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JOP. J Pancreas (Online) 2005; 6(5):449-454.
Mixed Exocrine-Endocrine Tumor of the Pancreas
Konstantinos D Ballas1, Savas F Rafailidis1, Charalampos Demertzidis1, Michael B Alatsakis1, Afroditi Pantzaki2, Athanassios K Sakadamis1
1Second Propedeutical Department of Surgery, Aristotles University of Thessaloniki and 2Department of Pathology, Hippokration General Hospital. Thessaloniki, Greece
Context Neoplasms of the pancreas usually show ductal, acinar or endocrine differentiation. Tumors with mixed exocrine and endocrine components are unusual. We herein describe a case of a mixed ductal-endocrine tumor.
Case report A 65-year-old woman was referred to our department with a diagnosis of carcinoma of the tail of the pancreas. The patient had a short history of upper abdominal pain, nausea and melena. Upper gastrointestinal endoscopy revealed gastric fundus varices and CT scan demonstrated an inhomogeneous tumor located in the tail of the pancreas infiltrating the spleen and the splenic vein. The patient underwent distal pancreatectomy and splenectomy, and had an uneventful recovery. Pathological examination revealed a mixed ductal-endocrine tumor. The endocrine component was immunoreactive for glucagon, gastrin and somatostatin, and non-reactive for insulin.
Conclusions Because of the rarity and unpredictable biologic behavior of these tumors, the need for adjuvant therapy has not yet been well-defined. The patient has had a follow-up CT scan every six months, and one and a half years later remains disease free.
Pancreatic cancer is one of the most lethal forms of human cancer. Malignant pancreatic tumors are usually classified into those of the exocrine pancreas or those of the endocrine pancreas, and are generally categorized into three types (ductal, acinar or endocrine) . Mixed exocrine-endocrine neoplasms of the pancreas are rare tumors, characterized by the association of an exocrine - ductal or acinar - component and a significant endocrine component which comprises at least one-third to one-half of the tumor tissue . The pathologic diagnosis of duct-islet cell carcinomas was initially based on endocrine-marker positivity plus histological demonstration of ductular formation and mucin production . However, this approach was not correct, as focal mucin production or glandular structure could simply be part of an endocrine tumor, not representing true ductal differentiation [2, 4]. On the other hand, 40 to 80% of pancreatic ductal carcinomas may contain endocrine cells, scattered among or under the tubules of ductal carcinoma cells. This endocrine element comprises only a small percentage of the tumor cell population (less than 30%) and does not have the histology of an endocrine carcinoma [5, 6, 7, 8, 9, 10, 11]. Therefore, it is now accepted that the diagnosis of ductal-endocrine cell tumors of the pancreas requires identification of endocrine marker reactivity in at least one-third to one-half of the tumor [6, 11, 12].
Furthermore, the small number of patients and differences in stage at presentation does not permit us to safely assess the level of aggressiveness of mixed pancreatic tumors, but aggressive behavior is likely. However, mixed ductal-endocrine carcinomas seem to have the same prognosis as common ductal pancreatic carcinomas [13, 14] and, as diagnosis is confirmed only postoperatively, the treatment approach does not seem to be altered.
We herein report a case of a mixed ductal-endocrine tumor in order to discuss histological findings and therapeutic dilemmas.
A 65-year-old woman was admitted to the Gastroenterology Department of our hospital because of melena. The patient had complained of progressive fatigue, weakness, upper abdominal pain, anorexia and nausea for three-months. The admission profile was normal apart from mild anemia and a remarkably elevated erythrocyte sedimentation rate. Upper gastrointestinal endoscopy revealed gastric fundus varices with superficial ulceration. CT scan demonstrated an inhomogeneous tumor located in the tail of the pancreas (Figure 1) while ultrasonography and MRI revealed ischemic splenic necrosis and splenic vein thrombosis. The patient, with a diagnosis of carcinoma of the tail of the pancreas, was referred to our department for surgical treatment.
At laparotomy, a large tumor was palpated in the splenic hilum. Dissection of gastrocolic ligament permitted a clearer view of the omental bursa and revealed the presence of a mass originating from the tail of the pancreas, infiltrating the spleen and the splenic vessels (Figure 2). There were no signs of invasion to other adjacent organs, no infiltrated nodes or any other sign of disseminated disease. The spleen and the tail of the pancreas were easily mobilized after ligation of the splenic artery on the superior border of the pancreas. The splenic vein was infiltrated by the tumor and thrombosed. Distal pancreatectomy and splenectomy were performed; the patient had an uneventful recovery and left hospital 8 days later.
The tumor measured 12x9x7cm and invaded the spleen. On light microscopy, a cellular neoplasm originating from the pancreatic parenchyma was revealed. Two distinct populations of neoplastic cells were present. One with features of well-differentiated ductal adenocarcinoma (Figure 3) and the second presenting features of an endocrine neoplasm (Figure 4). Interestingly, despite splenic invasion, none of the dissected lymph nodes at the splenic hilum, and the superior and inferior border of the pancreas were infiltrated by neoplastic cells.
Neoplastic cells were oval and/or polygonal with amphiphilic cytoplasm and were focally clear. The cells were small to medium in size with considerably polymorphic nuclei and few mitoses. The neoplastic cells were arranged in acini with central necrosis focally. Delicate strands consisting of connective tissue and vessels coursed the neoplasm. A trabecular pattern was also revealed focally, and considerable fibroblastic reaction was noticed around the acini.
On immunohistochemistry, the following were revealed:
intense diffuse cytoplasmic and membranous positivity of the neoplastic cells for AE1/AE3;
focal mild membranous and cytoplasmic positivity for CA 19-9 (Figure 5);
intense diffuse cytoplasmic positivity for neuron specific enolase (NSE);
negativity for CA 125, CA 15-3 and insulin;
focally granular cytoplasmic positivity for chromogranin (Figure 6);
diffuse cytoplasmic and membranous positivity for synaptophysin (Figure 7);
focal granular cytoplasmic positivity for gastrin, somatostatin and glucagon.
The endocrine component of the tumor represented almost 40% of the tumor cells and, therefore, the tumor can be classified as a mixed ductal-endocrine pancreatic tumor.
No adjuvant therapy was administered and the patient is enrolled in a strict follow up protocol and has remained disease free for one and a half years.
It is well-known that the pancreas is composed of two separate organs, namely an exocrine and an endocrine pancreas . The exocrine pancreas includes two types of cells, ductal and acinar cells, while the endocrine pancreas consists of islet cells. Pancreatic tumors usually originate from one of these cell types, most often from ductal cells [16, 17].
In a series of 645 pancreatic tumors reported by Cubilla and Fitzgerald , ductal cell carcinomas represented 88.8% of pancreatic tumors, while endocrine cell tumors and acinar cell carcinomas represented only 7.4% and 1.2% of tumors, respectively. Mixed cell type carcinomas were very rare representing only a 0.2% of all cases in the same report.
Eleven cases of mixed ductal-endocrine tumors of the pancreas have been previously reported in the literature [5, 6, 13, 14, 16, 17, 18, 19, 20, 21]. Chatelain et al.  reviewed these cases. Mixed ductal endocrine carcinomas of the pancreas are often described in middle-aged patients (mean age 58.5 years) with an equal distribution between men and women. They are usually large and located in the head of the pancreas (60% of cases). Patients complain of jaundice, weight loss or abdominal pain while an endocrine syndrome is rare (described only in 2 cases) [6, 18]. Summarizing data of all cases reported are presented in Table 1 (including our patient). Our patient presented with vague abdominal pain caused by a large tumor located in the tail of the pancreas. In the patients reported in the literature, four died from 5 to 24 months after diagnosis, while six (including our patient) were reported to be disease free 4 to 72 months after the initial diagnosis. In addition, in 1999, Terada et al.  reported an autopsy case of an endocrine tumor (gastrinoma with Zollinger-Ellison syndrome) that terminated as a mixed ductal-endocrine carcinoma 24 years later.
- Weight loss
- Verner-Morrison syndrome
- Zollinger-Ellison syndrome
- Equal to or greater than 100 mm
- Not specified
- Distal pancreatectomy
It is noteworthy that most of the cases reported referred to resectable tumors, thus permitting an accurate diagnosis of mixed ductal/endocrine tumor. Such a diagnosis is hard to prove in unresectable tumors by small biopsies or cytology, as a mixed ductal/endocrine tumor is defined as a tumor whose 30-50% cell population is immunoreactive to endocrine markers. However, real occurrence of these tumors is probably underestimated, as unresectable tumors are virtually undiagnosed.
The histogenesis of mixed exocrine-endocrine tumors of the pancreas is still controversial. The co-existence of exocrine and endocrine elements in these tumors can be attributed to their common embryologic origin. In recent years, Pearseĺs view that all endocrine cells are derived from the neural crest has largely been abandoned in favor of a common precursor stem cell of endodermal origin from which both endocrine and exocrine cells are derived [6, 22, 23, 24, 25].
Cases such as the one reported from Terada et al.  suggest that pancreatic endocrine tumors may evolve into mixed ductal-endocrine carcinomas, in this way reinforcing the hypothesis of the existence of a common stem cell, from which both exocrine and endocrine pancreatic elements derive. Moreover, in 2001, Regitnig et al.  reported a case of pancreatic insulinoma with insular-ductular differentiation in its liver metastasis, indicative of a common stem cell origin of the exocrine and endocrine components.
Pour and Schmied, in a recent review  of several human studies and experimental studies on Syrian hamsters conducted within the last 20 years, concluded that pancreatic cancer derives from pancreatic stem cells which are distributed within the ductal trees and within the islets. In the same review, it was noted that, in a hamster pancreatic cancer model, most pancreatic adenocarcinomas develop within islets, most probably from stem cells which are also considered the progenitor cells for tumors developing within ducts.
Finally, Peters et al. , in a review article on the embryologic development and growth of the endocrine pancreas, noted that, in the adult pancreas, ductal cells can be stimulated to differentiate into islet cells under certain conditions. However, it is not clarified and it remains to be seen whether all duct cells retain a stem cell potential and which transcription and growth factors are necessary for the induction of islet cell neogenesis. It is, therefore, more or less accepted that exocrine and endocrine cells of the pancreas originate from branching multipotential epithelial cells with the features of ductal cells.
Depending on the point at which neoplastic transformation occurs along the pathway of proliferation and differentiation of these cells, a pancreatic neoplasm may exhibit ductal, acinar, or endocrine features. If the transformation occurs at an early stage, more than one line of differentiation may be expressed.
Two types of ductal-endocrine cell carcinomas can be distinguished . One represents a collision of two histogenetically distinct tumors growing into one another, with the two components remaining largely restricted to separate regions despite some areas of intermingling. The tumor presented can be classified as this type, since two distinct neoplastic cell populations were present. The other type represents an amphicrine neoplasm with a uniform cell population in light microscopy, which shows bi-directional differentiation ultrastructurally or immunohistochemically.
In summary, mixed tumors of the pancreas are rare, and both their clinical features and pathogenesis remain unclear. They are considered to have the same prognosis as common ductal pancreatic carcinomas [13, 14] and their treatment approach remains unaltered as, in most cases, diagnosis is established postoperatively.
Kloppel G, Solcia E, Longnecker DS, Capella C, Sobin LH. Histological Typing of Tumors of the Exocrine Pancreas. In: World Health Organization. International Histological Classification of Tumours. 2nd ed. Berlin, Heidelberg, New York: Springer, 1996:15-21. [More details]
Kloppel G. Mixed exocrine-endocrine tumors of the pancreas. Sem Diagn Pathol 2000; 17:104-8. [More details]
Kamisawa T, Tu Y, Egawa N, Ishiwata J, Tsuruta K, Okamoto A, et al. Ductal and acinar differentiation in pancreatic endocrine tumors. Dig Dis Sci 2002; 47:2254-61. [More details]
Sieracki J, Marshall RB, Horn RC. Tumors of the pancreatic islets. Cancer 1960; 13:347-57. [More details]
Eusebi V, Capelle C, Bondi A, Sess F, Vezzandini P, Mancini AM. Endocrine-paracrine cells in pancreatic exocrine carcinomas. Histopathology 1981; 5:599-613. [More details]
Terada T, Matsunaga Y, Maeta H, Endo K, Horie S, Ohta T. Mixed ductal-endocrine carcinoma of the pancreas presenting as gastrinoma with Zollinger-Ellison syndrome: an autopsy case with a 24-year survival period. Virchows Arch 1999; 435:606-11. [More details]
Chen J, Balthun SI, Pollock DJ, Berry CL. Argyrophilic and hormone immunoreactive cells in normal and hyperplastic pancreatic ducts and exocrine pancreatic carcinoma. Virchows Arch 1988; 413:399-405. [More details]
Kamisawa T, Fukuyama M, Tabata I, Isawa T, Tsuruta K, Okamoto A, Kolke M. Neuroendocrine differentiation in pancreatic duct carcinoma special emphasis on duct-endocrine cell carcinoma of the pancreas. Pathol Res Pract 1996; 192:901-8. [More details]
Permert J, Mogaki M, Andren-Sandberg A, Kazakoff K, Pour PM. Pancreatic mixed ductal-islet tumors. Is this an entity? Int J Pancreatol 1992; 11:23-9. [More details]
Pour PM, Permert J, Mogaki M, Fujii H, Kazakoff K. Endocrine aspect of exocrine cancer of the pancreas: their pattern and suggested biological significance. Am J Clin Pathol 1993; 100:223-30. [More details]
Terada T, Ohta T, Kitamura Y, Ashida K, Matsynaga Y, Kato M. Endocrine cells in intraductal papillary-mucinous neoplasms of the pancreas: a histochemical and immunohistochemical study. Virchows Arch 1997; 431:31-6. [More details]
Klimstra DS, Rosai J, Heffess CS. Mixed acinar-endocrine carcinomas of the pancreas. Am J Surg Pathol 1994; 18:765-78. [More details]
Chatelain D, Parc Y, Christin-Maitre S, Parc R, Flejou JF. Mixed ductal-pancreatic polypeptide-cell carcinoma. Histopathology 2002; 41:122-6. [More details]
Schron DS, Mendelsohn G. Pancreatic carcinoma with duct, endocrine and acinar differentiation. A histologic, immunocytochemical and ultrastructural study. Cancer 1984; 54:1766-70. [More details]
Cubilla Al, Fitzgerald PJ. Tumors of the Exocrine Pancreas. In: Atlas of Tumor Pathology, 2nd series, fascicle 19. Washington, DC: Armed Forces Institute of Pathology, 1984:98-108. [More details]
Reid JD, Yuh SL, Petrelli M, Jaffe R. Ductuloinsular tumors of the pancreas: a light, electron microscopic and immunohistochemical study. Cancer 1982; 49:908-15. [More details]
Tanakaya K, Teramoto N, Konaga E, Takeuchi H, Yasui Y, Takeda A, et al. Mixed duct-acinar-islet cell tumor of the pancreas: report of a case. Surg Today 2001; 31:177-9. [More details]
Ordonez NG, Balsaver AM, Mackay B. Mucinous islet cell (amphicrine) carcinoma of the pancreas associated with watery diarrhea and hypokalemia syndrome. Hum Pathol 1988; 19:1458-62. [More details]
Laine VJ, Ekfors TO, Gullichsen R, Nevalainen TJ. Immunohistochemical characterization of an amphicrine mucinous islet-cell carcinoma of the pancreas. Case report. APMIS 1992; 100:335-40. [More details]
Hassan MO, Gogate PA. Malignant mixed exocrine-endocrine tumor of the pancreas with unusual intracytoplasmic inclusions. Ultrastruct Pathol 1993; 17:483-93. [More details]
Leteurtre E, Brami F, Kerr-Conte J, Quandalle P, Lecomte-Houcke M. Mixed ductal-endocrine carcinoma of the pancreas. A case study with mixed ductal-endocrine metastasis double labeled for cytokeratin and synaptophysin. Arch Pathol Lab Med 2000; 124:284-6. [More details]
Pour PM, Schmied B. The link between pancreatic cancer and the endocrine pancreas. Int J Pancreatol 1999; 25:77-87. [More details]
Cossel L. Electron microscopic demonstration of intermediate cells in the healthy adult human pancreas. Virchows Arch B Cell Pathol Incl Mol Pathol 1986; 52:283-7. [More details]
Yuan S, Rosenberg L, Paraskevas S, Agapitos D, Duguid WP. Transdifferentiation of human islets to pancreatic ductal cells in collagen matrix culture. Differentiation 1996; 61:67-75. [More details]
Regitnig P, Spuller E, Denk H. Insulinoma of the pancreas with insular-ductular differentiation in its liver metastasis: indication of a common stem-cell origin of the exocrine and endocrine components. Virchows Arch 2001; 438:624-8. [More details]
Peters J, Jurgensen A, Kloppel G. Ontogeny, differentiation and growth of the endocrine pancreas. Virchows Arch 2000; 436:527-38. [More details]
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Received June 2nd, 2005 - Accepted July 1st, 2005
Keywords Carcinoma, Acinar Cell; Carcinoma, Pancreatic Ductal; NeuroČendocrine Tumors; Mixed Tumor, Malignant; Pancreas; Pancreatic Neoplasms
Abbreviations NSE: neuron specific enolase
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