The patient underwent a computer tomography as part of a urological workup, which revealed an incidental lesion in the tail of the pancreas (Figure 1). The distal 3.2 cm segment of the pancreatic body appears irregularly enlarged measuring approximately 2.4 cm without associated attenuation and enhancement abnormalities. Distal to this segment, there is irregular dilatation of the pancreatic duct for approximately 6 cm extending all the way to the splenic hilum. The duct averages 8 mm throughout and measures approximately 1 cm in its greatest dimension. There was no evidence of abnormal masses to suggest lymphadenopathy. These findings were suggestive of an obstructive process in the distal pancreatic body. A magnetic resonance imaging and cholangiopancreatography confirmed the presence of segmental dilatation within the body and tail of the pancreas and of the main and adjacent side-branches of the pancreatic duct which extends for approximately 5 cm. No obstructing masses were visualized at the area of the main pancreatic ductal transition. There were no visualized abdominal lymphadenopathy and the surrounding structures were unremarkable. A laparoscopic distal pancreatectomy was performed and the patient was discharged without complications on postoperative day 6.

Histologically the tumor is composed of scattered carcinomatous nests and tubules (ducts) (Figure 2) in a background of dense fibrocollagenous tissue (Figure 2A). The cells have abundant eosinophilic granular cytoplasm (Figures 2C and 2D) and enlarged nuclei with a salt and pepper appearance (Figure 2D, arrow head) and occasional prominent nucleoli. The tumor cells focally invade into adjacent normal parenchyma and are intermixed with acinar-ductal metaplasia at the edge of carcinoma (Figures 2B and ​and4B).4B). The tumor and metaplastic cells are stained positively by PAS (Figure 3A) and the positive stain is resistant to digestion by diastase (PAS-D) (Figure 3B) stain. The immunohistochemical staining for pancreatic enzymes, antitrypsin, highlights the acinar component in approximately 40% of the tumor (Figure 4A). Ultrastructually, electron microscopy of the acinar component reveals the tumor cells with abundant mitochondria and rough endoplasmic reticulum. There are also cells containing large electron dense zymogen granules (Figure 3C). These results indicate the acinar differentiation of the cells. The areas of acinar-ductal metaplasia and possible ductal differentiation of carcinoma are stained strongly and weakly for cytokeratin 19, respectively (Figure 4B) and carcinoembryonic antigen (data not shown) in greater about 10% of the tumor. Furthermore, IHC reveals positivity for CD56 (Figure 4C), synaptophysin (Figure 4D), chromogranin (data not shown) in greater than 25% of the tumor. The ductal, neuroendocrine and acinar components of this tumor are all distinct on morphological, histochemical, electron microscopic and immunohistochemical levels. No apparent vascular, lymphatic or perineural invasion was appreciated. The adjacent benign pancreatic tissue shows atrophic chronic pancreatitis and islet cell hyperplasia.

Establishing the diagnosis of a mixed carcinoma requires qualitative and quantitative assessments of individual components in the tumor. In this case, initial morphological examination suggested that the tumor contains the ductal (tubular), acinar and neuroendocrine components and these components became more evident after ancillary studies. The acinar differentiation was confirmed by the production of pancreatic enzymes which were packaged in zymogen granules by the neoplastic cells as previously described [7], as well as positivity for periodic acid-Schiff (PAS), resistant to diastase digestion (dPAS) in 95% of acinar cell carcinomas [8]. The ductal component was less evident, but was supported by the presence of tubular structure on histology and positive staining for cytokeratin 19 and carcinoembryonic antigen. However, the majority of ductal component are those of acinar-ductal metaplasia. The neuroendocrine component was demonstrated by positive immunohistochemical staining for CD56, synaptophysin, and chromogranin. The tumor components were then strictly scrutinized further to assess the percentage of ductal, acinar and neuroendocrine composition. Each cell type composed greater than 25% of the tumor (acinar=40%, neuroendocrine=30%, and 30% unclassified or ductal component together with acinar-ductal metaplasia) defining this tumor as a mixed tumor with acinar, endocrine, and ductal differentiation.

The mixed or hybrid pancreatic tumors have multiple diagnostic pitfalls. The acinar component in these tumors tends to dominate, as in this case, and acinar tumors may contain focal neuroendocrine and/or ductal differentiation. Thus, one must assess the extent of the cellular components and multiple sections of tumor should be examined both histologically and immunohistochemically as was performed in this case.

The histogenesis of mixed pancreatic tumor with multilineage differentiation (acinar, neuroendocrine, and ductal) is of much debate. All three cell lineages develop from the embryonic foregut thus sharing a common origin during fetal development. Currently the leading theory suggests a possible origin from a stem or progenitor cell with the ability for multidirectional differentiation [9]. Thus, the presence of all three components in this tumor together with the other five reported cases supports a common ancestor theory.

The limited number of cases of mixed ductal, acinar and neuroendocrine carcinoma does not allow sufficient assessment of its biological behavior or prognosis. However, studies of mixed carcinoma suggest that a poor prognosis may be related to the cellular components of the tumor [10] and neuroendocrine differentiation may be related to a different prognosis [11]. Klimstra et al reported that all of these mixed acinar carcinomas are clinically aggressive, similar to pure acinar cell carcinomas [8, 12, 13]. This similarity may suggest that reports concerning acinar cell carcinoma may be extrapolated to include mixed pancreatic tumors. The small size of this tumor [1.2 cm], negative margins, lack of vascular, lymphatic or perineural invasion or metastatic disease may afford this patient a relatively better prognosis. The patient remains disease free 2 months post excision.