Pancreas and Ampulla

Abstract

This chapter provides a practical overview of frequently used markers in the diagnosis and differential diagnosis of both common and rare pancreatic and ampullary neoplasms, with a specific focus on pancreatic ductal adenocarcinoma and its mimickers, neuroendocrine neoplasms, acinar cell carcinoma, and solid pseudopapillary neoplasm of the pancreas. This chapter contains 47 questions; each question is addressed with tables, concise notes, and representative pictures, if applicable. In addition to the literature review, the authors have included their own experience and tested numerous antibodies reported in the literature. The most effective diagnostic panels of antibodies have been recommended for many entities, such as SMAD4/DPC4, pVHL, maspin, S100P, and IMP3 being suggested as the best diagnostic panel for identifying pancreatic ductal adenocarcinoma and Bcl10 to confirm a diagnosis of acinar cell carcinoma. Some newly described markers such as ATRX/DAXX, PAX6, INSM1, TTMP, islet-1, and PDX-1 for neuroendocrine neoplasm have been discussed. In addition, a small panel of IHC markers including pVHL, CRP, and albumin (by RNA in situ hybridization) has been recommended to confirm a diagnosis of intrahepatic cholangiocarcinoma since these three markers are usually negative in a pancreatic ductal adenocarcinoma. Furthermore, immunophenotypes of normal pancreatic and ampullary tissues have been described, which tends to be neglected in the literature.

FormalPara Pancreas

• 1. Summary of applications and limitations of useful markers (Table 26.1)

• 2. Summary of useful markers for common tumors (Table 26.2)

• 3. Markers for normal pancreatic ducts and acini (Table 26.3)

• 4. Markers for autoimmune pancreatitis (Table 26.4)

• 5. Markers for ductal adenocarcinoma of the pancreas (Table 26.5)

• 6. Markers for adenosquamous carcinoma of the pancreas (Table 26.6)

• 7. Markers for colloid carcinoma of the pancreas (Table 26.7)

• 8. Markers for medullary carcinoma of the pancreas (Table 26.8)

• 9. Markers for undifferentiated carcinoma of the pancreas (Table 26.9)

• 10. Markers for hepatoid carcinoma of the pancreas (Table 26.10)

• 11. Markers for signet ring cell carcinoma of the pancreas (Table 26.11)

• 12. Markers for undifferentiated carcinoma with osteoclast-like giant cells (Table 26.12)

• 13. Markers for acinar cell carcinoma (Table 26.13)

• 14. Markers for pancreatic neuroendocrine neoplasm (Table 26.14)

• 15. Markers for solid and pseudopapillary neoplasm of the pancreas (Table 26.15)

• 16. Markers for pancreatoblastoma (Table 26.16)

• 17. Markers for serous cystadenoma (Table 26.17)

• 18. Markers for mucinous cystic neoplasm (Table 26.18)

• 19. Markers for intraductal papillary mucinous neoplasm (Table 26.19)

• 20. Markers for intraductal oncocytic papillary neoplasm (Table 26.20)

• 21. Markers for pancreatic intraepithelial neoplasia 1 and 2 (Table 26.21)

• 22. Markers for pancreatic intraepithelial neoplasia 3 (Table 26.22)

• 23. Markers for intraductal tubulopapillary neoplasm of the pancreas (Table 26.23)

• 24. Markers for chronic pancreatitis (Table 26.24)

FormalPara Differential Diagnosis

• 25. Ductal adenocarcinoma versus chronic pancreatitis (Table 26.25)

• 26. Ductal adenocarcinoma versus intrahepatic cholangiocarcinoma (Table 26.26)

• 27. Useful IHC markers in differentiating well-differentiated neuroendocrine tumors from pancreatic islets/islet cell hyperplasia in FNA samples and small tissue biopsy (Table 26.27)

• 28. Useful IHC markers in differentiating pancreatic neuroendocrine tumors from well-differentiated neuroendocrine tumors of other organs (Table 26.28)

• 29. Pancreatic neuroendocrine neoplasm versus solid pseudopapillary neoplasm (Table 26.29)

• 30. Pancreatic neuroendocrine neoplasm versus acinar cell carcinoma (Table 26.30)

• 31. Pancreatic neuroendocrine neoplasm versus pancreatoblastoma (Table 26.31)

• 32. Useful IHC markers in differentiating pancreatic neuroendocrine tumor grade 3 from poorly differentiated neuroendocrine carcinoma (Table 26.32)

• 33. Acinar cell carcinoma versus solid pseudopapillary neoplasm (Table 26.33)

• 34. Acinar cell carcinoma versus ductal adenocarcinoma (Table 26.34)

• 35. Acinar cell carcinoma versus pancreatoblastoma (Table 26.35)

• 36. Solid pseudopapillary neoplasm versus pancreatoblastoma (Table 26.36)

• 37. Markers for hematopoietic malignancies in the pancreas (Table 26.37)

• 38. Markers for differentiating pancreatic spindle cell neoplasms (Table 26.38)

• 39. Metastases in the pancreas (Table 26.39)

• 40. Prognostic markers for pancreatic adenocarcinoma (Table 26.40)

• 41. Predictive markers for pancreatic neuroendocrine neoplasm (Table 26.41)

FormalPara Ampulla

• 42. Markers for normal ampulla of Vater (Table 26.42)

• 43. Markers for intestinal-type ampullary adenocarcinoma (Table 26.43)

• 44. Markers for pancreatobiliary-type ampullary adenocarcinoma (Table 26.44)

• 45. Intestinal-type ampullary adenocarcinoma versus pancreatobiliary-type (Table 26.45)

• 46. Ampullary adenocarcinoma versus pancreatic adenocarcinoma (Table 26.46)

• 47. What are the useful IHC markers in differentiating among ampullary normal/reactive mucosa from adenoma and adenocarcinoma (Table 26.47)

Table 26.1 Summary of applications and limitations of useful markers

Table 26.2 Summary of useful markers for common tumors

Table 26.3 Markers for normal pancreatic ducts and acini

Table 26.4 Markers for autoimmune pancreatitis

Fig. 26.1

Autoimmune pancreatitis on H&E stained slide

Fig. 26.2

Showing many IgG4-positive plasma cells

Table 26.5 Markers for ductal adenocarcinoma of the pancreas

Fig. 26.3

Invasive ductal adenocarcinoma showing loss of expression of pVHL, and normal ducts show membranous and cytoplasmic staining

Fig. 26.4

High-grade adenocarcinoma showing nuclear and cytoplasmic staining for maspin

Fig. 26.5

Nuclear and cytoplasmic positivity of S100P in ductal adenocarcinoma, whereas the normal ducts are negative. Note that only nuclear staining or nuclear and cytoplasmic staining is regarded as positive

Fig. 26.6

Strong cytoplasmic staining for IMP3 seen in ductal adenocarcinoma

Fig. 26.7

Double-staining technique (a) showing carcinoma positive for maspin (brown) and normal ducts positive for pVHL (purple). Double-staining technique (b) showing carcinoma positive for S100P (brown) and normal ducts positive for pVHL (purple)

Fig. 26.8

Ductal adenocarcinoma showing strongly positive cytoplasmic staining for MUC1

Fig. 26.9

MUC5AC

Fig. 26.10

CA19–9 is not a very useful marker since it is also expressed in normal ducts and acini as shown in this figure

Fig. 26.11

Ductal adenocarcinoma showing membranous staining for mesothelin

Fig. 26.12

Strong nuclear staining for p53 in ductal adenocarcinoma

Fig. 26.13

Ductal adenocarcinoma showing loss of expression of DPC4/SMAD4 (Fig. 26.13)

Fig. 26.14

Positive staining for DPC4/SMAD4 (Fig. 26.14). Note that inflammatory and stromal cells show nuclear positivity as an internal positive control

Table 26.6 Markers for adenosquamous carcinoma of the pancreas

Table 26.7 Markers for colloid carcinoma of the pancreas

Table 26.8 Markers for medullary carcinoma of the pancreas

Fig. 26.15

MUC2 is frequently positive in colloid carcinoma and negative in ductal adenocarcinoma

Table 26.9 Markers for undifferentiated carcinoma of the pancreas

Fig. 26.16

Medullary carcinoma on H&E-stained slide (Fig. 26.16) with loss of expression of mismatch repair (MMR) protein MSH6 (Fig. 26.17). Note that the lymphoid cells serve as an internal positive control

Fig. 26.17

Medullary carcinoma on H&E-stained slide (Fig. 26.16) with loss of expression of mismatch repair (MMR) protein MSH6 (Fig. 26.17). Note that the lymphoid cells serve as an internal positive control

Table 26.10 Markers for hepatoid carcinoma of the pancreas

Fig. 26.18

Hepatoid carcinoma of the pancreas on H&E-stained slide (Fig. 26.18), which shows positive for arginase-1 (Fig. 26.19)

Fig. 26.19

Hepatoid carcinoma of the pancreas on H&E-stained slide (Fig. 26.18), which shows positive for arginase-1 (Fig. 26.19)

Table 26.11 Markers for signet ring cell carcinoma of the pancreas

Table 26.12 Markers for undifferentiated carcinoma with osteoclast-like giant cells

Table 26.13 Markers for acinar cell carcinoma

Figs. 26.20

Undifferentiated carcinoma with osteoclast-like giant cells is shown in Fig. 26.20 on H&E-stained section. Multinucleated giant cells are positive for CD68 (Fig. 26.21), both histiocytes and tumor cells are positive for vimentin (Fig. 26.22), and tumor cells are positive for IMP3 (Fig. 26.23)

Fig. 26.21

Undifferentiated carcinoma with osteoclast-like giant cells is shown in Fig. 26.20 on H&E-stained section. Multinucleated giant cells are positive for CD68 (Fig. 26.21), both histiocytes and tumor cells are positive for vimentin (Fig. 26.22), and tumor cells are positive for IMP3 (Fig. 26.23)

Fig. 26.22

Undifferentiated carcinoma with osteoclast-like giant cells is shown in Fig. 26.20 on H&E-stained section. Multinucleated giant cells are positive for CD68 (Fig. 26.21), both histiocytes and tumor cells are positive for vimentin (Fig. 26.22), and tumor cells are positive for IMP3 (Fig. 26.23)

Fig. 26.23

Undifferentiated carcinoma with osteoclast-like giant cells is shown in Fig. 26.20 on H&E-stained section. Multinucleated giant cells are positive for CD68 (Fig. 26.21), both histiocytes and tumor cells are positive for vimentin (Fig. 26.22), and tumor cells are positive for IMP3 (Fig. 26.23)

Fig. 26.24

Acinar cell carcinoma with solid and trabecular growth pattern is shown in Fig. 26.24; and the tumor cells are diffusely positive for Bcl10 (Fig. 26.25), loss of SMAD4 expression (Fig. 26.26), and a high Ki-67 proliferative index (Fig. 26.27)

Fig. 26.25

Acinar cell carcinoma with solid and trabecular growth pattern is shown in Fig. 26.24; and the tumor cells are diffusely positive for Bcl10 (Fig. 26.25), loss of SMAD4 expression (Fig. 26.26), and a high Ki-67 proliferative index (Fig. 26.27)

Fig. 26.26

Acinar cell carcinoma with solid and trabecular growth pattern is shown in Fig. 26.24; and the tumor cells are diffusely positive for Bcl10 (Fig. 26.25), loss of SMAD4 expression (Fig. 26.26), and a high Ki-67 proliferative index (Fig. 26.27)

Fig. 26.27

Acinar cell carcinoma with solid and trabecular growth pattern is shown in Fig. 26.24; and the tumor cells are diffusely positive for Bcl10 (Fig. 26.25), loss of SMAD4 expression (Fig. 26.26), and a high Ki-67 proliferative index (Fig. 26.27)

Table 26.14 Markers for pancreatic neuroendocrine neoplasm

Fig. 26.28

Lipid-rich variant of pancreatic neuroendocrine tumor (Fig. 26.28) positive for chromogranin (Fig. 26.29)

Fig. 26.29

Lipid-rich variant of pancreatic neuroendocrine tumor (Fig. 26.28) positive for chromogranin (Fig. 26.29)

Fig. 26.30

Pancreatic neuroendocrine tumor (Fig. 26.30) with positive staining for PR (Fig. 26.31), PAX8 (Fig. 26.32), and islet-1 (Fig. 26.33)

Fig. 26.31

Pancreatic neuroendocrine tumor (Fig. 26.30) with positive staining for PR (Fig. 26.31), PAX8 (Fig. 26.32), and islet-1 (Fig. 26.33)

Fig. 26.32

Pancreatic neuroendocrine tumor (Fig. 26.30) with positive staining for PR (Fig. 26.31), PAX8 (Fig. 26.32), and islet-1 (Fig. 26.33)

Fig. 26.33

Pancreatic neuroendocrine tumor (Fig. 26.30) with positive staining for PR (Fig. 26.31), PAX8 (Fig. 26.32), and islet-1 (Fig. 26.33)

Fig. 26.34

P-NET (Fig. 26.34) with positive for PAX6 (Fig. 26.35), loss of expression of ATRX (Fig. 26.36), and intact expression of DAXX (Fig. 26.37)

Fig. 26.35

P-NET (Fig. 26.34) with positive for PAX6 (Fig. 26.35), loss of expression of ATRX (Fig. 26.36), and intact expression of DAXX (Fig. 26.37)

Fig. 26.36

P-NET (Fig. 26.34) with positive for PAX6 (Fig. 26.35), loss of expression of ATRX (Fig. 26.36), and intact expression of DAXX (Fig. 26.37)

Fig. 26.37

P-NET (Fig. 26.34) with positive for PAX6 (Fig. 26.35), loss of expression of ATRX (Fig. 26.36), and intact expression of DAXX (Fig. 26.37)

Table 26.15 Markers for solid pseudopapillary neoplasm of the pancreas

Table 26.16 Markers for pancreatoblastoma

Fig. 26.38

Solid pseudopapillary neoplasm (Fig. 26.38) showing nuclear and cytoplasmic staining for beta-catenin (Fig. 26.39), loss of E-cadherin (Fig. 26.40), and positive staining for CD10 (Fig. 26.41). Note that normal pancreatic ducts show membranous staining for beta-cadherin and E-cadherin

Fig. 26.39

Solid pseudopapillary neoplasm (Fig. 26.38) showing nuclear and cytoplasmic staining for beta-catenin (Fig. 26.39), loss of E-cadherin (Fig. 26.40), and positive staining for CD10 (Fig. 26.41). Note that normal pancreatic ducts show membranous staining for beta-cadherin and E-cadherin

Fig. 26.40

Solid pseudopapillary neoplasm (Fig. 26.38) showing nuclear and cytoplasmic staining for beta-catenin (Fig. 26.39), loss of E-cadherin (Fig. 26.40), and positive staining for CD10 (Fig. 26.41). Note that normal pancreatic ducts show membranous staining for beta-cadherin and E-cadherin

Fig. 26.41

Solid pseudopapillary neoplasm (Fig. 26.38) showing nuclear and cytoplasmic staining for beta-catenin (Fig. 26.39), loss of E-cadherin (Fig. 26.40), and positive staining for CD10 (Fig. 26.41). Note that normal pancreatic ducts show membranous staining for beta-cadherin and E-cadherin

Table 26.17 Markers for serous cystadenoma

Fig. 26.42

Solid variant of serous microcystic adenoma (Fig. 26.42) positive for pVHL (Fig. 26.43), MUC6 (Fig. 26.44), and inhibin-alpha (Fig. 26.45)

Fig. 26.43

Solid variant of serous microcystic adenoma (Fig. 26.42) positive for pVHL (Fig. 26.43), MUC6 (Fig. 26.44), and inhibin-alpha (Fig. 26.45)

Fig. 26.44

Solid variant of serous microcystic adenoma (Fig. 26.42) positive for pVHL (Fig. 26.43), MUC6 (Fig. 26.44), and inhibin-alpha (Fig. 26.45)

Fig. 26.45

Solid variant of serous microcystic adenoma (Fig. 26.42) positive for pVHL (Fig. 26.43), MUC6 (Fig. 26.44), and inhibin-alpha (Fig. 26.45)

Table 26.18 Markers for mucinous cystic neoplasm

Table 26.19 Markers for intraductal papillary mucinous neoplasm

Table 26.20 Markers for intraductal oncocytic papillary neoplasm

Table 26.21 Markers for pancreatic intraepithelial neoplasia 1 and 2

Table 26.22 Markers for pancreatic intraepithelial neoplasia 3

Table 26.23 Markers for intraductal tubulopapillary neoplasm of the pancreas

Table 26.24 Markers for chronic pancreatitis

Table 26.25 Ductal adenocarcinoma versus chronic pancreatitis

Table 26.26 Ductal adenocarcinoma versus intrahepatic cholangiocarcinoma

Fig. 26.46

Intrahepatic cholangiocarcinoma (Fig. 26.46) with positive staining for pVHL (Fig. 26.47), C-reactive protein (Fig. 26.48), and albumin (focal positivity) by RNA ISH (Fig. 26.49)

Fig. 26.47

Intrahepatic cholangiocarcinoma (Fig. 26.46) with positive staining for pVHL (Fig. 26.47), C-reactive protein (Fig. 26.48), and albumin (focal positivity) by RNA ISH (Fig. 26.49)

Fig. 26.48

Intrahepatic cholangiocarcinoma (Fig. 26.46) with positive staining for pVHL (Fig. 26.47), C-reactive protein (Fig. 26.48), and albumin (focal positivity) by RNA ISH (Fig. 26.49)

Fig. 26.49

Intrahepatic cholangiocarcinoma (Fig. 26.46) with positive staining for pVHL (Fig. 26.47), C-reactive protein (Fig. 26.48), and albumin (focal positivity) by RNA ISH (Fig. 26.49)

Table 26.27 Useful IHC markers in differentiating well-differentiated neuroendocrine tumors from pancreatic islets/islet cell hyperplasia

Table 26.28 Useful IHC markers in differentiating pancreatic neuroendocrine tumors from well-differentiated neuroendocrine tumors of other organs

Table 26.29 Pancreatic neuroendocrine tumor versus solid pseudopapillary neoplasm

Table 26.30 Pancreatic neuroendocrine neoplasm versus acinar cell carcinoma

Table 26.31 Pancreatic neuroendocrine tumor versus pancreatoblastoma

Table 26.32 Useful IHC markers in differentiating pancreatic well-differentiated neuroendocrine tumor grade 3 from poorly differentiated neuroendocrine carcinoma

Table 26.33 Acinar cell carcinoma versus solid pseudopapillary neoplasm

Table 26.34 Acinar cell carcinoma versus ductal adenocarcinoma

Table 26.35 Acinar cell carcinoma versus pancreatoblastoma

Table 26.36 Solid pseudopapillary neoplasm versus pancreatoblastoma

Table 26.37 Markers for hematopoietic malignancies in the pancreas

Table 26.38 Markers for differentiating pancreatic spindle cell neoplasms

Fig. 26.50

Pancreatic PEComa with a mixed population of spindle and epithelioid cells (Fig. 26.50). The neoplastic cells are diffusely positive for SMA (Fig. 26.51), focally positive for HMB-45 (Fig. 26.52), with a low Ki-67 index (Fig. 26.53)

Fig. 26.51

Pancreatic PEComa with a mixed population of spindle and epithelioid cells (Fig. 26.50). The neoplastic cells are diffusely positive for SMA (Fig. 26.51), focally positive for HMB-45 (Fig. 26.52), with a low Ki-67 index (Fig. 26.53)

Fig. 26.52

Pancreatic PEComa with a mixed population of spindle and epithelioid cells (Fig. 26.50). The neoplastic cells are diffusely positive for SMA (Fig. 26.51), focally positive for HMB-45 (Fig. 26.52), with a low Ki-67 index (Fig. 26.53)

Fig. 26.53

Pancreatic PEComa with a mixed population of spindle and epithelioid cells (Fig. 26.50). The neoplastic cells are diffusely positive for SMA (Fig. 26.51), focally positive for HMB-45 (Fig. 26.52), with a low Ki-67 index (Fig. 26.53)

Table 26.39 Metastases in the pancreas

Table 26.40 Prognostic markers for pancreatic adenocarcinoma

Table 26.41 Predictive markers for pancreatic neuroendocrine neoplasm

Table 26.42 Markers for normal ampulla of Vater

Table 26.43 Markers for intestinal-type ampullary adenocarcinoma

Table 26.44 Markers for pancreatobiliary-type ampullary adenocarcinoma

Table 26.45 Ampullary adenocarcinoma, intestinal type versus pancreatobiliary type

Table 26.46 Ampullary adenocarcinoma versus pancreatic ductal adenocarcinoma

Table 26.47 Useful IHC markers in differentiating among ampullary normal/reactive mucosa, adenoma, and adenocarcinoma

FormalPara Note for all tables

“+”—usually >70% of cases are positive; “−”—<5% of cases are positive; “+ or −”—usually >50% of cases are positive; “− or +”—<50% of cases are positive: ND—no data available; V—variable.