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Large cell neuroendocrine carcinoma with a solitary brain metastasis and low Ki-67: a unique subtype.

ABSTRACT: INTRODUCTION:Stage IV large cell neuroendocrine carcinoma (LCNEC) of the lung generally presents as disseminated and aggressive disease with a Ki-67 proliferation index (PI) 40-80%. LCNEC can be subdivided in two main subtypes: the first harboring TP53/RB1 mutations (small cell lung carcinoma (SCLC)-like), the second with mutations in TP53 and STK11/KEAP1 (non-small cell lung carcinoma (NSCLC)-like). Here we evaluated 11 LCNEC patients with only a solitary brain metastasis and evaluate phenotype, genotype and follow-up. METHODS:Eleven LCNEC patients with solitary brain metastases were analyzed. Clinical characteristics and survival data were retrieved from medical records. Pathological analysis included histomorphological analysis, immunohistochemistry (pRB and Ki-67 PI) and next generation sequencing (TP53, RB1, STK11, KEAP1 and MEN1). RESULTS:All patients had N0 or N1 disease. Median overall survival (OS) was 12 months (95% confidence interval (CI) 5.5-18.5 months). Mean Ki-67 PI was 59% (range 15-100%). In 6/11 LCNEC Ki-67 PI was ?40%. OS was longer for Ki-67 ?40% compared to >40% (17 months (95% CI 11-23 months) vs. 5 months (95% CI 0.7-9 months), p=0.007). Two patients were still alive at follow-up after 86 and 103 months, both had Ki-67 ?40%. 8/11 patients could be subclassified and both SCLC-like (n=6) and NSCLC-like (n=2) subtype were present. No MEN1 mutation was found. CONCLUSION:Stage IV LCNEC with a solitary brain metastasis and N0/N1 disease show in the majority of cases Ki-67 PI ?40% and prolonged survival, distinguishing them from general LCNEC. This unique subgroup can be both of the SCLC-like and NSCLC-like subtype.

SUBMITTER: Hermans BCM

PROVIDER: S-EPMC6933830 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Large cell neuroendocrine carcinoma with a solitary brain metastasis and low Ki-67: a unique subtype.

Hermans B C M BCM Derks J L JL Groen H J M HJM Stigt J A JA van Suylen R J RJ Hillen L M LM van den Broek E C EC Speel E J M EJM Dingemans A-M C AC

Endocrine connections 20191201 12

<h4>Introduction</h4>Stage IV large cell neuroendocrine carcinoma (LCNEC) of the lung generally presents as disseminated and aggressive disease with a Ki-67 proliferation index (PI) 40-80%. LCNEC can be subdivided in two main subtypes: the first harboring TP53/RB1 mutations (small-cell lung carcinoma (SCLC)-like), the second with mutations in TP53 and STK11/KEAP1 (non-small-cell lung carcinoma (NSCLC)-like). Here we evaluated 11 LCNEC patients with only a solitary brain metastasis and evaluate p ...[more]

PMID: 31751303

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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.

Project description:The clinical evolution of solitary fibrous tumors (SFTs) is often uncertain and several risk stratification systems (RSS) have been proposed. The Demicco et al. RSS is the most frequently implemented. In this study we aim to validate two alternative RSS (Sugita et al. and G-Score) using results for the Demicco RSS from a previous study of 97 SFTs. In addition, we aim to determine whether reclassified cases had any distinctive molecular features. As the Sugita et al. system substitutes mitotic count with Ki-67 index we also investigated whether Ki-67 results for tissue microarrays are comparable to those obtained using whole tissue sections. In the present study we detected that many cases classified by Demicco RSS as low-risk were reclassified as intermediate risk using the new system (G-score RSS). Kaplan-Meier survival plots for G-Score RSS showed that the low-risk and intermediate-risk SFTs had a similar evolution that contrasted with the more aggressive high-risk group. Moreover, the similar evolution in both low and intermediate-risk groups occurred despite the G-score system being stricter in classifying low-risk tumors. We observed that Sugita RSS does not provide any better risk stratification in comparison with the Demicco RSS, and testing both RSS in our series produced similar Kaplan-Meier survival data. We found some discordant results when comparing whole sections and the corresponding tissue microarrays samples, finding the hotspot areas easier to locate in whole sections. Forty-one SFTs with initial low-risk assigned by the Demicco RSS were reclassified as intermediate-risk by G-score finding both TP53 and HTER mutations in four cases, only HTER mutation in 11 cases, and only TP53 mutation in 2 cases. All six cases of SFT classified as high-risk by both the Demicco and G-score RSS suffered recurrence/metastasis, and half showed both TP53 and HTER mutations. Five SFTs were categorized as low-risk by both Demicco and G-score, of which 4 cases revealed HTER mutation. Regarding the outcome of these 5 patients, two were lost to follow-up, and one of the remaining three patients suffered recurrence. We believe that although the presence of both TP53 and HTER mutations may confer or be related to poor evolution, the isolated presence of HTER mutation alone would not necessarily be related to poor outcome. The G-score RSS more accurately identified low-risk patients than the other two risk models evaluated in the present series. Late recurrence/metastasis may occasionally be observed even in low-risk SFTs categorized by stricter classification systems such as the G-score RSS. These findings support the possibility that additional, as yet unknown factors may influence the clinical evolution of SFTs. In conclusion, given the possibility of late recurrence, long-term follow-up is recommended for all SFT patients, even in cases classified as low risk by the stricter G-score system. An integration of clinical, radiological, pathological, and molecular findings may improve SFT risk stratification and better predict patient outcome.

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:BackgroundNeuroendocrine neoplasm (NEN) is a group of rare tumors. Among which, gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) is the most common group. The World Health Organization (WHO) classified these tumors into three different grades (G1, G2, and G3) based on Ki-67 and mitotic rate, and updated the classification in 2019. Several previous studies proved that Ki-67 was related to tumor prognosis, but others still reported that Ki-67 had no predictive value for tumor prognosis. There are different conclusions between studies regarding the correlation between Ki-67 and tumor prognosis, and there is a lack of studies about this correlation of GEP-NENs. Further analysis is still needed to evaluate the prognostic value of Ki-67 in GEP-NENs, to provide reference for clinical decisions.MethodsA total of 303 studies were retrieved that included Ki-67, GEP-NENs, prognosis, survival, and other subject terms and keywords. We excluded studies that did not show complete Ki-67 index, number of patients and 5-year survival data available for meta-analysis, non-cohort studies, articles published before 2000 or not published in English. Fifteen studies were finally included to assess the value of Ki-67 in the prognosis of patients with GEP-NENs using a random-effects model.ResultsThe cumulative 5-year survival rate for GEP-NEN G1 (Ki-67 ≤2%), G2 (Ki-67 2-20%) and G3 (Ki-67 >20%) was 86%, 65%, 25% respectively. The 5-year survival rate of GEP-NEN G1 (Ki-67 <3%, first revised in WHO classification 2017, redefined WHO classification 2019) and G1 (Ki-67 ≤2%, WHO classification 2010) was 97% and 84% respectively.ConclusionsThe overall prognosis of GEP-NENs patients showed a decreasing trend with the increase of Ki-67, which confirmed the significance of Ki-67 index as a prognostic marker for the prognosis of GEP-NENs. Increasing the cut-off value of Ki-67 index for G1 grade from ≤2% to <3% according to WHO classification 2019 did not significantly decrease the 5-year survival rate.

Dataset Information

Large cell neuroendocrine carcinoma with a solitary brain metastasis and low Ki-67: a unique subtype.

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Large cell neuroendocrine carcinoma with a solitary brain metastasis and low Ki-67: a unique subtype.

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