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Synchronous pancreatic adenocarcinoma and intrahepatic cholangiocarcinoma arising in the context of intraductal papillary neoplasms
Clinical Imaging 40 (2016) 897–901
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: http://www.clinicalimaging.org
Synchronous pancreatic adenocarcinoma and intrahepatic cholangiocarcinoma arising in the context of intraductal papillary neoplasms Anmol Bansal a, Swan N. Thung b, Hongfa Zhu b, Myron Schwartz c, Sara Lewis a,⁎ a b c
Department of Radiology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029 The Lillian and Henry Stratton—Hans Popper Department of Pathology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029 Department of Surgery, RMTI Liver Surgery Program, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029
a r t i c l e
i n f o
Article history: Received 5 October 2015 Accepted 4 December 2015 Available online xxxx Keywords: Intraductal papillary mucinous neoplasm of pancreas Intraductal papillary neoplasm of the bile duct Cholangiocarcinoma Pancreatic adenocarcinoma Synchronous
a b s t r a c t Field cancerization theory provides rationale for the development of multiple pancreatic ductal and biliary lesions in a single patient through the development and accumulation of multiple genetic changes. Genetic alterations result in the development of precursor lesions including intraductal papillary mucinous neoplasms of the pancreas (IPMN), intraductal papillary neoplasm of the bile duct (IPN-B), and their malignant counterparts, pancreatic adenocarcinoma and cholangiocarcinoma. Although IPMN are frequently encountered, IPN-B are uncommon and the synchronous occurrence of both lesions is rare. We present a case of synchronous pancreatic adenocarcinoma and intrahepatic cholangiocarcinoma with histopathologic evidence of underlying precursor lesions, IPMN-P and IPN-B. © 2016 Elsevier Inc. All rights reserved.
1. Clinical and laboratory assessment A 70-year-old male presented to a gastroenterologist with a 1-month history of gas discomfort in the mid-abdominal region, flatulence, and eructation. Past medical history was significant for a recent diagnosis of type-2 diabetes. Past surgical history was positive for partial thyroidectomy more than 20 years prior. Social history revealed the patient to be a former smoker with a 50-pack-year smoking history. Physical examination was unremarkable. A borderline low hemoglobin level (13.5 g/dl) was identified. The remainder of the complete blood count and basic metabolic panel were normal. Notably, the following laboratory values were elevated (reference range): carcinoembryonic antigen, 3.5 ng/ml (0–3); chromogranin A, 183 ng/ml (0–95); C-reactive protein, 29.4 mg/l (0–5); erythrocyte sedimentation rate, 40 mm/h (0–15); gamma GT, 180 U/l (10–54); and CA, 19–9622.8 U/ml (0–35). 2. Imaging assessment An abdominal ultrasound performed at an outside institution was significant for a hypoechoic mass in region of pancreatic head measuring 3.7 cm × 3.1 cm × 3.0 cm. A hypoechoic mass within the right lobe of the liver measuring 4.5 cm×4.9 cm×4.8 cm was also seen. ⁎ Corresponding author. Icahn School of Medicine at Mount Sinai, Department of Radiology, One Gustave Levy Place, New York, NY 10029, USA. E-mail address: [email protected] (S. Lewis). http://dx.doi.org/10.1016/j.clinimag.2015.12.019 0899-7071/© 2016 Elsevier Inc. All rights reserved.
The lesions in the pancreas and liver were concerning for malignancy and the patient was referred for further characterization with crosssectional imaging. The MRI examination was performed on a 1.5-T Siemens Avanto (Siemens Healthcare, Malvern, PA, USA) using a torso phased array coil. The imaging protocol included coronal and axial HASTE, GRE T1weighted in and out of phase imaging, and precontrast and postcontrast enhanced T1 WI using axial breath-hold 3D T1 fat-suppressed spoiled gradient recalled echo sequence (VIBE). Postcontrast was performed following the dynamic intravenous injection of 20 ml gadoliniumbased contrast agent using 4 time points: late arterial, portal venous, equilibrium, and late venous phases (5 min following contrast injection). Gadoversetamide 20 ml was administered (Optimark, Mallinkrodt Pharmaceuticals, Dublin, Ireland). Fluoroscopic bolus tracking technique was used. A 2.3 cm×2.8 cm T2 hyperintense, T1 hypointense mass was identified in the head of the pancreas. There was distention of the pancreatic duct in the body and tail of pancreas, measuring up to 6 mm. The common bile duct was not dilated. The remaining pancreas was atrophic. The pancreatic mass was noted to abut the portal vein at its origin and less than 180° of abutment of the superior mesenteric vein. There was no evidence of portal vein, superior mesenteric vein, or splenic vein thrombosis. The fat plane surrounding the SMA was preserved. The pancreatic mass demonstrated hypovascular enhancement following contrast administration, with mild peripheral enhancement noted on late venous phase images (Fig. 1).
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Fig. 1. Axial MRI images from axial HASTE (A) and dynamic breath-hold VIBE images with fat saturation were obtained following the administration of intravenous contrast (20 ml gadoversetamide). The 2.8-cm pancreatic head mass (solid arrow) demonstrates T2 hyperintensity (A) and hypovascular enhancement on arterial (B) and portal venous phase (C) with minimal peripheral enhancement on late venous phase images (D). The mass demonstrates less than 180° of abutment of the patent superior mesenteric vein (dashed arrow). The superior mesenteric artery is patient and uninvolved.
A 5.0 cm×4.2 cm T2 hyperintense, T1 hypointense mass with lobulated margins was identified in segment 6 of the liver (Fig. 2). There was mild biliary distention in segments 6 and 7 peripheral to the mass. No fat or hemorrhage was detected within the lesion. No capsular retraction was present. No satellite lesion was identified. The right posterior portal vein branch abutted the mass, but without evidence for invasion or tumor thrombus. The lesion demonstrated mild continuous peripheral enhancement on arterial phase images with progressive rim enhancement on equilibrium and late venous phase images. Enhancing peripancreatic lymph nodes measuring up to 11 mm were identified. 3. Pathologic assessment Three weeks after the MRI examination, the patient underwent an upper endoscopy that confirmed the presence of a mass in the head of the pancreas. Fine-needle aspiration of this mass revealed adenocarcinoma. The patient also underwent CT-guided biopsy of the right hepatic mass that revealed poorly differentiated malignant neoplasm. Tumor cells were arranged in large groups and often showed marked nuclear pleomorphism and occasional tumor giant cells. Prominent cherry-red nucleoli were seen; the cytoplasm was amphophilic and dense. Degenerative changes and tumor necrosis were present. The uninvolved liver showed chronic portal inflammation, periportal fibrosis, and changes reflecting the vicinity of a space-occupying lesion. Immunostains were positive for CK7, CEA, p63, and CDX2 and negative for CK20, CD56, chromogranin, and S100. The immunohistochemical patterns combined with the morphological features were consistent with carcinoma with both glandular and squamous features. Approximately 3 weeks following the EUS on CT-guided liver biopsy, the patient underwent successful pylorus—preserving total pancreatectomy,
splenectomy, and resection of liver segments 6 and 7. Pathology showed a poorly differentiated pancreatic adenocarcinoma that extensively involved the pancreatic head, body, and tail (Fig. 3A). The main pancreatic duct also showed extensive carcinoma in situ with micropapillary features (Fig. 3B). Three of nine lymph nodes were positive for metastatic carcinoma. Pathology of the resected liver tumor demonstrated a 6.3-cm poorly differentiated adenocarcinoma with squamoid features (Fig. 4A). Focally, the tumor was papillary and glandular (Fig. 4B). Tumor extended along lymphovascular channels in portal tracts and invaded perineural spaces. Tumor cells with squamoid features and p63 reactivity were also observed lining a large bile duct with invasion into its surrounding stroma (Fig. 4C–E). 4. Discussion We demonstrate here a case of synchronous pancreatic adenocarcinoma and intrahepatic cholangiocarcinoma (ICC) arising in the context of IPN-B and IPMN-P, respectively. We believe that this is the first case of such an entity described in the radiology literature. Pancreatic adenocarcinoma and ICC are both highly malignant tumors and, as we have shown in our case, may not present with symptoms early in the disease course. The pathologic finding of the presence of dilated ducts with micropapillary and squamoid features within the tumors indicates that each of the malignant tumors arose from underlying corresponding precursor lesions (IPMN-P and IPN-B). At initial histopathologic examination, pancreatic adenocarcinoma and ICC may have similar appearance [1], and immunohistochemical analysis was essential in this case in making the distinction between these solid neoplasms. A relatively new thought emerging in the pathology and hepatology literature is the concept of biliary disease with a pancreatic counterpart
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Fig. 2. Axial MRI images from axial HASTE (A) and dynamic breath-hold VIBE images with fat saturation were obtained following the administration of intravenous contrast (20 ml gadoversetamide). A 5.0-cm segment 6 liver lesion (solid arrow) demonstrates mild heterogeneous T2 hyperintensity (A), peripheral mild continuous arterial phase rim enhancement (B) with persistent enhancement on venous phase, (C) and late venous phase images (D). Minimal enhancement of the central portion of the tumor is present on late venous phase images. Pancreatic ductal distention and parenchymal atrophy are also noted (dashed arrow), secondary to the pancreatic head mass (data not shown).
[2–4]. The concept suggests that biliary tumors including cholangiocarcinoma and its precursor lesions (including IPN-B) have a pancreatic counterpart including pancreatic adenocarcinoma and its precursor lesions (including IPMN-P). Biliary papillary neoplasms and precursor lesions are not well described in the literature, whereas the imaging and histopathologic characteristics of intraductal papillary mucinous neoplasm of the pancreas (IPMN-P) are well established. The synchronous occurrence of IPMN and IPN-B is also exceedingly rare. The first such case was described in 2000 [5], and since then, only less than 10 cases have been reported in the literature [6–12]. Of note and relevant to this case, the reported risk of malignant transformation of IPMN is
directly related to its site of origin within the ductal system with a risk of progression of 60–92% for main duct IPMN and 6–40% for branch duct IPMN [13–16]. Similarly, IPN-B lesions have a high risk of malignant transformation to invasive cholangiocarcinoma, which can develop in up to 83% of cases [17]. IPN-B resembles IPMN, characterized by the intraductal proliferation of papillary epithelium, ductal distention, and varying degrees of mucin production, both at pathology and imaging [11,18,19]. The concept of field cancerization has been proposed as a possible explanation for the synchronous appearance of IPMN and IPN-B involving the pancreas and liver, respectively. Field cancerization, introduced
Fig. 3. Adenocarcinoma of pancreas with areas of poorly differentiated adenocarcinoma (A. H&E, ×100) (solid white arrow) and main pancreatic duct with micropapillary features and carcinoma in situ and focal invasive areas (B. H&E, ×100) (dashed white arrow).
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Fig. 4. ICC with focal squamous features (A. H&E, ×200) and papillary areas (B. H&E, ×100) (solid white arrow in B). Tumor cells line large bile duct and invade the area around it (C. H&E, ×200) (white dashed arrow). The tumor cells are positive for CK7 (D. Immunostain, ×40) (black solid arrow) and p63 (E. Immunostain, ×200) (black dashed arrow).
by Slaughter et al. in 1953, is defined as presence of one or more mucosal areas consisting of epithelial cells that have cancer-associated genetic or epigenetic alterations [20,21] and has been utilized to explain the occurrence of multiple primary tumors [22]. Multiple lesions of IPMN, containing a variety of multiple and distinct genetic mutations within the ductal epithelium of a single pancreas, have been found to be consistent with the concept of field cancerization [23]. More recently, it has been proposed that, due to the common embryologic origin of the pancreatic and bile ducts [10,11], both the pancreas and the biliary tree may be affected. This description is highly relevant, as the concept of a possible relationship or common origin of biliary and pancreatic tumors and similarity at pathology is prompting further investigation and consideration, and possibly revision, to the current classification scheme of cholangiocarcinoma [24]. In addition, it remains to be determined whether awareness of this relationship should prompt careful assessment of pancreaticobiliary systems in patients with established precursor lesions. Contrast-enhanced CT and MRI are the established techniques for detecting and characterizing pancreatic and liver masses. The tumors in our case demonstrated the typical imaging characteristics of pancreatic adenocarcinoma and ICC. Arising from the pancreatic ductal epithelium, most pancreatic adenocarcinoma tumors occur in the head of the pancreas. Pancreatic adenocarcinomas tend to appear as poorly defined hypovascular masses at cross-sectional imaging [25]. Tumors arising in the pancreatic head tumors typically cause distention of both the pancreatic duct and common bile duct, termed the “double duct sign”. Atrophy of the distal pancreatic parenchyma is a common secondary finding due to chronic ductal obstruction. Signs of vascular invasion include arterial or venous occlusion, tumor abutment or encasement N180° around the vessels, loss of the fat plane separating the tumor from the vessel, and deformity or abnormal vessel contour or the development of collateral vessels [25,26]. ICC is typically a homogeneous solid mass with an irregular contour. Satellite nodules, peripheral biliary distention, overlying liver capsular retraction, and vascular encasement and/or occlusion are common secondary findings [27]. ICC is a highly desmoplastic tumor and contains variable amounts of fibrosis, necrosis, or mucin [28]. The interesting and complex composition of ICC at
pathology translates to the appearance at imaging. Variable enhancement patterns of ICC have been described at CT and MRI, and the most typical pattern is early, concentric rim enhancement with progressive peripheral or whole lesion enhancement on dynamic imaging. Other enhancement patterns include solid hypervascular enhancement with either persistent enhancement or washout occur less commonly. The central fibrosis within the lesions can be identified as areas of T2 hypointensity and delayed enhancement (1–4 h) after contrast administration on MRI [27–29]. The patient was felt to be a good surgical candidate and both the tumors met criteria for resectability based on imaging: the liver lesion was a solitary mass without satellite lesions and vascular or biliary invasion, and the pancreatic mass did not demonstrate vascular invasion or invasion of adjacent organs. Distant metastasis was not identified in this patient either. For both malignancies, surgical therapy is the only option to achieve cure [25,30]. The differential diagnosis at the time of presentation included primary pancreatic adenocarcinoma with large liver metastasis or synchronous cholangiocarcinoma and pancreatic adenocarcinoma. Pancreatic adenocarcinoma metastases to the liver are most commonly small and multiple. The presence of a single, dominant metastasis to the liver would have been a very unusual finding [31]. The patient thus underwent successful surgical resection of both lesions. In summary, there is increasing recognition of the concept that biliary disease has a pancreatic counterpart. The theory of field cancerization, suggesting that cancer associated or epigenetic alterations occur in the pancreaticobiliary ductal epithelial system, has been described to explain the development of multiple pancreatic or biliary precursor lesions, such as IPMN and IPN-B, respectively. These precursor lesions have significant potential to develop into invasive malignancy. We present a rare case of synchronous pancreatic adenocarcinoma and ICC with pathologic evidence supporting the presence of tumor arising from underlying precursor lesions, IPMN and IPN-B, respectively. Further work is necessary to elucidate genetic alterations that may predispose to the development of pancreaticobiliary precursor lesions and invasive malignancy and to determine the clinical implications for patients with established precursor lesions.
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References [1] Lok T, Chen L, Lin F, HL W. Immunohistochemical distinction between intrahepatic cholangiocarcinoma and pancreatic ductal adenocarcinoma. Hum Pathol 2014; 45(2):394–400. [2] Nakanuma Y. A novel approach to biliary tract pathology based on similarities to pancreatic counterparts: is the biliary tract an incomplete pancreas? Pathol Int 2010;60(6):419–29. [3] Nakanuma Y, Harada K, Sasaki M, Sato Y. Proposal of a new disease concept "biliary diseases with pancreatic counterparts". Anatomical and pathological bases. Histol Histopathol 2014;29(1):1–10. [4] Zen Y, Fujii T, Itatsu K, Nakamura K, Minato H, Kasashima S, et al. Biliary papillary tumors share pathological features with intraductal papillary mucinous neoplasm of the pancreas. Hepatology 2006;44(5):1333–43. [5] Joo YH, Kim MH, Lee SK, Seo DW, Yoo KS, Min YI, et al. A case of mucinhypersecreting intrahepatic bile duct tumor associated with pancreatic intraductal papillary mucinous tumor. Gastrointest Endosc 2000;52(3):409–12. [6] Ishida M, Seki K, Honda K, Kimura T, Katayama K, Hirose K, et al. Intraductal mucinous tumors occurring simultaneously in the liver and pancreas. J Gastroenterol 2002;37(12):1073–8. [7] Moon DB, Lee SG, Jung DH, Park GC, Park YH, Park HW, et al. Synchronous malignant intraductal papillary mucinous neoplasms of the bile duct and pancreas requiring left hepatectomy and total pancreatectomy. Korean J Gastroenterol 2014;63(2):129–33. [8] Park BH, Suh JH, Cha HJ, Kim YM, Choi HJ. Intraductal papillary mucinous tumor simultaneously involving the liver and pancreas—a case report. Korean J Pathol 2010;44:83–6. [9] Valente R, Capurso G, Pierantognetti P, Iannicelli E, Piciucchi M, Romiti A, et al. Simultaneous intraductal papillary neoplasms of the bile duct and pancreas treated with chemoradiotherapy. World J Gastrointest Oncol 2012;4(2):22–5. [10] Xu XW, Li RH, Zhou W, Wang J, Zhang RC, Chen K, et al. Laparoscopic resection of synchronous intraductal papillary mucinous neoplasms: a case report. World J Gastroenterol 2012;18(44):6510–4. [11] Yamaguchi Y, Abe N, Imase K, Mizuno H, Chinen K, Mori H, et al. A case of mucin hypersecreting intraductal papillary carcinomas occurring simultaneously in liver and pancreas. Gastrointest Endosc 2005;61(2):330–4. [12] Zalinski S, Paradis V, Valla D, Belghiti J. Intraductal papillary mucinous tumors of both biliary and pancreatic ducts. J Hepatol 2007;46(5):978–9. [13] Castelli F, Bosetti D, Negrelli R, Di Paola V, Zantedeschi L, Ventriglia A, et al. Multifocal branch-duct intraductal papillary mucinous neoplasms (IPMNs) of the pancreas: magnetic resonance (MR) imaging pattern and evolution over time. Radiol Med 2013;118(6):917–29. [14] Levy P, Jouannaud V, O’Toole D, Couvelard A, Vullierme MP, Palazzo L, et al. Natural history of intraductal papillary mucinous tumors of the pancreas: actuarial risk of malignancy. Clin Gastroenterol Hepatol 2006;4(4):460–8. [15] Salvia R, Crippa S, Partelli S, Armatura G, Malleo G, Paini M, et al. Differences between main-duct and branch-duct intraductal papillary mucinous neoplasms of the pancreas. World J Gastrointest Surg 2010;2(10):342–6.
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[16] Tanaka M, Chari S, Adsay V, Fernandez-del Castillo C, Falconi M, Shimizu M, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2006; 6(1–2):17–32. [17] Lee SS, Kim MH, Lee SK, Jang SJ, Song MH, Kim KP, et al. Clinicopathologic review of 58 patients with biliary papillomatosis. Cancer 2004;100(4):783–93. [18] Wan XS, Xu YY, Qian JY, Yang XB, Wang AQ, He L, et al. Intraductal papillary neoplasm of the bile duct. World J Gastroenterol 2013;19(46):8595–604. [19] Gupta R, Mortelé KJ, Tatli S, Girshman J, Glickman JN, Levy AD, et al. Pancreatic intraductal papillary mucinous neoplasms: role of CT in predicting pathologic subtypes. AJR Am J Roentgenol 2008;191(5):1458–64. [20] Leemans CR, Braakhuis BJ, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer 2011;11(1):9–22. [21] Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953; 6(5):963–8. [22] Braakhuis BJ, Tabor MP, Kummer JA, Leemans CR, Brakenhoff RH. A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications. Cancer Res 2003;63(8):1727–30. [23] Izawa T, Obara T, Tanno S, Mizukami Y, Yanagawa N, Kohgo Y. Clonality and field cancerization in intraductal papillary-mucinous tumors of the pancreas. Cancer 2001;92(7):1807–17. [24] Nakanuma Y, Kakuda Y. Pathologic classification of cholangiocarcinoma: new concepts. Best Pract Res Clin Gastroenterol 2015;29(2):277–93. [25] Low G, Pano A, Millo N, Leen E. Multimodality imaging of neoplastic and nonneoplastic solid lesions of the pancreas. Radiographics 2011;31(4): 993–1015. [26] Soriano A, Castells A, Ayuso C, Ayuso JR, de Caralt MT, Ginès MA, et al. Preoperative staging and tumor resectability assessment of pancreatic cancer: prospective study comparing endoscopic ultrasonography, helical computed tomography, magnetic resonance imaging, and angiography. Am J Gastroenterol 2004;99(3):492–501. [27] Chung YE, Kim MJ, Park YN, Choi JY, Pyo JY, Kim YC, et al. Varying appearances of cholangiocarcinoma: radiologic-pathologic correlation. Radiographics 2009;29(3): 683–700. [28] Maetani Y, Itoh K, Watanabe C, Shibata T, Ametani F, Yamabe H, et al. MR imaging of intrahepatic cholangiocarcinoma with pathologic correlation. AJR Am J Roentgenol 2001;176(6):1499–507. [29] Gabata T, Matsui O, Kadoya M, Yoshikawa J, Ueda K, Kawamori Y, et al. Delayed MR imaging of the liver: correlation of delayed enhancement of hepatic tumors and pathologic appearance. Abdom Imaging 1998;23(3):309–13. [30] Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet 2014;383(9935):2168–79. [31] Gabata T, Matsui O, Terayama N, Kobayashi S, Sanada J. Imaging diagnosis of hepatic metastases of pancreatic carcinomas: significance of transient wedge-shaped contrast enhancement mimicking arterioportal shunt. Abdom Imaging 2008; 33(4):437–43.
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: http://www.clinicalimaging.org
Synchronous pancreatic adenocarcinoma and intrahepatic cholangiocarcinoma arising in the context of intraductal papillary neoplasms Anmol Bansal a, Swan N. Thung b, Hongfa Zhu b, Myron Schwartz c, Sara Lewis a,⁎ a b c
Department of Radiology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029 The Lillian and Henry Stratton—Hans Popper Department of Pathology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029 Department of Surgery, RMTI Liver Surgery Program, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029
a r t i c l e
i n f o
Article history: Received 5 October 2015 Accepted 4 December 2015 Available online xxxx Keywords: Intraductal papillary mucinous neoplasm of pancreas Intraductal papillary neoplasm of the bile duct Cholangiocarcinoma Pancreatic adenocarcinoma Synchronous
a b s t r a c t Field cancerization theory provides rationale for the development of multiple pancreatic ductal and biliary lesions in a single patient through the development and accumulation of multiple genetic changes. Genetic alterations result in the development of precursor lesions including intraductal papillary mucinous neoplasms of the pancreas (IPMN), intraductal papillary neoplasm of the bile duct (IPN-B), and their malignant counterparts, pancreatic adenocarcinoma and cholangiocarcinoma. Although IPMN are frequently encountered, IPN-B are uncommon and the synchronous occurrence of both lesions is rare. We present a case of synchronous pancreatic adenocarcinoma and intrahepatic cholangiocarcinoma with histopathologic evidence of underlying precursor lesions, IPMN-P and IPN-B. © 2016 Elsevier Inc. All rights reserved.
1. Clinical and laboratory assessment A 70-year-old male presented to a gastroenterologist with a 1-month history of gas discomfort in the mid-abdominal region, flatulence, and eructation. Past medical history was significant for a recent diagnosis of type-2 diabetes. Past surgical history was positive for partial thyroidectomy more than 20 years prior. Social history revealed the patient to be a former smoker with a 50-pack-year smoking history. Physical examination was unremarkable. A borderline low hemoglobin level (13.5 g/dl) was identified. The remainder of the complete blood count and basic metabolic panel were normal. Notably, the following laboratory values were elevated (reference range): carcinoembryonic antigen, 3.5 ng/ml (0–3); chromogranin A, 183 ng/ml (0–95); C-reactive protein, 29.4 mg/l (0–5); erythrocyte sedimentation rate, 40 mm/h (0–15); gamma GT, 180 U/l (10–54); and CA, 19–9622.8 U/ml (0–35). 2. Imaging assessment An abdominal ultrasound performed at an outside institution was significant for a hypoechoic mass in region of pancreatic head measuring 3.7 cm × 3.1 cm × 3.0 cm. A hypoechoic mass within the right lobe of the liver measuring 4.5 cm×4.9 cm×4.8 cm was also seen. ⁎ Corresponding author. Icahn School of Medicine at Mount Sinai, Department of Radiology, One Gustave Levy Place, New York, NY 10029, USA. E-mail address: [email protected] (S. Lewis). http://dx.doi.org/10.1016/j.clinimag.2015.12.019 0899-7071/© 2016 Elsevier Inc. All rights reserved.
The lesions in the pancreas and liver were concerning for malignancy and the patient was referred for further characterization with crosssectional imaging. The MRI examination was performed on a 1.5-T Siemens Avanto (Siemens Healthcare, Malvern, PA, USA) using a torso phased array coil. The imaging protocol included coronal and axial HASTE, GRE T1weighted in and out of phase imaging, and precontrast and postcontrast enhanced T1 WI using axial breath-hold 3D T1 fat-suppressed spoiled gradient recalled echo sequence (VIBE). Postcontrast was performed following the dynamic intravenous injection of 20 ml gadoliniumbased contrast agent using 4 time points: late arterial, portal venous, equilibrium, and late venous phases (5 min following contrast injection). Gadoversetamide 20 ml was administered (Optimark, Mallinkrodt Pharmaceuticals, Dublin, Ireland). Fluoroscopic bolus tracking technique was used. A 2.3 cm×2.8 cm T2 hyperintense, T1 hypointense mass was identified in the head of the pancreas. There was distention of the pancreatic duct in the body and tail of pancreas, measuring up to 6 mm. The common bile duct was not dilated. The remaining pancreas was atrophic. The pancreatic mass was noted to abut the portal vein at its origin and less than 180° of abutment of the superior mesenteric vein. There was no evidence of portal vein, superior mesenteric vein, or splenic vein thrombosis. The fat plane surrounding the SMA was preserved. The pancreatic mass demonstrated hypovascular enhancement following contrast administration, with mild peripheral enhancement noted on late venous phase images (Fig. 1).
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Fig. 1. Axial MRI images from axial HASTE (A) and dynamic breath-hold VIBE images with fat saturation were obtained following the administration of intravenous contrast (20 ml gadoversetamide). The 2.8-cm pancreatic head mass (solid arrow) demonstrates T2 hyperintensity (A) and hypovascular enhancement on arterial (B) and portal venous phase (C) with minimal peripheral enhancement on late venous phase images (D). The mass demonstrates less than 180° of abutment of the patent superior mesenteric vein (dashed arrow). The superior mesenteric artery is patient and uninvolved.
A 5.0 cm×4.2 cm T2 hyperintense, T1 hypointense mass with lobulated margins was identified in segment 6 of the liver (Fig. 2). There was mild biliary distention in segments 6 and 7 peripheral to the mass. No fat or hemorrhage was detected within the lesion. No capsular retraction was present. No satellite lesion was identified. The right posterior portal vein branch abutted the mass, but without evidence for invasion or tumor thrombus. The lesion demonstrated mild continuous peripheral enhancement on arterial phase images with progressive rim enhancement on equilibrium and late venous phase images. Enhancing peripancreatic lymph nodes measuring up to 11 mm were identified. 3. Pathologic assessment Three weeks after the MRI examination, the patient underwent an upper endoscopy that confirmed the presence of a mass in the head of the pancreas. Fine-needle aspiration of this mass revealed adenocarcinoma. The patient also underwent CT-guided biopsy of the right hepatic mass that revealed poorly differentiated malignant neoplasm. Tumor cells were arranged in large groups and often showed marked nuclear pleomorphism and occasional tumor giant cells. Prominent cherry-red nucleoli were seen; the cytoplasm was amphophilic and dense. Degenerative changes and tumor necrosis were present. The uninvolved liver showed chronic portal inflammation, periportal fibrosis, and changes reflecting the vicinity of a space-occupying lesion. Immunostains were positive for CK7, CEA, p63, and CDX2 and negative for CK20, CD56, chromogranin, and S100. The immunohistochemical patterns combined with the morphological features were consistent with carcinoma with both glandular and squamous features. Approximately 3 weeks following the EUS on CT-guided liver biopsy, the patient underwent successful pylorus—preserving total pancreatectomy,
splenectomy, and resection of liver segments 6 and 7. Pathology showed a poorly differentiated pancreatic adenocarcinoma that extensively involved the pancreatic head, body, and tail (Fig. 3A). The main pancreatic duct also showed extensive carcinoma in situ with micropapillary features (Fig. 3B). Three of nine lymph nodes were positive for metastatic carcinoma. Pathology of the resected liver tumor demonstrated a 6.3-cm poorly differentiated adenocarcinoma with squamoid features (Fig. 4A). Focally, the tumor was papillary and glandular (Fig. 4B). Tumor extended along lymphovascular channels in portal tracts and invaded perineural spaces. Tumor cells with squamoid features and p63 reactivity were also observed lining a large bile duct with invasion into its surrounding stroma (Fig. 4C–E). 4. Discussion We demonstrate here a case of synchronous pancreatic adenocarcinoma and intrahepatic cholangiocarcinoma (ICC) arising in the context of IPN-B and IPMN-P, respectively. We believe that this is the first case of such an entity described in the radiology literature. Pancreatic adenocarcinoma and ICC are both highly malignant tumors and, as we have shown in our case, may not present with symptoms early in the disease course. The pathologic finding of the presence of dilated ducts with micropapillary and squamoid features within the tumors indicates that each of the malignant tumors arose from underlying corresponding precursor lesions (IPMN-P and IPN-B). At initial histopathologic examination, pancreatic adenocarcinoma and ICC may have similar appearance [1], and immunohistochemical analysis was essential in this case in making the distinction between these solid neoplasms. A relatively new thought emerging in the pathology and hepatology literature is the concept of biliary disease with a pancreatic counterpart
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Fig. 2. Axial MRI images from axial HASTE (A) and dynamic breath-hold VIBE images with fat saturation were obtained following the administration of intravenous contrast (20 ml gadoversetamide). A 5.0-cm segment 6 liver lesion (solid arrow) demonstrates mild heterogeneous T2 hyperintensity (A), peripheral mild continuous arterial phase rim enhancement (B) with persistent enhancement on venous phase, (C) and late venous phase images (D). Minimal enhancement of the central portion of the tumor is present on late venous phase images. Pancreatic ductal distention and parenchymal atrophy are also noted (dashed arrow), secondary to the pancreatic head mass (data not shown).
[2–4]. The concept suggests that biliary tumors including cholangiocarcinoma and its precursor lesions (including IPN-B) have a pancreatic counterpart including pancreatic adenocarcinoma and its precursor lesions (including IPMN-P). Biliary papillary neoplasms and precursor lesions are not well described in the literature, whereas the imaging and histopathologic characteristics of intraductal papillary mucinous neoplasm of the pancreas (IPMN-P) are well established. The synchronous occurrence of IPMN and IPN-B is also exceedingly rare. The first such case was described in 2000 [5], and since then, only less than 10 cases have been reported in the literature [6–12]. Of note and relevant to this case, the reported risk of malignant transformation of IPMN is
directly related to its site of origin within the ductal system with a risk of progression of 60–92% for main duct IPMN and 6–40% for branch duct IPMN [13–16]. Similarly, IPN-B lesions have a high risk of malignant transformation to invasive cholangiocarcinoma, which can develop in up to 83% of cases [17]. IPN-B resembles IPMN, characterized by the intraductal proliferation of papillary epithelium, ductal distention, and varying degrees of mucin production, both at pathology and imaging [11,18,19]. The concept of field cancerization has been proposed as a possible explanation for the synchronous appearance of IPMN and IPN-B involving the pancreas and liver, respectively. Field cancerization, introduced
Fig. 3. Adenocarcinoma of pancreas with areas of poorly differentiated adenocarcinoma (A. H&E, ×100) (solid white arrow) and main pancreatic duct with micropapillary features and carcinoma in situ and focal invasive areas (B. H&E, ×100) (dashed white arrow).
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Fig. 4. ICC with focal squamous features (A. H&E, ×200) and papillary areas (B. H&E, ×100) (solid white arrow in B). Tumor cells line large bile duct and invade the area around it (C. H&E, ×200) (white dashed arrow). The tumor cells are positive for CK7 (D. Immunostain, ×40) (black solid arrow) and p63 (E. Immunostain, ×200) (black dashed arrow).
by Slaughter et al. in 1953, is defined as presence of one or more mucosal areas consisting of epithelial cells that have cancer-associated genetic or epigenetic alterations [20,21] and has been utilized to explain the occurrence of multiple primary tumors [22]. Multiple lesions of IPMN, containing a variety of multiple and distinct genetic mutations within the ductal epithelium of a single pancreas, have been found to be consistent with the concept of field cancerization [23]. More recently, it has been proposed that, due to the common embryologic origin of the pancreatic and bile ducts [10,11], both the pancreas and the biliary tree may be affected. This description is highly relevant, as the concept of a possible relationship or common origin of biliary and pancreatic tumors and similarity at pathology is prompting further investigation and consideration, and possibly revision, to the current classification scheme of cholangiocarcinoma [24]. In addition, it remains to be determined whether awareness of this relationship should prompt careful assessment of pancreaticobiliary systems in patients with established precursor lesions. Contrast-enhanced CT and MRI are the established techniques for detecting and characterizing pancreatic and liver masses. The tumors in our case demonstrated the typical imaging characteristics of pancreatic adenocarcinoma and ICC. Arising from the pancreatic ductal epithelium, most pancreatic adenocarcinoma tumors occur in the head of the pancreas. Pancreatic adenocarcinomas tend to appear as poorly defined hypovascular masses at cross-sectional imaging [25]. Tumors arising in the pancreatic head tumors typically cause distention of both the pancreatic duct and common bile duct, termed the “double duct sign”. Atrophy of the distal pancreatic parenchyma is a common secondary finding due to chronic ductal obstruction. Signs of vascular invasion include arterial or venous occlusion, tumor abutment or encasement N180° around the vessels, loss of the fat plane separating the tumor from the vessel, and deformity or abnormal vessel contour or the development of collateral vessels [25,26]. ICC is typically a homogeneous solid mass with an irregular contour. Satellite nodules, peripheral biliary distention, overlying liver capsular retraction, and vascular encasement and/or occlusion are common secondary findings [27]. ICC is a highly desmoplastic tumor and contains variable amounts of fibrosis, necrosis, or mucin [28]. The interesting and complex composition of ICC at
pathology translates to the appearance at imaging. Variable enhancement patterns of ICC have been described at CT and MRI, and the most typical pattern is early, concentric rim enhancement with progressive peripheral or whole lesion enhancement on dynamic imaging. Other enhancement patterns include solid hypervascular enhancement with either persistent enhancement or washout occur less commonly. The central fibrosis within the lesions can be identified as areas of T2 hypointensity and delayed enhancement (1–4 h) after contrast administration on MRI [27–29]. The patient was felt to be a good surgical candidate and both the tumors met criteria for resectability based on imaging: the liver lesion was a solitary mass without satellite lesions and vascular or biliary invasion, and the pancreatic mass did not demonstrate vascular invasion or invasion of adjacent organs. Distant metastasis was not identified in this patient either. For both malignancies, surgical therapy is the only option to achieve cure [25,30]. The differential diagnosis at the time of presentation included primary pancreatic adenocarcinoma with large liver metastasis or synchronous cholangiocarcinoma and pancreatic adenocarcinoma. Pancreatic adenocarcinoma metastases to the liver are most commonly small and multiple. The presence of a single, dominant metastasis to the liver would have been a very unusual finding [31]. The patient thus underwent successful surgical resection of both lesions. In summary, there is increasing recognition of the concept that biliary disease has a pancreatic counterpart. The theory of field cancerization, suggesting that cancer associated or epigenetic alterations occur in the pancreaticobiliary ductal epithelial system, has been described to explain the development of multiple pancreatic or biliary precursor lesions, such as IPMN and IPN-B, respectively. These precursor lesions have significant potential to develop into invasive malignancy. We present a rare case of synchronous pancreatic adenocarcinoma and ICC with pathologic evidence supporting the presence of tumor arising from underlying precursor lesions, IPMN and IPN-B, respectively. Further work is necessary to elucidate genetic alterations that may predispose to the development of pancreaticobiliary precursor lesions and invasive malignancy and to determine the clinical implications for patients with established precursor lesions.
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