Abstract 2199P
Background
Multi-omic studies have identified three lung carcinoid (LC) subtypes (A1, A2, B) with unique expression for OTP, ASCL1 & HNF1a genes. We developed an immunohistochemical (IHC) panel for LC subtype identification and clinical-pathological correlation.
Methods
IHC was evaluated in a blinded fashion in mRNA-profiled LC (n=5 per A1/A2/B). IHC H-score was scored and positive for OTP/HNF1a if ≥50 & ASCL1 ≥10. Then, surgically resected pathology revised LC (2003-2012) from a Dutch population based cohort using the cancer/pathology registry (n=474) were evaluated including matching metastasis of 20 recurrent LC. Also, potential therapeutic targets (SSRT2a/DLL3) were assessed. Normal lung tissue distant to the primary LC (≈35/type) was screened for neuroendocrine cell hyperplasia (NECH) using OTP/ChrA IHC. Disease free survival (DFS) was calculated and evaluated using log rank test. Clinical caracteristics were compared using chi-square test.
Results
IHC and mRNA expression of matched primary samples were near-identical. IHC identified A1 in 44% and was classified as OTPHIGH/LOW/ASCL1HIGH/HNF1aLOW, A2 in 40% as OTPHIGH/ASCL1LOW/HNF1aHIGH and B in 16% as OTPLOW/ASCL1LOW/HNF1aHIGH/LOW. Patients with A1 LC generally were middle-aged/elderly females with a peripheral tumour (Table). By contrast, in A2 primarily young patients with endobronchial tumours were identified. In B, the rate of recurrence of disease and tumor size were highest. Patients with A2 had significantly longer DFS compared to A1 and B. Matching primary-metastatic tumours showed similar IHC expression patterns for OTP/ASCL1 and HNF1a. SSRT2a was highest in A2-B while DLL3 showed unique expression in A1. NECH was enriched in A1 and this NECH showed an IHC pattern similar to A1 (OTPHIGH/ASCL1HIGH). Table: 2199P
Clinical characteristics of LC subtypes
| A1 (%) n=210 | A2 (%) n=190 | B (%) n=72 | p-value *<0.01 **<0.001 | |
| % of cohort | 44 | 40 | 16 | |
| Atypical LC | 10 | 4 | 16 | * |
| Ki-67 | * | |||
| 0-4 | 92 | 97 | 89 | |
| 5-19 | 5 | 3 | 10 | |
| >20 | 3 | 0 | 1 | |
| Female | 82 | 60 | 40 | ** |
| Age | ** | |||
| <40 | 2 | 29 | 6 | |
| 41-50 | 15 | 24 | 13 | |
| >50 | 83 | 47 | 81 | |
| Tumour location | ** | |||
| Peripheral | 57 | 12 | 26 | |
| Endobronchial/central | 30 | 83 | 60 | |
| NECH (≥3x bronchi(ole) with >5 NE cells) | ||||
| Near tumour | 26 | 7 | 1 | * |
| Distant normal tissue | 37 | 25 | 6 | * |
| Tumour size (median, mm) | 18 | 20 | 23 | * |
| Recurrence | 12 | 6 | 20 | * |
| IHC (median, H-score) | ||||
| DLL3 | 82 | 0 | 0 | ** |
| SSRT2 | 5 | 150 | 140 | ** |
Conclusions
An OTP/ASCL1/HNF1a IHC panel enables separation of molecular LC types into clinically different groups with distinct therapeutic vulnerabilities.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
KWF Dutch Cancer Society, ENETS.
Disclosure
All authors have declared no conflicts of interest.
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