CASE REPORT
Carcinosarcoma of the Pancreas Case Report With Comprehensive Literature Review Dietrich A. Ruess, MD,* Claudia Kayser, MD,† Jakob Neubauer, MD,‡ Stefan Fichtner-Feigl, MD,* Ulrich T. Hopt, MD,* and Uwe A. Wittel, MD*
Abstract: Carcinosarcomas are rare biphasic neoplasms with distinct malignant epithelial and mesenchymal components. Most commonly, carcinosarcomas arise in the uterus as malignant mixed müllerian tumors, but also infrequently appear in other organs such as the ovaries and breast, the prostate and urinary tract, the lungs, or in the gastrointestinal system, among others. Pancreatic carcinosarcomas are exceedingly rare; only a few cases are reported in the English literature. Their pathogenesis remains to be fully clarified. We present here the case of a pancreatic carcinosarcoma with evidence for monoclonality via determination of Kras mutational status after microdissection and suggest a common origin of the 2 tumor components. Comprehensive review of the available literature allows the conclusion that most pancreatic carcinosarcomas appear to be of monoclonal origin and seem to have arisen from a carcinoma via metaplastic transformation of 1 part or subclone of the tumor, probably by epithelial-mesenchymal transition. All reported patients were treated with surgery. Adjuvant therapy, if administered, consisted predominantly of gemcitabine. Prognosis for this neoplasm occurs to be similar or even worse compared with classic pancreatic ductal adenocarcinoma. Despite the lack of evidence-based recommendations for its treatment, resection should be performed, if possible. Key Words: carcinosarcoma, Kras mutation, pancreas, pathogenesis, prognosis, treatment Abbreviations: CT - computed tomography, IPMN - intraductal papillary mucinous neoplasm, MCN - mucinous cystic neoplasm, PDAC - pancreatic ductal adenocarcinoma (Pancreas 2017;46: 1225–1233)
C
arcinosarcomas are rare neoplasms with distinct malignant epithelial (carcinomatous) and mesenchymal (sarcomatous) components. Each of these components exhibits a characteristic histological, immunohistochemical, and ultrastructural pattern, indicative of their dissimilar differentiation. For the pancreas, only a very few cases of carcinosarcomas have been reported to date. Pathogenesis and histogenesis of this entity remain to be clarified. Evidence-based treatment strategies are lacking because of the low incidence of this entity. We report a case of a pancreatic carcinosarcoma with evidence of monoclonality and a common origin of the 2 malignant components. In addition, we review and discuss the available English literature with a focus on terminology, pathogenesis, treatment, and prognosis.
From the *Department of Surgery, †Institute for Surgical Pathology, and ‡Department of Radiology, Faculty of Medicine, Medical Center–University of Freiburg, Freiburg, Germany. Received for publication November 16, 2016; accepted August 2, 2017. Address correspondence to: Dietrich A. Ruess, MD, Department of Surgery, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany (e‐mail: [email protected]). The authors declare no conflict of interest. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MPA.0000000000000904
Pancreas • Volume 46, Number 9, October 2017
CASE REPORT Patient Presentation, Diagnosis, and Treatment A 73-year-old white woman was referred to the Department of Surgery for workup of an indeterminate pancreatic lesion. The patient had undergone magnetic resonance imaging of the upper abdomen for evaluation of a renal mass, which turned out to be an angiomyolipoma. Incidental finding in this study was an abrupt change in main duct caliber at the head-body junction with upstream ductal dilation up to 10 mm (Figs. 1A, C, D), along with diffuse tubular dilatation of branch ducts in the pancreatic tail (Fig. 1B). Because of severe motion artifacts in this study, an additional multiphasic computed tomography (CT) examination was carried out, which confirmed the previous findings. There was no evidence of a tumor, extrapancreatic tumor growth, lymphadenopathy, or metastases. Combined-type intraductal papillary mucinous neoplasm (IPMN) with worrisome and high-risk features was suspected, and simple ductal dilatation related to mechanical obstruction of unknown and potential malignant cause was given as a differential diagnosis. Clinical chemistry revealed slightly elevated tumor markers carbohydrate antigen (CA) 19-9 (29.1 U/mL; reference, A
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TABLE 2. Previously Published Case Reports and Collections of Pancreatic Carcinosarcoma in the English Literature First Author (Reference)
Year of Publication
Age, y/ Sex
Symptoms
1994
50/F
NR
Wenig et al12 and van den Berg et al13
1997 and 2000
(1) 67/M (2) 48/F (3) 65/F
(1)–(3): Abdominal pain
(1)–(3): Pancreatic tail [(3) with omental metastases of SC]
(1) 19 × 14 × 8 cm (2) NR (3) 30 × 25 × 9.5 cm
Darvishian et al14
2002
74/M
Incidental finding upon workup of DVT
Pancreatic head, infiltrating peripancreatic adipose tissue and duodenal wall
4 × 3 cm
Bloomston et al15
2006
67/F
Nausea, emesis, painless jaundice
Pancreatic head, SC invading duodenum
Gelos et al16
2008
61/F
Anemia
Pancreatic head, infiltrating duodenum and peripancreatic fat
Nakano et al17
2008
82/F
Anorexia, right hypochondralgia
Pancreatic head
Shen et al18
2010
72/F
RUQ pain, nausea, emesis
Pancreatic head, infiltrating duodenum and peripancreatic fat
Okamura et al19
2010
64/F
Incidental finding
Pancreatic tail
Kim et al20
2011
48/M
Incidental finding
Pancreatic tail, infiltrating peripancreatic fat,
7 × 5 × 5 cm
Palaniappan et al21
2011
46/M
Jaundice
Pancreatic head, infiltrating duodenal wall
3 × 3 × 2 cm
Zhu et al22
2012
53/F
Epigastric, RUQ pain, jaundice
Pancreatic head
5 × 4 × 3 cm
Oymaci et al23
2013
66/M
Abdominal pain, jaundice
Pancreatic head, infiltrating duodenum and peripancreatic fat
Yao et al24
2013
48/M
Epigastric pain
Pancreatic tail (cystic and solid)
10 × 8 × 5 cm
Shi et al25
2015
74/F
Initially incidental MCN, on follow-up grown size, more thickened wall and solid components
Pancreatic tail (cystic lesion)
5 × 4 × 2 cm
Millis et al11
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Localization/Extent Pancreatic head/duodenal wall infiltration
Size NR
4 × 4 × 3 cm
7 × 6 × 3.5 cm
18 × 11 × 10 cm
5 × 4 × 4 cm 5 cm (liver lesion) 2 cm (gastric lesion) 3.5 × 2.1 × 1.4 cm
3.5 × 2 × 1.5 cm
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Carcinomatous Component (CC)
Sarcomatous Component (SC)
Report of a Rare Pancreatic Carcinosarcoma
Clonality/ Molecular Analysis Monoclonal (via HPRT-PCR)
Therapy
Follow-up/ Outcome
PD
NR
Adenocarcinoma
Leiomyosarcoma Vimentin, SMA+
(1) Mucinous cystadenocarcinoma (2), (3): only MCN (1)–(3): CK+, EMA+, CEA+, CA 19-9+, DUPAN-2+; vimentin− PDAC CK+, CEA+; Vimentin, SMA− Ki-67: 43% Mucinous cystadenocarcinoma CK1/3+, CK7+, CEA+ Adenocarcinoma pan-CK+, CK7+, CK20+
(1)–(3): DP [(3) with (1)–(3): Undifferentiated Monoclonal omentectomy] malignant spindle (LOH via MS cells [in (1) polymorphism, and possibly MPNST] Kras mutational status) (1)–(3): Vimentin+, SMA+; CK, EMA− ND PD MFH Vimentin+; CK focal + Ki-67: 30% Invasive ND PD sarcomatous stroma + Vimentin Poorly differentiated ND PD (R1), additive sarcomatoid cells gemcitabine + − Vimentin ; pan-CK , (6 cycles) − − CK7 , CK20
Adenocarcinoma CK1/3+, CK7+, CEA+, CA 19-9+; Vimentin−
Spindle-shaped ND (Kras mutational tumor cells status only in SC) + + + Vimentin , CD10 , p53 ; + CK1/3 focal ; CEA−, CA 19-9−
Adenocarcinoma MFH CK18+, EMA+, CEA+; Vimentin+; CK−, − vimentin Ki-67: 90% Ki-67: NR
ND
IPMC, adenocarcinoma CK1/3+, CK7+
Osteosarcoma with Common origin heterologous (Kras and p53 components mutational status) + Vimentin Mucinous Malignant, pleomorphic Monoclonal (Kras mutational status, cystadenocarcinoma spindle cells + + p53-IHC) (pan-CK , CK7/8/18 , Vimentin+; pan-CK−, + − − − CEA , vimentin ) and CK7/8/18 , CEA anaplastic carcinoma (pan-CK+, CK7/8/18+, CEA+, vimentin+) Adenosquamous ND Leiomyosarcoma carcinoma Vimentin, SMA+; CK− + − CK ; vimentin Ki-67: high Ki-67: high PDAC Pleomorphic malignant ND CK18+, EMA+ spindle cells + SMA ; CK18−, EMA− Adenocarcinoma High grade pleomorphic ND Pan-CK+, CEA+; spindle cells − + Vimentin ; vimentin pan-CK−, CEA− Adenocarcinoma Spindle cells with ND CK18+; vimentin− pleomorphic nuclei Vimentin+; CK18−
Mucinous cystadenocarcinoma CK1/3+, CK7+, CK19+; vimentin−
Malignant spindle cells Vimentin+
ND
PD
PD + left hepatic lobe resection + local gastric resection DP
(1)/(3): Deceased 15 mo/9 mo after surgery (tumor recurrence) (2) Well after 12 mo
Comments Polar malignancy: CC in pancreatic head, SC in duodenal wall: authors suggest organ-induced differentiation of malignancy Initial authors suggest ovarian-like stroma as progenitor for SC (Wenig et al). Later, monoclonality is shown (van den Berg et al)
Alive and well 4 mo after surgery
Died 4 mo after surgery (liver and peritoneal metastasis) 9 mo complete CT-radiographic remission, died 11 mo after surgery (peritoneal recurrence) Deceased 13 d after SC with KRAS mutation surgery: sepsis in codons 12 and 34. with DIC Authors suggest correlation between codon 34 mutation and sarcomatous characteristics Died 2 mo after surgery Simultaneous resection of MOV (local of liver metastasis and recurrence and low grade gastric GIST liver metastasis) Well, recurrence free 12 mo after surgery
DP with colonic Deceased 4 mo segmental resection, after surgery adjuvant gemcitabine (metastatic disease) (3 cycles)
PD, adjuvant Well, 28 mo gemcitabine (6 cycles) after diagnosis
PD, adjuvant gemcitabine, adriamycin, cisplatin (5 cycles) PD
Laparoscopic spleen-preserving DP, adjuvant gemcitabine (1 cycle) DP
Free of recurrence for 20 mo
Deceased 20 d after surgery (bleeding complication) Succumbed to tumor recurrence 3 mo after surgery
Authors' terminology: sarcomatoid carcinoma as well as carcinosarcoma
NR
(Continued on next page)
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TABLE 2. (Continued) First Author (Reference)
Year of Publication
Age, y/ Sex
Katsourakis et al
2015
70/M
Bai et al27
2016
(1) 71/M (2) 49/M (3) 74/M (4) 38/M (5) 67/M (6) 60/F (7) 75/F (8) 59/M
26
Symptoms
Localization/Extent
Anemia
Pancreatic head
Not specifically reported. General symptoms such as abdominal pain, jaundice, nausea, vomiting, anemia, weight loss, or as incidental finding
(1)–(3), (5), (7): Pancreatic head (4), (6), (8): Pancreatic body/tail
Size 11 × 9 × 6 cm
(1) 5 cm (2) 5 cm (3) 8 cm (4) 16 cm (5) 3 cm (6) 7.5 cm (7) 4.5 cm (8) 5.5 cm
Only truly biphasic tumors with (virtually) keratin-negative and simultaneously (more than focally) vimentin-positive sarcomatous components were included. OGTPs with carcinomatous components were excluded. CK indicates cytokeratin; DIC, disseminated intravascular coagulation; DP, distal pancreatectomy; DVT, deep vein thrombosis; EMA, epithelial membrane antigen; GIST, gastrointestinal stromal tumor; HPRT-PCR, polymerase chain reaction for hypoxanthine phosphorybosyltransferase; IHC, immunohistochemistry; IPMC, intraductal papillary mucinous carcinoma; LOH, loss of heterozygosity; MFH, malignant fibrous histiocytoma; MOV, multiorgan failure; MPNST, malignant peripheral nerve sheath tumor; MS, microsatellite; NR, not reported; ND, not determined; OGTP, osteoclast-like giant cell tumor of the pancreas; OS, osteosarcoma; PD, pancreaticoduodenectomy; RUQ, right upper quadrant; SMA, smooth muscle actin.
exon 2 of the KRAS gene in both parts. The same c.35G > A substitution leading to a p.G12D mutation (most frequent KRAS mutation in PDAC) was detected in both malignant components (Table 1).
DISCUSSION We report an uncommon case of a pancreatic carcinosarcoma, a biphasic neoplasm with malignant components of carcinomatous and sarcomatous differentiation, accompanied by molecular evidence of a common origin. Preoperative diagnostic imaging provided only indirect signs of malignancy. Early death after resection may have resulted from quick recurrence of the tumor, although this could not be proven. Carcinosarcomas are rare tumors with a biphasic histological pattern of carcinomatous and sarcomatous components. These dual malignancies most frequently arise in the uterus, but also in many other organs such as the ovaries, prostate, breast, urinary tract, the lungs, larynx, and parotid gland, as well as in the gastrointestinal system such as in the esophagus, stomach, liver, bile ducts, gallbladder, duodenum, and the pancreas. Historically, theories for the histogenesis of carcinosarcomas, exemplified by uterine carcinosarcomas (UCSs) (malignant mixed müllerian tumors) have been the following: (1) collision theory: 2 independent malignancies colliding, (2) combination theory: both components have arisen from a common stem cell with early divergence of 2 entities, (3) conversion theory: the sarcomatous part derives from the carcinomatous part via metaplastic transformation, (4) composition theory: the carcinoma drives a pseudosarcomatous stromal reaction.1 More recently, accumulating data have led to the consensus that most (uterine) carcinosarcomas are combination or conversion tumors, and only a minority is true collision neoplasms.1–4 Therefore, the terminology metaplastic carcinoma has been suggested for the majority of carcinosarcomas.1,5 For the pancreas, only a small number of case reports of carcinosarcomas exists in the English literature. Reviewing these reports, an unclarity and inconsistency regarding the terminology especially in regard to sarcomatoid
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carcinoma versus carcinosarcoma becomes evident. The World Health Organization Classification of Tumours of the Exocrine Pancreas lists sarcomatoid carcinoma and carcinosarcoma, together with giant cell and pleomorphic carcinoma, as well as osteoclast-like giant cell tumors under the section of undifferentiated (anaplastic) carcinoma, a variant of ductal adenocarcinoma.6 Sarcomatoid carcinomas histologically appear as malignant spindle cell tumors but show evidence of epithelial derivation, for example, immunohistochemically displaying expression of epithelial markers, such as cytokeratins. They may, not necessarily, express mesenchymal markers such as vimentin, but might still have a carcinomatous component and thus appear like a dual malignancy.7–10 However, carcinosarcomas by definition display biphasic epithelial and mesenchymal differentiation. Only truly dual tumors, at least immunohistochemically demonstrating a carcinomatous component (positive for epithelial markers and negative for mesenchymal markers) and a distinct sarcomatous component (positive for mesenchymal markers and negative for epithelial markers), should be called carcinosarcomas. Carcinosarcomas may show heterologous mesenchymal elements (osteo-/cartilaginous, lipogenic, muscular, vascular, peripheral nerve sheath components).10 On this basis, we excluded some articles in our summary of case reports (Table 2), for instance, when the terminology of carcinosarcoma or carcinosarcomatous histology was used, but the sarcomatous components of the dual malignancy showed expression of cytokeratins,28–30 or the information for expression of epithelial markers was lacking,31 or where the dual, biphasic character of the tumor was not clearly evident from the data provided.32 We also excluded all reports including osteoclast-like giant cell tumors, because these frequently contain a carcinomatous component.6,28,33–35 The resulting collection of thus defined pancreatic carcinosarcomas in the English literature (Table 2) comprised 23 cases with equal distribution of sexes and an age at diagnosis ranging from 38 to 82 years. Similar to PDAC, symptoms leading to diagnostic workup included abdominal pain, jaundice, nausea, emesis, anemia, and weight loss. Some tumors, such as in our case, were discovered incidentally. Most tumors were located in © 2017 Wolters Kluwer Health, Inc. All rights reserved.
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Pancreas • Volume 46, Number 9, October 2017
Carcinomatous Component (CC)
Sarcomatous Component (SC)
Adenocarcinoma CK7+
Malignant spindle cells Vimentin+
(1)–(3), (5), (7), (8): PDAC (4), (6): Mucinous cystadenocarcinoma All: epithelial markers+
(1), (6), (8): MFH/ undifferentiated pleomorphic sarcoma (2) OS/MFH (3), (4), (7): Pleomorphic spindle cell sarcoma (5) Embryonal rhabdomyosarcoma All: vimentin+; epithelial markers−
Report of a Rare Pancreatic Carcinosarcoma
Clonality/ Molecular Analysis ND
(1), (2), (3), (4), (8): Monoclonal (Kras mutational status) (5)–(7): ND
the pancreatic head (n = 15), and the remainder in the body/tail of the gland (n = 8). Most tumors harbored a (ductal) adenocarcinoma as carcinomatous component (n = 16, 1 derived from IPMN), less frequently appearing mucinous cystadenocarcinoma (n = 6), and adenosquamous carcinoma (n = 1). The sarcomatous components mostly were simply described as malignant spindle cell proliferations (n = 13), in some cases as malignant fibrous histiocytoma (n = 5) or leiomyosarcoma (n = 2). Two cases showed osteosarcoma (with heterologous components); 1 case presented with embryonal rhabdomyosarcoma. All tumors were treated by surgery, followed by adjuvant/additive chemotherapy in 11 cases (gemcitabine: n = 5, gemcitabine/adriamycin/cisplatin: n = 1, not specifically reported: n = 5). The majority of patients had a dismal outcome. Most (n = 11) died within the first 15 months after surgery because of tumor recurrence. For most of the cases being reported to be free of recurrence, follow-up was short (n = 8; follow-up of 6–36 months). In 9 cases, clonality of the 2 distinct tumor components was assessed by microdissection with subsequent genetic analysis for microsatellite polymorphisms or Kras mutations. All cases showed the same genetic alterations in the carcinomatous and sarcomatous components, strongly suggesting a common origin. Especially in the 3 cases of mucinous cystic neoplasm (MCN)–derived mucinous cystadenocarcinomas13,20,27 this is intriguing, because benign MCNs have been suggested to possibly induce (metastatic) sarcomas in their ovarianlike stroma.36,37 Thus, like in our case, most pancreatic carcinosarcomas seem to be of monoclonal origin, often bearing identical Kras mutations characteristic for PDAC and seem to have arisen by metaplastic transformation of parts of the epithelial component. These observations justify the listing of pancreatic carcinosarcoma in the section for undifferentiated (anaplastic) PDAC in the World Health Organization classification.6 Furthermore, primary sarcomas of the pancreas are extremely rare, with leiomyosarcomas and liposarcomas yet being the most common subentities.6,38–41 Therefore, a collision tumor, where 2 independent infrequent malignancies (rather low incidence: PDAC, and very low incidence: © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Follow-up/ Outcome
Therapy PD, adjuvant gemcitabine (8 cycles)
Comments
Recurrence-free 16 mo after surgery (1) Rec. 9 mo, died 11 mo (2) Well 39 mo (3) Rec. 9 mo, died 10 mo (4) Rec. 12 mo, alive 26 mo (5) No rec. until 44 mo, died 47 mo (6) Rec. 12 mo, died 15 mo (7) Well 29 mo (8) Well 17 mo
(1)–(3), (5)–(8): PD (4) DP (1), (2), (4), (5), (8): Postoperative chemotherapy (4) Gamma knife (7) Traditional Chinese medical herbal treatment
pancreatic primary sarcoma) merge to form a single tumor, is highly unlikely. In contrast, a metaplastic transformation in a process called epithelial-mesenchymal transition (EMT) is observed in many pancreatic carcinomas and is associated with decreased survival and chemoresistance.42–46 While EMTwas initially considered a process of cell plasticity in development and disease involving a single binary decision between epithelial and mesenchymal phenotype, more recently it has become evident that EMT is a complex program with multiple transition phases and intermediary states between the full epithelial and mesenchymal phenotypes.47,48 In this light, pancreatic sarcomatoid carcinomas could be considered as intermediate but stabilized-stage, partial-EMT tumors, having acquired some mesenchymal properties while still demonstrating epithelial traits. Pancreatic carcinosarcomas, especially those with assumedly monoclonal origin, would harbor a component that dedifferentiated from the initial, and still present, carcinoma via a more complete EMT into a tumor with (exclusively) mesenchymal characteristics, to form a dual malignancy. Simple (immuno)histological diagnosis and subtyping of tumors with occasional selective genetic analyses are still the mainstay of daily clinical practice. However, with the advent of global gene expression and genomic analyses, subtyping of PDAC is gaining complexity. Recently, 3 groups have suggested transcriptomics-/genomics-based subtypes of PDAC and have linked them to patients' prognosis49–52: The dedifferentiated, mesenchymal-like, EMT-associated subtypes of Collisson et al49 (quasi-mesenchymal subtype), Moffitt et al51 (basal-like subtype), and Bailey et al52 (squamous subtype) all display a worse prognosis compared with their more epithelial or classic counterparts. On a histological level, these subtypes might appear as undifferentiated/ anaplastic carcinomas, some probably as sarcomatoid carcinomas or carcinosarcomas. Outcome after resection of undifferentiated, anaplastic pancreatic cancer has been described to be at least equal to,53,54 if not worse than for55, differentiated classic PDAC. Furthermore, the most frequent type of carcinosarcoma, UCS, is a far more aggressive tumor than high-grade endometrial carcinoma. In most cases, UCS presents with metastatic disease at www.pancreasjournal.com
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the time of diagnosis. Despite surgery and adjuvant chemotherapy, recurrence rates are high, and prognosis is poor.4 The vast majority of carcinosarcoma cases discussed here receiving adjuvant/additive chemotherapy were treated with gemcitabine. Given the very low incidence of this malignancy, no evidence exists for a treatment recommendation in a first-line or adjuvant/additive therapy setting. Considering the fact discussed here that pancreatic carcinosarcomas are most likely combination or conversion tumors (PDACs with a dedifferentiated component) and that according to Collisson et al49 quasi-mesenchymal–like subtypes are even more sensitive to gemcitabine, currently a treatment strategy similar to PDAC seems reasonable. This implicates, if feasible, a resection with subsequent adjuvant chemotherapy with gemcitabine. However, EMT and dedifferentiation have also been linked to chemoresistance.43,46 Clearly, more research and evidence are essential for improvement of therapeutic approaches for this rare and aggressive malignancy.
15. Bloomston M, Chanona-Vilchis J, Ellison EC, et al. Carcinosarcoma of the pancreas arising in a mucinous cystic neoplasm. Am Surg. 2006;72: 351–355. 16. Gelos M, Behringer D, Philippou S, et al. Pancreatic carcinosarcoma. Case report of multimodal therapy and review of the literature. JOP. 2008;9:50–55. 17. Nakano T, Sonobe H, Usui T, et al. Immunohistochemistry and K-ras sequence of pancreatic carcinosarcoma. Pathol Int. 2008;58:672–677. 18. Shen ZL, Wang S, Ye YJ, et al. Carcinosarcoma of pancreas with liver metastasis combined with gastrointestinal stromal tumour of the stomach: is there a good prognosis with the complete resection? Eur J Cancer Care (Engl). 2010;19:118–123. 19. Okamura J, Sekine S, Nara S, et al. Intraductal carcinosarcoma with a heterologous mesenchymal component originating in intraductal papillary-mucinous carcinoma (IPMC) of the pancreas with both carcinoma and osteosarcoma cells arising from IPMC cells. J Clin Pathol. 2010;63:266–269.
1. McCluggage WG. Malignant biphasic uterine tumours: carcinosarcomas or metaplastic carcinomas? J Clin Pathol. 2002;55:321–325.
20. Kim H, Joo SH, Yang DM, et al. Carcinosarcoma of the pancreas: a unique case with emphasis on metaplastic transformation and the presence of undifferentiated pleomorphic high-grade sarcoma. J Gastrointestin Liver Dis. 2011;20:197–200.
2. Thompson L, Chang B, Barsky SH. Monoclonal origins of malignant mixed tumors (carcinosarcomas). Evidence for a divergent histogenesis. Am J Surg Pathol. 1996;20:277–285.
21. Palaniappan M, Jose W, Bindhu MR, et al. Carcinosarcoma of the pancreas: report of a case with a concise review of the literature. J Clin Diagn Res. 2011;5:621–624.
3. Wada H, Enomoto T, Fujita M, et al. Molecular evidence that most but not all carcinosarcomas of the uterus are combination tumors. Cancer Res. 1997;57:5379–5385.
22. Zhu WY, Liu TG, Zhu H. Long-term recurrence-free survival in a patient with pancreatic carcinosarcoma: a case report with a literature review. Med Oncol. 2012;29:140–143.
4. Cantrell LA, Blank SV, Duska LR. Uterine carcinosarcoma: a review of the literature. Gynecol Oncol. 2015;137:581–588.
23. Oymaci E, Argon A, Coşkun A, et al. Pancreatic carcinosarcoma: case report of a rare type of pancreatic neoplasia. JOP. 2013;14:212–215.
5. Wick MR, Swanson PE. Carcinosarcomas: current perspectives and an historical review of nosological concepts. Semin Diagn Pathol. 1993;10: 118–127.
24. Yao J, Qian JJ, Zhu CR, et al. Laparoscopic left pancreatectomy for pancreatic sarcomatoid carcinoma: a case report and review of the literature. Oncol Lett. 2013;6:568–570.
6. Bosman F, Carneiro F, Hruban R, et al Ductal adenocarcinoma variants and mixed neoplasms of the pancreas. In: World Health Organization Classification of Tumours of the Digestive System. 4th ed. Lyon, France: IARC Press; 2010:292–295.
25. Shi HY, Xie J, Miao F. Pancreatic carcinosarcoma: first literature report on computed tomography imaging. World J Gastroenterol. 2015;21: 1357–1361.
REFERENCES
7. Higashi M, Takao S, Sato E. Sarcomatoid carcinoma of the pancreas: a case report with immunohistochemical study. Pathol Int. 1999;49: 453–456. 8. Ren CL, Jin P, Han CX, et al. Unusual early-stage pancreatic sarcomatoid carcinoma. World J Gastroenterol. 2013;19:7820–7824. 9. Lu BC, Wang C, Yu JH, et al. A huge adenosquamous carcinoma of the pancreas with sarcomatoid change: an unusual case report. World J Gastroenterol. 2014;20:16381–16386. 10. Kane JR, Laskin WB, Matkowskyj KA, et al. Sarcomatoid (spindle cell) carcinoma of the pancreas: a case report and review of the literature. Oncol Lett. 2014;7:245–249. 11. 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: 132–137. 12. 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;21:70–80.
26. Katsourakis A, Svoronos C, Chatzitheoklitos E, et al. Carcinosarcoma of the pancreas: how a common blood disorder can hide an extremely rare tumour. JOP. 2015;16:310–312. 27. Bai Q, Zhang X, Zhu X, et al. Pancreatic carcinosarcoma with the same KRAS gene mutation in both carcinomatous and sarcomatous components: molecular evidence for monoclonal origin of the tumour. Histopathology. 2016;69:393–405. 28. Watanabe M, Miura H, Inoue H, et al. Mixed osteoclastic/pleomorphic-type giant cell tumor of the pancreas with ductal adenocarcinoma: histochemical and immunohistochemical study with review of the literature. Pancreas. 1997;15:201–208. 29. Barkatullah SA, Deziel DJ, Jakate SM, et al. Pancreatic carcinosarcoma with unique triphasic histological pattern. Pancreas. 2005;31:291–292. 30. Kim HS, Kim JI, Jeong M, et al. Pancreatic adenocarcinosarcoma of monoclonal origin: a case report. World J Gastroenterol. 2014;20: 12682–12686. 31. Yamazaki K. A unique pancreatic ductal adenocarcinoma with carcinosarcomatous histology, immunohistochemical distribution of hCG-beta, and the elevation of serum alpha-feto-protein. J Submicrosc Cytol Pathol. 2003;35:343–349.
13. 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;13:86–91.
32. Lee J, Hyun JJ, Lee HS. A rare cause of abdominal pain by pancreatic mass in a young female patient. carcinosarcoma of the pancreas. Gastroenterology. 2015;149:e3–e5.
14. 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;126:1114–1117.
33. Posen JA. Giant cell tumor of the pancreas of the osteoclastic type associated with a mucous secreting cystadenocarcinoma. Hum Pathol. 1981;12:944–947.
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34. Trepeta RW, Mathur B, Lagin S, et al. Giant cell tumor (“osteoclastoma”) of the pancreas: a tumor of epithelial origin. Cancer. 1981;48: 2022–2028.
45. Takahashi K, Hisaka T, Horiuchi H, et al. Neoplastic spindle cells are an independent prognostic factor in pancreatic cancer. Pancreas. 2015;44: 742–749.
35. Fischer HP, Altmannsberger M, Kracht J. Osteoclast-type giant cell tumour of the pancreas. Virchows Arch A Pathol Anat Histopathol. 1988;412: 247–253.
46. Zheng X, Carstens JL, Kim J, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015;527:525–530.
36. Tsujimura T, Kawano K, Taniguchi M, et al. Malignant fibrous histiocytoma coexistent with mucinous cystadenoma of the pancreas. Cancer. 1992;70:2792–2796.
47. Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7:415–428.
37. Wayne M, Gur D, Ascunce G, et al. Pancreatic mucinous cystic neoplasm with sarcomatous stroma metastasizing to liver: a case report and review of literature. World J Surg Oncol. 2013;11:100.
48. Nieto MA, Huang RY, Jackson RA, et al. EMT: 2016. Cell. 2016;166: 21–45.
38. Kim JY, Song JS, Park H, et al. Primary mesenchymal tumors of the pancreas: single-center experience over 16 years. Pancreas. 2014;43: 959–968. 39. Zhang H, Jensen MH, Farnell MB, et al. Primary leiomyosarcoma of the pancreas: study of 9 cases and review of literature. Am J Surg Pathol. 2010; 34:1849–1856. 40. Xu J, Zhang T, Wang T, et al. Clinical characteristics and prognosis of primary leiomyosarcoma of the pancreas: a systematic review. World J Surg Oncol. 2013;11:290. 41. Machado MC, Fonseca GM, de Meirelles LR, et al. Primary liposarcoma of the pancreas: a review illustrated by findings from a recent case. Pancreatology. 2016;16:715–718. 42. Hotz B, Arndt M, Dullat S, et al. Epithelial to mesenchymal transition: expression of the regulators snail, slug, and twist in pancreatic cancer. Clin Cancer Res. 2007;13:4769–4776. 43. Arumugam T, Ramachandran V, Fournier KF, et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 2009;69:5820–5828. 44. Rhim AD, Mirek ET, Aiello NM, et al. EMT and dissemination precede pancreatic tumor formation. Cell. 2012;148:349–361.
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49. Collisson EA, Sadanandam A, Olson P, et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med. 2011; 17:500–503. 50. Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518: 495–501. 51. Moffitt RA, Marayati R, Flate EL, et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet. 2015;47:1168–1178. 52. Bailey P, Chang DK, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531:47–52. 53. Paniccia A, Hosokawa PW, Schulick RD, et al. A matched-cohort analysis of 192 pancreatic anaplastic carcinomas and 960 pancreatic adenocarcinomas: a 13-year North American experience using the National Cancer Data Base (NCDB). Surgery. 2016;160: 281–292. 54. Clark CJ, Arun JS, Graham RP, et al. Clinical characteristics and overall survival in patients with anaplastic pancreatic cancer. Am Surg. 2014;80: 117–123. 55. Strobel O, Hartwig W, Bergmann F, et al. Anaplastic pancreatic cancer: presentation, surgical management, and outcome. Surgery. 2011;149: 200–208.
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Carcinosarcoma of the Pancreas Case Report With Comprehensive Literature Review Dietrich A. Ruess, MD,* Claudia Kayser, MD,† Jakob Neubauer, MD,‡ Stefan Fichtner-Feigl, MD,* Ulrich T. Hopt, MD,* and Uwe A. Wittel, MD*
Abstract: Carcinosarcomas are rare biphasic neoplasms with distinct malignant epithelial and mesenchymal components. Most commonly, carcinosarcomas arise in the uterus as malignant mixed müllerian tumors, but also infrequently appear in other organs such as the ovaries and breast, the prostate and urinary tract, the lungs, or in the gastrointestinal system, among others. Pancreatic carcinosarcomas are exceedingly rare; only a few cases are reported in the English literature. Their pathogenesis remains to be fully clarified. We present here the case of a pancreatic carcinosarcoma with evidence for monoclonality via determination of Kras mutational status after microdissection and suggest a common origin of the 2 tumor components. Comprehensive review of the available literature allows the conclusion that most pancreatic carcinosarcomas appear to be of monoclonal origin and seem to have arisen from a carcinoma via metaplastic transformation of 1 part or subclone of the tumor, probably by epithelial-mesenchymal transition. All reported patients were treated with surgery. Adjuvant therapy, if administered, consisted predominantly of gemcitabine. Prognosis for this neoplasm occurs to be similar or even worse compared with classic pancreatic ductal adenocarcinoma. Despite the lack of evidence-based recommendations for its treatment, resection should be performed, if possible. Key Words: carcinosarcoma, Kras mutation, pancreas, pathogenesis, prognosis, treatment Abbreviations: CT - computed tomography, IPMN - intraductal papillary mucinous neoplasm, MCN - mucinous cystic neoplasm, PDAC - pancreatic ductal adenocarcinoma (Pancreas 2017;46: 1225–1233)
C
arcinosarcomas are rare neoplasms with distinct malignant epithelial (carcinomatous) and mesenchymal (sarcomatous) components. Each of these components exhibits a characteristic histological, immunohistochemical, and ultrastructural pattern, indicative of their dissimilar differentiation. For the pancreas, only a very few cases of carcinosarcomas have been reported to date. Pathogenesis and histogenesis of this entity remain to be clarified. Evidence-based treatment strategies are lacking because of the low incidence of this entity. We report a case of a pancreatic carcinosarcoma with evidence of monoclonality and a common origin of the 2 malignant components. In addition, we review and discuss the available English literature with a focus on terminology, pathogenesis, treatment, and prognosis.
From the *Department of Surgery, †Institute for Surgical Pathology, and ‡Department of Radiology, Faculty of Medicine, Medical Center–University of Freiburg, Freiburg, Germany. Received for publication November 16, 2016; accepted August 2, 2017. Address correspondence to: Dietrich A. Ruess, MD, Department of Surgery, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany (e‐mail: [email protected]). The authors declare no conflict of interest. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MPA.0000000000000904
Pancreas • Volume 46, Number 9, October 2017
CASE REPORT Patient Presentation, Diagnosis, and Treatment A 73-year-old white woman was referred to the Department of Surgery for workup of an indeterminate pancreatic lesion. The patient had undergone magnetic resonance imaging of the upper abdomen for evaluation of a renal mass, which turned out to be an angiomyolipoma. Incidental finding in this study was an abrupt change in main duct caliber at the head-body junction with upstream ductal dilation up to 10 mm (Figs. 1A, C, D), along with diffuse tubular dilatation of branch ducts in the pancreatic tail (Fig. 1B). Because of severe motion artifacts in this study, an additional multiphasic computed tomography (CT) examination was carried out, which confirmed the previous findings. There was no evidence of a tumor, extrapancreatic tumor growth, lymphadenopathy, or metastases. Combined-type intraductal papillary mucinous neoplasm (IPMN) with worrisome and high-risk features was suspected, and simple ductal dilatation related to mechanical obstruction of unknown and potential malignant cause was given as a differential diagnosis. Clinical chemistry revealed slightly elevated tumor markers carbohydrate antigen (CA) 19-9 (29.1 U/mL; reference, A
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TABLE 2. Previously Published Case Reports and Collections of Pancreatic Carcinosarcoma in the English Literature First Author (Reference)
Year of Publication
Age, y/ Sex
Symptoms
1994
50/F
NR
Wenig et al12 and van den Berg et al13
1997 and 2000
(1) 67/M (2) 48/F (3) 65/F
(1)–(3): Abdominal pain
(1)–(3): Pancreatic tail [(3) with omental metastases of SC]
(1) 19 × 14 × 8 cm (2) NR (3) 30 × 25 × 9.5 cm
Darvishian et al14
2002
74/M
Incidental finding upon workup of DVT
Pancreatic head, infiltrating peripancreatic adipose tissue and duodenal wall
4 × 3 cm
Bloomston et al15
2006
67/F
Nausea, emesis, painless jaundice
Pancreatic head, SC invading duodenum
Gelos et al16
2008
61/F
Anemia
Pancreatic head, infiltrating duodenum and peripancreatic fat
Nakano et al17
2008
82/F
Anorexia, right hypochondralgia
Pancreatic head
Shen et al18
2010
72/F
RUQ pain, nausea, emesis
Pancreatic head, infiltrating duodenum and peripancreatic fat
Okamura et al19
2010
64/F
Incidental finding
Pancreatic tail
Kim et al20
2011
48/M
Incidental finding
Pancreatic tail, infiltrating peripancreatic fat,
7 × 5 × 5 cm
Palaniappan et al21
2011
46/M
Jaundice
Pancreatic head, infiltrating duodenal wall
3 × 3 × 2 cm
Zhu et al22
2012
53/F
Epigastric, RUQ pain, jaundice
Pancreatic head
5 × 4 × 3 cm
Oymaci et al23
2013
66/M
Abdominal pain, jaundice
Pancreatic head, infiltrating duodenum and peripancreatic fat
Yao et al24
2013
48/M
Epigastric pain
Pancreatic tail (cystic and solid)
10 × 8 × 5 cm
Shi et al25
2015
74/F
Initially incidental MCN, on follow-up grown size, more thickened wall and solid components
Pancreatic tail (cystic lesion)
5 × 4 × 2 cm
Millis et al11
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Localization/Extent Pancreatic head/duodenal wall infiltration
Size NR
4 × 4 × 3 cm
7 × 6 × 3.5 cm
18 × 11 × 10 cm
5 × 4 × 4 cm 5 cm (liver lesion) 2 cm (gastric lesion) 3.5 × 2.1 × 1.4 cm
3.5 × 2 × 1.5 cm
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Pancreas • Volume 46, Number 9, October 2017
Carcinomatous Component (CC)
Sarcomatous Component (SC)
Report of a Rare Pancreatic Carcinosarcoma
Clonality/ Molecular Analysis Monoclonal (via HPRT-PCR)
Therapy
Follow-up/ Outcome
PD
NR
Adenocarcinoma
Leiomyosarcoma Vimentin, SMA+
(1) Mucinous cystadenocarcinoma (2), (3): only MCN (1)–(3): CK+, EMA+, CEA+, CA 19-9+, DUPAN-2+; vimentin− PDAC CK+, CEA+; Vimentin, SMA− Ki-67: 43% Mucinous cystadenocarcinoma CK1/3+, CK7+, CEA+ Adenocarcinoma pan-CK+, CK7+, CK20+
(1)–(3): DP [(3) with (1)–(3): Undifferentiated Monoclonal omentectomy] malignant spindle (LOH via MS cells [in (1) polymorphism, and possibly MPNST] Kras mutational status) (1)–(3): Vimentin+, SMA+; CK, EMA− ND PD MFH Vimentin+; CK focal + Ki-67: 30% Invasive ND PD sarcomatous stroma + Vimentin Poorly differentiated ND PD (R1), additive sarcomatoid cells gemcitabine + − Vimentin ; pan-CK , (6 cycles) − − CK7 , CK20
Adenocarcinoma CK1/3+, CK7+, CEA+, CA 19-9+; Vimentin−
Spindle-shaped ND (Kras mutational tumor cells status only in SC) + + + Vimentin , CD10 , p53 ; + CK1/3 focal ; CEA−, CA 19-9−
Adenocarcinoma MFH CK18+, EMA+, CEA+; Vimentin+; CK−, − vimentin Ki-67: 90% Ki-67: NR
ND
IPMC, adenocarcinoma CK1/3+, CK7+
Osteosarcoma with Common origin heterologous (Kras and p53 components mutational status) + Vimentin Mucinous Malignant, pleomorphic Monoclonal (Kras mutational status, cystadenocarcinoma spindle cells + + p53-IHC) (pan-CK , CK7/8/18 , Vimentin+; pan-CK−, + − − − CEA , vimentin ) and CK7/8/18 , CEA anaplastic carcinoma (pan-CK+, CK7/8/18+, CEA+, vimentin+) Adenosquamous ND Leiomyosarcoma carcinoma Vimentin, SMA+; CK− + − CK ; vimentin Ki-67: high Ki-67: high PDAC Pleomorphic malignant ND CK18+, EMA+ spindle cells + SMA ; CK18−, EMA− Adenocarcinoma High grade pleomorphic ND Pan-CK+, CEA+; spindle cells − + Vimentin ; vimentin pan-CK−, CEA− Adenocarcinoma Spindle cells with ND CK18+; vimentin− pleomorphic nuclei Vimentin+; CK18−
Mucinous cystadenocarcinoma CK1/3+, CK7+, CK19+; vimentin−
Malignant spindle cells Vimentin+
ND
PD
PD + left hepatic lobe resection + local gastric resection DP
(1)/(3): Deceased 15 mo/9 mo after surgery (tumor recurrence) (2) Well after 12 mo
Comments Polar malignancy: CC in pancreatic head, SC in duodenal wall: authors suggest organ-induced differentiation of malignancy Initial authors suggest ovarian-like stroma as progenitor for SC (Wenig et al). Later, monoclonality is shown (van den Berg et al)
Alive and well 4 mo after surgery
Died 4 mo after surgery (liver and peritoneal metastasis) 9 mo complete CT-radiographic remission, died 11 mo after surgery (peritoneal recurrence) Deceased 13 d after SC with KRAS mutation surgery: sepsis in codons 12 and 34. with DIC Authors suggest correlation between codon 34 mutation and sarcomatous characteristics Died 2 mo after surgery Simultaneous resection of MOV (local of liver metastasis and recurrence and low grade gastric GIST liver metastasis) Well, recurrence free 12 mo after surgery
DP with colonic Deceased 4 mo segmental resection, after surgery adjuvant gemcitabine (metastatic disease) (3 cycles)
PD, adjuvant Well, 28 mo gemcitabine (6 cycles) after diagnosis
PD, adjuvant gemcitabine, adriamycin, cisplatin (5 cycles) PD
Laparoscopic spleen-preserving DP, adjuvant gemcitabine (1 cycle) DP
Free of recurrence for 20 mo
Deceased 20 d after surgery (bleeding complication) Succumbed to tumor recurrence 3 mo after surgery
Authors' terminology: sarcomatoid carcinoma as well as carcinosarcoma
NR
(Continued on next page)
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TABLE 2. (Continued) First Author (Reference)
Year of Publication
Age, y/ Sex
Katsourakis et al
2015
70/M
Bai et al27
2016
(1) 71/M (2) 49/M (3) 74/M (4) 38/M (5) 67/M (6) 60/F (7) 75/F (8) 59/M
26
Symptoms
Localization/Extent
Anemia
Pancreatic head
Not specifically reported. General symptoms such as abdominal pain, jaundice, nausea, vomiting, anemia, weight loss, or as incidental finding
(1)–(3), (5), (7): Pancreatic head (4), (6), (8): Pancreatic body/tail
Size 11 × 9 × 6 cm
(1) 5 cm (2) 5 cm (3) 8 cm (4) 16 cm (5) 3 cm (6) 7.5 cm (7) 4.5 cm (8) 5.5 cm
Only truly biphasic tumors with (virtually) keratin-negative and simultaneously (more than focally) vimentin-positive sarcomatous components were included. OGTPs with carcinomatous components were excluded. CK indicates cytokeratin; DIC, disseminated intravascular coagulation; DP, distal pancreatectomy; DVT, deep vein thrombosis; EMA, epithelial membrane antigen; GIST, gastrointestinal stromal tumor; HPRT-PCR, polymerase chain reaction for hypoxanthine phosphorybosyltransferase; IHC, immunohistochemistry; IPMC, intraductal papillary mucinous carcinoma; LOH, loss of heterozygosity; MFH, malignant fibrous histiocytoma; MOV, multiorgan failure; MPNST, malignant peripheral nerve sheath tumor; MS, microsatellite; NR, not reported; ND, not determined; OGTP, osteoclast-like giant cell tumor of the pancreas; OS, osteosarcoma; PD, pancreaticoduodenectomy; RUQ, right upper quadrant; SMA, smooth muscle actin.
exon 2 of the KRAS gene in both parts. The same c.35G > A substitution leading to a p.G12D mutation (most frequent KRAS mutation in PDAC) was detected in both malignant components (Table 1).
DISCUSSION We report an uncommon case of a pancreatic carcinosarcoma, a biphasic neoplasm with malignant components of carcinomatous and sarcomatous differentiation, accompanied by molecular evidence of a common origin. Preoperative diagnostic imaging provided only indirect signs of malignancy. Early death after resection may have resulted from quick recurrence of the tumor, although this could not be proven. Carcinosarcomas are rare tumors with a biphasic histological pattern of carcinomatous and sarcomatous components. These dual malignancies most frequently arise in the uterus, but also in many other organs such as the ovaries, prostate, breast, urinary tract, the lungs, larynx, and parotid gland, as well as in the gastrointestinal system such as in the esophagus, stomach, liver, bile ducts, gallbladder, duodenum, and the pancreas. Historically, theories for the histogenesis of carcinosarcomas, exemplified by uterine carcinosarcomas (UCSs) (malignant mixed müllerian tumors) have been the following: (1) collision theory: 2 independent malignancies colliding, (2) combination theory: both components have arisen from a common stem cell with early divergence of 2 entities, (3) conversion theory: the sarcomatous part derives from the carcinomatous part via metaplastic transformation, (4) composition theory: the carcinoma drives a pseudosarcomatous stromal reaction.1 More recently, accumulating data have led to the consensus that most (uterine) carcinosarcomas are combination or conversion tumors, and only a minority is true collision neoplasms.1–4 Therefore, the terminology metaplastic carcinoma has been suggested for the majority of carcinosarcomas.1,5 For the pancreas, only a small number of case reports of carcinosarcomas exists in the English literature. Reviewing these reports, an unclarity and inconsistency regarding the terminology especially in regard to sarcomatoid
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carcinoma versus carcinosarcoma becomes evident. The World Health Organization Classification of Tumours of the Exocrine Pancreas lists sarcomatoid carcinoma and carcinosarcoma, together with giant cell and pleomorphic carcinoma, as well as osteoclast-like giant cell tumors under the section of undifferentiated (anaplastic) carcinoma, a variant of ductal adenocarcinoma.6 Sarcomatoid carcinomas histologically appear as malignant spindle cell tumors but show evidence of epithelial derivation, for example, immunohistochemically displaying expression of epithelial markers, such as cytokeratins. They may, not necessarily, express mesenchymal markers such as vimentin, but might still have a carcinomatous component and thus appear like a dual malignancy.7–10 However, carcinosarcomas by definition display biphasic epithelial and mesenchymal differentiation. Only truly dual tumors, at least immunohistochemically demonstrating a carcinomatous component (positive for epithelial markers and negative for mesenchymal markers) and a distinct sarcomatous component (positive for mesenchymal markers and negative for epithelial markers), should be called carcinosarcomas. Carcinosarcomas may show heterologous mesenchymal elements (osteo-/cartilaginous, lipogenic, muscular, vascular, peripheral nerve sheath components).10 On this basis, we excluded some articles in our summary of case reports (Table 2), for instance, when the terminology of carcinosarcoma or carcinosarcomatous histology was used, but the sarcomatous components of the dual malignancy showed expression of cytokeratins,28–30 or the information for expression of epithelial markers was lacking,31 or where the dual, biphasic character of the tumor was not clearly evident from the data provided.32 We also excluded all reports including osteoclast-like giant cell tumors, because these frequently contain a carcinomatous component.6,28,33–35 The resulting collection of thus defined pancreatic carcinosarcomas in the English literature (Table 2) comprised 23 cases with equal distribution of sexes and an age at diagnosis ranging from 38 to 82 years. Similar to PDAC, symptoms leading to diagnostic workup included abdominal pain, jaundice, nausea, emesis, anemia, and weight loss. Some tumors, such as in our case, were discovered incidentally. Most tumors were located in © 2017 Wolters Kluwer Health, Inc. All rights reserved.
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Pancreas • Volume 46, Number 9, October 2017
Carcinomatous Component (CC)
Sarcomatous Component (SC)
Adenocarcinoma CK7+
Malignant spindle cells Vimentin+
(1)–(3), (5), (7), (8): PDAC (4), (6): Mucinous cystadenocarcinoma All: epithelial markers+
(1), (6), (8): MFH/ undifferentiated pleomorphic sarcoma (2) OS/MFH (3), (4), (7): Pleomorphic spindle cell sarcoma (5) Embryonal rhabdomyosarcoma All: vimentin+; epithelial markers−
Report of a Rare Pancreatic Carcinosarcoma
Clonality/ Molecular Analysis ND
(1), (2), (3), (4), (8): Monoclonal (Kras mutational status) (5)–(7): ND
the pancreatic head (n = 15), and the remainder in the body/tail of the gland (n = 8). Most tumors harbored a (ductal) adenocarcinoma as carcinomatous component (n = 16, 1 derived from IPMN), less frequently appearing mucinous cystadenocarcinoma (n = 6), and adenosquamous carcinoma (n = 1). The sarcomatous components mostly were simply described as malignant spindle cell proliferations (n = 13), in some cases as malignant fibrous histiocytoma (n = 5) or leiomyosarcoma (n = 2). Two cases showed osteosarcoma (with heterologous components); 1 case presented with embryonal rhabdomyosarcoma. All tumors were treated by surgery, followed by adjuvant/additive chemotherapy in 11 cases (gemcitabine: n = 5, gemcitabine/adriamycin/cisplatin: n = 1, not specifically reported: n = 5). The majority of patients had a dismal outcome. Most (n = 11) died within the first 15 months after surgery because of tumor recurrence. For most of the cases being reported to be free of recurrence, follow-up was short (n = 8; follow-up of 6–36 months). In 9 cases, clonality of the 2 distinct tumor components was assessed by microdissection with subsequent genetic analysis for microsatellite polymorphisms or Kras mutations. All cases showed the same genetic alterations in the carcinomatous and sarcomatous components, strongly suggesting a common origin. Especially in the 3 cases of mucinous cystic neoplasm (MCN)–derived mucinous cystadenocarcinomas13,20,27 this is intriguing, because benign MCNs have been suggested to possibly induce (metastatic) sarcomas in their ovarianlike stroma.36,37 Thus, like in our case, most pancreatic carcinosarcomas seem to be of monoclonal origin, often bearing identical Kras mutations characteristic for PDAC and seem to have arisen by metaplastic transformation of parts of the epithelial component. These observations justify the listing of pancreatic carcinosarcoma in the section for undifferentiated (anaplastic) PDAC in the World Health Organization classification.6 Furthermore, primary sarcomas of the pancreas are extremely rare, with leiomyosarcomas and liposarcomas yet being the most common subentities.6,38–41 Therefore, a collision tumor, where 2 independent infrequent malignancies (rather low incidence: PDAC, and very low incidence: © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Follow-up/ Outcome
Therapy PD, adjuvant gemcitabine (8 cycles)
Comments
Recurrence-free 16 mo after surgery (1) Rec. 9 mo, died 11 mo (2) Well 39 mo (3) Rec. 9 mo, died 10 mo (4) Rec. 12 mo, alive 26 mo (5) No rec. until 44 mo, died 47 mo (6) Rec. 12 mo, died 15 mo (7) Well 29 mo (8) Well 17 mo
(1)–(3), (5)–(8): PD (4) DP (1), (2), (4), (5), (8): Postoperative chemotherapy (4) Gamma knife (7) Traditional Chinese medical herbal treatment
pancreatic primary sarcoma) merge to form a single tumor, is highly unlikely. In contrast, a metaplastic transformation in a process called epithelial-mesenchymal transition (EMT) is observed in many pancreatic carcinomas and is associated with decreased survival and chemoresistance.42–46 While EMTwas initially considered a process of cell plasticity in development and disease involving a single binary decision between epithelial and mesenchymal phenotype, more recently it has become evident that EMT is a complex program with multiple transition phases and intermediary states between the full epithelial and mesenchymal phenotypes.47,48 In this light, pancreatic sarcomatoid carcinomas could be considered as intermediate but stabilized-stage, partial-EMT tumors, having acquired some mesenchymal properties while still demonstrating epithelial traits. Pancreatic carcinosarcomas, especially those with assumedly monoclonal origin, would harbor a component that dedifferentiated from the initial, and still present, carcinoma via a more complete EMT into a tumor with (exclusively) mesenchymal characteristics, to form a dual malignancy. Simple (immuno)histological diagnosis and subtyping of tumors with occasional selective genetic analyses are still the mainstay of daily clinical practice. However, with the advent of global gene expression and genomic analyses, subtyping of PDAC is gaining complexity. Recently, 3 groups have suggested transcriptomics-/genomics-based subtypes of PDAC and have linked them to patients' prognosis49–52: The dedifferentiated, mesenchymal-like, EMT-associated subtypes of Collisson et al49 (quasi-mesenchymal subtype), Moffitt et al51 (basal-like subtype), and Bailey et al52 (squamous subtype) all display a worse prognosis compared with their more epithelial or classic counterparts. On a histological level, these subtypes might appear as undifferentiated/ anaplastic carcinomas, some probably as sarcomatoid carcinomas or carcinosarcomas. Outcome after resection of undifferentiated, anaplastic pancreatic cancer has been described to be at least equal to,53,54 if not worse than for55, differentiated classic PDAC. Furthermore, the most frequent type of carcinosarcoma, UCS, is a far more aggressive tumor than high-grade endometrial carcinoma. In most cases, UCS presents with metastatic disease at www.pancreasjournal.com
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the time of diagnosis. Despite surgery and adjuvant chemotherapy, recurrence rates are high, and prognosis is poor.4 The vast majority of carcinosarcoma cases discussed here receiving adjuvant/additive chemotherapy were treated with gemcitabine. Given the very low incidence of this malignancy, no evidence exists for a treatment recommendation in a first-line or adjuvant/additive therapy setting. Considering the fact discussed here that pancreatic carcinosarcomas are most likely combination or conversion tumors (PDACs with a dedifferentiated component) and that according to Collisson et al49 quasi-mesenchymal–like subtypes are even more sensitive to gemcitabine, currently a treatment strategy similar to PDAC seems reasonable. This implicates, if feasible, a resection with subsequent adjuvant chemotherapy with gemcitabine. However, EMT and dedifferentiation have also been linked to chemoresistance.43,46 Clearly, more research and evidence are essential for improvement of therapeutic approaches for this rare and aggressive malignancy.
15. Bloomston M, Chanona-Vilchis J, Ellison EC, et al. Carcinosarcoma of the pancreas arising in a mucinous cystic neoplasm. Am Surg. 2006;72: 351–355. 16. Gelos M, Behringer D, Philippou S, et al. Pancreatic carcinosarcoma. Case report of multimodal therapy and review of the literature. JOP. 2008;9:50–55. 17. Nakano T, Sonobe H, Usui T, et al. Immunohistochemistry and K-ras sequence of pancreatic carcinosarcoma. Pathol Int. 2008;58:672–677. 18. Shen ZL, Wang S, Ye YJ, et al. Carcinosarcoma of pancreas with liver metastasis combined with gastrointestinal stromal tumour of the stomach: is there a good prognosis with the complete resection? Eur J Cancer Care (Engl). 2010;19:118–123. 19. Okamura J, Sekine S, Nara S, et al. Intraductal carcinosarcoma with a heterologous mesenchymal component originating in intraductal papillary-mucinous carcinoma (IPMC) of the pancreas with both carcinoma and osteosarcoma cells arising from IPMC cells. J Clin Pathol. 2010;63:266–269.
1. McCluggage WG. Malignant biphasic uterine tumours: carcinosarcomas or metaplastic carcinomas? J Clin Pathol. 2002;55:321–325.
20. Kim H, Joo SH, Yang DM, et al. Carcinosarcoma of the pancreas: a unique case with emphasis on metaplastic transformation and the presence of undifferentiated pleomorphic high-grade sarcoma. J Gastrointestin Liver Dis. 2011;20:197–200.
2. Thompson L, Chang B, Barsky SH. Monoclonal origins of malignant mixed tumors (carcinosarcomas). Evidence for a divergent histogenesis. Am J Surg Pathol. 1996;20:277–285.
21. Palaniappan M, Jose W, Bindhu MR, et al. Carcinosarcoma of the pancreas: report of a case with a concise review of the literature. J Clin Diagn Res. 2011;5:621–624.
3. Wada H, Enomoto T, Fujita M, et al. Molecular evidence that most but not all carcinosarcomas of the uterus are combination tumors. Cancer Res. 1997;57:5379–5385.
22. Zhu WY, Liu TG, Zhu H. Long-term recurrence-free survival in a patient with pancreatic carcinosarcoma: a case report with a literature review. Med Oncol. 2012;29:140–143.
4. Cantrell LA, Blank SV, Duska LR. Uterine carcinosarcoma: a review of the literature. Gynecol Oncol. 2015;137:581–588.
23. Oymaci E, Argon A, Coşkun A, et al. Pancreatic carcinosarcoma: case report of a rare type of pancreatic neoplasia. JOP. 2013;14:212–215.
5. Wick MR, Swanson PE. Carcinosarcomas: current perspectives and an historical review of nosological concepts. Semin Diagn Pathol. 1993;10: 118–127.
24. Yao J, Qian JJ, Zhu CR, et al. Laparoscopic left pancreatectomy for pancreatic sarcomatoid carcinoma: a case report and review of the literature. Oncol Lett. 2013;6:568–570.
6. Bosman F, Carneiro F, Hruban R, et al Ductal adenocarcinoma variants and mixed neoplasms of the pancreas. In: World Health Organization Classification of Tumours of the Digestive System. 4th ed. Lyon, France: IARC Press; 2010:292–295.
25. Shi HY, Xie J, Miao F. Pancreatic carcinosarcoma: first literature report on computed tomography imaging. World J Gastroenterol. 2015;21: 1357–1361.
REFERENCES
7. Higashi M, Takao S, Sato E. Sarcomatoid carcinoma of the pancreas: a case report with immunohistochemical study. Pathol Int. 1999;49: 453–456. 8. Ren CL, Jin P, Han CX, et al. Unusual early-stage pancreatic sarcomatoid carcinoma. World J Gastroenterol. 2013;19:7820–7824. 9. Lu BC, Wang C, Yu JH, et al. A huge adenosquamous carcinoma of the pancreas with sarcomatoid change: an unusual case report. World J Gastroenterol. 2014;20:16381–16386. 10. Kane JR, Laskin WB, Matkowskyj KA, et al. Sarcomatoid (spindle cell) carcinoma of the pancreas: a case report and review of the literature. Oncol Lett. 2014;7:245–249. 11. 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: 132–137. 12. 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;21:70–80.
26. Katsourakis A, Svoronos C, Chatzitheoklitos E, et al. Carcinosarcoma of the pancreas: how a common blood disorder can hide an extremely rare tumour. JOP. 2015;16:310–312. 27. Bai Q, Zhang X, Zhu X, et al. Pancreatic carcinosarcoma with the same KRAS gene mutation in both carcinomatous and sarcomatous components: molecular evidence for monoclonal origin of the tumour. Histopathology. 2016;69:393–405. 28. Watanabe M, Miura H, Inoue H, et al. Mixed osteoclastic/pleomorphic-type giant cell tumor of the pancreas with ductal adenocarcinoma: histochemical and immunohistochemical study with review of the literature. Pancreas. 1997;15:201–208. 29. Barkatullah SA, Deziel DJ, Jakate SM, et al. Pancreatic carcinosarcoma with unique triphasic histological pattern. Pancreas. 2005;31:291–292. 30. Kim HS, Kim JI, Jeong M, et al. Pancreatic adenocarcinosarcoma of monoclonal origin: a case report. World J Gastroenterol. 2014;20: 12682–12686. 31. Yamazaki K. A unique pancreatic ductal adenocarcinoma with carcinosarcomatous histology, immunohistochemical distribution of hCG-beta, and the elevation of serum alpha-feto-protein. J Submicrosc Cytol Pathol. 2003;35:343–349.
13. 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;13:86–91.
32. Lee J, Hyun JJ, Lee HS. A rare cause of abdominal pain by pancreatic mass in a young female patient. carcinosarcoma of the pancreas. Gastroenterology. 2015;149:e3–e5.
14. 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;126:1114–1117.
33. Posen JA. Giant cell tumor of the pancreas of the osteoclastic type associated with a mucous secreting cystadenocarcinoma. Hum Pathol. 1981;12:944–947.
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Pancreas • Volume 46, Number 9, October 2017
Report of a Rare Pancreatic Carcinosarcoma
34. Trepeta RW, Mathur B, Lagin S, et al. Giant cell tumor (“osteoclastoma”) of the pancreas: a tumor of epithelial origin. Cancer. 1981;48: 2022–2028.
45. Takahashi K, Hisaka T, Horiuchi H, et al. Neoplastic spindle cells are an independent prognostic factor in pancreatic cancer. Pancreas. 2015;44: 742–749.
35. Fischer HP, Altmannsberger M, Kracht J. Osteoclast-type giant cell tumour of the pancreas. Virchows Arch A Pathol Anat Histopathol. 1988;412: 247–253.
46. Zheng X, Carstens JL, Kim J, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015;527:525–530.
36. Tsujimura T, Kawano K, Taniguchi M, et al. Malignant fibrous histiocytoma coexistent with mucinous cystadenoma of the pancreas. Cancer. 1992;70:2792–2796.
47. Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7:415–428.
37. Wayne M, Gur D, Ascunce G, et al. Pancreatic mucinous cystic neoplasm with sarcomatous stroma metastasizing to liver: a case report and review of literature. World J Surg Oncol. 2013;11:100.
48. Nieto MA, Huang RY, Jackson RA, et al. EMT: 2016. Cell. 2016;166: 21–45.
38. Kim JY, Song JS, Park H, et al. Primary mesenchymal tumors of the pancreas: single-center experience over 16 years. Pancreas. 2014;43: 959–968. 39. Zhang H, Jensen MH, Farnell MB, et al. Primary leiomyosarcoma of the pancreas: study of 9 cases and review of literature. Am J Surg Pathol. 2010; 34:1849–1856. 40. Xu J, Zhang T, Wang T, et al. Clinical characteristics and prognosis of primary leiomyosarcoma of the pancreas: a systematic review. World J Surg Oncol. 2013;11:290. 41. Machado MC, Fonseca GM, de Meirelles LR, et al. Primary liposarcoma of the pancreas: a review illustrated by findings from a recent case. Pancreatology. 2016;16:715–718. 42. Hotz B, Arndt M, Dullat S, et al. Epithelial to mesenchymal transition: expression of the regulators snail, slug, and twist in pancreatic cancer. Clin Cancer Res. 2007;13:4769–4776. 43. Arumugam T, Ramachandran V, Fournier KF, et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 2009;69:5820–5828. 44. Rhim AD, Mirek ET, Aiello NM, et al. EMT and dissemination precede pancreatic tumor formation. Cell. 2012;148:349–361.
© 2017 Wolters Kluwer Health, Inc. All rights reserved.
49. Collisson EA, Sadanandam A, Olson P, et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med. 2011; 17:500–503. 50. Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518: 495–501. 51. Moffitt RA, Marayati R, Flate EL, et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet. 2015;47:1168–1178. 52. Bailey P, Chang DK, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531:47–52. 53. Paniccia A, Hosokawa PW, Schulick RD, et al. A matched-cohort analysis of 192 pancreatic anaplastic carcinomas and 960 pancreatic adenocarcinomas: a 13-year North American experience using the National Cancer Data Base (NCDB). Surgery. 2016;160: 281–292. 54. Clark CJ, Arun JS, Graham RP, et al. Clinical characteristics and overall survival in patients with anaplastic pancreatic cancer. Am Surg. 2014;80: 117–123. 55. Strobel O, Hartwig W, Bergmann F, et al. Anaplastic pancreatic cancer: presentation, surgical management, and outcome. Surgery. 2011;149: 200–208.
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