis to the sternum. In addition pancreatic GPs were larger (mean diameter: 35 mm) than duodenal GPs (24.2 mm). These results are consistent with the greater difficulty detecting early stage pancreatic than duodenal tumors. Furthermore, pancreatic GPs may have a higher potential for malignancy than duodenal GPs.
Table 2
Summary of clinical features of pancreatic gangliocytic paraganglioma
| 1996 | 74 | Female | 40 | Abdominal pain, Diarrhea, Steatorrhea, Nausea, Vomiting, | (+) lymph node | PD | NER 20 |
| 2003 | 50 | Male | 25 | Cholestatic jaundice | (+) sternum | PD, followed by sternal resection | NER 18 from the second operation |
| 2008 | 60 | Female | 53 | Fever, Abdominal pain, Jaundice | NR | PD | NER 12 |
Present case | 2016 | 68 | Female | 22 | None | (+) lymph node | PPPD | NER 12 |
Pancreatic paraganglioma is important in the differential diagnosis of pancreatic GP, as the epithelioid cell component of GP is morphologically and immunohistochemically similar to paraganglioma [
15,
16]. Moreover, most pancreatic paragangliomas are nonfunctional and located in the pancreatic head [
17]. To distinguish GP from paraganglioma, we therefore immunohistochemically stained the tumor in our patient for catecholamine-synthesizing enzymes and pancytokeratin (Table
1). Most paragangliomas, including the non-functioning type, are positive for catecholamine-synthesizing enzymes [
20] but negative for pancytokeratin [
15]. To date, the details of catecholamine-synthesizing enzyme expression in GP have not been studied. However, the epithelioid cell component of GP in our patient was negative for catecholamine-synthesizing enzyme expression, suggesting that the functionality of this cellular component of GP may differ from paraganglioma.
Expression of PgR and PP may differentiate “duodenal” GP from “duodenal” NET G1 [
16]. Assessment of 12 duodenal GPs showed that the epithelioid cell component in 11 (91.7%) were positive for PgR and PP. In contrast, duodenal NETs G1 were uniformly negative for PgR and PP expression. To date, no study has assessed the expression of PgR and PP in pancreatic GP. Interestingly, the immunohistochemical profile of PgR and PP expression in this patient were similar in the epithelioid cell component of the pancreatic GP and the NET, a result that may help in differentiating between pancreatic and duodenal GP. Further analysis is required to confirm the usefulness of PgR and PP expression in the diagnosis and differentiation of pancreatic GP.
Contrast-enhanced CT revealed differences in the contrast-enhanced patterns of GP in the pancreatic head and NET G1 in the pancreatic tail. FDG PET has been considered inadequate for the diagnosis of well-differentiated NETs due to their very slow growth [
21]. The GP in this case, however, exhibited high
18F–FDG uptake, indicating that
18F–FDG PET could be a practical tool for detecting pancreatic GPs or to differentiate pancreatic GPs from NETs.
Several somatostatin analogs (SAs), including octreotide, lanreotide, and pasireotide, have been shown to have therapeutic benefits in patients with advanced pancreatic NETs [
18]. The effectiveness of SA therapy for patients with GPs is entirely unknown, as none of these patients to date has been treated with SA. The present study, along with a previously reported case of GP in the ampulla of Vater, showed that the epithelioid cell component was immunohistochemically positive for SSTR2A [
22], suggesting that SA therapy may have benefit GPs. Further study is warranted.
The co-occurrence of three distinct endocrine tumors in one patient suggests the possibility of a genetic predisposition in this patient. The genetic and biological backgrounds of this peculiar combination of three different endocrine neoplasms remain largely unknown. Although we found nothing indicating an inherited condition, the patient should be carefully monitored to allow for the early detection of other endocrine-related neoplastic lesions.
Conclusion
This report describes the fourth reported case of pancreatic GP. Compared with duodenal GPs, pancreatic GPs were larger and had a higher incidence of metastasis, suggesting a greater potential for malignancy. Therefore, the primary organ of GP may be an important prognostic factor.