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Abstract
Carcinosarcoma of the pancreas is extremely rare and its histogenesis is still unclear. This is a report on a 64-year-old female patient with an intraductal carcinosarcoma arising from intraductal papillary-mucinous carcinoma (IPMC) in the pancreas tail. The carcinosarcoma grew as a polypoid mass within the main pancreatic duct. Histologically, the tumour consisted of adenocarcinoma covering the luminal surface of the lesion with minimal stromal invasion, and osteosarcoma occupying the stroma. Immunohistochemical and gene mutation analyses revealed that both the carcinomatous and sarcomatous tumour cells of the carcinosarcoma, as well as the IPMC cells, expressed TP53 and had identical mutations in KRAS and TP53 genes, indicating that these two neoplastic components of the carcinosarcoma shared a common tumorigenesis and arose from the IPMC. This is the first report of a carcinosarcoma originating in IPMC. These findings imply that carcinosarcoma with a heterologous mesenchymal component is of ductal origin.
- Carcinosarcoma
- intraductal papillary-mucinous neoplasm
- heterologous mesenchymal component
- pancreas
- gene mutation
- cancer
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- Carcinosarcoma
- intraductal papillary-mucinous neoplasm
- heterologous mesenchymal component
- pancreas
- gene mutation
- cancer
Introduction
Carcinosarcoma of the pancreas is a very rare tumour and only several cases have been reported hitherto.1–6 These cases were diagnosed as carcinosarcoma histopathologically and immunohistochemically on the basis of the presence of both malignant epithelial and malignant mesenchymal components. Only two of the reported cases showed heterologous mesenchymal components.1 2 The histogenesis of this tumour is still unclear, although there have been several hypotheses that it originates from epithelial cells, mesenchymal cells, undifferentiated precursor cells or stem cells. It has been difficult to assess its histogenesis, because pancreatic carcinosarcoma is extremely rare and is usually advanced at the time of diagnosis.
Here we present the first reported case of pancreatic intraductal carcinosarcoma with a heterologous mesenchymal component (osteosarcoma), which is located in an intraductal papillary-mucinous carcinoma (IPMC). This case is thought to be important for considering the histogenesis of pancreatic carcinosarcoma with a heterologous mesenchymal component.
Case report
A 64-year-old Japanese woman who attended our hospital for a health check-up was found by abdominal ultrasonography to have a cystic tumour in the tail of the pancreas. She had no symptoms and all clinical and laboratory data were normal. The serum concentrations of tumour markers were elevated (CA19-9, 87 U/ml; carcinoembryonic antigen (CEA), 2.7 ng/ml). She had been treated for diabetes mellitus for 11 years. Abdominal CT revealed a 2 cm cystic mass in the pancreatic tail (figure 1A). Within the cyst, there were irregular and solid nodules with calculus. The tail of the pancreas had been totally replaced by the tumour. No lymphadenopathy, ascites, liver metastasis or mass in the soft tissues was found. Distal pancreatectomy was performed under a preoperative diagnosis of invasive carcinoma originating in IPMC. The operation was uneventful, and 12 months after surgery, the patient is well without any tumour recurrence or metastasis.
(A) Abdominal CT image showing a 2 cm cystic mass in the pancreatic tail. (B) Fresh cut view of the body and tail of the pancreas.
Pathological and genetic findings
A grossly elastic, hard, solid, spherical mass measuring 35×21×14 mm was present in the tail of the pancreas. At the cut surface, there was a papillary-to-polypoid projection located in the main and branch pancreatic ducts, which were cystically dilated and filled with clear yellowish mucinous fluid (figure 1B). These intraductal lesions were surrounded by yellowish-grey solid and nodular components of the tumour from the side of the pancreatic tail.
Histologically, the tumour comprised an intraductal neoplasm and a derivative invasive carcinoma (figure 2). The luminal surface of the dilated pancreatic ducts was covered with atypical mucin-secreting columnar epithelial cells showing papillary growth (figure 2A,B), indicating a diagnosis of IPMC. No ovarian-type stroma was evident. It was noteworthy that biphasic histological features were found in the polypoid lesion in the main pancreatic duct, which consisted of papillary proliferation of adenocarcinoma covering the luminal surface of the projecting mass with infrequent and minimal stromal invasion and an osteosarcoma occupying the stroma. The osteosarcoma showed invasive growth, but its extension was limited to the stroma of the IPMC, which was not beyond the duct wall (figure 2C–E). The osteosarcoma was characterised by a dense proliferation of malignant spindle-shaped and pleomorphic cells with mononucleated and multinucleated giant cells that had atypical and bizarre nuclei and formed osteoid and bone (figure 2E). Occasional infiltration of osteoclast-like multinucleated giant cells without nuclear atypia was evident. This intraductally proliferating mixed epithelial and mesenchymal tumour was diagnosed as carcinosarcoma, which seemed to have originated in the IPMC. Formation of osteoid and/or bone is rare but possible in cases of undifferentiated carcinoma with osteoclast-like giant cells, although the osteoid and/or bone is a result of reactive stromal metaplasia without any atypia in such cases.7
(A, B) Histopathological features of intraductal papillary-mucinous carcinoma (IPMC) (A) and invasive adenocarcinoma arising from IPMC (B). (C–E) Histopathological features of intraductal carcinosarcoma originating in IPMC. (C) A very-low-power view of the polypoid lesion in the main pancreatic duct. (D, E) Mid-power view of the polypoid lesion. (F) Immunohistochemical expression of TP53 in intraductal carcinosarcoma originating in IPMC.
In addition to the intraductal tumour, IPMC cells had infiltrated beyond the duct wall and reached the surrounding stroma, showing a marked desmoplastic reaction at the side of the pancreatic tail bearing the tumour (figure 2B). The infiltrating cancer cells proliferated with poorly formed glands and solid to nested growth, indicating poorly differentiated adenocarcinoma. The infiltrating adenocarcinoma formed a nodular mass measuring 25×21×14 mm, although the invasive adenocarcinoma was not connected to the intraductal carcinosarcoma.
Immunohistochemical examination revealed expression of cytokeratins (AE1/AE3 and CK7) and vimentin, which confirmed the epithelial and mesenchymal components of tumour cells detected histologically. TP53 was expressed in the nuclei of most of the intraductal and invasive epithelial tumour cells as well as the mesenchymal tumour cells (figure 2F). CD68 antigen was expressed in some of the multinucleated giant cells without nuclear atypia. These CD68-positive osteolclast-like giant cells did not express TP53.
Four distinct tumour components (epithelial and mesenchymal tumour cells in the carcinosarcoma, IPMC cells and invasive adenocarcinoma cells) were separately laser-microdissected and analysed for KRAS and TP53 mutations. DNA samples extracted from the microdissected tissues were subjected to PCR with a pair of specific primers to amplify exon 1 of KRAS or exon 4 of TP53, and isolated PCR products were sequenced bidirectionally. The analysis revealed identical KRAS (G35A mutation in exon 1) and TP53 (T337A mutation in exon 4) mutations in all four tumour components examined (figure 3). Non-neoplastic pancreatic parenchyma adjacent to the tumour exhibited wild-type sequences, confirming the somatic nature of the mutations.
Mutations of KRAS and TP53 genes in each tumour component. All four tumour components examined (epithelial and mesenchymal tumour cells in the carcinosarcoma, intraductal papillary-mucinous carcinoma (IPMC) cells and invasive adenocarcinoma cells), harboured identical KRAS and TP53 mutations. The sequences were read with reverse primers. Triangles indicate locations of point mutations.
Discussion
Carcinosarcoma is a biphasic tumour consisting of an intimate admixture of malignant epithelial and mesenchymal components identifiable on the basis of their morphological, immunohistochemical and sometimes ultrastructural features. Nine cases of carcinosarcoma of the pancreas have been reported,1–6 including two with heterologous mesenchymal components; one of the latter cases exhibited leiomyosarcoma, chondrosarcoma and rhabdomyosarcoma,1 and the other showed malignant nerve sheath tumour as heterologous mesenchymal components.2 No case of either carcinosarcoma arose from intraductal papillary-mucinous neoplasm (IPMN) and all were found at an advanced stage, with an average tumour diameter of 9.6 cm (range 2.5–19 cm).
To our knowledge, the present case of carcinosarcoma with a heterologous mesenchymal component originating in IPMN is the first of its kind to have been reported. Immunohistochemical and gene mutation analyses revealed that both the carcinomatous and sarcomatous tumour cells in the carcinosarcoma as well as the IPMC cells expressed TP53 and had common mutations in KRAS and TP53 genes, indicating that these two neoplastic components of the carcinosarcoma had a common origin, IPMC. This case provides new findings supporting the hypothesis that carcinosarcoma with a heterologous mesenchymal component is of ductal origin and arises from IPMN.
The histogenesis of carcinosarcoma is still controversial, but the previously proposed hypotheses have now been combined as the following: (1) it is a combination tumour in which carcinomatous and sarcomatous elements arise from a multipotential stem cell; (2) it is a collision tumour in which two independent neoplasia, carcinoma and sarcoma, develop; (3) it is a carcinoma showing metaplastic changes to sarcoma components. The definition of carcinosarcoma in the WHO histological classification differs according to the organ in which the tumour develops. A mixed epithelial and mesenchymal tumour with heterologous mesenchymal components is defined as carcinosarcoma in the histological classification of tumours of many organs, including the colon and rectum, gallbladder and extrahepatic bile ducts, and lung.8 In contrast, a mixed epithelial and mesenchymal tumour, regardless of the presence of heterologous mesenchymal components, is defined as carcinosarcoma in the histological classification of tumours of the breast and female genital tract. It is thought that most, but not all, of the mesenchymal components in carcinosarcoma of the female genital tract arise from the carcinoma through metaplastic change and that the small population of the carcinosarcoma left is formed by collision of carcinoma and sarcoma.9 The present case suggests that carcinosarcoma of the pancreas arises from a carcinoma with metaplastic changes, although the WHO histological classification of pancreatic tumours includes no specific category for carcinosarcoma.8 According to the previous report,2 a sarcomatous component is speculated to arise from ovarian-type stroma characteristic of mucinous cystic neoplasm. In such a case, carcinosarcoma should be formed as a collision tumour.
In summary, we have presented a case of pancreatic intraductal carcinosarcoma originating in IPMC. Our morphological, immunohistochemical and genetic findings suggest that the carcinosarcoma with a heterologous mesenchymal component was ductal in origin.
Take-home messages
Carcinosarcoma of the pancreas is extremely rare and its histogenesis is still unclear.
We describe an intraductal carcinosarcoma arising from intraductal papillary-mucinous carcinoma (IPMC) in the pancreas tail.
Both the epithelial component (adenocarcinoma) and heterologous mesenchymal component (osteosarcoma) of the carcinosarcoma, as well as the IPMC, expressed TP53 and had identical mutations in KRAS and TP53 genes, indicating that these two neoplastic components of the carcinosarcoma shared a common tumorigenesis and arose from the IPMC. These findings imply that carcinosarcoma with a heterologous mesenchymal component is of ductal origin.
Acknowledgments
We thank Ms Rie Itoh for technical assistance. This work was supported by a Grant-in-Aid for Third Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. We have no direct or indirect commercial and financial incentive associated with publishing the article.
Footnotes
Funding The Ministry of Health, Labor and Welfare of Japan and the Ministry of Education, Culture, Sports, Science and Technology of Japan.
Competing interests None.
Ethics approval This study was conducted with the approval of the ethics committee of the National Cancer Center, Tokyo, Japan.
Patient consent Obtained.
Provenance and peer review Not commissioned; not externally peer reviewed.