Invasive ductal adenocarcinoma of the pancreas may originate from the larger pancreatic duct: a study of 13 tumors less than 2cm in diameter

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1 J Hepatobiliary Pancreat Surg (2007) 14: DOI /s x Invasive ductal adenocarcinoma of the pancreas may originate from the larger pancreatic duct: a study of 13 tumors less than 2cm in diameter Koichi Suda 1, Bunsei Nobukawa 1, Shigetaka Yamasaki 1, Keiko Abe 1, Susumu Matsukuma 2, and Fujihiko Suzuki 3 1 Department of Pathology, Juntendo University School of Medicine, Hongo, Bunkyo-ku, Tokyo , Japan 2 Department of Research and Laboratory, Japan Self Defense Forces Central Hospital, Tokyo Japan 3 Division of Pathology, Clinical laboratory, Juntendo Urayasu Hospital, Chiba, Japan Abstract Background/Purpose. We aimed to elucidate the origin/ primary site of invasive ductal adenocarcinoma of the pancreas, based on the distribution of intraductal carcinoma components. These components were identified by a mural elastic fiber cuff. Methods. Thirteen specimens from patients with invasive ductal adenocarcinoma (microscopically, less than 2 cm in diameter) of the pancreas were studied histopathologically. Variants of invasive ductal adenocarcinoma and intraductal papillary-mucinous carcinoma were excluded. Results. Intraductal carcinoma components of invasive ductal adenocarcinoma were found in 12 of the specimens 13 (92%), and were observed within the tumor mass and/or on its boundary, or outside the tumor mass. Intraductal components were characterized by low papillary projections lacking a fibrovascular core, with/without surrounding tubular structures, or by irregular stratification and pleomorphism of the epithelial cells. Invasive components mostly showed a tubular pattern with desmoplasia. The distribution of the intraductal components in the 12 specimens was as follows: in 9 (75%), they were in both the main pancreatic duct and large branch ducts; and in 3, they were in the smaller branch ducts only. Conclusions. Invasive ductal adenocarcinomas of the pancreas may originate most frequently from the main pancreatic duct or larger branch ducts, while the smaller ducts are less often the site of cancer origin. Key words Invasive ductal adenocarcinoma Carcinoma in situ Intraductal spread Primary site Introduction Invasive ductal adenocarcinoma of the pancreas (IDAP) is the most fatal/aggressive tumor of the human Offprint requests to: K. Suda Received: March 31, 2006 / Accepted: May 17, 2006 body and, anecdotally it has been believed to arise from the peripheral/smaller pancreatic ducts or ductules. 1,2 Because of the thinner walls of the smaller-caliber ducts, and the high proliferative activity of the tumor, carcinomas arising from the peripheral/smaller pancreatic ducts or ductules have been thought to readily break/invade the ductal wall and to be difficult to detect the primary site/origin early. 3 Proliferative epithelial lesions in the smaller-caliber ducts and ductules have been the subject of a quest for precursor lesions of IDAP. 4 Hruban et al. 5 proposed a revised definition of pancreatic intraepithelial neoplasia (PanlN), which is defined as noninvasive epithelial neoplasms, as precursor lesions of IDAP, arising in any parts of the pancreatic ducts including the main duct, whereas PanINs in the nonrevised definition usually involve ducts that are less than 5mm in diameter. 6 Most of the PanINs studied intensively to date have involved the smaller-caliber ducts or ductules, but not the main pancreatic duct (MPD). 6,7 Recently, small carcinomas of the pancreas, grossly less than 2cm in diameter, have been detected, frequently because of the development of such diagnostic imaging procedures as endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance imaging cholangiopancreatography (MRCP), computerized axial tomography (CT) scans, magnetic resonance imaging (MRI), and endoscopic ultrasonography (EUS) According to Furukawa et al. 10 among 31 small IDAPs 2cm or less in greater dimension in their collective study, abnormal findings of the MPD, such as obstruction or narrowing, were observed in 27 of 29 patients (93.1%). That is, these small carcinomas were found close to or around the MPD with/without distal dilatation of the duct, suggesting that they arose from either the MPD or a large branch duct, or the peripheral ducts near the MPD, based on the theory of the peripheral/smaller-duct origin of IDAP, 1,2 mentioned above.

2 284 K. Suda et al.: Primary site of origin of pancreatic carcinoma is larger pancreatic duct In this study, we investigated the distribution of intraductal carcinoma components, which were identified by mural elastic fiber cuff, of IDAP lesions that were, microscopically, less than 2 cm in diameter, in relation to the tumor mass. We also attempted to determine the origin/primary site of IDAP, which, theoretically, originates from the pancreatic ductal epithelia. Patients, materials, and methods Thirteen specimens of IDAP lesions that were, microscopically, less than 2 cm in diameter (range, 1.0 to 2.0 cm) were obtained from Juntendo University Hospital, Tokyo, between 1978 and 2005, and from the National Defense Medical College Hospital, Saitama, Japan, between 1980 and Variants of IDAP and intraductal papillary-mucinous carcinoma (IPMC) were excluded. The specimens were from 13 patients who had undergone Whipple s pancreatoduodenectomy or distal pancreatectomy. Five of the tumors were in the pancreatic head, and the remaining eight were in the body. Six of the patients were men, and seven women, ranging in age from 40 to 74 years (mean, 57.7 years), as shown in Table 1. The specimens were fixed in 10% buffered formalin. For the assessment of IDAP spread, the entire surgical specimen was serially sectioned at 0.5-cm intervals in the plane perpendicular to the MPD. Three to five paraffin blocks (mean, four blocks), which included the whole tumor, were, thus, prepared per patient and coded according to anatomic location. From each block, 3- to 4-mm-thick serial sections were cut and stained with hematoxylin and eosin (H&E) and elastica van Gieson (EVG). The pancreatic duct was analyzed and EVG staining confirmed the presence of a periductal elastic fiber cuff All carcinoma foci in the pancreatic ducts were defined as intraductal carcinoma components of IDAP, which showed a low papillary pattern, except for some foci that showed a tubular pattern with/without desmoplasia, which was thought to be intraductal invasion, or cancerization of the ducts. 14 Based on subgross and microscopic studies of the whole specimen from each patient, precise mapping of the intraductal carcinoma components was performed on actual-size photocopies of each specimen. The intraductal spread of carcinoma was assessed by determining the ductal type affected and by zonal distribution. Small branch ducts, such as intralobular ducts and ductules, were defined as intralobular ducts, while the large branch ducts were defined as interlobular ducts, except for the MPD, which was identified from its thick mural elastic fiber cuff, the size of the duct, and its location. The assessment of ductal type with carcinoma involvment was done by determining the relationship of the duct to the identified MPD in the pre/post sections of the tumor mass. Table 1. Clinicopathological findings of invasive ductal adenocarcinoma of the pancreas (IDAP), microscopically less than 2cm in diameter Distribution of intraductal carcinoma components a and relationship to IDAP PanIN lesions Patient no. Age (years) Sex Site Size (cm) Histology MPD LBD SBD Close Distant 1 49 F H 1.5 Mod + (B) + (B, O) 1A 2 61 F B 1.8 Well + (B) + (I, B, O) 3 68 M B 1.2 Mod + Por + (B) + (I, B, O) 2 1A 4 66 F H 2.0 Mod + (I, B) + (B) 5 67 M B 2.0 Mod + (B) + (I, B) 6 40 F H 1.3 Mod + (I, B, O) + (I, B, O) 1A 1A 7 43 F B 1.0 Mod + (I, B, O) + (I, B, O) 1B 1A 8 58 F B 1.6 Mod + (I, B) + (B) 9 66 M B 1.3 Well + (I) + (B, O) 1A F B 1.5 Mod + (I) 1B 1A M H 1.7 Mod + (I, B) 1B M H 1.5 Mod + (I, B, O) 1B M B 1.6 Mod H, head; B, body; well, well-differentiated tubular adenocarcinoma; mod, moderately differentiated tubular adenocarcinoma; por, poorly differentiated carcinoma; MPD, main pancreatic duct; LBD, large branch duct defined as an interlobular duct, except for the MPD; SBD, small branch duct defined as an intralobular duct; PanIN, pancreatic intraepithelial neoplasia; close, close to the IDAP; distant, distant from the IDAP a Relationship to IDAP was classified as: within the tumor mass (I), on or within the boundary of the mass (B), and outside the mass (O)

3 K. Suda et al.: Primary site of origin of pancreatic carcinoma is larger pancreatic duct 285 a b Fig. 1a,b. Intraductal carcinoma components in invasive ductal adenocarcinoma of the pancreas (IDAP) that were, microscopically, less than 2cm in diameter. a IDAP consisted of both intraductal components (large arrow, main pancreatic duct [MPD]; small arrows, large branch ducts) indicated by the encircling well-preserved mural elastic fiber cuff and invasive components. b The intraductal components were distributed within the tumor mass (I; see Table 1) and showed low papillary carcinoma. The invasive components showed tubular adenocarcinoma (a, b). Arrow in b shows intraductal carcinoma component in MPD. a Elastica van Gieson 50; b H&E, 100 Fig. 2. Intraductal component within a tumor mass (I; see Table 1). Intraductal components (arrows, MPD) were observed in the invasive ductal adenocarcinoma. Elastica van Gieson. 50 Fig. 3. Intraductal component on or within the boundary of the tumor mass (B; see Table 1). Intraductal component (arrow, large branch duct) was found in the marginal area of invasive ductal adenocarcinoma. Elastica van Gieson. 50 Results All 13 cases of IDAP showed mainly desmoplastic moderately differentiated adenocarcinoma, without macroscopically visible papillae and mucin. Tumor necrosis was found in 1 case. Intraductal carcinoma components of IDAP, which were identified by the presence of a mural elastic fiber cuff, were found in 12 of the 13 cases; the distribution of intraductal carcinoma components was as follows: in 9 cases (75%) they were in both the MPD and large branch ducts (Fig. 1a) and in the remaining 3 case, these components were in the smaller branch ducts only, as shown in Table 1. The intraductal carcinoma components occurred focally in the pancreatic ducts (that is, they did not correspond to PanIN-3), or they occurred as rather diffuse lesions involving the MPD and the large branch ducts (seen within the tumor [Figs. 1, 2], they occurred on or within the boundary of the tumor [Fig. 3], or outside the tumor [Fig. 4], as shown in Table 1). These relationships, shown as a map of a typical case, are seen in Fig. 5. Intraductal carcinoma components were not macroscopically identified as visible papillae, and were microscopically characterized by low papillary projections lacking a fibrovascular

4 286 K. Suda et al.: Primary site of origin of pancreatic carcinoma is larger pancreatic duct Fig. 4. Intraductal component outside the tumor (O; see Table 1). Intraductal component (large branch duct) was found in the interlobular area (arrow). Note, no invasive ductal adenocarcinoma was found around the intraductal component. Elastica van Gieson. 100 Fig. 6. Intraductal component and invasive components of invasive ductal adenocarcinoma of the pancreas. Tubular structures surrounding the low papillary intraductal proliferation had invaded the periductal elastic fiber layer and had become transformed into invasive components. Elastica van Gieson PanIN 1A lesions were distant from the IDAP (Table 1). Discussion Fig. 5. Mapping of invasive ductal adenocarcinoma arising from the main pancreatic duct (MPD), as found in patient 6. Intraductal carcinoma components (black area) were distributed in the MPD and large branch duct within and outside the tumor mass (oblique lines). CBD, common bile duct; PV, papilla of Vater; open circles, pancreatic intraepithelial neoplasia (PanIN)-1A core (Fig. 1b) with/without surrounding tubular structures, in contrast to the tubular pattern with/without desmoplasia seen in the invasive components. 14 Alternatively, the intraductal carcinoma components, showed irregular stratification with less cytologic atypia than that of the invasive components. 15 Tubular structures surrounding the low papillary intraductal proliferation were found in the elastic fiber layer in a few cases, and had become transformed in to invasive components (Fig. 6). Of the PanIN lesions 5 in the 13 patients, 6 up to PanIN 2 lesions were found close to the IDAP, and In the present study, intraductal carcinoma components of IDAP, which were identified by the presence of a mural elastic fiber cuff and were characterized by low papillary projections lacking a fibrovascular core, were observed in 12 of 13 cases (92%). Intraductal carcinoma components were excluded because of intraductal invasion, or cancerization of the ducts, because the intraductal carcinoma foci of IDAP included carcinoma in situ (CIS), intraductal spreading of CIS, and intraductal invasion of IDAP. 4,14 The findings in other authors studies concerning intraductal components were as follows: Yamasaki et al.: 16 37/54 cases (69%) for intraductal carcinoma components; Klimstra et al.: 17 94/182 cases (52%) for CIS; Fukushima et al.: 18 33/67 cases (49.3%) for intraductal papillary components; Klöppel et al.: 19 4/ 37 cases (10.8%) for CIS; and Wilentz et al.: 7 9/29 cases (31%) for CIS. Our high frequency could be attributed to the multislice study, identifying the mural elastic fiber cuff, and the small lesion size, less than 2 cm in diameter, and to a lack of necrosis. Regarding histological patterns, according to Yamasaki et al., 16 the intraductal components of IDAP show low papillary projections, lacking a fibrovascular core, or they show irregular stratification and pleomorphism of the epithelial cells of the duct. In the present study, most of the intraductal components showed low papillary projections, not papillae as in intraductal papillary-mucinous neoplasia

5 K. Suda et al.: Primary site of origin of pancreatic carcinoma is larger pancreatic duct 287 (IPMN), 5 similar to the description by Yamasaki et al., 16 but admixed with a tubular pattern in the surrounding area in a few cases. This surrounding tubular pattern may be one type of the beginning of invasion, breaking the periductal elastic fiber layer, but it does not seem to indicate the multifocal development of invasive cancer from CIS. The other authors mentioned above, 4,7,17 19 however, did not describe any characteristic histological features of the intraductal components, apart from reporting numbers of cases. In our study, intraductal components were frequently found in IDAP, and their histology except for intraductal invasion, was identified simply as a low papillary pattern, as mentioned by Tanase et al. 14 In the present study the intraductal components were distributed within the tumor mass (I), on the boundary of the tumor (B), and outside the tumor (O). Most intraductal components, which were thought to be in the larger pancreatic ducts, were diffuse lesions involving I and B or B and O, and I, B, and O. Hence, the intraductal components within the tumor and in the boundary areas were mostly considered to be CIS and the intraductal spreading of CIS, respectively, while those outside the tumor were thought to be intraductal spreading. Intraductal components were more frequently found in the larger ducts than in the smaller ducts in this study of tumors less than 2cm in diameter. Pour et al. 20 incidentally found ten small carcinomas in human necropsies (two early carcinomas, one ductal carcinoma in situ, and seven ductular carcinomas in situ), all of which were located in the branch duct. Tajiri et al. 21 reported that 28 infiltrating carcinomas in experimental animals did not originate in the main duct. From these data, it seems highly probable that IDAP originates from the branch ducts in many cases in humans and animals. Recent experimental data, 22 moreover, have suggested that the cellular origin of ductal carcinoma might be found in the most peripheral segments of the duct system. According to Furuta et al., of 36 IDAPs originated from the branch ducts, but they could not deny the possibility that the cancer tissues arose from the MPD and then spread to the branch ducts and into the stroma. Also, Klimstra et al. 17 stated that CIS, a precursor to invasive carcinoma rather than an extension of established invasive carcinoma into the duct, most commonly involved interlobular and large intralobular ducts; occasionally, the major ducts or smaller intralobular ducts were involved. In addition, there is no strong evidence to deny that some IDAPs may arise from the MPD or secondary ducts of larger caliber. In the majority of patients with small-size IDAP, however, imaging studies show obstruction or stenosis of the MPD; 24 this is particularly notable in the collective study of Furukawa et al.: 10 abnormal findings on ERCP of the MPD were observed in 27 of 29 patients (93.1%) with small pancreatic carcinomas 2 cm or less in greater dimension. Because small IDAP without MPD involvement is difficult to discover clinically, one may consider that small tumors only with MPD stenosis/dilatation may have been discovered and resected. So, there remains a possibility that IDAP originates from small ducts away from the MPD. However, there has been no evidence of small IDAP without MPD involvement/dilatation. It may be true that IDAPs originating from the peripheral ducts may subsequently involve the MPD by the time a diagnosis of pancreatic carcinoma is made, but there may also be IDAPs arising from the MPD. 25 Moreover, there are case reports of patients with CIS lesions in the larger/ central-side pancreatic ducts 26,27 These findings indicate that small pancreatic carcinomas, including CIS, were situated very close to or had originated from the MPD. Therefore, invasive ductal adenocarcinoma of the pancreas may originate from the larger pancreatic ducts, and, less often, from the smaller/peripheral ducts. Acknowledgments. We thank Professor Seiichi Tamai, M.D., Department of Laboratory Medicine, National Defence medical College Hospital, for providing materials. We also thank Mr. H. Abe for his skillful technical assistance, and Miss K. Kagoshima for typing the manuscript. References 1. Klöppel G. Pathology of nonendocrine pancreatic tumors. 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