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pancreatic endocrine tumors

Sunday 3 October 2004

Digital case

- JRC:475 : Islet cell tumor (glucagonoma)
- JRC:476 : Islet cell tumor (VIPoma)
- JRC:14919 : Pancreatic endocrine tumor (NOS)
- JRC:18769 : Pancreatic islet cell carcinoma, metastatic to liver; probable Zollinger-Ellison syndrome.
- JRC:18770 : Islet cell tumor (beta cell type)

Definition: Pancreatic endocrine tumors (PETs) account for 1% to 2% of all pancreatic tumors. In recent years, small, asymptomatic tumors are increasingly detected by modern imaging techniques.


- insulinoma
- glucagonoma
- VIPoma


- multiple endocrine neoplasia syndromes (MENs)
- neurofibromatosis type 1 (16861979)


- hormone expression

  • Pancreatic neuroendocrine tumors (PanNETs) produce variable peptide hormones.
  • The expression status of some hormones has been linked to the biological and clinical behaviors of PanNETs.
  • Gastrin expression, increased age, and tumor grade were negative prognostic factors in multivariate analysis.
  • As the number of hormones expressed increased, the survival rate of PanNET patients increased.
  • PanNET patients showing insulin or glucagon-like peptide 1 expression and increased numbers of expressed hormones had a better survival outcome by univariate analysis, whereas gastrin expression was a negative prognostic indicator in surgically resected PanNET patients. (25602797)

- PAX8 expression in well-differentiated pancreatic endocrine tumors (PETs) (20414099)

  • PAXs (paired box) genes encode a family of transcription factors that regulate organogenesis and cell-lineage specification in multiple organ systems.
  • In the pancreas, PAXs proteins play a critical role in islet cell differentiation. We recently observed that islet cells show strong, diffuse staining for PAX8 by immunohistochemistry.
  • PAX8 is expressed in normal pancreatic islet cells and in a high proportion of primary and metastatic PETs.
  • In the GI tract, PAX8 is positive in the majority of duodenal and rectal carcinoid tumors, and in a minor subset of appendiceal and gastric carcinoids.
  • PAX8 expression is absent in ileal and pulmonary carcinoid tumors.
  • PAX8 immunostaining may be helpful in determining the primary site for a WDNET metastatic to the liver, as ileal (PAX8 negative) and pancreatic (PAX8 positive) tumors most often present as a metastasis from an occult primary.
  • PAX8 may also be a prognostic marker in PETs, as loss of expression is associated with malignant behavior.


PETs may metastasize years after resection. Many proposals have been made to predict their biologic behavior.

It is difficult to predict the biologic behavior of pancreatic endocrine tumors in absence of metastases or invasion into adjacent organs.

The World Health Organization (WHO) has proposed in 2004 size, angioinvasion, mitotic activity, and MIB1 proliferation index as prognostic criteria.

The stratification of the patients into 4 risk groups according to the 2004 WHO classification is reliable with regard to both time span to relapse and tumor-specific death.

The 2004 WHO classification with 4 risk groups is very reliable for predicting both disease-free survival and the time span until tumor-specific death. (18059224)

In a multivariate analysis, the CK19 status is shown to be independent of the WHO criteria. CK19 staining is a potential additional prognostic marker independent from the WHO criteria for pancreatic endocrine tumors. (18059224)

By contrast, the prognostic significance of COX2, p27, and CD99 could not be confirmed. (18059224)

The most recent World Health Organization (WHO) classification evolved from an earlier proposal by Capella et al. The WHO classification is based on expert opinion and only limited published data.

The clinicopathologic criteria used include:
- presence of metastasis
- gross invasion
- tumor diameter
- angioinvasion
- mitoses
- proliferative index (based on the MIB1 reaction).

According to these criteria, PETs are classified into 4 groups (18059224):
- well differentiated PETs (WHO 1a): in the absence of all adverse
- well differentiated PETs of uncertain behavior (WHO 1b), in the presence of tumor diameter @<@ 2cm or mitoses/10 high-power field (HPF) or angioinvasion or MIB1 index >2%,
- well-differentiated pancreatic endocrine carcinomas (WHO 2) in the presence of gross local invasion or metastasis),
- poorly differentiated pancreatic endocrine carcinomas (WHO 3) in the presence of > 10 mitoses/10HPF).

The uncommon occurrence of PETs, the small number of patients included in studies and the compulsory long follow-up have precluded a validation of this
classification system, which is, therefore, not fully accepted by all pathologists. Especially, the necessity of the WHO 1b group is disputed.

Several studies have recently reported the prognostic significance of a variety of immunohistochemical markers, such as CK19, COX2 p27and CD99. These results have not been verified in independent patient cohorts or controversial data were reported.


- Clinicopathologic and Prognostic Significance of Multiple Hormone Expression in Pancreatic Neuroendocrine Tumors. Kim JY, Kim MS, Kim KS, Song KB, Lee SH, Hwang DW, Kim KP, Kim HJ, Yu E, Kim SC, Jang HJ, Hong SM. Am J Surg Pathol. 2015 Jan 19. PMID: 25602797

- PAX8 Expression in well-differentiated pancreatic endocrine tumors: correlation with clinicopathologic features and comparison with gastrointestinal and pulmonary carcinoid tumors. Long KB, Srivastava A, Hirsch MS, Hornick JL. Am J Surg Pathol. 2010 May;34(5):723-9. PMID: 20414099

- WHO 2004 criteria and CK19 are reliable prognostic markers in pancreatic endocrine tumors. Schmitt AM, Anlauf M, Rousson V, Schmid S, Kofler A, Riniker F, Bauersfeld J, Barghorn A, Probst-Hensch NM, Moch H, Heitz PU, Kloeppel G, Komminoth P, Perren A. Am J Surg Pathol. 2007 Nov;31(11):1677-82. PMID: 18059224

- Pancreatic endocrine tumors are a rare manifestation of the neurofibromatosis type 1 phenotype: molecular analysis of a malignant insulinoma in a NF-1 patient. Perren A, Wiesli P, Schmid S, Montani M, Schmitt A, Schmid C, Moch H, Komminoth P. Am J Surg Pathol. 2006 Aug;30(8):1047-51. PMID: 16861979

- Chromogranin A in human neuroendocrine tumors: an immunohistochemical study with region-specific antibodies. Portel-Gomes GM, Grimelius L, Johansson H, Wilander E, Stridsberg M. Am J Surg Pathol. 2001 Oct;25(10):1261-7. PMID: 11688460

- Multihormone-producing islet cell tumor of the pancreas associated with somatostatin-immunoreactive amyloid: immunohistochemical and immunoelectron microscopic studies. Takahashi M, Hoshii Y, Kawano H, Setoguchi M, Gondo T, Yamashita Y, Nakayasu K, Kamei T, Ishihara T. Am J Surg Pathol. 1998 Mar;22(3):360-7. PMID: 9500779

- Immunodetection of proliferating cell nuclear antigen assesses the growth fraction and predicts malignancy in endocrine tumors of the pancreas. Pelosi G, Zamboni G, Doglioni C, Rodella S, Bresaola E, Iacono C, Serio G, Iannucci A, Scarpa A. Am J Surg Pathol. 1992 Dec;16(12):1215-25. PMID: 1281387

- Immunological studies on the occurrence and properties of chromogranin A and B and secretogranin II in endocrine tumors. Weiler R, Fischer-Colbrie R, Schmid KW, Feichtinger H, Bussolati G, Grimelius L, Krisch K, Kerl H, O’Connor D, Winkler H. Am J Surg Pathol. 1988 Nov;12(11):877-84. PMID: 2847571