The main differential diagnoses in this case include poorly-differentiated ductal carcinoma, acinar cell carcinoma, pancreatoblastoma, and mixed acinar-endocrine carcinoma. The diagnosis of pancreatoblastoma can essentially be ruled out due to the patient's age and morphology of the tumor. Pancreatoblastoma resembles acinar cell carcinoma except for squamoid corpuscles, which are not present in this case. In addition, pancreatoblastoma is usually partially encapsulated, often lobulated and has a mean size of 10 cm; none of these is present in this case.
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
]. 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.
In summary, we report the clinicopathological features of a pancreatic carcinoma with acinar, neuroendocrine, and ductal differentiation. The cases like the reported herein often present diagnostic and clinical problems due to their rarity and unclear histological classification. Close morphological examination and extensive sectioning of the tumor are needed when suspecting a pancreatic tumor with trilineage origin. Immunohistochemical staining and electron microscopy are pivotal in making an accurate diagnosis. Better understanding of the behavior and prognosis of pancreatic tumor with trilineage origin requires evaluation of additional cases due to its rarity.