Cells from IDAType Cells

Arrangement

Small papillary-cohesive and compact clusters are the most consistent features of PanIN-3 (upper portion of figs. 11a, b and 13a, b) [5, 41, 46-49]. Small papillary-cohesive clusters appeared to result from excessive proliferation and strong cohesion of well-preserved epithelial cells within strong uninfiltrated ducts. These reflect low papillary projections/palisades that are a histologic characteristic of PanIN-3 (right portion of fig. 12 and upper portion of fig. 14) [1, 5, 7, 23, 31, 32, 41, 46-49]. IDA-type cells are loose sheet-solid clusters (lower portions of figs. 11a, c and 13 a, c) reflecting histologically well/poorly differentiated tubular formation (left portion of fig. 12 and lower portion of fig. 14). These observations seem to support the concept that as a result of the weakening of intercellular cohesion, cell clusters become loose [50]. Nuclear crowding and/or overlapping and nuclear contour irregularities have been cytologically reported as indexes of malignancy [20], but these two features were common in the cytologic profiles of both PanIN-3 [41, 46-49, 51] and IDA [20, 21, 52]. For these reasons, it seems to have been reported that CIS is indistinguishable from IDA. However, peer reviewing nuclear crowding and/or

Fig. 9. Invasive IPMC (Invasive components IDA). a and b are the same sample. a The upper part (showing sheet clusters) shows noninvasive IPMC components, and the lower part is the invasive component that exhibits IDAP. The noninvasive IPMC has euchromatin, while the invasive component has coarsely granular chromatin. b The left part (showing sheet clusters), the right central part (showing palisading clusters) and the right lower part (showing papillary clusters) are noninvasive IPMC components and with clearly defined cytoplasmic borders. Noninvasive IPMC and the invasive component are both monoclonal-like. Scrap smear, Papanicolaou stain. X400.

Fig. 9. Invasive IPMC (Invasive components IDA). a and b are the same sample. a The upper part (showing sheet clusters) shows noninvasive IPMC components, and the lower part is the invasive component that exhibits IDAP. The noninvasive IPMC has euchromatin, while the invasive component has coarsely granular chromatin. b The left part (showing sheet clusters), the right central part (showing palisading clusters) and the right lower part (showing papillary clusters) are noninvasive IPMC components and with clearly defined cytoplasmic borders. Noninvasive IPMC and the invasive component are both monoclonal-like. Scrap smear, Papanicolaou stain. X400.

overlapping, in the invasive component-type cells, the cytoplasm between nuclei was poorly preserved, and the nuclei tended to adhere to each other [5]. In contrast, in PanIN-3, the cytoplasm between the nuclei tended to be well preserved, the nuclei tended to be separate from each other when focusing the microscope up and down, and the cytoplasmic borders between nuclei tended to be clearly defined. These findings appear to be one of the differences between PanIN-3 and IDAP type cells [5].

Nuclei

Small nuclei without anisonucleosis (upper portions of figs. 11a, b and 13a, b) are characteristic of PanIN-3 [5, 41, 46-49, 51]. In order to differentiate between PanIN-3 and IDA type cells, however, it is more useful to focus on the paired hyperchromatin and large nuclei [5]. The combination of large nuclei

Fig. 10. Invasive IPMC (Invasive components IDA). Histology corresponds to figure 9. The major portion corresponds to noninvasive IPMC, and the right end corresponds to the invasive component (IDAP) HE. X200.

(>15 |xm at the shortest diameter) and hyperchromatin is never observed in PanIN-3, but often observed in IDAP (the lower portion of figs. 11a, c and 13a, c) [5]. IDAP is conclusive for malignancy, while PanIN-3 is mostly strongly suspicious of malignancy [5]. Hyperplasia, adenoma, and moderate dysplasia are all benign [5]. Although cytologic materials of CIS [41, 46-49]. were previously reported to be all pancreatic juice, the assessment was cancer cells (the detection rate was 6 of 11 patients: 6/11 [41], 2/2 [49], 2/3 [48] and 1/1 [46]), suspicious for malignancy (1/1 [47-48]), atypia (3/11 [41]) and no abnormality (2/11 [41]). Accordingly, small monotonous nuclei, no combination of large nuclei and hyperchromatin, and being strongly suspicious of malignancy are characteristic of PanIN-3.

Cytoplasm

Clearly defined cytoplasmic borders are observed in cytologic views of SD [51]/CIS [41, 46-49] and PanIN-3 [5, 20]. According to Monzat et al. [53], gap junctions play a crucial role in proliferation, differentiation and secretion processes, and during the growth of human pancreatic duct cells in vitro and in vivo, gap junctions develop progressively. Hence, clearly defined cytoplasmic borders seem to result from the double factors of strong intercellular cohesion b m

Fig: 11. IDAP with PanIN-3. a PanIN-3 (the upper portion) and IDA (the lower portion) type cells. ^ = Neutrocyte. b PanIN-3 type cells. c IDA type cells (a-c: scrap smear, Papanicolaou stain. X400). b and c are the same magnification of the same preparation. PanIN-3 type cells have small papillary-cohesive and compact clusters, and the cytoplasm is dense and well preserved, but meager, without prominent anisocytosis and with no cytoplasm >21 ^m in the short diameter. The nuclei tended to be separated from each other (as seen when focusing the microscope up and down), and were often centrally located. In contrast, IDAP type cells were composed of loose sheet-solid clusters, the cytoplasm was poorly preserved, and the nuclei tended to adhere to each other. A combination of large nuclei (short diameter >15 ^m) and hyperchromatin is observed in IDAP (the lower portion of a and c). Commonly, IDAP is conclusive for malignancy, while PanIN-3 is strongly suspicious for malignancy. However, this PanIN-3 case is conclusive for malignancy.

a c by highly developed gap junctions and pressure on the cytoplasmic border due to excessive proliferation. The cytoplasm of SD [51]/CIS [47] and PanIN-3 [5] has individually well enveloped and often centrally located nuclei, tending to be well preserved. In invasive component cells, there is a tendency for nuclei to protrude from the cytoplasm, and preservation of the cytoplasm is lost [5]. Whether the nucleus is included within, or protrudes from, the cytoplasm appeared to be due to the degree of preservation of the cytoplasm and its

Fig. 12. IDAP with PanIN-3. Histology corresponds to IDAP of figure 11. The left side is PanIN-3 with small papillary-compactly packed patterns with small regular nuclei and dense cytoplasm, and the right side is the invasive component (IDAP) with a tubular pattern with large nuclei HE. X200.

membrane. Consequently, a nucleus individually enveloped in well-preserved cytoplasm and centrally located nuclei may be also characteristic of PanIN-3. Small and dense cytoplasm without prominent anisocytosis seemed to be characteristic of the cytologic profile of SD [51]/CIS [41, 46-49] and the description of PanIN-35, but in order to differentiate between PanIN-3 and IDAP-type cells, it is more useful to focus on abundant cytoplasm rather than small dense cytoplasm, because abundant cytoplasm (>21 |xm at the shortest diameter) is never observed in SD [51]/CIS [41, 46-49] and PanIN-3 [5], but is observed in most IDAP [5, 20] The nuclear arrangement of PanIN-3-type cells is regular compared with that of IDA-type cells. The irregularity of the nuclear arrangement generally appeared to be due to prominent anisocytosis. In IDA-type cells, the nuclei in large amounts of cytoplasm appeared to contain a greater quantity of total chromatin than the nuclei in a small amount of cytoplasm. Namely, cytoplasmic size appeared to be proportional to the total quantity of chromatin. Consequently, a large amount of cytoplasm itself could be used to make a diagnosis of IDAP. Accordingly, cytoplasm that is dense and meager (without prominent anisocytosis and abundant cytoplasm >21 |xm in diameter) may be characteristic of PanIN-3.

Fig. 13. IDAP with PanIN-3. PanIN-3 type cells (the upper portion of a and b) and IDAP type cells (the lower portion of a and c) (a-c: scrap smear, Papanicolaou stain. X400). (b) and (c) are the same magnification of the same preparation. PanIN-3 type cells form compactly packed clusters with small regular nuclei and are polyclonal-like (arrow cells are yellow, the other cells are green). In contrast, IDAP type cells form loose tubular clusters with anisonucleosis with large nuclei and are monoclonal-like.

Fig. 13. IDAP with PanIN-3. PanIN-3 type cells (the upper portion of a and b) and IDAP type cells (the lower portion of a and c) (a-c: scrap smear, Papanicolaou stain. X400). (b) and (c) are the same magnification of the same preparation. PanIN-3 type cells form compactly packed clusters with small regular nuclei and are polyclonal-like (arrow cells are yellow, the other cells are green). In contrast, IDAP type cells form loose tubular clusters with anisonucleosis with large nuclei and are monoclonal-like.

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