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

Abstract

IntroductionStage 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.MethodsEleven 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).ResultsAll 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) subtypes were present. No MEN1 mutation was found.ConclusionStage 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.

Neuroendocrine Carcinomas with Atypical Proliferation Index and Clinical Behavior: A Systematic Review

“…The eight studies finally selected were all retrospective studies [ 6 , 9 , 10 , 18 , 19 , 20 , 21 , 22 ] including a total of 268 patients with NECs in which Ki67 LI was specified to distinguish two subcategories: NECs with Ki67 LI <55% and NECs with Ki67 LI ≥55% ( Table 1 ).…”

“…All studies differed according to types of NEN enrolled and treatments received. Specifically, four studies considered both WD G3 NENs and PD-NENs [ 6 , 19 , 21 , 22 ], while four studies [ 9 , 10 , 18 , 20 ] included only patients presenting the specific subgroup of NECs. NENs derived from different primary sites, the most frequent one being the GEP tract.…”

“…The study of Milione et al considered patients treated with chemotherapy: platinum-etoposide ( n = 59), other platinum-based regimen ( n = 31), non-platinum-based chemotherapy ( n = 12), and other non-cytotoxic therapy ( n = 8), but unfortunately when the authors stratified the tumors according to the Ki67 LI, they did not provide specific data on the chemotherapy regimen [ 6 ]. In four studies, chemotherapy was used combined with other treatment strategies (radiotherapy and/or surgery), specific data on use and outcome of standard first line therapy cannot be extracted from these studies [ 18 , 20 , 21 , 22 ]. One study evaluated PRRT efficacy [ 19 ].…”

“…Three studies [ 9 , 20 , 21 ] reported on patients’ age: the median age was 51 years (range 41.3–52.6) vs. 64.6 (53.4–71) in the subgroup with Ki67 LI ≥55%. Four studies [ 6 , 9 , 20 , 21 ] reported on gender: males were 26/49 (53%) among patients with a Ki67 LI <55% NEC, while 59/96 (61.4%) among those with a Ki67 LI ≥55%.…”

Challenges in Ki‐67 assessments in pulmonary large‐cell neuroendocrine carcinomas*

“…A significant difference in OS (Figure 7), but not in DFS, was observed using ≥25 as the mitotic rate cut‐point (log‐rank P = 0.032), while no significant correlation with OS or DFS was observed using ≥20 or ≥30 as the mitotic rate cut‐point (log‐rank P = 0.47 and P = 0.24, respectively). The systematic review of the literature identified 14 original papers that evaluated ≥10 LCNEC without comingling the results for LCNEC and SCLC 6,9,13,21,42–51 . As shown in Table 1, these reports provided varied incomplete information regarding the method/protocol utilised and/or number of tumour cells assessed to determine Ki‐67%.…”