Endocrine tumors of the pancreas: Ki-67 immunoreactivity on paraffin sections is an independent predictor for malignancy: A comparative study with proliferating-cell nuclear antigen and progesterone receptor protein immunostaining, mitotic index, and other clinicopathologic variables

University of Verona, Verona, Veneto, Italy
Human Pathlogy (Impact Factor: 2.81). 12/1996; 27(11):1124-34. DOI: 10.1016/S0046-8177(96)90303-2
Source: PubMed

ABSTRACT Prediction for malignancy of pancreatic endocrine tumors (PET) is often a formidable challenge for the pathologist. The authors evaluated the role of the proliferative activity and progesterone receptor protein (PgRP) in predicting prognosis and survival of PET. Twenty-three functioning (FT) and 31 nonfunctioning tumors (NFT) were evaluated for mitotic activity and immunostaining for Ki-67 antigen, proliferating cell nuclear antigen (PCNA), and progesterone receptor protein (PgRP) on paraffin sections. The results were expressed as a percentage (index) of immunoreactive or mitosing cells. All 54 cases showed immunostaining for Ki-67 and PCNA, and valuable mitotic index, whereas only a fraction of tumors (25 of 54 cases) exhibited PgRP expression. Ki-67 and PCNA indexes correlated strongly between themselves and to mitotic index, whereas an inverse relationship was observed between cell proliferation and PgRP status in both FT and NFT. Although univariate analysis showed that Ki-67, PCNA, mitotic and PgRP indexes, stage, immunoreactivity for hormones other than insulin, diameter, and nonfunctioning type of tumor were statistically correlated to survival, Cox's regression method let only Ki-67 index emerge as an independent predictor of survival using a cutoff value of 5% in both FT and NFT.

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    ABSTRACT: Background: The latest WHO classification for neuroendocrine neoplasms (NEN) of the gastrointestinal tract defines grade according to Ki-67 and mitotic indices. Some have questioned the reproducibility and thus the reliability of Ki-67 assessment. We therefore investigated the accuracy of this proliferation marker in NEN. Methods: The Ki-67 index of tumor specimens of NEN (n = 73) was assessed by two pathologists as in routine practice with eyeballing and twice by image analysis using ImageJ freeware at different magnifications. Results were correlated with overall survival. Results: The intraclass correlation coefficient (ICC) between pathologists was 0.88. The ICC for the measurements using image analysis was 0.85. The ICC between all four measurements (pathologists and ImageJ) was 0.80. If the Ki-67 index was translated to grade as prescribed by the current WHO classification (<3% = grade 1, 3-20% = grade 2, >20% = grade 3), kappa was between 0.61 and 0.75. Grades based on pathologist scoring were often (16-29%) higher than grades assigned by image analysis (p < 0.001). Grade was significantly correlated with survival (p < 0.0001) irrespective of the way Ki-67 was assessed. Conclusion: Assessment of the Ki-67 index by eyeballing correlates remarkably well with the Ki-67 index as calculated by image analysis and is therefore an accurate parameter. Moreover, it is significantly related to survival irrespective of the method used. Yet if the Ki-67 index is translated to grade, the grade should be interpreted with caution due to values around threshold levels. © 2014 S. Karger AG, Basel.
    Neuroendocrinology 08/2014; 100(4). DOI:10.1159/000367713 · 4.93 Impact Factor
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    ABSTRACT: In the last decades, the incidence of neuroendocrine tumors (NETs) has been rising and this might be due to more awareness, improved diagnostic tools and a change in definition. The histopathological type of the tumor, its Ki-67 or MIB-1 proliferation index, size and location, as well as the age of the patient, seems to be the most important factor that affects prognosis and survival. In 2008, in one of our studies, we concluded that the cytological Ki-67 may improve the preoperative assessment of pancreatic NETs (pNETs), helping the clinician choosing the optimal therapeutical approach". Although the literature reports discordant opinions on the value of tumor proliferation markers in predicting a patient's prognosis, many studies have then reinforced the idea that Ki-67 expression in histological sections obtained from pNETs is an important predictor of their biological behaviour. The WHO classification of pNETs includes Ki-67 expression in the list of parameters (together with distant metastases, organ infiltration, dimension, angio/neuroinvasion, number of mitosis) determining the patient's prognosis. In conclusion we think that any study aimed to assess the correct biology and proliferative pattern of NETs contributes to the already known but still unclear attempt to define the correct individualized therapeutic strategy for each patient before surgery or any other therapeutic approach.
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    ABSTRACT: Objective: Patients with nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) have poorer survival than those with functional PNETs. Our objective was to identify risk factors for recurrence after resection to better define surveillance parameters to improve long-term outcomes. Methods: A retrospective analysis was performed for NF-PNET patients who underwent resection at the University of Michigan from 1995 to 2012. Immunohistochemical staining of tissues from patients with and without disease recurrence was performed for Ki-67 and the macrophage marker CD68, as tumor-associated macrophages are important for PNET development and progression. Clinicopathological factors and patient outcomes were measured. Results: Ninety-seven NF-PNET patients underwent surgical resection. There was a recurrence rate of 14.4% (14/97). The median time to recurrence was 0.61 years, with 10 (71%) patients recurring within the first 2 years. Six of 7 patients (86%) monitored at 6-month surveillance intervals were diagnosed with recurrence on their first computed tomographic scan or during the intervening intervals. By Cox proportional hazards analysis, the most significant independent risk factors for recurrence were higher grade, stage, and intraoperative blood loss. High CD68 score and Ki-67 index correlated with recurrence risk, and Ki-67 index inversely correlated with time to recurrence. In patients who otherwise had few risk factors, a high CD68 score was a significant prognostic factor for recurrence. Conclusions: In patients with NF-PNETs, risk factors associated with recurrence were high EBL, grade, stage, CD68 score, and Ki-67 index. The CD68 score was an important prognostic factor in patients who otherwise had few clinicopathological risk factors; therefore, the CD68 score should be considered when planning surveillance strategies. We recommend that NF-PNET patients at high risk of recurrence undergo initial surveillance every 3 months for 2 years after surgery.
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