Advertisement

Immunohistochemistry and In Situ Hybridization in Pancreatic Neoplasia

  • Robb E. Wilentz
  • Ayman Rahman
  • Pedram Argani
  • Christine Iacobuzio-Donahue
Part of the Methods in Molecular Medicine™ book series (MIMM, volume 103)

Abstract

There are many types of pancreatic neoplasms. Pathologic examination, which includes both routine (e.g., hematoxylin-and-eosin staining) and ancillary (e.g., immunohistochemistry and in situ hybridization) techniques, is essential in correctly typing a pancreatic neoplasm. This chapter focuses on the use of immunohistochemistry and in situ hybridization in the differentiation of pancreatic neoplasms. The materials and methods of these two techniques are described in detail.

Key Words

Pancreatic cancer pancreas ductal adenocarcinoma immunohistochemistry in situ hybridization 

References

  1. 1.
    Cubilla, A. L. and Fitzgerald, P. J. (1984) Tumors of the Exocrine Pancreas, 2nd Series ed. Washington, D. C.: Armed Forces Institute of Pathology.Google Scholar
  2. 2.
    O’Connor, T. P., Wade, T. P., Sunwoo, Y. C., et al. (1992) Small cell undifferentiated carcinoma of the pancreas. Report of a patient with tumor marker studies. Cancer 70, 1514–1519.CrossRefGoogle Scholar
  3. 3.
    Kim, J., Ho, S. B., Montgomery, C. K., and Kim, Y. S. (1990) Cell lineage markers in human pancreatic cancer. Cancer 66, 2134–2143.PubMedCrossRefGoogle Scholar
  4. 4.
    Loy, T. S., Springer, D., Chapman, R. K., Diaz-Arias, A. A., Bulatao, I. S., and Bickel, J. T. (1991) Lack of specificity of monoclonal antibody B72.3 in distinguishing chronic pancreatitis from pancreatic adenocarcinoma. Am. J. Clin. Pathol. 96, 684–688.PubMedGoogle Scholar
  5. 5.
    Shimizu, M., Saitoh, Y., Ohyanagi, H., and Itoh, H. (1990) Immunohistochemical staining of pancreatic cancer with CA19-9, KM01, unabsorbed CEA, and absorbed CEA. Arch. Pathol. Lab. Med. 114, 195–200.PubMedGoogle Scholar
  6. 6.
    Hahn, S. A., Schutte, M., Hoque, A. T. M. S., et al. (1996) DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271, 350–353.PubMedCrossRefGoogle Scholar
  7. 7.
    Hahn, S. A., Hoque, A. T. M. S., Moskaluk, C. A., et al. (1996) Homozygous deletion map at 18q21.1 in pancreatic cancer. Cancer Res. 56, 490–494.PubMedGoogle Scholar
  8. 8.
    Schutte, M., Hruban, R. H., Hedrick, L., et al. (1996) DPC4 gene in various tumor types. Cancer Res. 56, 2527–2530.PubMedGoogle Scholar
  9. 9.
    Rozenblum, E., Schutte, M., Goggins, M., et al. (1997) Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res. 57, 1731–1734.PubMedGoogle Scholar
  10. 10.
    Wilentz, R. E., Su, G. H., Dai, J. L., et al. (2000) Immunohistochemical labeling for Dpc4 mirrors genetic status in pancreatic: A new marker of DPC4 inactivation. Am. J. Pathol. 156, 37–43.PubMedCrossRefGoogle Scholar
  11. 11.
    Wilentz, R. E., Iacobuzio-Donahue, C. A., Argani, P., et al. (2000) Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: Evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res. 60, 2002–2006.PubMedGoogle Scholar
  12. 12.
    Goggins, M., Offerhaus, G. J. A., Hilgers, W., et al. (1998) Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology: Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+. Am. J. Pathol. 152, 1501–1507.PubMedGoogle Scholar
  13. 13.
    Wilentz, R. E., Goggins, M., Redston, M., et al. (2000) Genetic, immunohistochemical, and clinical features of medullary carcinomas of the pancreas: A newly described and characterized entity. Am. J. Pathol. 156, 1641–1651.PubMedCrossRefGoogle Scholar
  14. 14.
    Miller, J. R., Baggenstoss, A. H., and Comfort, M. W. (1951) Carcinoma of the pancreas. Effect of histological type and grade of malignancy on its behavior. Cancer 4, 233–241.PubMedCrossRefGoogle Scholar
  15. 15.
    Chen, J. and Baithun, S. I. (1985) Morphological study of 391 cases of exocrine pancreatic tumours with special reference to the classification of exocrine pancreatic carcinoma. J. Pathol. 146, 17–29.PubMedCrossRefGoogle Scholar
  16. 16.
    Morohoshi, T., Held, G., and Klöppel, G. (1983) Exocrine pancreatic tumours and their histological classification. A study based on 167 autopsy and 97 surgical cases. Histopathology 7, 645–661.PubMedCrossRefGoogle Scholar
  17. 17.
    Hoorens, A., Lemoine, N. R., McLellan, E., et al. (1993) Pancreatic acinar cell carcinoma: An analysis of cell lineage markers, p53 expression, and Ki-ras mutation. Am. J. Pathol. 143, 685–698.PubMedGoogle Scholar
  18. 18.
    Klimstra, D. S., Heffess, C. S., Oertel, J. E., and Rosai, J. (1992) Acinar cell carcinoma of the pancreas: A clinicopathologic study of 28 cases. Am. J. Surg. Pathol. 16, 815–837.PubMedCrossRefGoogle Scholar
  19. 19.
    MacMahon, H. E., Brown, P. A., and Shen, E. M. (1965) Acinar cell carcinoma of the pancreas with subcutaneous fat necrosis. Gastroenterology 49, 555–559.PubMedGoogle Scholar
  20. 20.
    Mah, P., Loo, D. C., and Tock, E. P. C. (1974) Pancreatic acinar cell carcinoma in childhood. Am. J. Dis. Child. 128, 101–104.PubMedGoogle Scholar
  21. 21.
    Robertson, J. C. and Eeles, G. H. (1970) Syndrome associated with pancreatic acinar cell carcinoma. Br. Med. J. 2, 708–709.PubMedCrossRefGoogle Scholar
  22. 22.
    Stamm, B., Burger, H., and Hollinger, A. (1987) Acinar cell cystadenocarcinoma of the pancreas. Cancer 60, 2542–2547.PubMedCrossRefGoogle Scholar
  23. 23.
    Ulich, T., Cheng, L., and Lewin, K. J. (1982) Acinar-endocrine cell tumor of the pancreas. Report of a pancreatic tumor containing both zymogen and neuroendocrine granules. Cancer 50, 2099–2105.PubMedCrossRefGoogle Scholar
  24. 24.
    Webb, J. N. (1977) Acinar cell neoplasms of the exocrine pancreas. J. Clin. Path. 30, 103–112.PubMedCrossRefGoogle Scholar
  25. 25.
    Abraham, S. C., Wu, T. T., Hruban, R. H., et al. (2002) Genetic and immunohistochemical analysis of pancreatic acinar cell carcinoma: Frequent allelic loss on chromosome 11p and alterations in the APC/beta-catenin pathway. Am. J. Pathol. 160, 953–962.PubMedCrossRefGoogle Scholar
  26. 26.
    Auger, C. (1947) Acinous cell carcinoma of the pancreas with extensive fat necrosis. Arch. Pathol. 43, 400–405.Google Scholar
  27. 27.
    Burns, W. A., Matthews, M. J., Hamosh, M., Weide, G. V., Blum, R., and Johnson, F. B. (1974) Lipase-secreting acinar cell carcinoma of the pancreas with polyarthropathy. A light and electron microscopic, histochemical, and biochemical study. Cancer 33, 1002–1009.PubMedCrossRefGoogle Scholar
  28. 28.
    Osborne, R. R. (1950) Functioning acinous cell carcinoma of the pancreas accompanied with widespread focal fat necrosis. Arch. Intern. Med. 85, 933–943.Google Scholar
  29. 29.
    Hruban, R. H., Molina, J. M., Reddy, M. N., and Boitnott, J. K. (1987) A neoplasm with pancreatic and hepatocellular differentiation presenting with subcutaneous fat necrosis. Am. J. Clin. Pathol. 88, 639–645.PubMedGoogle Scholar
  30. 30.
    Belsky, H. and Cornell, N. W. (1955) Disseminated focal fat necrosis following radical pancreatico-duodenectomy for acinous carcinoma of head of pancreas. Ann. Surg. 141, 556–562.PubMedCrossRefGoogle Scholar
  31. 31.
    Buchino, J. J., Castello, F. M., and Nagaraj, H. S. (1984) Pancreatoblastoma. A histochemical and ultrastructural analysis. Cancer 53, 963–969.PubMedCrossRefGoogle Scholar
  32. 32.
    Benjamin, E. and Wright, D. H. (1980) Adenocarcinoma of the pancreas of childhood: A report of two cases. Histopathology 4, 87–104.PubMedCrossRefGoogle Scholar
  33. 33.
    Frable, W. J., Still, W. J. S., and Kay, S. (1971) Carcinoma of the pancreas, infantile type. A light and electron microscopic study. Cancer 27, 667–673.PubMedCrossRefGoogle Scholar
  34. 34.
    Horie, A., Yano, Y., Kotoo, Y., and Miwa, A. (1977) Morphogenesis of pancreatoblastoma, infantile carcinoma of the pancreas. Report of two cases. Cancer 39, 247–254.PubMedCrossRefGoogle Scholar
  35. 35.
    Taxy, J. B. (1976) Adenocarcinoma of the pancreas in childhood. Report of a case and a review of the English language literature. Cancer 37, 1508–1518.PubMedCrossRefGoogle Scholar
  36. 36.
    Tsukimoto, I., Watanabe, K., Lin, J., and Nakajima, T. (1973) Pancreatic carcinoma in children in Japan. Cancer 31, 1203–1207.PubMedCrossRefGoogle Scholar
  37. 37.
    Abraham, S. C., Wu, T. T., Klimstra, D. S., et al. (2001) Distinctive molecular genetic alterations in sporadic and familial adenomatous polyposis-associated pancreatoblastomas: Frequent alterations in the APC/beta-catenin pathway and chromosome 11p. Am. J. Pathol. 159, 1619–1627.PubMedCrossRefGoogle Scholar
  38. 38.
    Albores-Saavedra, J., Angeles-Angeles, A., Nadji, M., Henson, D. E., and Alvarez, L. (1987) Mucinous cystadenocarcinoma of the pancreas. Morphologic and immunocytochemical observations. Am. J. Surg. Pathol. 11, 11–20.PubMedCrossRefGoogle Scholar
  39. 39.
    Yu, H. C. and Shetty, J. (1985) Mucinous cystic neoplasm of the pancreas with high carcinoembryonic antigen. Arch. Pathol. Lab. Med. 109, 375–377.PubMedGoogle Scholar
  40. 40.
    Yamaguchi, K. and Enjoji, M. (1987) Cystic neoplasms of the pancreas. Gastroenterology 92, 1934–1943.PubMedGoogle Scholar
  41. 41.
    Iacobuzio-Donahue, C. A., Wilentz, R. E., Argani, P., et al. (2000) Dpc4 protein in mucinous cystic neoplasms of the pancreas: Frequent loss of expression in invasive carcinomas suggests a role in genetic progression. Am. J. Surg. Pathol. 24, 1544–1548.PubMedCrossRefGoogle Scholar
  42. 42.
    Iacobuzio-Donahue, C. A., Klimstra, D., Adsay, N. V., et al. (2000) DPC-4 protein is expressed in virtually all human intraductal papillary mucinous neoplasms of the pancreas: Comparison with conventional ductal carcinomas. Am. J. Pathol. 157, 755–761.PubMedCrossRefGoogle Scholar
  43. 43.
    Learmonth, G. M., Price, S. K., Visser, A. E., and Emms, M. (1985) Papillary and cystic neoplasm of the pancreas—an acinar cell tumour? Histopathology 9, 63–79.PubMedCrossRefGoogle Scholar
  44. 44.
    Boor, P. J. and Swanson, M. R. (1979) Papillary-cystic neoplasm of the pancreas. Am. J. Surg. Pathol. 3, 69–75.PubMedCrossRefGoogle Scholar
  45. 45.
    Wilentz, R. E., Chung, C. H., Sturm, P. D. J., et al. (1998) K-ras mutations in the duodenal fluid of patients with pancreatic carcinoma. Cancer 82, 96–103.PubMedCrossRefGoogle Scholar
  46. 46.
    Klöppel, G., Morohoshi, T., John, H. D., et al. (1981) Solid and cystic acinar cell tumour of the pancreas. A tumor in young women with favorable prognosis. Virchows Arch. [A] 392, 171–183.CrossRefGoogle Scholar
  47. 47.
    Schlosnagle, D. C. and Campbell, W. G. (1981) The papillary and solid neoplasm of the pancreas: A report of two cases with electron microscopy, one containing neurosecretory granules. Cancer 47, 2603–2610.PubMedCrossRefGoogle Scholar
  48. 48.
    Riela, A., Zinsmeister, A. R., Melton, L. J. I., Weiland, L. H., and DiMagno, E. (1992) Increasing incidence of pancreatic cancer among women in Olmsted County, Minnesota, 1940 through 1988. Mayo Clin. Proc. 67, 839–845.PubMedGoogle Scholar
  49. 49.
    Morrison, D. M., Jewell, L. D., McCaughey, W. T. E., Danyluk, J., Shnitka, T. K., and Manickavel, V. (1984) Papillary cystic tumor of the pancreas. Arch. Pathol. Lab. Med. 108, 723–727.PubMedGoogle Scholar
  50. 50.
    Kuo, T.-T., Su, I.-J., and Chien, C.-H. (1984) Solid and papillary neoplasm of the pancreas. Report of three cases from Taiwan. Cancer 54, 1469–1474.PubMedCrossRefGoogle Scholar
  51. 51.
    Hamoudi, A. B., Misugi, K., Grosfeld, J. L., and Reiner, C. B. (1970) Papillary epithelial neoplasm of pancreas in a child. Report of a case with electron microscopy. Cancer 26, 1126–1134.PubMedCrossRefGoogle Scholar
  52. 52.
    Abraham, S. C., Klimstra, D. S., Wilentz, R. E., Wu, T. T., and Hruban, R. H. (2002) Solid-pseudopapillary tumors of the pancreas frequently harbor alterations in the APC/β-catenin pathway. Am. J. Pathol. 160, 1361–1369.PubMedCrossRefGoogle Scholar
  53. 53.
    La Rosa, S., Sessa, F., Capella, C., et al. (1996) Prognostic criteria in nonfunctioning pancreatic endocrine tumors. Virchows Arch. 429, 323–333.PubMedCrossRefGoogle Scholar
  54. 54.
    Wilson, B. S. and Lloyd, R. V. (1984) Detection of chromogranin in neuroendocrine cells with a monoclonal antibody. Am. J. Pathol. 115, 458–468.PubMedGoogle Scholar
  55. 55.
    Chejfec, G., Falkmer, S., Grimelius, L., et al. (1987) Synaptophysin. A new marker for pancreatic neuroendocrine tumors. Am. J. Surg. Pathol. 11, 241–247.PubMedCrossRefGoogle Scholar
  56. 56.
    Hoefler, H., Denk, H., Lackinger, E., Helleis, G., Polak, J. M., and Heitz, P. U. (1986) Immunocytochemical demonstration of intermediate filament cytoskeleton proteins in human endocrine tissues and (neuro-) endocrine tumors. Virchows Arch. [A] 409, 609–626.CrossRefGoogle Scholar
  57. 57.
    Perez, M. A., Saul, S. H., and Trojanowski, J. Q. (1990) Neurofilament and chromogranin expression in normal and neoplastic neuroendocrine cells of the human gastrointestinal tract and pancreas. Cancer 65, 1219–1227.PubMedCrossRefGoogle Scholar
  58. 58.
    Klöppel, G. and Heitz, P. U. (1988) Pancreatic endocrine tumors. Pathol. Res. Pract. 183, 155–168.PubMedGoogle Scholar
  59. 59.
    Heitz, P. U., Kasper, M., Polak, J. M., and Klöppel, G. (1982) Pancreatic endocrine tumors: Immunocytochemical analysis of 125 tumors. Hum. Pathol. 13, 263–271.PubMedCrossRefGoogle Scholar
  60. 60.
    Kimura, W., Kuroda, A., and Morioka, Y. (1991) Clinical pathology of endocrine tumors of the pancreas. Analysis of autopsy cases. Dig. Dis. Sci. 36, 933–942.PubMedCrossRefGoogle Scholar
  61. 61.
    Capella, C., Heitz, P. U., Höfler, H., Solcia, E., and Klöppel, G. (1995) Revised classification of neuroendocrine tumors of the lung, pancreas and gut. Virchows Arch. 425, 547–560.PubMedCrossRefGoogle Scholar
  62. 62.
    Kruseman, A. C., Knijnenburg, G., de la Riviere, G. B., and Bosman, F. T. (1978) Morphology and immunohistochemically-defined endocrine function of pancreatic islet cell tumours. Histopathology 2, 389–399.PubMedCrossRefGoogle Scholar
  63. 63.
    Reyes, C. V. and Wang, T. (1981) Undifferentiated small cell carcinoma of the pancreas: A report of five cases. Cancer 47, 2500–2502.PubMedCrossRefGoogle Scholar
  64. 64.
    Hobbs, R. D., Stewart, A. F., Ravin, N. D., and Carter, D. (1984) Hypercalcemia in small cell carcinoma of the pancreas. Cancer 53, 1552–1554.PubMedCrossRefGoogle Scholar
  65. 65.
    Ibrahim, N. B. N., Briggs, J. C., and Corbishley, C. M. (1984) Extrapulmonary oat cell carcinoma. Cancer 54, 1645–1661.PubMedCrossRefGoogle Scholar
  66. 66.
    Morant, R. and Bruckner, H. W. (1989) Complete remission of refractory small cell carcinoma of the pancreas with cisplatin and etoposide. Cancer 64, 2007–2009.PubMedCrossRefGoogle Scholar
  67. 67.
    Solcia, E., Capella, C., and Klöppel, G. (1997) Atlas of tumor pathology: Tumors of the pancreas, 3rd Series ed. Washington, D. C.: Armed Forces Institute of Pathology.Google Scholar
  68. 68.
    Sessa, F., Bonato, M., Frigerio, B., et al. (1990) Ductal cancers of the pancreas frequently express markers of gastrointestinal epithelial cells. Gastroenterology 98, 1655–1665.PubMedGoogle Scholar
  69. 69.
    de Alava, E., Torramadé, J., and Vázquez, J. J. (1993) Leiomyosarcoma of the pancreas. Virchows Arch. [A] 422, 419–422.CrossRefGoogle Scholar
  70. 70.
    Elliott, T. E., Albertazzi, V. J., and Danto, L. A. (1980) Pancreatic liposarcoma. Case report with review of retroperitoneal liposarcomas. Cancer 45, 1720–1723.PubMedCrossRefGoogle Scholar
  71. 71.
    Ishikawa, O., Matsui, Y., Aoki, Y., Iwanaga, T., Terasawa, T., and Wada, A. (1981) Leiomyosarcoma of the pancreas. Report of a case and review of the literature. Am. J. Surg. Pathol. 5, 597–602.PubMedCrossRefGoogle Scholar
  72. 72.
    Pascal, R. R., Sullivan, L., Hauser, L., and Ferzli, G. (1989) Primary malignant fibrous histiocytoma of the pancreas. Hum. Pathol. 20, 1215–1217.PubMedCrossRefGoogle Scholar
  73. 73.
    Ross, C. F. (1951) Leiomyosarcoma of the pancreas. Br. J. Surg. 39, 53–56.PubMedCrossRefGoogle Scholar
  74. 74.
    Suster, S., Phillips, M., and Robinson, M. J. (1989) Malignant fibrous histiocytoma (giant cell type) of the pancreas. A distinctive variant of osteoclast-type giant cell tumor of the pancreas. Cancer 64, 2303–2308.PubMedCrossRefGoogle Scholar
  75. 75.
    Danner, D. B., Hruban, R. H., Pitt, H. A., Hayashi, R., Griffin, C. A., and Perlman, E. J. (1994) Primitive neuroectodermal tumor arising in the pancreas. Mod. Pathol. 7, 200–204.PubMedGoogle Scholar
  76. 76.
    Urban, B. A., Fishman, E. K., Hruban, R. H., and Cameron, J. L. (1992) CT findings in cystic schwannoma of the pancreas. J. Comput. Assist. Tomogr. 16, 492–496.PubMedCrossRefGoogle Scholar
  77. 77.
    Brown, D., Lydon, J., McLaughlin, M., Stuart-Tilley, A., Tyszkowski, R., and Alper, S. (1996) Antigen retrieval in cryostat tissue sections and cultured cells by treatment with sodium dodecyl sulfate (SDS). Histochem. Cell Biol. 105, 261–267.Google Scholar
  78. 78.
    Iacobuzio-Donahue, C. A., Ryu, B., Hruban, R. H., and Kern, S. E. (2002) Exploring the host desmoplastic response to pancreatic carcinoma: Gene expression of stromal and neoplastic cells at the site of primary invasion. Am. J. Pathol. 160, 91–99.PubMedCrossRefGoogle Scholar
  79. 79.
    Kononen, J., Bubendorf, L., Kallioniemi, A., et al. (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat. Med. 4, 844–847.PubMedCrossRefGoogle Scholar
  80. 80.
    Mucci, N. R., Akdas, G., Manely, S., and Rubin, M. A. (2000) Neuroendocrine expression in metastatic prostate cancer: Evaluation of high throughput tissue microarrays to detect heterogeneous protein expression. Hum. Pathol. 31, 406–414.PubMedCrossRefGoogle Scholar
  81. 81.
    Kallioniemi, O. P., Wagner, U., Kononen, J., and Sauter, G. (2001) Tissue microarray technology for high-throughput molecular profiling of cancer. Hum. Mol. Genet. 10, 657–662.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2005

Authors and Affiliations

  • Robb E. Wilentz
    • 1
  • Ayman Rahman
    • 1
  • Pedram Argani
    • 1
  • Christine Iacobuzio-Donahue
    • 1
  1. 1.Department of PathologyThe Johns Hopkins University School of MedicineBaltimore

Personalised recommendations