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Including Grade Status Marker Levels in the Staging of Neuroendocrine Tumors

In a sense, the pancreatic cancer research underlying this blog posting is a bookend to the one that we discussed here in the Pancreatica Blog about a month ago.  Then, researchers had incorporated the Ki-67 cell proliferation marker into a standard Tumor-Node-Metastasis system (American Joint Committee on Cancer – AJCC) to see if the novel schema improved concurrence between staging and survival duration prediction in pancreatic adenocarcinoma – the most common form of pancreatic cancer.  It did.

In the present study, the researchers also tried to discern a relationship between a standard TNM system (European Neuroendocrine Tumor Society – ENETS) and the grade of cell proliferation as represented by Ki-67 level, but now in neuroendocrine tumors.

Ki-67 is an antigen, also known as MKI67 that appears to be essential for cell proliferation in humans. It is integral to ribosomal RNA transcription, and is encoded by the human gene MKI167.  Its name is derived by the city of its discovery (researchers in Kiel, Germany), and the number of the lab dish on which it was found. As evolved, the referent labeling index represents that portion of sample cells which are Ki-67 positive.  At its most basic level, the Ki-67 index IS a measure of cell proliferation. This index number appears to be correlated with the clinical history in a number of tumor types. The higher the index, the more aggressive the clinical course of the cancer.

Frilling and colleagues from the Imperial College London UK published the results of their work in the area of TNM staging and Ki-67 marker levels in neuroendocrine tumors on February 4, 2014 in the World Journal of Surgery, a publication of the International Society of Surgery.  In this retrospective study, the researchers reviewed the records and laboratory results of 161 patients with neuroendocrine tumors of the GI-pancreatic organ system seen at the Imperial College Healthcare Trust between the years 2010 and 2012. The patients were divided into three Ki-67 level cell differentiation categories according to ENETS recommendations: G1 (low to intermediate grade cell differentiation), G2 (well to moderate grade cell differentiation), and G3 (moderate to poor cell differentiation).

The researchers found that in patients with neuroendocrine tumors, the more advanced the stage the higher the Ki-67 index levels. This finding was tempered by the observation that the organ of origin also was strongly correlated with Ki-67 levels.

The findings of this study move our understanding forward.  One point to note is that in the United States’ SEERS cancer registry data show about 27% of patients with neuroendocrine tumors as having distal metastases, whereas the European registry databases typically show this figure at 44% to 73%. Whether this staging difference represents a different natural history, a difference in staging criteria, or a difference in diagnosis, remains to be seen.

Nevertheless, this is an interesting finding that appears to further integrate our understanding of TNM staging and cell dynamics, as we try to better integrate staging with prognosis in neuroendocrine tumors.

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Dale O’Brien, MD