Islet 1 (Isl1) expression is a reliable marker for pancreatic endocrine tumors and their metastases.

BACKGROUND: Tracing the origin of a metastasis of a neuroendocrine carcinoma is a challenge. The transcription factors Cdx2 and TTF1 have been found to be helpful in identifying well-differentiated neuroendocrine tumors of gastrointestinal and pulmonary origin, respectively. So far, such a marker is lacking for pancreatic neuroendocrine tumors (PETs) and metastases thereof. Islet1 (Isl1) is a transcription factor expressed in pancreatic islet cells. The aim of this study was (1) to test the specificity and sensitivity of Isl1 as a marker of PETs, and (2) to test the specificity and sensitivity of a panel of markers, including Isl1, Cdx2, and TTF1, for the localization of the primary. DESIGN: One hundred eighty-eight primary gastroenteropancreatic and pulmonary endocrine tumors and 49 metastases thereof were examined. Immunohistochemistry using antibodies directed against Isl1, Cdx2, and TTF1 was performed and the staining results were scored semiquantitatively. RESULTS: Isl1 proved to be a highly specific marker for pancreatic endocrine tumors. In 84 primary PET its specificity was 78.4% (sensitivity 74.3%) and in 18 metastases of PET the specificity reached 100% (sensitivity 77.8%). Strong Cdx2 staining showed a specificity for gastrointestinal origin of 83.9% (sensitivity 82%) in primary tumors and of 100% (sensitivity 40%) in metastases. Including weakly positive tumors lead to a decreased specificity but an increased sensitivity. TTF1 expression was detected in 2 PET and 1 ileal primary tumor only and was absent in all metastases of gastroenteropancreatic endocrine tumors. CONCLUSIONS: Isl1 is a reliable marker of pancreatic endocrine tumors and metastases thereof. It shows a comparable sensitivity and specificity as Cdx2 as a marker of ileal and appendiceal neuroendocrine tumors and their metastases. TTF1 is very rarely expressed in well-differentiated gastroentero-PETs. Therefore, the panel of Isl1, Cdx2, and TTF1 seems useful for examining metastases of well-differentiated endocrine carcinomas of unknown origin.

WHO 2004 criteria and CK19 are reliable prognostic markers in pancreatic endocrine tumors.

BACKGROUND: 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. Our aim was to test retrospectively the predictive value of these 2004 WHO criteria and of CK19, CD99, COX2, and p27 immunohistochemistry in a large series of patients with long-term follow-up. DESIGN: The histology of 216 pancreatic endocrine tumor specimens was reviewed and the tumors were reclassified according to the 2004 WHO classification. The prognostic value of the WHO classification and the histopathologic criteria necrosis and nodular fibrosis was tested in 113 patients. A tissue microarray was constructed for immunohistochemical staining. The staining results were scored quantitatively for MIB1 and semiquantitatively for CK19, COX2, p27, and CD99. The prognostic value of these markers was tested in 93 patients. RESULTS: The stratification of the patients into 4 risk groups according to the 2004 WHO classification was reliable with regard to both time span to relapse and tumor-specific death. In a multivariate analysis, the CK19 status was shown to be independent of the WHO criteria. By contrast, the prognostic significance of COX2, p27, and CD99 could not be confirmed. CONCLUSIONS: 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. CK19 staining is a potential additional prognostic marker independent from the WHO criteria for pancreatic endocrine tumors.