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Fine-Needle Aspiration-Based Grading of Pancreatic Neuroendocrine Neoplasms Using Ki-67: Is Accurate WHO Grading Possible on Cytologic Material?

ABSTRACT: Introduction:The World Health Organization (WHO) has provided grading guidelines for pancreatic neuroendocrine neoplasms (PanNENs) based on mitotic count and Ki-67 proliferation index. Due to the desire to provide earlier tumor grading for clinical management decisions, some groups have proposed grading PanNENs at the time of fine needle aspiration (FNA) using Ki-67 proliferation rates. While a Ki-67 can be performed on FNA cell blocks, there are potential sampling limitations with this technique that may affect the reliability of the Ki-67 result. Materials and Methods:Forty-nine PanNENs with FNA cell blocks and corresponding resection material were evaluated by immunohistochemistry for expression of Ki-67. Ki-67 proliferation rate was calculated based on cell counts of >500 cells in the highest staining areas. Ki-67 scores from FNA cell blocks were correlated with Ki-67 scores from resection specimens. Results:The FNA Ki-67 proliferation rates overall did not correlate well with the resection specimen. A linear regression analysis of the correlation between FNA %Ki-67 and resection %Ki-67 showed a slope of 3.2 and an R2=0.58. The average difference in Ki-67 proliferation rate between FNA and resection was 5.9%. Thirty-nine percent (19/49 cases) of PanNENs showed discordant grading between the FNA cell block and resection specimen. Almost all (18/19) discordant cases demonstrated a lower FNA-based grade as compared to the resection grade. Conclusions:FNA cell block grading using Ki-67 frequently led to under-grading of the tumor. This finding is consistent with concerns that FNA may not provide accurate grading due to the limited sampling of the tumor.

SUBMITTER: Weiss VL

PROVIDER: S-EPMC6054317 | biostudies-literature | 2018 May-Jun

REPOSITORIES: biostudies-literature

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Fine-Needle Aspiration-Based Grading of Pancreatic Neuroendocrine Neoplasms Using Ki-67: Is Accurate WHO Grading Possible on Cytologic Material?

Weiss Vivian L VL Kiernan Colleen C Wright Jesse J Merchant Nipun B NB Coogan Alice C AC Shi Chanjuan C

Journal of the American Society of Cytopathology 20180213 3

<h4>Introduction</h4>The World Health Organization (WHO) has provided grading guidelines for pancreatic neuroendocrine neoplasms (PanNENs) based on mitotic count and Ki-67 proliferation index. Due to the desire to provide earlier tumor grading for clinical management decisions, some groups have proposed grading PanNENs at the time of fine needle aspiration (FNA) using Ki-67 proliferation rates. While a Ki-67 can be performed on FNA cell blocks, there are potential sampling limitations with this ...[more]

PMID: 30038894

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Project description:Although thyroid fine-needle aspiration (FNA) and core needle biopsy (CNB) are commonly utilized modalities in the evaluation of thyroid nodules, metastatic tumors to the thyroid are only rarely encountered. We aspired to determine the incidence and primary origin of metastases to the thyroid at our institution and to examine their clinicopathologic and cytomorphologic features.A search of our database was undertaken to review all thyroid FNA and/or CNB examined between January 2004 and December 2013.During our 10 year study period, 7497 patients underwent 13,182 FNA and/or CNB. Four hundred sixty one (6%) patients were diagnosed with neoplasms. Only five (1.1%) were found to have metastatic tumors to the thyroid involving three females and two males. Two were diagnosed by FNA, one by CNB, and two by both FNA and CNB, with rapid on-site evaluation (ROSE) employed in all cases. The primary malignancies in the five cases were pulmonary and nasopharyngeal squamous cell carcinomas, renal cell carcinoma, pancreatic adenocarcinoma, and olfactory neuroblastoma. The cytomorphologic features of these metastases to the thyroid aided in their distinction from primary thyroid carcinoma. Two of these metastases, a renal cell carcinoma and pancreatic adenocarcinoma, were the first clinical manifestations of cancer.Metastases to the thyroid diagnosed by FNA and/or CNB are exceedingly rare in our institution, comprising only 0.04% of total FNA/CNB and only 1.1% of all thyroid neoplasms. We report the first known case of metastatic olfactory neuroblastoma to the thyroid diagnosed by aspiration cytology. In addition, an occult primary may present as a thyroid mass on FNA or CNB as occurred with two of our cases. FNA/CNB proved to be highly effective in the diagnosis of metastases to the thyroid, with ROSE proving valuable in assuring specimen adequacy. Thyroid FNA and CNB demonstrated great utility in the setting of metastatic disease, obviating the need for more invasive procedures.

Project description:Ki-67 assessment is a key step in the diagnosis of neuroendocrine neoplasms (NENs) from all anatomic locations. Several challenges exist related to quantifying the Ki-67 proliferation index due to lack of method standardization and inter-reader variability. The application of digital pathology coupled with machine learning has been shown to be highly accurate and reproducible for the evaluation of Ki-67 in NENs. We systematically reviewed all published studies on the subject of Ki-67 assessment in pancreatic NENs (PanNENs) employing digital image analysis (DIA). The most common advantages of DIA were improvement in the standardization and reliability of Ki-67 evaluation, as well as its speed and practicality, compared to the current gold standard approach of manual counts from captured images, which is cumbersome and time consuming. The main limitations were attributed to higher costs, lack of widespread availability (as of yet), operator qualification and training issues (if it is not done by pathologists), and most importantly, the drawback of image algorithms counting contaminating non-neoplastic cells and other signals like hemosiderin. However, solutions are rapidly developing for all of these challenging issues. A comparative meta-analysis for DIA versus manual counting shows very high concordance (global coefficient of concordance: 0.94, 95% CI: 0.83-0.98) between these two modalities. These findings support the widespread adoption of validated DIA methods for Ki-67 assessment in PanNENs, provided that measures are in place to ensure counting of only tumor cells either by software modifications or education of non-pathologist operators, as well as selection of standard regions of interest for analysis. NENs, being cellular and monotonous neoplasms, are naturally more amenable to Ki-67 assessment. However, lessons of this review may be applicable to other neoplasms where proliferation activity has become an integral part of theranostic evaluation including breast, brain, and hematolymphoid neoplasms.

Project description:BackgroundLong-acting somatostatin analogs (SSAs) are the primary first-line treatment of well-differentiated advanced gastroenteropancreatic neuroendocrine tumors (NETs), but data about their efficacy in pancreatic NETs (panNETs) with Ki-67 ≥10% are still limited.Materials and methodsTo assess the clinical outcomes of advanced, nonfunctioning, well-differentiated panNETs with Ki-67 ≥10% receiving first-line long-acting SSAs in a real-world setting, we carried out a retrospective, multicenter study including patients treated between 2014-2018 across 10 centers of the NET CONNECT Network. The primary endpoints were time to next treatment (TNT) and progression-free survival (PFS), whereas overall survival (OS) and treatment safety were secondary endpoints.ResultsA total of 73 patients were included (68 grade [G]2, 5 G3), with liver metastases in 61 cases (84%). After a median follow-up of 36.4 months (range, 6-173), the median TNT and PFS were 14.2 months (95% confidence interval [CI], 11.6-16.2) and 11.9 months (95% CI, 8.6-14.1) respectively. No statistically significant difference was observed according to the somatostatin analog used (octreotide vs. lanreotide), whereas increased tumor grade (hazard ratio [HR], 4.4; 95% CI, 1.2-16.6; p = .04) and hepatic tumor load (HR, 2; 95% CI, 1-4; p = .03) were independently associated with shortened PFS. The median OS recorded was 86 months (95% CI, 56.8-86 months), with poor outcomes observed when the hepatic tumor burden was >25% (HR, 3.4; 95% CI, 1.2-10; p = .01). Treatment-related adverse events were reported in 14 patients, most frequently diarrhea.ConclusionSSAs exert antiproliferative activity in panNETs with Ki-67 ≥10%, particularly in G2 tumors, as well as when hepatic tumor load is ≤25%.Implications for practiceThe results of the study call into question the antiproliferative activity of somatostatin analogs (SSAs) in pancreatic neuroendocrine tumors with Ki-67 ≥10%. Patients with grade 2 tumors and with hepatic tumor load ≤25% appear to derive higher benefit from SSAs. Prospective studies are needed to validate these results to optimize tailored therapeutic strategies for this specific patient population.

Dataset Information

Fine-Needle Aspiration-Based Grading of Pancreatic Neuroendocrine Neoplasms Using Ki-67: Is Accurate WHO Grading Possible on Cytologic Material?

Publications

Fine-Needle Aspiration-Based Grading of Pancreatic Neuroendocrine Neoplasms Using Ki-67: Is Accurate WHO Grading Possible on Cytologic Material?

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