Variability of Ki67 labeling index in multiple neuroendocrine tumors specimens over the course of the disease

doi:10.1016/j.ejso.2014.06.016

European Journal of Surgical Oncology (EJSO)

Volume 40, Issue 11, November 2014, Pages 1517-1522

https://doi.org/10.1016/j.ejso.2014.06.016 Get rights and content

Abstract

Background

The Ki67-LI is a valid surrogate for biologic behavior of neuroendocrine tumors (NETs), with higher levels associated with aggressive behavior. The World Health Organization (WHO) classifies NETs according to Ki67-LI (G1: <3%; G2 : 3–20%; G3: >20%). Little is known about the evolution of NETs histologic characteristics over the disease course. We sought to evaluate variations in Ki67-LI throughout NETs disease course.

Methods

We retrospectively reviewed the Sunnybrook Odette Cancer Center NET database for patients with multiple pathology specimens. Primary outcome was the WHO NET class based on Ki67-LI for each specimen. We assessed change in WHO class between specimens.

Results

Forty-three patients were retrieved, of which 39 had specimens from the primary tumor and a metastatic focus, and 4 had specimens from multiple metastatic foci. Sixteen (37.0%) were identified with Ki67-LI falling in different WHO classes on distinct biopsies. For 12 (75.0%) of those 16 patients, Ki67-LI showed enough variability for WHO class to be upstaged: 5 (31%) from G1 to G2, 2 (13%) from G2 to G3, and 5 (31%) from G1 to G3.

Conclusion

When multiple pathology specimens were available, Ki67-LI varied throughout NETs disease course, with a majority of cases upgraded to a higher WHO class. If confirmed, this finding may have implications in how neuroendocrine tumors are monitored and treated. Further research is warranted to confirm these findings, understand better the underlying mechanisms of Ki67 variability, and define its relationship to prognosis.

Introduction

Identified in 1991, Ki67 is a protein antigen found on the long arm of chromosome 10, and universally expressed in the nucleus of proliferating cells, while remaining absent in quiescent cells.1, 2 It has become a useful marker in assessing the proliferation of malignant cell populations.¹ A Ki67 labeling index (Ki67-LI) is computed by analyzing the fraction of cells containing the Ki67 antigen.

The Ki67-LI is increasingly being recognized as a prognostic factor and valid surrogate of biologic behavior for neuroendocrine tumors (NETs), with a higher labeling index associated with poor outcomes.3, 4, 5, 6 As such, a grading system incorporating the Ki67-LI was proposed by the European Neuroendocrine Tumor Society (ENETS) in 2006, and was later endorsed by the World Health Organization (WHO) in 2010.7, 8, 9 Neuroendocrine tumors are now divided into three grades according to the Ki67-LI: G1 tumors with a Ki67-LI < 3%, G2 tumors 3–20%, and G3 tumors >20%.⁹ The WHO tumor grading system has become an instrumental tool in decision making.10, 11

Despite being recognized for their often indolent behavior, NETs are heterogeneous malignancies that display a variable natural history.12, 13 Classification based on Ki67-LI allows for identification of the aggressive subset of NETs associated with a poor prognosis,13, 14 which is paramount in determining appropriate treatment options such as systemic therapy, with higher Ki67 demonstrating better response to chemotherapy, and evaluating prognosis.¹⁴ Due in large part to the low prevalence of these tumors and lack of data on large patient populations, very little is known about how neuroendocrine tumor histologic characteristics, and specifically the Ki67-LI change throughout the disease course. Even though there are no current consensus guidelines on taking multiple biopsy specimens throughout the disease course of NETs, this is not an uncommon practice depending on clinical presentation.

The aim of this study was to evaluate change in Ki67-LI throughout the course of disease. We hypothesized that the Ki67-LI may vary during the disease course, including from primary to metastasis, from primary to recurrence, or during progression. As decision-making, including how and when to initiate systemic therapy, relies more and more on the Ki67-LI, changes throughout the course of disease would have significant impact on NETs monitoring and management.

Section snippets

Methods

This study received Ethics approval from the Sunnybrook Health Sciences Centre Research Ethics Board.

Results

Among 327 patients with NET diagnosis, 43 had multiple pathology specimens (Fig. 1). Of those, 39 had pathology from the primary tumor and a metastatic focus, and 4 had specimens from multiple metastatic foci. Baseline characteristics of included patients are presented in Table 1. A majority of patients (46.5%) presented with small bowel NET, and most 70.0% of patients presented with metastatic disease at the time of diagnosis.

Overall, 16 (37.0%) patients were identified with Ki67-LI falling in

Discussion

This review highlights that the Ki67-LI in neuroendocrine tumors may change throughout the disease course, often behaving more aggressively as the disease progresses. In our database, 37.2% of 43 patients with multiple pathology specimens analyzed had a Ki67-LI indices falling in different WHO classes. For 75.0% of those patients, this represented an upstaging of the WHO class. Our institution's approach is to administer systemic chemotherapy to G3 NETs. As such, 44% of patients with

Conclusion

In our study, we identified variability in Ki67 labeling index over the course of NET disease, when multiple pathology specimens were available. A majority of cases showed variation towards a more aggressive WHO class, perhaps indicating changes in tumor characteristics over time and/or from one disease site to the other. The exact mechanism behind this variability is yet to be determined, and beyond the scope of this study. However, as this finding may affect how NETs are monitored and

Funding source

This work was supported by the Susan Leslie Neuroendocrine Tumors Fund. The study sponsors had no involvement in the design, conduction or report of this study.

Conflict of interest statement

The authors declare that they have no conflict of interest.

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Proliferative activity examined by Ki67 labeling index (LI) plays pivotal role for managing gastrointestinal neuroendocrine tumor (GI-NET). Few reports indicated the intra-patient heterogeneity of Ki67-LI among metastatic tumor sites. We report a case of brain and orbital metastases from GI-NET that showed discrepancy of the Ki67-LI. A 71 year-old woman who was diagnosed as GI-NET with liver and bone metastases and performed medical therapy, had headache, right exophthalmos, and pain of right eye and was referred to our department. Magnetic resonance image revealed that tumors in the left occipital region and right orbit. We diagnosed as metastatic brain and orbital tumors from GI-NET. Surgical removal of both symptomatic lesions was performed and the diagnosis was pathologically confirmed. Immunohistochemical studies revealed the discrepancy of the Ki67-LI of the lesions (brain tumor: 8% versus orbital tumor: 22%). Sampling of multiple metastatic sites may prevent underestimate tumor proliferative activity.
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Citation Excerpt :
However, studies have shown that 49% of patients with G1/G2 tumors (and even 21%–40% with G1 disease) can have FDG uptake, which is associated with a worse prognosis.38–40 This paradox may be explained by biopsy sampling error, tumor heterogeneity, and Ki-67 grading observer intervariability during initial evaluation as well as tumor progression during the disease course.48,49 There may also be unknown tumor characteristics that could promote tumor aggressiveness.
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Also, there is variability in SUV measurements across different timepoints and institutions (40,41). We do not expect this variability to be a fundamental hindrance in implementation of the FDZ score, given the universal use of Ki67 index despite its significant variability (38,42,43). While the distribution of SUVmax was not significantly different between the two academic centers involved, we still suggest determination of the SUVmax distribution at each medical center for calculation of the FDZ score.
High-grade gastroenteropancreatic neuroendocrine neoplasms (G3 GEP-NENs) are pathologically classified into well differentiated neuroendocrine tumors (G3 NETs) and poorly differentiated neuroendocrine carcinomas (G3 NECs). Using a novel parameter, we examined the prognostic value of ¹⁸F-FDG and ⁶⁸Ga-DOTATATE PET/CT quantification in comparison to pathologic assessment in G3 GEP-NENs.
A total of 31 patients with G3 GEP-NENs were reviewed. For each patient, the SUVmax on ¹⁸F-FDG and ⁶⁸Ga-DOTATATE PET/CT were used to calculate the FDG-DOTATATE-Z (FDZ) score: a continuous parameter that increases with ⁶⁸Ga-DOTATATE uptake and decreases with ¹⁸F-FDG uptake. The variation in the FDZ score with respect to pathologic variables was examined. Kaplan-Meier and Cox regression analyses were performed to evaluate the effect of FDZ score on overall survival. An external cohort of 21 patients was used for validation.
The FDZ score was significantly higher in G3 NETs compared to G3 NECs (p<0.001), and was inversely correlated with Ki67 index (R²=0.33, p<0.001). Patients in the FDZ>0.05 group showed significantly longer survival compared to those in the FDZ≤0.05 group, with median of 34.9 vs. 12.0 months (p<0.001). On univariate regression, FDZ>0.05 (p=0.005), well differentiated disease (p=0.044), and lower Ki67 index (p=0.042) were predictors of survival. On multivariate regression, only FDZ>0.05 could independently predict longer survival with HR=0.16 (p=0.018), which was reproduced in the external validation cohort.
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Variability of Ki67 labeling index in multiple neuroendocrine tumors specimens over the course of the disease

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Methods

Results

Discussion

Conclusion

Funding source

Conflict of interest statement

Hum Pathol

Best Pract Res Clin Gastroenterol

Lancet

J Surg Res

The Ki-67 protein: from the known and the unknown

J Cell Physiol

Immunobiochemical and molecular biologic characterization of the cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67

Am J Pathol

High resolution allelotype of nonfunctional pancreatic endocrine tumors: identification of two molecular subgroups with clinical implications

Cancer Res

Importance of proliferation markers in gastrointestinal carcinoid tumors: a clinicopathologic study

Hepatogastroenterology

Predicting prognosis in gastroentero-pancreatic neuroendocrine tumors: an overview and the value of Ki-67 immunostaining

Endocr Pathol

Consensus guidelines for the management of patients with digestive neuroendocrine tumors: the second event and some final considerations

Neuroendocrinology

Consensus guidelines for the management of patients with digestive neuroendocrine tumors: why such guidelines and how we went about it

Neuroendocrinology

WHO classification of tumours of the digestive system

Comparison of WHO classifications (2004, 2010), the Hochwald grading system, and AJCC and ENETS staging systems in predicting prognosis in locoregional well-differentiated pancreatic neuroendocrine tumors

Am J Surg Pathol