Noninvasive IPMC

Analysis of PanIN-3 and IPMC (with Dense Cytoplasms and

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Both PanIN-3 and IPMC tumors are similar in terms of small papillary-cohesive clusters, small nuclei (about 10 |xm at the shortest diameter) without prominent anisonucleosis (fig. 15a-e). As for nuclear crowding/overlapping, the nuclei of both tumors tend to exist in the well-preserved cytoplasm and to be separated from each other; the cytoplasmic borders between the nuclei can be clearly defined by focusing the microscope up and down (fig. 15a-f).

Differences between PanIN-3 and IPMC

Compactly packed clusters are often observed in PanIN-3 (fig. 15a, b), but are rare in IPMC. The cytoplasm is relatively abundant in most IPMC (fig. 15c, f),

Fig. 14. IDAP with PanIN-3. Histology corresponds to figure 13. The upper half of (a-c) is PanIN-3. The epithelium has a different quality of cytoplasm to polyclonality and is similar to the upper portion of figure 13. The lower half of (a-c) shows a tubular pattern, composed of invasive components, and the quality of the cytoplasm is regular and monoclonal-like. HE. X400. b is an elastica van Gieson stain corresponding with the hematoxylin-eosin stain in (a) and shows that PanIN-3 is surrounded by elastic fibers, while the invasive component is not. Elastica van Gieson stain. X200.

Fig. 14. IDAP with PanIN-3. Histology corresponds to figure 13. The upper half of (a-c) is PanIN-3. The epithelium has a different quality of cytoplasm to polyclonality and is similar to the upper portion of figure 13. The lower half of (a-c) shows a tubular pattern, composed of invasive components, and the quality of the cytoplasm is regular and monoclonal-like. HE. X400. b is an elastica van Gieson stain corresponding with the hematoxylin-eosin stain in (a) and shows that PanIN-3 is surrounded by elastic fibers, while the invasive component is not. Elastica van Gieson stain. X200.

but is small in most PanIN-3 (fig. 15a). The cytoplasm, including apparently abundant mucin, is large in IPMC (fig. 15c, e and f), but small in PanIN-3 (fig. 15a). Euchromatin is largest in IPMC (fig. 15c-f), but is small in PanIN-3. IPMC cells have mostly polyclonality (figs. 15d-f and 16d-f). Most cases with polyclonality progress to mucinous noncystic carcinoma later (figs. 15d, e and 16d, e). However, there are cases in which most cells have monoclonality (figs. 15c and 16c) and these progress to IDA later. PanIN-3 cells are mostly monoclonal (figs. 15a and 16a), but there was a rare case that showed polyclonality (figs. 15b and 16b) (mixture of dense cytoplasm and mucin-producing cytoplasm) but the tumor size was small (1.8 cm in diameter), and the prognosis was very good (there has been no recurrence for nine years since the operation). Consequently, the good prognosis is considered to be due to tumor size and/or polyclonality.

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Fig: 15. PanIN-3 and noninvasive IPMC. a, b are PanIN-3-type cells in IDAP cases. c-f are noninvasive IPMC-type cells. a-c, e: scrap smear, d: vinyl tube aspiration of the main duct of the resected pancreas,f: ERCP, a-f: Papanicolaou stain. X400. a is an ordinary type of PanIN-3 that has a bad prognosis. b is a rare case of PanIN-3 that has a good prognosis. c is noninvasive IPMC that is simultaneously accompanied by IDAP. d and e were only nonin-vasive IPMC at first surgery, but histology at re-operation after several years showed features of mucinous noncystic carcinoma. f Although the carcinoma was neglected for two years from the first surgery, the histology of re-operation remained noninvasive IPMC. a and c are monoclonal-like. b, d-f are polyclonal-like (arrows show translucent/yellow mucin).

Clonality of Cytoplasm

As mentioned above, in IDAP cases, there is a rare case with a very good prognosis. In such IDAP cases, the columnar cells of PanIN-3 are peculiar in that the morphology of each cell is different (figs. 15b and 16b). These make the tendency towards polyclonality more prominent like the mixture of gobletlike cells in IPMC. The findings that the papillary epithelium of IPMNs is typically composed of various cytoplasms of tall columnar cells with a slightly basophilic dense cytoplasm, tall columnar cells with clear cytoplasm, or round-to-cuboidal cells with eosinophilic dense cytoplasm [12, 25] suggest polyclonality

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Fig. 16. PanIN-3 and noninvasive IPMC. Histology corresponds to each cytologic feature of noninvasive carcinoma in figure 15. HE X200.

(figs. 15d-f and 16d-f). One of the important clinicopathologic and molecular features of IPMT is that multifocal occurrence of IPMTs has been observed in the same pancreas (9.8-32%) [54-56], there was genetic heterogeneity in an individual IPMN focus [57], and a hyperplasia-adenoma-carcinoma sequence in the evolution of IPMT has also been recognized [58-61]. Histomor-phologically, IPMNs may have a variety of different cytoarchitectural features, even in different regions of a single neoplasm [40]. Comparative genetic studies of different regions of IPMN suggest that multiple clones may evolve independently [57, 62]. Namely, IPMN comes to have substantial allelic heterogeneity [57]. This marked heterogeneity may, in part, be due to the slow growth rate of these neoplasms [57]. In clonality analysis of IPMN [62], clonality of a single focus of the normal pancreatic duct/acinar epithelium is characteristic of the polyclonal pattern. In contrast, the clonality of a single focus of IDA cells is a monoclonal pattern. Although a single focus of IPMN (including IPMC) had both a polyclonal and monoclonal pattern, the monoclonal pattern was more pronounced than the polyclonal pattern. However, comparing different foci of a single neoplasm, the types of clonality are different. Consequently, on the whole IPMN (including IPMC) becomes polyclonal [62]. Reviewing a table of clonality of a single IPMC focus, there is a single focus with polyclonal clonal-ity [62]. On IPMC, that single focus has a polyclonal pattern suggesting that the focus retains the nature of normal epithelial cytoplasm. Consequently, despite malignancy, cases showing a polyclonal pattern may be determined to be IPMC. The cytoplasm of IDAP is different in size and shape, but assumes a monoclonal pattern, giving the impression that the product is produced homogeneously, artificially and uniformly (figs. 1c, 2c, 3c, 4c, 11c and 13c). However, the cytoplasm of PanIN-3 has a short diameter and is relatively clear at the border, but assumes a monoclonal aspect (upper portion of figs. 11a, 15a and 16a). In a rare case of PanIN-3, the size, height, shape and quality of the cytoplasms were slightly different. The cells seemed independent, although they gave a faint impression on high magnification. They assumed a polyclonal aspect impression, similar to plants that independently and separately result from the same kind of seeds (upper portion of figs. 13a, b, 15b and 16b).

Differences between PanIN-3 de novo and PanIN-3 in IDAP

PanIN-3 exists in the pancreatic ducts, while the invasive component exists in the stroma. Studies on p53 protein overexpression were done on both the infiltrating and intraductal carcinoma components [31, 63, 64]. These revealed that IDA has a tendency to spread intraductally [31]. However, studies with Ki67 [31], cell proliferative activity [65-67] and Dpc4 [68] suggest that the biologic behavior of intraductal spread carcinoma is suited to PanIN-3 de novo [31, 65-68]. Consequently, PanIN-3 in IDAP was the same as the intra-ductal spread of infiltrating carcinoma, but the biologic behavior suggested PanIN-3 de novo.

Significance of Identification of PanIN-3 Type Cells in IDAP

IDAP can spread through the ducts beyond the tumor mass, and such intra-ductal extension has been cited as a particular problem in determining the appropriate surgical resection margin [69]. A study on the extent of intraductal spread shows that has limited to 2.0 cm [31]. Consequently, detection of PanIN-3 type cells in IDAP decides the appropriate surgical resection margin. Prognostic factors include grade [1, 23, 31, 70], diameter (survival time is longer in patients with <3 cm) [1, 23, 71], site (carcinomas of the body or tail are more advanced) [1, 23, 72, 73], and stage (lymph node metastasis is worse) [1, 23, 71, 72]. Accordingly, if the size, site, stage and other factors are similar, IDAP cases with PanIN-3 will have a good outcome compared with IDAP cases without PanIN-3. This means that IDAP cases with PanIN-3 are useful when choosing treatment and determining prognosis.

Clinical Application at Diagnosis of PanIN-3

Invasion was found when group IV (corresponding to PanIN-3) epithelia spread 5-8 mm (rarely infiltrated when it spread <4 mm) [2]. Molecular studies revealed that PanIN-2 and PanIN-3 lesions represent a distinct step toward invasive carcinoma [74]. Thus, invasion begins at the occult stage nearby. However, the survival rate after complete resection at the PanIN-3 stage is very good [3]. Consequently, in order to improve prognosis in pancreatic carcinoma, diagnosis and resection at the PanIN-3 stage is necessary. Practically speaking, in PanIN-3, no pancreatic mass could be detected by traditional radiography, ultrasonogra-phy (US), endoscopic ultrasonography (EUS) or computed tomography (CT), nor was any ductal stenosis or obstruction detected by endoscopic retrograde pancreatography (ERP) [48]. Furthermore, the original, occult site cannot be visualized even during laparotomy [75]. Total pancreatectomy requires that patients manage diabetes for the rest of their lives [75]. With regard to searching for the original site of such an occult cancer, cytologic examination is very useful [49, 75-79]. To avoid blind total resection and leave a much greater volume and endocrine function, one institution precisely locates the original site by means of a Whipple procedure with the aid of intraoperative cytodiagnosis and then decides on the appropriate extent of pancreatectomy [49, 75-79]. Thus, concerning determining the stage of PanIN-3 and locating the original site, the present cytologic findings are useful.

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