Carcinosarcomas of the pancreas are extremely rare. We report a case of pancreatic carcinosarcoma that contained histologic components of both leiomyosarcoma and carcinoma. Millis and associates authored the only reported case of pancreatic carcinosarcoma with these components, identified in a mass that invaded the duodenum.¹ Due to polar distribution and the proximity of the sarcomatous portion of that tumor to the duodenum, it was hypothesized that organ-induced differentiation caused the formation of these two distinct phenotypes. Although our patient's mass was similar to the one reported by Millis and colleagues, it arose at a site remote from the duodenum. This suggests that random gene activation may be a more plausible explanation for the divergent differentiation of this carcinosarcoma.

Case report
A 67-year-old African American woman went to her primary care physician to report a 6-week history of right upper quadrant pain and a 10-lb weight loss. Her medical history was significant for chronic renal failure and well-controlled hypercholesterolemia and hypertension. Right upper quadrant ultrasonography revealed a mass in the body and tail of the pancreas and normal kidneys and gallbladder. Subsequent computed tomography scans and magnetic resonance imaging (MRI) confirmed the presence of a 3.5 x 5.9-cm mass in the body of the pancreas, probable encasement of the splenic vein and superior mesenteric vessels, and invasion of the posterior wall of the stomach (Figure 1).

The patient was referred to our clinic to discuss surgical options. At laparotomy, her mesenteric vessels were found to be densely adhered to the mass, but the stomach was not involved. A distal pancreatectomy and splenectomy were performed, and the tumor was resected en bloc. Pathology revealed tumor at the medial resection margin, near the mesenteric vessels. On gross examination, the tumor measured 3.7 x 3.5 x 8.5 cm. It was tan and solid, with focal areas of necrosis. A pathology examination determined that one of the 12 superior peripancreatic lymph nodes was positive for metastasis. Portions of the tumor were seen microscopically to contain duct-like structures and small cystic formations, consistent with carcinoma. These cells had hyperchromatic and pleomorphic nuclei and were associated with focal mucin production. Other areas of the tumor contained spindle cells with large, pleomorphic nuclei and frequent mitotic figures, more consistent with sarcoma (Figure 2A). The carcinomatous areas were predominant in sections taken from the proximal edge of the specimen.

Immunohistochemically, the carcinomatous areas stained strongly for a cytokeratin cocktail and epithelial membrane antigen (EMA) and were negative for antibodies to vimentin, desmin, and smooth muscle antigen (SMA; Figure 2B). In contrast, the spindled cells of the sarcomatous component stained negatively for cytokeratin cocktail (Figure 2C), S100 protein, and EMA, but positively for vimentin, SMA, and desmin, indicating leiomyosarcomatous differentiation (Table).

The patient's recovery was uneventful, and she was discharged home on postoperative day 6. She underwent a palliative course of radiation and chemotherapy with 5-fluorouracil. She died 10 months after surgery due to metastatic spread of her disease.

Discussion
Carcinosarcomas are unusual neoplasms that contain both epithelial and mesenchymal elements. These tumors are most often associated with mixed müllerian tumors of the uterus. Reports of these mixed tumors associated with other organ systems are rare, and only seven cases of carcinosarcomas of the pancreas have been reported in the English-language literature.²

The histogenesis of carcinosarcoma of the pancreas is not well understood. One theory proposes that two malignant cell lines form independently and then collide to form a mixed tumor. Another theory suggests that a neoplastic cell within a specific malignant cell line subsequently de-differentiates to create a cell line with characteristics different from the original tumor.¹ The latter was supported by van den Berg and associates, who found that the genetic alterations in the epithelial and sarcomatous components of three pancreatic carcinosarcomas were nearly identical.³ They found identical changes in both the epithelial and sarcomatous sections at six chromosomal loci in two masses and at five of six loci in the other mass. These results support the idea that the heterogeneous mass arose from a common cell line.

Leiomyosarcoma was the stromal component of the mixed tumor in only one of the seven previously reported cases of carcinosarcoma of the pancreas.¹ In the other cases, mucinous cystadenoma, adenosarcoma, malignant fibrous histiocytoma, and osteoclastic giant cell tumor were the stromal component.^2,4-6 In the report of the leiomyosarcoma, the mixed tumor of the head of the pancreas was histologically oriented with the sarcomatous component invading the duodenum.¹ Millis and colleagues postulated that organ-induced differentiation, mediated by organ-specific trophic factors, was responsible for the cell line divergence.¹ They thought that factors within the smooth muscle wall of the duodenum acted to influence sarcomatous change of the invading portion. Millis and colleagues' theory is challenged by two points. First, although our case involves a similarly constituted mass of leiomyosarcoma and adenocarcinoma remote from the duodenum with the sarcomatous component in the distal portion of the pancreas, the orientation and location of this tumor did not allow it to be influenced by the duodenal smooth muscle trophic factors. Our report depicts a mass in the body of the pancreas, whereas the case reported by Millis and colleagues showed an intimate relationship between the sarcomatous component and the duodenum. Second, Darvishian and colleagues also describe a carcinosarcoma of the pancreatic head that eroded into the duodenum. A pathology evaluation found the carcinomatous segment of this tumor infiltrating the wall of the duodenum rather than the sarcomatous component.² The duodenal smooth muscle could not have caused the sarcomatous differentiation in this case either, because the duodenum was remote from the malignant, fibrous histiocytoma. We propose random gene activation as a more likely explanation for the phenotypic divergence in these carcinosarcomas.

Mixed tumors within the pancreas, as with other cancers, arise due to omission of tumor suppressor genes or activation of pro-oncogenes.⁷ If trophic factors from other organs do not cause this differentiation, the signal to change must come from some alternative source within the pancreas or from the genetic material of the mass itself.

Carcinosarcoma of the pancreas is an aggressive tumor with a poor prognosis. Five of the seven patients in the previously reported cases died within 1 year of diagnosis.² Our patient underwent 51 Gy radiation and received four cycles of 5-fluorouracil despite scant evidence that adjuvant chemotherapy and radiation are beneficial. She died 10 months after surgery. Like adenocarcinoma, carcinosarcoma of the pancreas is a highly aggressive disease, and surgical resection with negative margins offers the only possible cure.

Conclusion
Carcinosarcomas of the pancreas are extremely rare. The seven previously reported cases show different compositions and polarity of the sarcomatous and carcinomatous regions. There is much speculation as to the pathogenesis of these masses. One hypothesis suggests that organ-induced differentiation may be responsible for the cell line differentiation within the carcinosarcoma. Our case appears to refute this position. We propose that the differentiation is due to random gene activation. Regardless, pancreatic carcinosarcoma carries a very poor prognosis and, if complete surgical resection is not possible, current treatment options are limited. 

References
1. Millis JM, Chang B, Zinner MJ, et al. Malignant mixed tumor (carcinosarcoma) of the pancreas: a case report supporting organ-induced differentiation of malignancy. Surgery. 1994;115(1):132-137.

2. Darvishian F, Sullivan J, Teichberg S, et al. Carcinosarcoma of the pancreas: a case report and review of the literature. Arch Pathol Lab Med. 2002;126(9):1114-1117.

3. van den Berg W, Tascilar M, Offerhaus GJ, et al. Pancreatic mucinous cystic neoplasms with sarcomatous stroma: molecular evidence for monoclonal origin with subsequent divergence of the epithelial and sarcomatous components. Mod Pathol. 2000;13(1):86-91.

4. Wenig BM, Albores-Saavedra J, Buetow PC, et al. Pancreatic mucinous cystic neoplasm with sarcomatous stroma: a report of three cases. Am J Surg Pathol. 1997;21(1):70-80.

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6. Fischer HP, Altmannsberger M, Kracht J. Osteoclast-type giant cell tumour of the pancreas. Virchows Arch A Pathol Anat Histopathol. 1988;412(3):247-253.

7. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194(4260):23-28.